Here are the studies that match your search criteria. If you are interested in participating, please reach out to the contact listed for the study. If no contact is listed, contact us and we'll help you find the right person.
Peri-Operative Ipilimumab+Nivolumab and Cryoablation in Women With Triple-negative Breast Cancer
The purpose of this study is to determine the impact of pre-operative cryoablation,
ipilimumab and nivolumab on on 3-year Event Free Survival (EFS), in women with residual
hormone receptor negative, HER2-negative ("triple negative") resectable breast cancer after
taxane-based neoadjuvant chemotherapy.
• Women age 18 years or older
• Confirmed histologic diagnosis of invasive carcinoma of the breast
• Pathology confirmation of invasive carcinoma (reported or requested and pending)
• ER, PR and HER2 negative on outside or Cedars Sinai biopsy report, where ER and PR
negative are defined as staining present in ≤10% of invasive cancer cells by IHC, and
HER2-negative is defined as IHC 0-1+ or FISH <2.0. If ER, PR and HER2 status are not
reported the results must be requested and pending.
• Operable tumor measuring ≥1.0 cm in maximal diameter
• Any nodal status
• Multifocal and multicentric disease is permitted.
• Synchronous bilateral invasive breast cancer is permitted
• No indication of distant metastases
• Total mastectomy or lumpectomy planned
• Tumor amenable to cryoablation as determined by a study radiologist
• ECOG performance status score of 0 or 1.
• Screening laboratory values must meet the following criteria:
• White blood cells (WBCs) ≥ 2000/μL
• Absolute neutrophil count (ANC) ≥ 1500/μL
• Platelets ≥ 100 x 103/μL ii. Hemoglobin ≥ 9.0 g/dL iii. Serum creatinine ≤ 1.5 x ULN
or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula
below): Female CrCl = (140 •age in years) x weight in kg x 0.85 72 x serum creatinine
in mg/dL
• AST/ALT ≤ 3 x upper limit of normal (ULN)
• Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert's syndrome, who must have total
bilirubin < 3.0 mg/dL)
• No history of known HIV
• No history of known active hepatitis B or hepatitis C
• Women of childbearing potential** (WOCBP) must use appropriate method(s) of
contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30
days plus the time required for nivolumab and ipilimumab to undergo five half-lives)
after the last dose of investigational drug
• Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG)
• Women must not be breastfeeding
• Willing to adhere to the study visit schedule and the prohibitions and restrictions
specified in this protocol.
• Prior checkpoint blockade administration is permitted with a washout period of 3 weeks
• "Women of childbearing potential" is defined as any female who has experienced
menarche and who has not undergone surgical sterilization (hysterectomy or
bilateral oophorectomy) or who is not postmenopausal. Menopause is defined
clinically as 12 months of amenorrhea in a woman over 45 in the absence of other
biological or physiological causes.
Women of childbearing potential (WOCBP) receiving nivolumab and ipilimumab will be
instructed to adhere to contraception for a period of 23 weeks after the last dose of
investigational product. Men receiving nivolumab and who are sexually active with WOCBP
will be instructed to adhere to contraception for a period of 31 weeks after the last dose
of investigational product. These durations have been calculated using the upper limit of
the half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP
use contraception for 5 half-lives plus 30 days and men who are sexually active with WOCBP
use contraception for 5 half-lives plus 90 days.
Exclusion Criteria:
• Medical history and concurrent diseases
• Has an active autoimmune disease that has required systemic treatment in the past
2 years (i.e., with use of disease modifying agents, corticosteroids, or
immunosuppressive drugs). Note: Replacement therapy (eg, thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency) is not considered a form of systemic treatment.
• Any underlying medical or psychiatric condition, which in the opinion of the
investigator, will make the administration of study drug hazardous or obscure the
interpretation of AEs, such as a condition associated with frequent or poorly
controlled diarrhea.
• Prohibited Treatments and/or Therapies
• Chronic use of immunosuppressants and/or systemic corticosteroids (used in the
management of cancer or non-cancer-related illnesses). Brief periods of steroid
use, for example for the management of chemotherapy-associated toxicities, are
allowed. The use of corticosteroids on study is allowed for the treatment of
immune related adverse events (irAEs) and other medical conditions including
adrenal insufficiency.
• Any non-oncology live vaccine therapy used for prevention of infectious diseases
within 3 weeks prior to first dose of ipilimumab.
• Prior investigational agents within 3 weeks prior to ipilimumab/nivolumab
Drug: Ipilimumab, Drug: Nivolumab, Procedure: Core Biopsy/Cryoablation, Procedure: Breast Surgery
Breast Cancer, Breast - Female
Hormone Receptor Negative, Her2- Negative, Resectable Breast Cancer, breast cancer, immunotherapy, Ipilimumab, Nivolumab, Cryoablation
A Research Study to Look Into How Well Semaglutide Medicine Works at Different Doses in People With Type 2 Diabetes and Overweight
This study compares how three doses of semaglutide work in participants with type 2 diabetes
(T2D) and overweight who are taking metformin. The study will look mainly at how well
participant's blood sugar and participant's body weight are controlled when they are taking
the study medicine at different doses. Participants will either get semaglutide [2 milligrams
(mg), 8 mg, or 16 mg] or semaglutide placebo (a dummy medicine). Participants will take the
study medicine with an injection pen called NovoPen®4. The injection pen is a medical tool
with a needle used to inject the study medicine under the skin. The study will last for about
52 weeks. Participants will have 13 clinic visits and 4 phone calls.
• Male or female.
• Aged 18-64 years (both inclusive) at the time of signing informed consent.
• Diagnosed with type 2 diabetes mellitus greater than equal to (≥) 180 days prior to
the day of screening.
• Glycosylated haemoglobin (HbA1c) of 7.0 •10.5 percentage (%) [53 •91 millimoles per
mole (mmol/mol)] (both inclusive).
• Body Mass Index (BMI) ≥ 27.0 kilograms per meter square (kg/m^2).
• Stable daily dose(s) ≥ 90 days prior to the day of screening of any metformin
formulations.
Exclusion Criteria:
• Treatment with any medication for the indication of diabetes or obesity other than
stated in the inclusion criteria within 90 days before screening. However, short term
insulin treatment for a maximum of 14 days prior to the day of screening is allowed,
as is prior insulin treatment for gestational diabetes.
• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by
a fundus examination performed within the past 90 days prior to day of screening or in
the period between screening and randomisation. Pharmacological pupil-dilation is a
requirement unless using a digital fundus photography camera specified for non-dilated
examination.
• Renal impairment measured as estimated glomerular filtration rate (eGFR) value of less
than (<) 30 milliliters per minute (mL/min)/1.73 meter square (m^2) at screening.
Efficacy and Safety of QGE031 (Ligelizumab) in Patients With Peanut Allergy
This is a 52-week, Phase 3 multi-center, randomized, double-blind and placebo-controlled
study to assess the safety and clinical efficacy of two dosing regimens of ligelizumab (240
mg and 120 mg) subcutaneous injection every 4 weeks (SCq4w) in participants with a medically
confirmed diagnosis of IgE-mediated peanut allergy.
• Male or female participants who are ≥ 6 and ≤ 55 years of age at the time of signing
informed consent/assent.
• Documented medical history of allergy to peanuts or peanut-containing foods.
• Positive peanut-specific immunoglobulin E (peanut sIgE), ≥ 0.35 kUA/L at Screening
visit 1 (Screening 1).
• Positive skin prick test (SPT) for peanut allergen at Screening 1 defined as an
average diameter (Longest diameter and mid-point orthogonal diameter) ≥ 4 mm wheal
compared to saline control.
• A positive peanut DBPCFC at baseline (Screening Visit 2, Part 1 and Part 2 DBPCFC)
defined as the occurrence of dose-limiting symptoms at a single dose ≤ 100 mg of
peanut protein. Eligibility to proceed with the DBPCFC requires fulfillment of all
other eligibility criteria.
• Participants must weigh ≥ 20 kg at Screening 1.
Exclusion Criteria:
• Total IgE >2000 IU/mL at Screening 1.
• History of severe or life-threatening hypersensitivity event needing an ICU admission
or intubation within 60 days prior to baseline DBPCFC (Screening visit 2).
• Participants with uncontrolled asthma (according to GINA guidelines, GINA 2020) who
meet any of the following criteria:
• FEV1 <80% of subject's predicted normal value at Screening visit 1
• One hospitalization for asthma within 12 months prior to Screening visit 1
Other protocol-defined inclusion/exclusion criteria may apply.
Tiragolumab and Atezolizumab for the Treatment of Relapsed or Refractory SMARCB1 or SMARCA4 Deficient Tumors
This phase I/II trial studies how well tiragolumab and atezolizumab works when given to
children and adults with SMARCB1 or SMARCA4 deficient tumors that that has either come back
(relapsed) or does not respond to therapy (refractory). SMARCB1 or SMARCA4 deficiency means
that tumor cells are missing the SMARCB1 and SMARCA4 genes, seen with some aggressive cancers
that are typically hard to treat. Immunotherapy with monoclonal antibodies, such as
tiragolumab and atezolizumab, may help the body's immune system attack the cancer, and may
interfere with the ability of tumor cells to grow and spread.
• Patients must be >= 12 months of age at the time of study enrollment. For part A,
patients must be <18 years old at enrollment. For part B, there is no upper age limit
• The Part B (phase 2) cohorts will initially open concurrently with the part A but
will only enroll patients at least 18 years of age. Patients <18 years of age
will be included in the part B cohorts only after the tiragolumab monotherapy
dose has been assessed to be safe in the part A portion
• Patients must have SMARCB1 (INI1) or SMARCA4 deficient tumors verified through
institutional immunohistochemistry (IHC) or molecular confirmation of a pathologic
tumor bi-allelic SMARCB1 (INI1) or SMARCA4 loss or mutation from a Clinical Laboratory
Improvement Act (CLIA) certified lab with the following disease histologies:
• Renal medullary carcinoma
• Malignant rhabdoid tumor (extra-CNS)
• Atypical teratoid rhabdoid tumor (CNS)
• Poorly differentiated chordoma
• Epithelioid sarcoma
• Other SMARCB1 or SMARCA4 deficient tumors
• Note: Documentation of the institutional IHC or molecular testing must be
uploaded via the RAVE system
• Part A: Patients must have either measurable or evaluable disease Part B: Patients
must have either measurable disease per RECIST v1.1 for non-CNS tumors or CNS response
criteria for CNS tumors
• Patients must have relapsed, refractory disease or newly diagnosed disease for which
there is no known curative therapy or therapy proven to prolong survival with an
acceptable quality of life
• Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1 or 2 (Karnofsky/Lansky score of > 50). Use Karnofsky for
patients > 16 years of age and Lansky for patients =< 16 years of age. Note:
Neurologic deficits in patients with CNS tumors must have been stable for at least 7
days prior to study enrollment. Patients who are unable to walk because of paralysis,
but who are up in a wheelchair, will be considered ambulatory for the purpose of
assessing the performance score
• Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer therapy and must meet the following minimum duration from prior
anti-cancer directed therapy prior to enrollment. If after the required timeframe, the
numerical eligibility criteria are met, e.g., blood count criteria, the patient is
considered to have recovered adequately
• Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive:
See Developmental Therapeutics (DVL) homepage on the Children's Oncology Group
(COG) Members site for commercial and investigational agent classifications. For
agents not listed, the duration of this interval must be discussed with the study
chair and the study-assigned Research Coordinator prior to enrollment
• >= 21 days after the last dose of myelosuppressive chemotherapy (42 days if
prior nitrosourea). Please refer to the table of myelosuppressive/Anticancer
Agents on the COG website:
https://www.cogmembers.org/uploadedFiles/Site/Disc/DVL/Documents/TableOfMyel
osuppressiveAnti-CancerAgents.pdf
• Anti-cancer agents not known to be myelosuppressive (e.g., not associated with
reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the
last dose of agent. See the DVL homepage on the COG Members site for commercial
and investigational agent classifications. For agents not listed, the duration of
this interval must be discussed with the study chair and the study-assigned
Research Coordinator prior to enrollment
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,
and toxicity related to prior antibody therapy must be recovered to grade =< 1
• Hematopoietic growth factors: >= 14 days after the last dose of a long-acting
growth factor (e.g., pegfilgrastim) or 7 days for short acting growth factor. For
agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur
• Interleukins, interferons and cytokines (other than hematopoietic growth
factors): >= 21 days after the completion of interleukins, interferon or
cytokines (other than hematopoietic growth factors)
• Stem cell infusions (with or without total-body irradiation [TBI]):
• Autologous stem cell infusion including boost infusion: >= 30 days
• Cellular therapy: >= 30 days after the completion of any type of cellular therapy
(e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.)
• External radiation therapy (XRT)/external beam irradiation including protons: >=
14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation
to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM)
radiation
• Radiopharmaceutical therapy (e.g., radiolabeled antibody, iodine I 131
metaiodobenzylguanidine [131I MIBG]): >= 42 days after systemically administered
radiopharmaceutical therapy
• Patients must not have had prior TIGIT targeting therapy
• Patients must not have received prior therapy with an anti- PD-1, anti-PD-L1,
anti-PD-L2, or anti-CTLA4 agent or with an agent directed to another stimulatory
or co-inhibitory T cell receptor (i.e. OX-40, CD137)
• Patients must not have received live/attenuated vaccine within 30 days of first
dose of treatment
• Patients must not be receiving concomitant systemic steroid medications and > 14
days must have elapsed since last dose of systemic corticosteroid with the
following exceptions:
• The use of physiologic doses of corticosteroids (5 mg/m^2/day up to 10
mg/day of prednisone equivalent) is acceptable
• The use of topical, inhaled, or ophthalmic corticosteroids are acceptable
• The use of acute, low-dose systemic immunosuppressant medication or a
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours
of corticosteroids for a contrast allergy) are acceptable
• Treatment with systemic immunosuppressive medication (including, but not limited
to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor-alpha [TNF-alpha] agents) must have concluded >= 14 days prior to
study enrollment
• For patients with solid tumors without known bone marrow involvement
• Peripheral absolute neutrophil count (ANC) >= 1000/uL (must be performed within 7
days prior to enrollment)
• For patients with solid tumors without known bone marrow involvement
• Platelet count >= 100,000/uL (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment) (must be performed
within 7 days prior to enrollment)
• Patients with known bone marrow metastatic disease will be eligible for study provided
they meet the blood counts above (may receive transfusions provided they are not known
to be refractory to red cell or platelet transfusions). These patients will not be
evaluable for hematologic toxicity
• A creatinine based on age/gender as follows (must be performed within 7 days prior to
enrollment):
• Age; Maximum Serum Creatinine (mg/dL)
• 1 to < 2 years; Male: 0.6; Female: 0.6
• 2 to < 6 years; Male: 0.8; Female: 0.8
• 6 to < 10 years; Male: 1; Female: 1
• 10 to < 13 years; Male: 1.2; Female: 1.2
• 13 to < 16 years; Male: 1.5; Female: 1.4
• >= 16 years; Male: 1.7; Female: 1.4 OR- a 24 hour urine creatinine clearance
>= 70 mL/min/1.73 m^2 (must be performed within 7 days prior to enrollment)
OR- a glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2. GFR must be
performed using direct measurement with a nuclear blood sampling method OR
direct small molecule clearance method (iothalamate or other molecule per
institutional standard) (must be performed within 7 days prior to
enrollment)
• Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates
are not acceptable for determining eligibility
• Bilirubin (sum of conjugated + unconjugated or total) =< 1.5 x upper limit of normal
(ULN) for age (must be performed within 7 days prior to enrollment)
• Patients with known Gilbert disease: Total bilirubin < 3 x ULN
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L
(must be performed within 7 days prior to enrollment). For the purpose of this study,
the ULN for SGPT is 45 U/L
• Albumin >= 2 g/dL (must be performed within 7 days prior to enrollment)
• Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled as evidenced by no increase in seizure frequency in the prior 7 days
• Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] v5)
resulting from prior therapy must be =< grade 2, with the exception of decreased
tendon reflex (DTR). Any grade of DTR is eligible
• International normalized ratio (INR) =< 1.5 (must be performed within 7 days prior to
enrollment)
• Serum amylase =< 1.5 x ULN (must be performed within 7 days prior to enrollment)
• Serum lipase =< 1.5 x ULN (must be performed within 7 days prior to enrollment)
• Grade 1 or lower calcium level
• Note: can have history of hypercalcemia as long as controlled and asymptomatic
Exclusion Criteria:
• Pregnant or breast-feeding women will not be entered on this study due to risks of
fetal and teratogenic adverse events as seen in animal/human studies, OR because there
is yet no available information regarding human fetal or teratogenic toxicities.
Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of
reproductive potential may not participate unless they have agreed to use two
effective methods of birth control, including a medically accepted barrier or
contraceptive method (e.g., male or female condom) for the duration of therapy and at
least 90 days after final dose of tiragolumab and 150 days after final dose of
atezolizumab, whichever is later. Abstinence is an acceptable method of birth control.
• It is not known if atezolizumab or tiragolumab are present in breast milk;
however, IgG immunoglobulins are found in milk. Due to the potential for serious
adverse reactions in the breastfed infant, breastfeeding is not recommended
during therapy and for at least 150 days after the last dose of atezolizumab and
90 days after the last dose of tiragolumab, whichever is later
• Concomitant medications:
• Corticosteroids:
• Patients must not be receiving concomitant systemic steroid medications and
>= 14 days must have elapsed since last dose of systemic corticosteroid with
the following exceptions:
• The use of physiologic doses of corticosteroids (5 mg/m^2/day up to 10
mg/day of prednisone equivalent) is acceptable
• The use of topical, inhaled, or ophthalmic corticosteroids are
acceptable
• The use of acute, low-dose systemic immunosuppressant medication or a
one-time pulse dose of systemic immunosuppressant medication (e.g. 48
hours of corticosteroids for a contrast allergy) are acceptable
• Investigational drugs: Patients who are currently receiving another
investigational drug are not eligible
• Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents
are not eligible
• Systemic immunosuppressive medications (including, but not limited to,
cyclophosphamide, azathioprine, methotrexate, and thalidomide) during study
treatment because these agents could potentially alter the efficacy and safety of
study treatments would not be eligible
• Patients must not have a known hypersensitivity to any component of tiragolumab or
atezolizumab injection
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
or fusion proteins
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of
the atezolizumab or tiragolumab formulation
• Patients who have undergone allogeneic bone marrow or stem cell transplant are not
eligible
• Patients with known, untreated CNS metastases will be excluded with the following
exceptions:
• Patients with a history of CNS metastases that have been previously treated may
enroll if sequential imaging shows no evidence for active disease in the CNS
• Patients must not have active autoimmune disease that has required systemic treatment
in the past 12 months, or a documented history of clinically severe autoimmune
disease, or a syndrome that requires systemic steroids or immunosuppressive agents.
Subjects with vitiligo or resolved childhood asthma/atopy are not excluded.
Replacement therapy (e.g. thyroxine, insulin, physiologic corticosteroid replacement
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of
systemic treatment and these patients are eligible
• Patients who have active immune deficiency are not eligible
• Patients who have known active tuberculosis are not eligible
• Hepatitis B or C infection:
• Patients < 18 years old at enrollment, who have known hepatitis B or C
• Patients >= 18 years old at enrollment with:
• Positive hepatitis B surface antigen (HBsAg), OR
• Positive total hepatitis B core antibody (HBcAb) who have a quantitative
hepatitis B virus (HBV) deoxyribonucleic acid (DNA) >= 500 IU/mL, OR
• Positive hepatitis C virus (HCV) antibody with a positive HCV ribonucleic acid
(RNA) test
• Note: For adults (>= 18 years old at enrollment), hepatitis B serology testing is
required to determine eligibility. The HBV DNA test is required only for patients
who have a negative HBsAg test, a negative HBsAb test, and a positive total HBcAb
test. For adults (>= 18 years old at enrollment), hepatitis C serology testing is
required to determine eligibility. The HCV RNA test is required only for patients
who have a positive HCV antibody test
• Patients who have a known, recent Epstein-Barr virus (EBV) infection or known history
of chronic, active infection are not eligible
• Patients who have history of or active human immunodeficiency virus (HIV) are not
eligible except patients who are stable on anti-retroviral therapy, have a CD4 count
>= 200/uL, and have an undetectable viral load
• Patients who have significant cardiovascular disease (such as New York Heart
Association class III or IV congestive heart failure, myocardial infarction, or
cerebrovascular accident) within 3 months prior to study enrollment, unstable
arrhythmia, or unstable angina are not eligible
• Patients who have a major surgical procedure, other than for diagnosis, within 4 weeks
prior to study enrollment, or the anticipation of the need for a major surgical
procedure during the study are not eligible
• Patients who have a history of idiopathic pulmonary fibrosis, organizing pneumonia,
drug-induced pneumonitis, idiopathic pneumonitis, or known active pneumonitis are not
eligible. History of radiation pneumonitis in the radiation field is permitted
• Patients who have uncontrolled pleural effusion, pericardial effusion, or ascites
requiring recurrent drainage procedures (once monthly or more frequently) are not
eligible. Patients with indwelling catheters (e.g., PleurX) are allowed
• Patients who have an uncontrolled infection are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study are not eligible
• Subject has a clinical diagnosis of epilepsy and, in the opinion of the Investigator,
may need benzodiazepine intervention for seizure control.
• Subjects having either partial or generalized epilepsy with motor seizures or seizures
with clear alteration of awareness, for which rescue medications have been used at
least once in the last 3 months or in the opinion of the investigator, may need a
benzodiazepine intervention for seizure control 1-2 times every 3 months on average.
Exclusion Criteria:
• Subjects whose body weight are < 6 kg or > 33 kg.
• Subject is undergoing intracranial electroencephalogram (EEG) monitoring.
• In the opinion of the investigator, a history of clinically significant medical
history that would jeopardize the safety of the subject or impact the validity of the
study results (such as significant gastrointestinal, renal, nasal polyps or any nasal
passage abnormality that could interfere with nasal spray administration.
• Subject has had significant traumatic injury, major surgery or open biopsy within 30
days prior to study screening.
• Participation in a clinical trial within 30 days prior to the first dose of study
drug.
• Inadequate or difficult venous access that may jeopardize the quality or timing of the
PK samples.
A Study of Tirzepatide (LY3298176) in Participants With Heart Failure With Preserved Ejection Fraction and Obesity (SUMMIT) (SUMMIT)
The main purpose of this study is to assess the efficacy and safety of Tirzepatide
(LY3298176) in participants with heart failure with preserved ejection fraction and obesity.
• Have a diagnosis of stable heart failure (NYHA class II-IV) and left ventricular
ejection fraction (LVEF) ≥50%
• Elevated NT-proBNP (N-terminal pro B-type natriuretic peptide) > 200 pg/ml for
participants without atrial fibrillation (AF), or >600 picogram/milliliter (pg/ml) for
participants with AF, Structural heart disease (Left atrial enlargement) or Elevated
left ventricular filling pressure
• Estimated glomerular filtration rate (eGFR) <70 milliliter (ml)/minute (min)/1.73m² at
screening, or HF decompensation within 12 months of screening,
• Stable dose of heart failure medications within 4 weeks of screening
• Body mass index (BMI) ≥30 kilograms per meter squared (kg/m²)
• 6MWD 100-425m
• KCCQ CSS ≤80
Exclusion Criteria:
• Have had a major cardiovascular event within the last 90 days of screening
• Have had acute decompensated heart failure within 4 weeks of screening
• Have non cardiac causes of functional impairment such as pulmonary arterial
hypertension (PAH), severe chronic obstructive pulmonary disease (COPD), anemia,
thyroid disease, musculoskeletal disease or orthopedic conditions
• Presence of cardiac amyloidosis, cardiac accumulation disease, cardiomyopathy and
severe valvular hear disease
• HbA1c ≥9.5% or uncontrolled diabetes
• History of proliferative diabetic retinopathy or diabetic maculopathy
• Have a history of pancreatitis
• eGFR <15 mL/min/1.73 m² or requiring dialysis at screening
Drug: Tirzepatide, Other: Placebo
Heart Failure With Preserved Ejection Fraction, Obesity
Heart Failure with Preserved Ejection Fraction (HFpEF)
A Research Study to See How Well CagriSema Helps People With Excess Body Weight Lose Weight (REDEFINE 1)
This study has 2 parts: First part is the main study and second part is the extension study.
During the main study participants will receive 1 of 4 study medicines. If participants
continue in the extension study, they will not receive any study medicine during the
extension. The main study will look at how well CagriSema helps participants with excess body
weight lose weight compared to a "dummy" medicine and 2 other medicines, cagrilintide and
semaglutide. Participants will either get CagriSema, cagrilintide,semaglutide or "dummy"
medicine. Which treatment participants get is decided by chance. They will take one injection
once a week. The study medicine is injected briefly with a thin needle, typically in the
stomach, thighs or upper arms.
Extension study: After the main study, not all participants will continue in the extension
study. The study staff will tell the participant if they will continue or not into the
extension study. In the extension study we will look at what happens to the participant's
body weight and diseases related to excess body weight after the participant stops taking the
study medicine. The main study will last for about 1½ years and the extension study will last
for another 2 years.
• Male or female
• Age above or equal to 18 years at the time of signing informed consent
• Body mass index (BMI) greater than or equal to 30.0 kilograms per square meter
(kg/m^2) or b) BMI greater than or equal to 27.0 kg/m^2 with the presence of at least
one weight-related comorbidity including, but not limited to hypertension,
dyslipidaemia, obstructive sleep apnoea or cardiovascular disease
Exclusion Criteria:
•Glycaemia related: a) Glycated Haemoglobin (HbA1c) greater than or equal to 6.5 percent
(48 millimoles per mole [mmol/mol]) as measured by the central laboratory at screening b)
History of type 1 or type 2 diabetes mellitus
Open-label Extension Study of GB002 in Adult Subjects With Pulmonary Arterial Hypertension (PAH)
This open-label extension study will evaluate the long-term effects of GB002 (seralutinib) in
subjects who previously participated in a GB002 PAH study.
Type of Subject and Disease Characteristics
1. Subjects must have completed a prior GB002 PAH study and, in the opinion of the
Investigator and Sponsor, have been compliant with study procedures and have completed
treatment with IP through parent study end-of-treatment (EOT) visit.
2. Treatment with standard of care PAH disease-specific background therapies (stable
dose).
Informed Consent
3. Review and signature of an IRB-approved informed consent form.
Exclusion Criteria:
Medical Conditions
1. Persistent and clinically significant systemic hypertension or hypotension.
2. Interval history of newly developed left-sided heart disease.
3. Potentially life-threatening cardiac arrhythmia with an ongoing risk.
4. Uncontrolled bacterial, viral, or fungal infections which require systemic therapy.
5. Other severe acute or chronic medical or laboratory abnormality that may increase the
risk associated with study participation or GB002 administration or may interfere with
the interpretation of study results and, in the judgment of the Investigator, would
make the subject inappropriate for entry into this study.
6. History of portopulmonary hypertension or portal hypertension due to cirrhosis
classified as Child-Pugh Class A or higher.
7. Subjects with a history of severe milk protein allergy. In addition, subjects with
known intolerance or hypersensitivity to lactose who, in the opinion of the
investigator, may experience severe symptoms following the ingestion of lactose.
8. Current use of inhaled tobacco and/or inhaled marijuana. Ingestible or topical
marijuana is allowed, per local restrictions and regulations.
9. Current alcohol use disorder as defined by DSM-5, and/or history of current
utilization of drugs of abuse (amphetamines, methamphetamines, cocaine, phencyclidine
[PCP]).
10. Have any other condition or reason that, in the opinion of the Investigator and/or the
Sponsor's Medical Monitor (or designee), would prohibit the subject from participating
in the study.
Diagnostic Assessments
11. Chronic renal insufficiency
12. Hemoglobin (Hgb) concentration <8.5 g/dL.
13. Absolute neutrophil count (ANC) < 1x 10^9/L.
14. Platelet count <50 x 10^9/L.
Prior Therapy
15. Use of inhaled prostanoids.
16. Chronic use of oral anticoagulants (ie, vitamin K antagonist such as warfarin or novel
oral anticoagulant [NOAC]/direct oral anticoagulant [DOAC]).
17. Chronic use of any prohibited medication.
NOTE: Additional inclusion/exclusion criteria may apply, per protocol.
A Study for Oral SY-2101 for Participants With Acute Promyelocytic Leukemia
SY-2101 is being studied as a treatment for participants with a type of leukemia called acute
promyelocytic leukemia (APL). SY-2101 is an oral formulation of a drug called arsenic
trioxide (ATO). ATO is already used to treat APL in a formulation that is given as an
intravenous (IV) infusion (through a needle in the arm). SY-2101 is a formulation of ATO that
is taken orally (by mouth).
This trial will include participants with APL in remission, who are receiving standard of
care (SOC) treatment with all-trans-retinoic acid (ATRA) and IV ATO, during the consolidation
phase of chemotherapy or within the past 6 months. The participants in this trial will
receive continued treatment with ATO and ATRA to help keep their cancer from coming back.
There will be some weeks when participants receive IV ATO and others when they receive
SY-2101 (ATO taken orally). Participants with high-risk APL may be eligible for part 1 or 4
of the study for the 6 months following completion of their standard of care ATRA and ATO
treatment.
• Participants must have a diagnosis of APL characterized by the presence of the
t(15;17) translocation or PML/RARA gene expression via reverse transcription
polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), or
cytogenetics. Participants with low-risk APL may be eligible for all parts of this
study; participants with high-risk APL are only eligible for the single-dose modules
if they have completed a treatment regimen that included ATO within 6 months prior to
the Screening Visit.
• Participants must have received ATO plus ATRA induction therapy and must have received
or be eligible and planning to receive consolidation therapy with ATO plus ATRA in
alignment with National Comprehensive Cancer Network (NCCN) guidelines for low-risk
APL prior to their enrollment in the study; or participants must have completed a
treatment regimen that included ATO within 6 months prior to the Screening Visit.
• Participants must be able to tolerate full dose ATO per NCCN guidelines.
• Participants must be in morphological complete remission (CR) at the end of induction.
• Participants must have a serum or high-sensitivity urine pregnancy test (for females
of childbearing potential) that is negative at the Screening Visit and immediately
prior to initiation of study treatment (first dose of study drug).
Key
Exclusion Criteria:
• Participants who have demonstrated relapse and therefore are not eligible for further
consolidation.
• Participants currently receiving treatment for a non-APL malignancy (not including
basal cell carcinoma, non-melanoma skin cancer, cervical carcinoma in situ, or
localized prostate cancer treated with hormone therapy). Participants with history of
other cancers should be free of disease for at least 2 years prior to the Screening
Visit.
• Participants with an active, life-threatening, or clinically-significant uncontrolled
systemic infection requiring hospitalization.
• Immunocompromised participants with increased risk of opportunistic infections,
including known human immunodeficiency virus (HIV)-positive participants with cluster
of differentiation 4 (CD4) counts ≤350 cells/millimeters (mm^3) or history of
opportunistic infection in the last 12 months.
• Participants with a known active or chronic hepatitis B or active hepatitis C virus
(HCV) infection. Participants with a history of HCV infection who have completed
curative therapy for HCV at least 12 weeks before the Screening Visit and have a
documented undetectable viral load at the Screening Visit are eligible for enrollment.
• Participants who have not adequately recovered from a major surgery within 4 weeks of
starting study drug administration.
• Participants who received any other investigational agents within 4 weeks of the
Screening Visit or <5 half-lives since completion of previous investigational therapy
have elapsed, whichever is shorter.
• Participants who have a hypersensitivity to arsenic.
• Participants who have experienced the following Grade ≥3 non-hematologic toxicities
associated with ATO administration: QT prolongation, hepatotoxicity, neurotoxicity,
cardiac function abnormalities. Participants who experienced other severe and
life-threatening clinically-significant ATO-related AEs that are considered, in the
judgement of the investigator, to increase participant risk with continued ATO
treatment are also excluded.
Other inclusion/exclusion criteria may apply.
Drug: SY-2101, Drug: Arsenic Trioxide
Myeloid and Monocytic Leukemia, Acute Promyelocytic Leukemia
A Study to Evaluate the Efficacy and Safety of Mitapivat in Pediatric Participants With Pyruvate Kinase Deficiency (PKD) Who Are Not Regularly Transfused, Followed by a 5-Year Extension Period (ACTIVATE-Kids)
Study ACTIVATE-Kids (AG348-C-023) will evaluate the efficacy and safety of orally
administered mitapivat as compared with placebo in pediatric participants with pyruvate
kinase deficiency (PKD) who are not regularly receiving blood transfusions. Participants will
be randomized 2:1 to receive either mitapivat or matching placebo. Randomization will be
stratified by age (1 to < 6 years, 6 to < 12 years, 12 to < 18 years). Participants will be
dosed by age and weight during a double-blind period consisting of an 8-week dose titration
period followed by a 12-week fixed-dose period. Participants who complete the double-blind
period will be eligible to receive mitapivat for up to 5 years in the open-label extension
(OLE) period.
• Written informed consent from the participant, or the participant's legally authorized
representative, parent(s), or legal guardian, and the participant's assent, where
applicable (informed consent/assent) must be obtained before any study-related
procedures are conducted, and participants must be willing to comply with all study
procedures for the duration of the study;
• Aged 1 to <18 years. Participants between 12 and 24 months of age must weigh a minimum
of 7 kilograms (kg);
• Clinical laboratory confirmation of pyruvate kinase deficiency (PKD), defined as
documented presence of at least 2 mutant alleles in the pyruvate kinase L/R (PKLR)
gene, of which at least 1 is a missense mutation, as determined per the genotyping
performed by the study central genotyping laboratory;
• No more than 5 red blood cell (RBC) transfusions in the 52-week period before
providing informed consent/assent and no RBC transfusions ≤12 weeks before
administration of the first dose of study drug;
• Hemoglobin concentration ≤10 grams per deciliter (g/dL) for participants 12 to <18
years of age or ≤9 g/dL for participants 1 to <12 years of age during the screening
period. Hb concentration must be based on an average of at least 2 Hb concentration
measurements (separated by ≥7 days) collected during the screening period;
• Receiving folic acid supplementation as part of routine clinical care for at least 21
days before administration of the first dose of study drug, to be continued during
study participation;
• Female participants who have attained menarche and/or breast development in Tanner
Stage 2, as well as male participants with partners who have attained menarche, must
be abstinent of sexual activities that may induce pregnancy as part of their usual
lifestyle, or agree to use 2 forms of contraception, 1 of which must be considered
highly effective, from the time of informed consent/assent, throughout the study, and
for 28 days after the last dose of study drug (including the time required to dose
taper) for female participants who have attained menarche and 90 days after the last
dose of study drug (including the time required to dose taper) for male participants .
The second form of contraception can include an acceptable barrier method.
Exclusion Criteria:
• Pregnant or breastfeeding;
• Homozygous for the R479H mutation or have 2 nonmissense mutations, without the
presence of another missense mutation, in the PKLR gene as determined per the
genotyping performed by the study central genotyping laboratory;
• History of malignancy;
• History of active and/or uncontrolled cardiac or pulmonary disease or clinically
relevant QT prolongation within 6 months before providing informed consent/assent;
• Hepatobiliary disorders including, but not limited to:
• Liver disease with histopathological evidence of cirrhosis or severe fibrosis;
• Clinically symptomatic cholelithiasis or cholecystitis (participants with prior
cholecystectomy are eligible);
• History of drug-induced cholestatic hepatitis;
• Aspartate aminotransferase >2.5×upper limit of normal (ULN) (unless due to
hemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5×ULN
(unless due to hepatic iron deposition);
• Renal dysfunction as defined by an estimated glomerular filtration rate <60
milliliters per minute (mL/min)/1.73 m^2;
• Nonfasting triglycerides >440 milligrams per deciliter (mg/dL) (5 millimoles per liter
[mmol/L]);
• Active uncontrolled infection requiring systemic antimicrobial therapy;
• Participants with a high likelihood of exposure to, or parental history of, hepatitis
B or hepatitis C who subsequently test positive for hepatitis B antigen or hepatitis C
virus antibody with signs of active hepatitis B or hepatitis C virus infection;
• Participants with a high likelihood of exposure to, or parental history of, human
immunodeficiency virus (HIV) who subsequently test positive for HIV-1 or -2
antibodies;
• History of major surgery (including splenectomy) ≤6 months before providing informed
consent/assent and/or planning on undergoing a major surgical procedure during the
screening or double-blind period;
• Current enrollment or past participation (within 90 days before the first dose of
study drug or a time frame equivalent to 5 half-lives of the investigational study
drug, whichever is longer) in any other clinical study involving an investigational
study drug or device;
• Prior bone marrow or stem cell transplantation;
• Currently receiving hematopoietic stimulating agents; the last dose must have been
administered at least 28 days or a time frame equivalent to 5 half-lives (whichever is
longer) before randomization;
• Receiving products that are strong inhibitors of CYP3A4/5 that have not been stopped
for ≥5 days or a time frame equivalent to 5 half-lives (whichever is longer), or
strong inducers of CYP3A4 that have not been stopped for ≥28 days or a time frame
equivalent to 5 half-lives (whichever is longer), before randomization;
• Receiving anabolic steroids, including testosterone preparations, that have not been
stopped for at least 28 days before randomization;
• Known allergy to mitapivat or its excipients (microcrystalline cellulose,
croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate);
• Any medical, hematologic, psychological, or behavioral condition(s) or prior or
current therapy that, in the opinion of the Investigator, may confer an unacceptable
risk to participating in the study and/or could confound the interpretation of the
study data.
Comparison of Chronocort Versus Standard Hydrocortisone Replacement Therapy in Participants Aged 16 Years and Over With Congenital Adrenal Hyperplasia (CONnECT)
This study is a randomized, double-blind, active-controlled, phase III study of Chronocort®
compared with immediate-release hydrocortisone replacement therapy in participants aged 16
years and over with Congenital Adrenal Hyperplasia.
• Male or female participants must be aged 16 years or older at the time of signing the
informed consent/assent.
• In participants aged <18 years, height velocity must be less than 2 cm/year in the
last year and puberty must be completed (Tanner stage V).
• Participants with known classic CAH due to 21 hydroxylase deficiency diagnosed in
childhood with documented (at any time) elevated 17-OHP and with or without elevated
A4 and currently treated with hydrocortisone, prednisone, prednisolone or
dexamethasone (or a combination of the aforementioned glucocorticoids) and on stable
glucocorticoid therapy for a minimum of 3 months.
• Participants who are receiving fludrocortisone must be on a documented stable dose for
a minimum of 3 months prior to enrollment and must have stable renin levels at
screening.
• Female participants of childbearing potential and all male participants must agree to
the use of an accepted method of contraception during the study.
• A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and she is either not a woman of childbearing potential (WOCBP) or has
a negative pregnancy test at entry into the study. Note: females presenting with
oligomenorrhea or amenorrhea who are aged ≤55 years should be considered potentially
fertile and therefore should undergo pregnancy testing like all other female
participants.
• Capable of giving signed informed consent/assent which includes compliance with
requirements and restrictions listed in the informed consent form (ICF) and in this
protocol.
Exclusion Criteria:
• Clinical or biochemical evidence of hepatic or renal disease e.g. creatinine >2 times
the upper limit of normal (ULN) or elevated liver function tests (alanine
aminotransferase [ALT] or aspartate aminotransferase [AST] >2 times the ULN).
• History of bilateral adrenalectomy.
• History of malignancy (other than basal cell carcinoma successfully treated >26 weeks
prior to entry into the study).
• Participants who have type 1 diabetes or receive regular insulin, have uncontrolled
diabetes, or have a screening HbA1c greater than 8%..
• Persistent signs of adrenal insufficiency or the participant does not tolerate
treatment at the end of the 4-week run-in period.
• Participants with any other significant medical or psychiatric conditions that in the
opinion of the Investigator would preclude participation in the study.
• Participants on regular daily inhaled, topical, nasal or oral steroids for any
indication other than CAH.
• Co-morbid condition requiring daily administration of a medication or consumption of
any material that interferes with the metabolism of glucocorticoids.
• Participants who are receiving <10 mg hydrocortisone dose at screening or the
hydrocortisone dose equivalent.
• Participants anticipating regular prophylactic use of additional steroids e.g. for
strenuous exercise.
• Participation in another clinical study of an investigational or licensed drug or
device within the 12 weeks prior to screening.
• Inclusion in any natural history or translational research study that would require
evaluation of androgen levels during the study period outside of this protocol's
assessments.
• Participants who have previously been exposed to Chronocort in any Diurnal study.
• Participants who routinely work night shifts and so do not sleep during the usual
night-time hours.
• Participants, who in the opinion of the Investigator, will be unable to comply with
the requirements of the protocol.
• Participants with a known hypersensitivity to any of the components of the Chronocort
capsules, the Cortef tablets, or the placebo capsules.
• Participants with congenital galactosemia, malabsorption of glucose and galactose, or
who are lactase deficient.
• Participants with a body weight of 45 kg or less.
A Research Study to See How Well CagriSema Helps People With Type 2 Diabetes and Excess Body Weight Lose Weight (REDEFINE 2)
This study will look at how well the new medicine CagriSema helps people living with excess
body weight and type 2 diabetes losing weight. Participants will either get CagriSema or a
dummy medicine. Which treatment they get is decided by chance.
The study will last for about 1½ years. Women cannot take part if pregnant, breast-feeding or
plan to get pregnant during the study period.
• Male or female
• Age above or equal to 18 years at the time of signing informed consent
• BMI greather than or equal to 27.0 kg/m^2
• Diagnosed with type 2 diabetes mellitus greater than or equal to 180 days before
screening
• Treatment with either lifestyle intervention, or treatment with 1-3 marketed oral
antidiabetic drugs (OAD)s (metformin, α-glucosidase inhibitors (AGI), glinides,
sodium-glucose co-transporter 2 inhibitor (SGLT2i), thiazolidinediones, or
sulphonylureas (SU)s as a single agent or in combination) according to local label
• Treatment with oral antidiabetic drugs should be stable (same drug(s), dose and dosing
frequency) for at least 90 days before screening
• HbA1c 7%-10% (53-86 mmol/mol) (both inclusive) as measured by the central laboratory
at screening
Exclusion Criteria:
• Clinically significant or severe hypoglycaemia within 6 months before screening or
history of hypoglycaemia unawareness
• Renal impairment with estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73
m^2, as measured by the central laboratory at screening
• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by
a fundus examination performed within 90 days before screening or in the period
between screening and randomisation. Pharmacological pupil-dilation is a requirement
unless using a digital fundus photography camera specified for non-dilated
examination.
Clinical Medication Development for Bipolar Disorder and Alcohol Use Disorders
Preclinical and clinical data as well as mechanistic justification have been presented
suggesting citicoline and pregnenolone are each promising treatments for alcohol use in BPD.
Both appear to have favorable side effect profiles and no known drug-drug interactions. Thus,
they have the potential to be safely used in a dual diagnosis population already taking other
medications. A 12-week, randomized, double-blind, parallel-group, placebo-controlled adaptive
design study of citicoline and pregnenolone is proposed in 199 persons with alcohol use
disorder and bipolar I or II disorder or schizoaffective disorder (bipolar type). The primary
aim will be to assess change in alcohol use. Biomarkers of alcohol use, alcohol craving, mood
and cognition will also be assessed. Relationships between neurosteroid and choline levels
and the outcome measures will be explored.
• Outpatient men and women age 18-70 years old with bipolar I or II disorder or
schizoaffective disorder (bipolar type)
• English or Spanish speaking
• Current diagnosis of alcohol use disorder with at least moderate severity (DSM-5
terminology)
• Alcohol use of at least an average of 28 drinks a week if male or an average of 21
drinks per week if female and an average of 3 drinking days a week in the 28 days
prior to intake
• Current mood stabilizer therapy (defined as lithium, lamotrigine, carbamazepine,
oxcarbazepine or an atypical antipsychotic) with stable dose for ≥ 28 days prior to
randomization or valproate/divalproex at a stable dose for ≥ 90 days (longer period
due to data suggesting valproate may decrease alcohol use in BPD)
• Diagnosis of substance use disorder other than alcohol, caffeine or nicotine is
allowed if 1) alcohol is the self-identified substance of choice and 2) severity of
other substance use disorder is ≤ moderate
Exclusion Criteria:
• Mood disorders other than bipolar I or II disorders or schizoaffective disorder
bipolar type (e.g. bipolar NOS, cyclothymic disorders, schizophrenia, schizoaffective
disorder depressive type, or unipolar depression based on the SCID); other disorders
(e.g. anxiety, will be allowed)
• Baseline HRSD17 or YMRS scores ≥ 35 to exclude those with very severe mood symptoms at
baseline
• Evidence of clinically significant alcohol withdrawal symptoms defined as a CIWA-Ar
score of ≥ 10
• Current (last 28 days) treatment with naltrexone, acamprosate, disulfiram, or
topiramate as these may also decrease alcohol use
• Oral contraceptives and hormone replacement therapy. This exclusion is due to a
possible interaction with pregnenolone.
• Women with hormone sensitive conditions such as breast cancer, uterine cancer, ovarian
cancer, endometriosis, uterine fibroids. These persons are excluded because
pregnenolone is converted to estrogens.
• Vulnerable populations (e.g. pregnant, nursing, cognitively impaired, incarcerated)
• High risk for suicide defined as > 1 attempt in past 12 months that required medical
attention, any attempt in the past 3 months or current suicidal ideation with plan and
intent such that outpatient care is precluded
• Intensive outpatient treatment (defined as ≥3 visits each week) for substance abuse
(AA, NA meetings, or less intensive counseling at baseline will be allowed)
• Severe/unstable condition (e.g. cirrhosis, poorly controlled hypertension) or
laboratory/physical exam findings consistent with serious illness (e.g. abnormal
electrolytes) or AST or ALT >3 times normal
Neo-adjuvant SABR for IVC Tumor Thrombus in Newly Diagnosed RCC
To evaluate the safety and feasibility of pre-operative SABR of RCC IVC tumor thrombus.
To evaluate the effect of pre-operative SABR in RCC IVC tumor thrombus on relapse free
survival at one year.
1. Radiographic evidence of renal cancer with IVC tumor thrombus
2. Tumor thrombus must be ≥ level II (As per Mayo classification, it would be ≥ level I
[Refer to NEVES, R. and ZINCKE, H. (1987), Surgical Treatment of Renal Cancer with
Vena Cava Extension. British Journal of Urology, 59: 390-395.
doi:10.1111/j.1464-410X.1987.tb04832.x])
3. Patient eligible for SABR to the IVC tumor thrombus as decided by the treating
radiation oncologist
4. Patient eligible for IVC tumor thrombectomy as decided by the treating urologist
5. Any number of metastatic disease is allowed in the Pilot phase of the trial
• For Phase II, metastatic patients will be allowed only if all sites of metastasis
has been treated either surgically or radio-surgically (If limited sites of metastasis
are present, all of which can be resected during the nephrectomy, then the patient can
be eligible)
6. Age ≥ 18 years.
7. Performance status ECOG 0-2
8. Any serum Albumin is allowed, but ≥ 3.4 g/dL is strongly encouraged
• Serum albumin <3.4 is a significant predictor of peri-operative mortality(12)
9. Any serum AST is allowed but serum AST ≤ 34 IU/L is strongly encouraged
• Significant predictor of mortality in univariate but not multivariate analysis(12)
10. Women of childbearing potential and men must agree to use adequate contraception
(hormonal such as birth control pills, patch or ring; Depo-Provera, Implanon or
barrier method, such as condom or diaphragm used with a spermicide of birth control;
abstinence) prior to study entry, for the duration of study treatment, and for 90 days
following completion of radiation therapy. Should a woman become pregnant or suspect
she is pregnant while participating in this study, she should inform her treating
physician immediately.
10.1 A female of childbearing potential is any woman (regardless of sexual
orientation, marital status, having undergone a tubal ligation, or remaining celibate
by choice) who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
has had menses at any time in the preceding 12 consecutive months).
11. Ability to understand and the willingness to sign a written informed consent.
12. Subjects must be able to undergo either MRI or CT.
Exclusion Criteria:
1. Subjects who have had radiotherapy to a target within 3 cm of the IVC tumor thrombus.
2. Subjects may have received any other investigational agents or chemotherapy as long as
they are eligible for SABR and surgery
3. Subjects with brain metastases should be excluded from this clinical trial unless all
the metastasis are treated surgically or radio-surgically
4. Subjects with a history of pulmonary embolism is excluded
5. Subjects with a history of pulmonary hypertension is excluded
6. Subjects must not be pregnant due to the potential for congenital abnormalities.
7. Contraindication for contrast-enhanced MRI as defined by the standard operating
procedures of the Department of Radiology at UT Southwestern. Briefly, these include
medically unstable; cardiac pacemaker; intracranial clips, metal implants; metal in
the eyes; pregnant or nursing; claustrophobia; and impairment of the renal function
with estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2. Patients with one
or more of these contraindications but eligible to undergo contrast-enhanced CT can
participate in this study and will not receive an MRI
A Study of Pembrolizumab (MK-3475) in Pediatric Participants With an Advanced Solid Tumor or Lymphoma (MK-3475-051/KEYNOTE-051)
This is a two-part study of pembrolizumab (MK-3475) in pediatric participants who have any of
the following types of cancer:
- advanced melanoma (6 months to <18 years of age),
- advanced, relapsed or refractory programmed death-ligand 1 (PD-L1)-positive malignant
solid tumor or other lymphoma (6 months to <18 years of age),
- relapsed or refractory classical Hodgkin lymphoma (rrcHL) (3 years to <18 years of age),
or
- advanced relapsed or refractory microsatellite-instability-high (MSI-H) solid tumors (6
months to <18 years of age).
Part 1 will find the maximum tolerated dose (MTD)/maximum administered dose (MAD), confirm
the dose, and find the recommended Phase 2 dose (RP2D) for pembrolizumab therapy. Part 2 will
further evaluate the safety and efficacy at the pediatric RP2D.
The primary hypothesis of this study is that intravenous (IV) administration of pembrolizumab
to children with either advanced melanoma; a PD-L1 positive advanced, relapsed or refractory
solid tumor or other lymphoma; advanced, relapsed or refractory MSI-H solid tumor; or rrcHL,
will result in an Objective Response Rate (ORR) greater than 10% for at least one of these
types of cancer.
• Between 6 months and <18 years of age (or between 3 years and <18 years of age for
rrcHL participants) on day of signing informed consent/assent (the first 3
participants dosed in Part 1 are to be ≥ 6 years of age)
• Histologically- or cytologically-documented, locally-advanced, or metastatic solid
malignancy or lymphoma that is incurable and has failed prior standard therapy, or for
which no standard therapy exists, or for which no standard therapy is considered
appropriate
• Any number of prior treatment regimens
• Tissue (or lymph node biopsy for rrcHL participants) available from an archival tissue
sample or, if appropriate, a newly obtained core or excisional biopsy of a tumor
lesion not previously irradiated
• Advanced melanoma or PD-L1-positive advanced, relapsed, or refractory solid tumor or
lymphoma
• Measurable disease based on RECIST 1.1 (Or based on IWG [Cheson, 2007] [i.e.,
measurement must be >15 mm in longest diameter or >10 mm in short axis] for rrcHL
participants)
• Participants with neuroblastoma with only metaiodobenzylguanidine (MIBG)-positive
evaluable disease may be enrolled
• Lansky Play Scale ≥50 for participants from 6 months up to and including 16 years of
age; or Karnofsky score ≥50 for participants >16 years of age
• Adequate organ function
• Female participants of childbearing potential should have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study medication
• Female participants of childbearing potential must be willing to use 2 methods of
contraception or be surgically sterile, or abstain from heterosexual activity for the
course of the study through 120 days after the last dose of study medication
• Male participants of reproductive potential must agree to use an adequate method of
contraception starting with the first dose of study medication through 120 days after
the last dose of study medication
Exclusion Criteria:
• Currently participating and receiving study therapy in, or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the date of allocation/randomization
• Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form
of immunosuppressive therapy within 7 days prior to the date of
allocation/randomization
• Prior systemic anti-cancer therapy including investigational agent within 2 weeks
prior to study Day 1 or not recovered from adverse events due to a previously
administered agent
• Prior radiotherapy within 2 weeks of start of study treatment
• Known additional malignancy that is progressing or requires active treatment with the
exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin or
carcinoma in situ (eg, breast carcinoma, cervical carcinoma in situ) with potentially
curative therapy, or in situ cervical cancer
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Tumor(s) involving the brain stem
• Severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients
• Active autoimmune disease that has required systemic treatment in past 2 years;
replacement therapy (such as thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency) is acceptable
• Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis.
• Active infection requiring systemic therapy
• Pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial through 120 days after the last dose of study
medication
• Prior therapy with an anti-programmed cell death (PD)-1, anti-PD-ligand 1
(anti-PD-L1), anti-PD-L2 agent, or any agent directed to another stimulatory or
inhibitory T-cell receptor (eg, cytotoxic lymphocyte associated protein-4 [CTLA-4],
OX-40, CD137)
• Human immunodeficiency virus (HIV)
• Hepatitis B or C
• Known history of active tuberculosis (TB; Bacillus tuberculosis)
• Received a live vaccine within 30 days of planned start of study medication
• Has undergone solid organ transplant at any time, or prior allogeneic hematopoietic
stem cell transplantation within the last 5 years. (Participants who have had an
allogeneic hematopoietic transplant >5 years ago are eligible as long as there are no
symptoms of Graft Versus Host Disease [GVHD].)
• History or current evidence of any condition, therapy, or laboratory abnormality, or
known severe hypersensitivity to any component or analog of the trial treatment, that
might confound the results of the trial, or interfere with the participant's
participation for the full duration of the study
• Known psychiatric or substance abuse disorders that would interfere with the
requirements of the study
Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
This Pediatric MATCH screening and multi-sub-study phase II trial studies how well treatment
that is directed by genetic testing works in pediatric patients with solid tumors,
non-Hodgkin lymphomas, or histiocytic disorders that have progressed following at least one
line of standard systemic therapy and/or for which no standard treatment exists that has been
shown to prolong survival. Genetic tests look at the unique genetic material (genes) of
patients' tumor cells. Patients with genetic changes or abnormalities (mutations) may benefit
more from treatment which targets their tumor's particular genetic mutation, and may help
doctors plan better treatment for patients with solid tumors or non-Hodgkin lymphomas.
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients must be >= 12 months and
=< 21 years of age at the time of study enrollment
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients with recurrent or
refractory solid tumors, including non-Hodgkin lymphomas, histiocytoses (e.g.
langerhans cell histiocytosis [LCH], juvenile xanthogranuloma [JXG], histiocytic
sarcoma), and central nervous system (CNS) tumors are eligible; patients must have had
histologic verification of malignancy at original diagnosis or relapse except in
patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with
pineal tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers
including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG); in cases where
patient enrolls prior to histologic confirmation of recurrent disease, patient is
ineligible and should be withdrawn from study if histology fails to confirm
recurrence; please note: Patients with Hodgkin lymphoma and plexiform neurofibroma are
not eligible
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Tumor Testing Requirement: Tumor
sample availability requirement for stage 1 of Pediatric MATCH (patients enrolled from
start of study in July 2017 through 12/31/21); Patients must have an formalin-fixed
paraffin-embedded (FFPE) tumor sample available for MATCH study testing from a biopsy
or surgery that was performed at any point after initial tumor recurrence/progression,
or be planned to have a procedure to obtain such a sample that is considered to be of
potential benefit by the treating clinicians; a tumor sample from a clinically
performed diagnostic (pre-treatment) biopsy will be acceptable for enrollment onto
Pediatric MATCH only for children with high-grade gliomas of the brainstem (diffuse
intrinsic pontine gliomas) or thalamus
• Please note: Samples that have been decalcified using standardly utilized
acid-based decalcification methods are not generally suitable for MATCH study
testing; the nucleic acids will have been degraded in the decalcification process
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Tumor molecular profiling report
availability requirement for Stage 2 of Pediatric MATCH (patients enrolled starting
2022): In stage 2 of the study, no tumor samples will be submitted for centralized
clinical tumor profiling; instead, a tumor molecular profiling report from a College
of American Pathologists (CAP)/ Clinical Laboratory Improvements Amendments
(CLIA)-approved testing laboratory must be submitted for review by the Molecular
Review Committee (MRC)
• This molecular profiling must have been performed on a tumor sample that was
obtained at any point after initial tumor recurrence/progression and must be
accompanied by a pathology report for the same tumor specimen; a molecular
profiling report for a diagnostic (pre-treatment) tumor sample will be acceptable
for enrollment onto Pediatric MATCH only for children with high-grade gliomas of
the brainstem (diffuse intrinsic pontine gliomas) or thalamus. In the event that
molecular profiling reports are available from multiple timepoints, the most
recent report should be prioritized for study submission
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Karnofsky >= 50% for patients >
16 years of age and Lansky >= 50 for patients =< 16 years of age); note: neurologic
deficits in patients with central nervous system (CNS) tumors must have been stable
for at least 7 days prior to study enrollment; patients who are unable to walk because
of paralysis, but who are up in a wheelchair, will be considered ambulatory for the
purpose of assessing the performance score
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients must have
radiographically measurable disease; measurable disease based on imaging obtained less
than or equal to 56 days prior to enrollment; patients with neuroblastoma who do not
have measurable disease but have metaiodobenzylguanidine (MIBG) positive (+) evaluable
disease are eligible; measurable disease in patients with CNS involvement is defined
as any lesion that is at minimum 10 mm in one dimension on standard magnetic resonance
imaging (MRI) or computed tomography (CT)
• Note: The following do not qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or
positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or CSF
• Previously radiated lesions that have not demonstrated clear progression
post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: NOTE: patient does not need to meet all
subprotocol criteria at time of enrollment onto the APEC1621SC screening protocol, but
will need to meet all criteria prior to enrollment on any assigned treatment
subprotocol. Patients must be enrolled onto a subprotocol within 2 weeks (14 days) of
treatment assignment
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Karnofsky >= 50% for patients > 16 years
of age and Lansky >= 50 for patients =< 16 years of age); Note: neurologic deficits in
patients with CNS tumors must have been stable for at least 7 days prior to study
enrollment; patients who are unable to walk because of paralysis, but who are up in a
wheelchair, will be considered ambulatory for the purpose of assessing the performance
score
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: At the time of treatment with subprotocol
specified therapy, the patients must have radiographically measurable disease;
patients with neuroblastoma who do not have measurable disease but have MIBG+
evaluable are eligible; measurable disease in patients with CNS involvement is defined
as any lesion that is at minimum 10 mm in one dimension on standard MRI or CT
• Note: The following do not qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or
positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or CSF
• Previously radiated lesions that have not demonstrated clear progression
post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for
RECIST 1.1
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: At the time of enrollment onto a
subprotocol, the following general criteria for initiation of therapy will be
required:
• Patients must have fully recovered from the acute toxic effects of all prior
anticancer therapy and must meet the following minimum duration from prior
anticancer directed therapy prior to enrollment to the subprotocol; if after the
required timeframe, the numerical eligibility criteria are met, e.g. blood count
criteria, the patient is considered to have recovered adequately
• Cytotoxic chemotherapy or other anticancer agents known to be
myelosuppressive: for agents not listed, the duration of this interval must
be discussed with the study chair and the study-assigned research
coordinator prior to enrollment >= 21 days after the last dose of cytotoxic
or myelosuppressive chemotherapy (42 days if prior nitrosourea)
• Anticancer agents not known to be myelosuppressive (e.g. not associated with
reduced platelet or absolute neutrophil counts [ANC]): >= 7 days after the
last dose of agent; for agents not listed, the duration of this interval
must be discussed with the study chair and the study-assigned research
coordinator prior to enrollment
• Antibodies: >= 21 days must have elapsed from infusion of last dose of
antibody, and toxicity related to prior antibody therapy must be recovered
to grade =< 1
• Corticosteroids: If used to modify immune adverse events related to prior
therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Hematopoietic growth factors: >= 14 days after the last dose of a
long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth
factor; for agents that have known adverse events occurring beyond 7 days
after administration, this period must be extended beyond the time during
which adverse events are known to occur; the duration of this interval must
be discussed with the study chair and the study-assigned research
coordinator
• Interleukins, interferons and cytokines (other than hematopoietic growth
factors): >= 21 days after the completion of interleukins, interferon or
cytokines (other than hematopoietic growth factors)
• Stem cell infusions (with or without total-body irradiation [TBI]):
• Allogeneic (non-autologous) bone marrow or stem cell transplant, or any
stem cell infusion including donor lymphocyte infusion (DLI) or boost
infusion: >= 84 days after infusion and no evidence of graft versus
host disease (GVHD)
• Autologous stem cell infusion including boost infusion: >= 42 days
• Cellular therapy: >= 42 days after the completion of any type of cellular
therapy (e.g. modified T cells, natural killer (NK) cells, dendritic cells,
etc.)
• X-ray therapy (XRT)/External Beam Irradiation including Protons: >= 14 days
after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to
>= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM)
radiation; note: radiation may not be delivered to "measurable disease"
tumor site(s) being used to follow response to subprotocol treatment
• Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42
days after systemically administered radiopharmaceutical therapy
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: For patients with solid tumors without
known bone marrow involvement:
• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment)
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Patients with known bone marrow
metastatic disease will be eligible for study provided they meet the blood counts (may
receive transfusions provided they are not known to be refractory to red cell or
platelet transfusions); these patients will not be evaluable for hematologic toxicity
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Creatinine clearance or radioisotope
glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or a serum creatinine based on
age/gender as follows:
• Age: 1 to < 2 years; maximum serum creatinine (mg/dL): male 0.6; female 0.6
• Age: 2 to < 6 years; maximum serum creatinine (mg/dL): male 0.8; female 0.8
• Age: 6 to < 10 years; maximum serum creatinine (mg/dL): male 1; female 1
• Age: 10 to < 13 years; maximum serum creatinine (mg/dL): male 1.2; female 1.2
• Age: 13 to < 16 years; maximum serum creatinine (mg/dL): male 1.5; female 1.4
• Age: >= 16 years; maximum serum creatinine (mg/dL): male 1.7; female 1.4
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Bilirubin (sum of conjugated +
unconjugated) =< 1.5 x upper limit of normal (ULN) for age
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Serum glutamate pyruvate transaminase
(SGPT) (alanine transferase [ALT]) =< 135 U/L (for the purpose of this study, the ULN
for SGPT is 45 U/L)
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Patients must be able to swallow intact
capsules/tablets, unless otherwise specified in the subprotocol to which they are
assigned
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Agent specific limitations on prior
therapy will be included with specific treatment subprotocols
Exclusion Criteria:
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Pregnant or breast-feeding women will not
be entered on this study due to risks of fetal and teratogenic adverse events as seen
in animal/human studies, or because there is currently no available information
regarding human fetal or teratogenic toxicities; pregnancy tests must be obtained in
females who are post-menarchal; males or females of reproductive potential may not
participate unless they have agreed to use an effective contraceptive method
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Concomitant medications
• Corticosteroids: at the time of consent and enrollment to regimen specific
subprotocols, patients receiving corticosteroids who have not been on a stable or
decreasing dose of corticosteroid for at least 7 days prior to enrollment to the
subprotocol will not be eligible; if used to modify immune adverse events related
to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Investigational drugs: patients must meet criteria for prior therapy at the time
of consent and enrollment to a subprotocol; other investigational agents may not
be administered to patients while they are receiving study drug as part of a
subprotocol
• Anticancer agents: patients must meet criteria for prior therapy at the time of
consent and enrollment to a subprotocol; other investigational agents may not be
administered to patients while they are receiving study drug as part of a
subprotocol
• Anti-GVHD agents post-transplant: patients who are receiving cyclosporine,
tacrolimus or other agents to prevent graft-versus-host disease post bone marrow
transplant are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Patients who have an uncontrolled
infection are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Patients who have had a prior solid organ
transplant are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Additional agent specific criteria will
be included with specific treatment subprotocols
AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke (ARCADIA)
Objectives
- Primary: To test the hypothesis that apixaban is superior to aspirin for the prevention
of recurrent stroke in patients with cryptogenic ischemic stroke and atrial cardiopathy.
- Secondary: To test the hypothesis that the relative efficacy of apixaban over aspirin
increases with the severity of atrial cardiopathy.
• Age ≥ 45 years.
• Clinical diagnosis of ischemic stroke + brain imaging to rule out hemorrhagic stroke.
• Modified Rankin Scale (MRS) score ≤ 4.
• Ability to be randomized within 3 to 180 days after stroke onset.
• ESUS, defined as all of the following:
• Stroke detected by CT or MRI that is not lacunar. Lacunar is defined as a
subcortical (this includes pons and midbrain) infarct in the distribution of the
small, penetrating cerebral arteries whose largest dimension is ≤1.5 cm on CT or
≤2.0 cm on MRI diffusion images/<1.5 cm on T2 weighted MR images. The following
are not considered lacunes: multiple simultaneous small deep infarcts, lateral
medullary infarcts, and cerebellar infarcts. Patients with a clinical lacunar
stroke syndrome and no infarct on imaging are excluded.
• Absence of extracranial or intracranial atherosclerosis causing ≥50 percent
luminal stenosis of the artery supplying the area of ischemia. Patients must
undergo vascular imaging of the extracranial and intracranial vessels using
either catheter angiography, CT angiogram (CTA), MR angiogram (MRA), or
ultrasound, as considered appropriate by the treating physician and local
principal investigator.
• No major-risk cardioembolic source of embolism, including intracardiac thrombus,
mechanical prosthetic cardiac valve, atrial myxoma or other cardiac tumors,
moderate or severe mitral stenosis, myocardial infarction within the last 4
weeks, left ventricular ejection fraction <30 percent, valvular vegetations, or
infective endocarditis). Patent foramen ovale is not an exclusion. All patients
must undergo electrocardiogram, transthoracic or transesophageal echocardiography
(TTE or TEE) and at least 24 hours of cardiac rhythm monitoring (Holter monitor
or telemetry or equivalent). Additional cardiac imaging, such as cardiac MRI, or
cardiac CT will be performed at the discretion of the local treating physician
and principal investigator. Additional cardiac rhythm monitoring, such as
monitored cardiac outpatient telemetry (MCOT) or an implanted cardiac monitor,
will be at the discretion of the treating physician and local principal
investigator.
• No other specific cause of stroke identified, such as arteritis, dissection,
migraine, vasospasm, drug abuse, or hypercoagulability. Special testing, such as
toxicological screens, serological testing for syphilis, and tests for
hypercoagulability, will be performed at the discretion of the treating physician
and local principal investigator.
Exclusion Criteria:
• History of atrial fibrillation (AF), AF on 12-lead ECG, or any AF of any duration
during heart-rhythm monitoring prior to randomization.
• Clear indication for treatment-dose anticoagulant therapy, such as venous
thromboembolism or a mechanical heart valve.
• Need for antiplatelet agent, such as aspirin or clopidogrel
• History of spontaneous intracranial hemorrhage.
• Chronic kidney disease with serum creatinine ≥2.5 mg/dL.For Canadian sites only,
estimated creatinine clearance (eCrCl) <15 mL/min is also an exclusion criterion.
• Active hepatitis or hepatic insufficiency with Child-Pugh score B or C.
• Clinically significant bleeding diathesis.
• Unresolved anemia (hemoglobin <9 g/dL) or thrombocytopenia (<100 x 10E9/L).
• Clinically significant gastrointestinal bleeding within the past year (e.g., not due
to external hemorrhoids).
• At risk for pregnancy: premenopausal or postmenopausal woman within 12 months of last
menses without a negative pregnancy test or not committing to adequate birth control,
which includes an oral contraceptive, two methods of barrier birth control such as
condom with or without spermicidal lubricant + diaphragm, or abstinence.
• Known allergy or intolerance to aspirin or apixaban.
• Concomitant participation in another clinical trial involving a drug or acute stroke
intervention.
• Considered by the investigator to have a condition that precludes follow-up or safe
participation in the trial.
• Inability of either participant or surrogate to provide written, informed consent for
trial participation.
Imatinib Mesylate and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
This randomized phase III trial studies how well imatinib mesylate works in combination with
two different chemotherapy regimens in treating patients with newly diagnosed Philadelphia
chromosome positive acute lymphoblastic leukemia (ALL). Imatinib mesylate has been shown to
improve outcomes in children and adolescents with Philadelphia chromosome positive (Ph+) ALL
when given with strong chemotherapy, but the combination has many side effects. This trial is
testing whether a different chemotherapy regimen may work as well as the stronger one but
have fewer side effects when given with imatinib. The trial is also testing how well the
combination of chemotherapy and imatinib works in another group of patients with a type of
ALL that is similar to Ph+ ALL. This type of ALL is called "ABL-class fusion positive ALL",
and because it is similar to Ph+ ALL, is thought it will respond well to the combination of
agents used to treat Ph+ ALL.
• For patients enrolled on APEC14B1 prior to enrollment on AALL1631, the required
diagnostic bone marrow sample has been fulfilled
• For patients who have not previously enrolled on APEC14B1 prior to enrollment on
AALL1631, a baseline diagnostic sample (or peripheral blood sample with blasts if
marrow sample unavailable) must be available to develop an MRD probe
• In addition, laboratory reports detailing evidence of BCR-ABL1 fusion or
ABL-class fusion must be submitted for rapid central review within 72 hours of
study enrollment
• >= 1 year (365 days) and =< 21 years at ALL diagnosis
• Ph+ (BCR-ABL1 fusion): newly diagnosed de novo ALL (B-ALL or T-ALL) or mixed
phenotypic acute leukemia (MPAL meeting 2016 World Health Organization [WHO]
definition) with definitive evidence of BCR-ABL1 fusion by karyotype, fluorescence in
situ hybridization (FISH) and/or molecular methodologies
• ABL-class fusion: newly diagnosed B-ALL with definitive evidence of ABL-class fusions.
ABL-class fusions are defined as those involving the following genes: ABL1, ABL2,
CSF1R, PDGFRB, PDGFRA. Methods of detection include fluorescence in-situ hybridization
(FISH, e.g. using break-apart or colocalization signals probes), multiplex or
singleplex reverse-transcription polymerase chain reaction (RT-PCR), whole
transcriptome or panel-based ribonucleic acid (RNA)-sequencing (e.g. TruSight RNA
Pan-Cancer Panel; Illumina, San Diego, CA, USA or similar)
• Ph+ patients must have previously started Induction therapy, which includes
vincristine, a corticosteroid, pegaspargase, with or without anthracycline, and/or
other standard cytotoxic chemotherapy
• Ph+ patients have not received more than 14 days of multiagent Induction therapy
beginning with the first dose of vinCRIStine
• Ph+ patients may have started imatinib prior to study entry but have not received more
than 14 days of imatinib
• ABL-class fusion patients must have previously completed the 4 or 5 weeks of
multiagent Induction chemotherapy (Induction IA phase)
• ABL-class fusion patients may have started imatinib during Induction IA, at the same
time of or after the first vinCRIStine dose
• Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1, or 2
• Direct bilirubin =< 2.0 mg/dL
• Shortening fraction of >= 27% by echocardiogram
• Ejection fraction of >= 50% by radionuclide angiogram or echocardiogram
• Corrected QT interval, QTc < 480 msec
• Note: Repeat echocardiogram and electrocardiogram are not required if they were
performed at or after initial ALL diagnosis, before study enrollment
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or serum creatinine within normal limits based on age/gender, as
follows:
• 1 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female)
• 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female)
• 6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female)
• 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female)
• 13 to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)
• >= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)
Exclusion Criteria:
• Known history of chronic myelogenous leukemia (CML)
• ALL developing after a previous cancer treated with cytotoxic chemotherapy
• Active, uncontrolled infection, or active systemic illness that requires ongoing
vasopressor support or mechanical ventilation
• Down syndrome
• Pregnancy and breast feeding
• Female patients who are pregnant since fetal toxicities and teratogenic effects
have been noted for several of the study drugs; a pregnancy test is required for
female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of treatment according to
protocol
• Patients with congenital long QT syndrome, history of ventricular arrhythmias or heart
block
• Prior treatment with dasatinib, or any TKI other than imatinib
Active Surveillance, Bleomycin, Etoposide, Carboplatin or Cisplatin in Treating Pediatric and Adult Patients With Germ Cell Tumors
This phase III trial studies how well active surveillance help doctors to monitor subjects
with low risk germ cell tumors for recurrence after their tumor is removed. When the germ
cell tumors has spread outside of the organ in which it developed, it is considered
metastatic. Drugs used in chemotherapy, such as bleomycin, carboplatin, etoposide, and
cisplatin, work in different ways to stop the growth of tumor cells, either by killing the
cells, by stopping them from dividing, or by stopping them from spreading. The trial studies
whether carboplatin or cisplatin is the preferred chemotherapy to use in treating metastatic
standard risk germ cell tumors.
• There is no age limit for the low risk stratum (stage I ovarian immature teratoma and
stage I non-seminoma or seminoma malignant GCT [all sites])
• Standard risk 1: Patient must be < 11 years of age at enrollment
• Standard risk 2: Patients must be >= 11 and < 25 years of age at enrollment
• Patients enrolling on one of the low risk arms must be newly diagnosed with a stage I
germ cell tumor; for the standard risk arms, patients must be newly diagnosed with
metastatic germ cell tumor (stage II or higher); histologic confirmation of a primary
extracranial germ cell tumor in any of the categories outlined below is required of
all patients at enrollment except for those who were initially diagnosed with stage I
non-seminoma malignant GCT and later recur during observation post surgery off study;
for these patients, if elevated tumor markers rise to > 5 x upper limit of normal
(ULN) on at least 2 measurements taken at least 1 week apart, a diagnostic biopsy is
not required for enrollment
• Low risk stage I immature teratoma (IT); site: ovarian; stage: Children's Oncology
Group (COG) stage I, Federation of Gynecology and Obstetrics (FIGO) stage IA and IB;
grade: 2 or 3; histology: pure immature teratoma (may contain microscopic foci of yolk
sac tumor), mixed immature and mature teratoma, (no pathological evidence of MGCT);
tumor markers: alpha-FP =< 1,000 ng/mL, beta-HCG institutional normal; all ages
• Low risk stage I non-seminoma MGCT; site: ovarian, testicular, or extragonadal; stage:
COG stage I, FIGO stage IA and IB, American Joint Committee on Cancer (AJCC)
testicular stage IA, IB and IS; histology: must contain at least one of the following:
yolk sac tumor, embryonal carcinoma, or choriocarcinoma (pure or mixed); all ages
• Low risk stage I seminoma-MGCT; site: testicular; stage: COG stage I; AJCC testicular
stage IA IB, and IS; histology: must contain at least one of the following: may
contain immature/mature teratoma; may NOT contain yolk sac tumor, embryonal carcinoma,
or choriocarcinoma; all ages
• Standard risk 1 (SR1); site: ovarian, testicular, or extragonadal; stage: COG stage
II-IV, FIGO stage IC, FIGO stage II-IV (International Germ Cell Consensus
Classification [IGCCC] criteria DO NOT apply); histology: must contain at least one of
the following: yolk sac tumor, embryonal carcinoma, or choriocarcinoma; age (years) <
11
• Standard risk 2 (SR2)
• Site: ovarian; stage: COG stage II and III, FIGO stage IC, II and III; histology:
must contain at least one of the following: yolk sac tumor, embryonal carcinoma,
or choriocarcinoma; age (years) >= 11 and < 25
• Site: testicular; stage: COG stage II-IV, AJCC stage II, III, IGCCC good risk;
histology: must contain at least one of the following: yolk sac tumor, embryonal
carcinoma, or choriocarcinoma; tumor markers: must be IGCCC good risk; post op:
alpha-FP < 1,000 ng/mL, beta-HCG < 5,000 IU/mL and lactate dehydrogenase (LDH) <
3.0 x normal; age (years) >= 11 and < 25
• Site: extragonadal; stage: COG stage II; histology: must contain at least one of
the following: yolk sac tumor, embryonal carcinoma, or choriocarcinoma; age
(years) >= 11 and < 25
• Notes:
• IGCCC criteria only apply to SR2 patients with a testicular primary tumor
• Use post-op tumor marker levels to determine IGCCC risk group
• Stage 1 seminoma patients are not eligible for the standard risk arms of the
study
• For the low risk stage I non-seminoma MGCT and the standard risk arms, components
of yolk sac tumor, embryonal carcinoma, or choriocarcinoma can be mixed with
other forms of GCT, such as seminoma or mature or immature teratoma; if yolk sac
tumor is the only malignant component present, then it must be deemed by the
pathologist to be greater than a "microscopic component" of yolk sac tumor
• Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1, 2 or 3; use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age
• Organ function requirements apply ONLY to patients who will receive chemotherapy (SR1
and SR2 patients)
• Adequate renal function defined as:
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 (within 7 days prior to enrollment) OR
• A serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
(mg/dL)
• 1 month to < 6 months male: 0.4 female: 0.4
• 6 months to < 1 year male: 0.5 female: 0.5
• 1 to < 2 years male: 0.6 female: 0.6
• 2 to < 6 years male: 0.8 female: 0.8
• 6 to < 10 years male: 1 female: 1
• 10 to < 13 years male: 1.2 female: 1.2
• 13 to < 16 years: male: 1.5 female: 1.4
• >= 16 years male: 1.7 female: 1.4
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to
enrollment)
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x
upper limit of normal (ULN) for age (for the purpose of this study, the ULN for SGPT
is 45 U/L) (within 7 days prior to enrollment)
• Peripheral absolute neutrophil count (ANC) >= 1,000/mm^3 (within 7 days prior to
enrollment) AND
• Platelet count >= 100,000/mm^3 (within 7 days prior to enrollment)
• Patients enrolling on the standard risk arms must be medically fit to receive protocol
treatment and with no contraindications to protocol treatment
• Eligibility criteria to participate in the pilot study of the AYA-Hears instrument
(patient reported outcomes [PROs] of ototoxicity) Note: participants in group 1 will
not receive AGCT1531 protocol-directed therapy; all other AYA-HEARS patients must be
enrolled on the AGCT1531 SR2 arm in order to participate
• >= 11 and < 25 years old at enrollment
• Able to fluently speak and read English
• Has received prior cisplatin- or carboplatin-based chemotherapy regimen for malignancy
including diagnoses other than germ cell tumor
• Followed for cancer or survivorship care at one of the following institutions:
• Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
• Dana Farber/Harvard Cancer Center
• Hospital for Sick Children
• Children's Hospital of Eastern Ontario
• Oregon Health and Science University
• Seattle Children's Hospital
• Yale University
Exclusion Criteria:
• Patients with any diagnoses not listed including:
• Stage I testicular cancer patients who have undergone primary RPLND
(retroperitoneal lymph node dissection)
• Pure dysgerminoma
• Pure mature teratoma
• Pure immature teratoma COG stage I, grade I
• Pure immature teratoma COG stage I, grade 2,3 with alpha-fetoprotein (AFP) >=
1000 ng/mL
• Pure immature teratoma COG stage II •IV or FIGO stage IC to IV
• "Poor risk" GCT (age >= 11 years old and COG stage IV ovarian, COG stage III or
IV EG, or IGCCC intermediate or poor risk testicular), or
• Primary central nervous system (CNS) germ cell tumor
• Germ cell tumor with somatic malignant transformation
• Spermatocytic seminoma
• Patients must have had no prior systemic therapy for the current cancer diagnosis
• Patients must have had no prior radiation therapy with the exception of CNS
irradiation of brain metastases; (this exception only applies to SR1 patients; any
patients over age 11 with distant metastases to brain [stage IV disease] would be
considered poor risk and therefore not eligible for this trial)
• Patients with significant, pre-existing co-morbid respiratory disease that
contraindicate the use of bleomycin are ineligible for the standard risk arms of the
trial
• Female patients who are pregnant since fetal toxicities and teratogenic effects have
been noted for several of the study drugs; a pregnancy test is required for female
patients of childbearing potential; (this criteria applies ONLY to patients who will
receive chemotherapy [SR1 and SR2 patients])
• Lactating females who plan to breastfeed their infants; (this criteria applies ONLY to
patients who will receive chemotherapy [SR1 and SR2 patients])
• Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation; (this
criteria applies ONLY to patients who will receive chemotherapy [SR1 and SR2
patients])
Childhood Extracranial Germ Cell Tumor, Malignant Germ Cell Tumor, Germ Cell Tumor, Extragonadal Embryonal Carcinoma, Stage I Ovarian Choriocarcinoma, Stage II Ovarian Choriocarcinoma, Stage III Ovarian Choriocarcinoma, Stage IV Ovarian Choriocarcinoma, Testicular Mixed Choriocarcinoma and Embryonal Carcinoma, Testicular Mixed Choriocarcinoma and Teratoma, Testicular Mixed Choriocarcinoma and Yolk Sac Tumor, Stage I Testicular Choriocarcinoma AJCC v6 and v7, Stage I Testicular Embryonal Carcinoma AJCC v6 and v7, Stage I Testicular Yolk Sac Tumor AJCC v6 and v7, Stage II Testicular Choriocarcinoma AJCC v6 and v7, Stage II Testicular Embryonal Carcinoma AJCC v6 and v7, Stage II Testicular Yolk Sac Tumor AJCC v6 and v7, Stage III Testicular Choriocarcinoma AJCC v6 and v7, Stage III Testicular Embryonal Carcinoma AJCC v6 and v7, Stage III Testicular Yolk Sac Tumor AJCC v6 and v7, Malignant Ovarian Teratoma, Stage I Ovarian Embryonal Carcinoma AJCC v6 and v7, Stage I Ovarian Teratoma AJCC v6 and v7, Stage I Ovarian Yolk Sac Tumor AJCC v6 and v7, Stage II Ovarian Embryonal Carcinoma AJCC v6 and v7, Stage II Ovarian Yolk Sac Tumor AJCC v6 and v7, Stage III Ovarian Embryonal Carcinoma AJCC v6 and v7, Stage III Ovarian Yolk Sac Tumor AJCC v6 and v7, Stage IV Ovarian Embryonal Carcinoma AJCC v6 and v7, Stage IV Ovarian Yolk Sac Tumor AJCC v6 and v7, Other Female Genital, Other Male Genital, Ovary, Unknown Sites, Stage I Testicular Seminoma AJCC v6 and v7
UT Southwestern; Children’s Health; Parkland Health & Hospital System
Testing Docetaxel-Cetuximab or the Addition of an Immunotherapy Drug, Atezolizumab, to the Usual Chemotherapy and Radiation Therapy in High-Risk Head and Neck Cancer
This phase II/III trial studies how well radiation therapy works when given together with
cisplatin, docetaxel, cetuximab, and/or atezolizumab after surgery in treating patients with
high-risk stage III-IV head and neck cancer the begins in the thin, flat cells (squamous
cell). Specialized radiation therapy that delivers a high dose of radiation directly to the
tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in
chemotherapy, such as cisplatin and docetaxel, work in different ways to stop the growth of
tumor cells, either by killing the cells or by stopping them from dividing. Cetuximab is a
monoclonal antibody that may interfere with the ability of tumor cells to grow and spread.
Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune
system attack the cancer, and may interfere with the ability of tumor cells to grow and
spread. The purpose of this study is to compare the usual treatment (radiation therapy with
cisplatin chemotherapy) to using radiation therapy with docetaxel and cetuximab chemotherapy,
and using the usual treatment plus an immunotherapy drug, atezolizumab.
• PHASE II INCLUSION CRITERIA (COMPLETE AS OF 20-MAR-2020)
• Pathologically (histologically or cytologically) proven diagnosis of head and neck
squamous cell carcinoma (HNSCC) involving the oral cavity (excluding lips), oropharynx
(p16 negative), larynx, or hypopharynx
• Patients must have undergone gross total surgical resection of high-risk oral cavity,
oropharynx (p16 negative), larynx, or hypopharynx within 63 days prior to
registration; Note: patients may have biopsy under general anesthesia in an operating
room followed by definitive ablative cancer surgery representing gross total
resection; the gross total resection has to be done within 63 days prior to
registration; if, however, patients have ablative resection but shortly recur or are
determined to have persisting disease requiring re-resection to achieve gross total
resection, then the patient is not eligible
• Patients must have at least 1 of the following high-risk pathologic features:
extracapsular nodal extension or invasive cancer at the primary tumor resection margin
(tumor on ink)
• Pathologic stage III or IV HNSCC, including no distant metastases, based upon the
following minimum diagnostic workup:
• General history and physical examination by a radiation oncologist and/or medical
oncologist within 84 days prior to registration;
• Examination by an ear nose throat (ENT) or head & neck surgeon prior to surgery;
a laryngopharyngoscopy (mirror and/or fiber optic and/or direct procedure), if
appropriate, is recommended but not required; intra-operative examination is
acceptable documentation
• Pre-operative (op) Imaging of the head and neck: A neck computed tomography (CT)
(with contrast) or CT/positron emission tomography (PET) (with contrast) and/or
an magnetic resonance imaging (MRI) of the neck (T1 with gadolinium and T2)
within 84 days prior to surgery; Note: this imaging data (diagnostic
pre-operative scan showing gross disease) is to be submitted in Digital Imaging
and Communications in Medicine (DICOM) format via TRIAD; the report is to be
uploaded into Rave
• Chest CT scan (with or without contrast) or CT/PET that includes the chest (with
or without contrast) either within 84 days prior to surgery or within 120 days
prior to registration; Note: if the CT/PET with or without contrast is done
within 84 days prior to surgery, it fulfills the chest imaging requirement
• Zubrod performance status of 0-1 within 14 days prior to registration
• Age >= 18
• Absolute granulocyte count (AGC) >= 1,500 cells/mm^3 (obtained within 14 days prior to
registration on study)
• Platelets >= 100,000 cells/mm^3 (obtained within 14 days prior to registration on
study)
• Hemoglobin >= 8.0 g/dl (Note: the use of transfusion or other intervention to achieve
hemoglobin [Hgb] >= 8.0 g/dl is acceptable)
• Total bilirubin < 2 x institutional upper limit of normal (ULN) within 14 days prior
to registration
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x institutional
ULN within 14 days prior to registration
• Serum creatinine institutional ULN within 14 days prior to registration or; creatinine
clearance (CC) >= 50 ml/min within 14 days prior to registration determined by 24-hour
collection or estimated by Cockcroft-Gault formula
• Negative urine or serum pregnancy test within 14 days prior to registration for women
of childbearing potential
• The following assessments are required within 14 days prior to registration: sodium
(Na), potassium (K), chloride (Cl), glucose, calcium (Ca), magnesium (Mg), and
albumin; Note: patients with an initial magnesium < 0.5 mmol/L (1.2 mg/dl) may receive
corrective magnesium supplementation but should continue to receive either
prophylactic weekly infusion of magnesium and/or oral magnesium supplementation (e.g.,
magnesium oxide) at the investigator's discretion
• Patients with feeding tubes are eligible for the study
• Women of childbearing potential and male participants who are sexually active must
agree to use a medically effective means of birth control
• Patient must provide study specific informed consent prior to study entry, including
consent for mandatory tissue submission for epidermal growth factor receptor (EGFR)
analysis and for oropharyngeal cancer patients, human papilloma virus (HPV) analysis
• PHASE III: Pathologically (histologically or cytologically) proven diagnosis of head
and neck squamous cell carcinoma (HNSCC) involving the oral cavity (excluding lips),
oropharynx (p16 negative), larynx, or hypopharynx
• PHASE III: Patients with oropharyngeal cancer must have p16-negative based on central
review prior to Step 2 registration; all patients with oropharyngeal primary must
consent for mandatory tissue submission for central p16 confirmation
• PHASE III: Patients must have undergone gross total surgical resection of high-risk
oral cavity, oropharynx (p16 negative), larynx, or hypopharynx within 63 days prior to
registration; note: patients may have biopsy under general anesthesia in an operating
room followed by definitive ablative cancer surgery representing gross total
resection; the gross total resection has to be done within 63 days prior to
registration; if, however, patients have ablative resection but shortly recur or are
determined to have persisting disease requiring re-resection to achieve gross total
resection, then the patient is not eligible
• PHASE III: Patients must have at least 1 of the following high-risk pathologic
features: extracapsular nodal extension or invasive cancer at the primary tumor
resection margin (tumor on ink or tumor in a final separately submitted margin)
• PHASE III: Pathologic stage III or IV HNSCC (American Joint Committee on Cancer [AJCC]
7th edition), including no distant metastases, based upon the following minimum
diagnostic workup:
• General history and physical examination by a radiation oncologist or medical
oncologist within 84 days prior to registration;
• Examination by an ENT or head & neck surgeon prior to surgery; a
laryngopharyngoscopy (mirror or fiberoptic or direct procedure), if appropriate,
is recommended but not required. Intra-operative examination is acceptable
documentation.
• Pre-op Imaging of the head and neck: A neck CT (with contrast and of diagnostic
quality) or PET/CT (with contrast and of diagnostic quality) and/or an MRI of the
neck of diagnostic quality (T1 with gadolinium and T2) within 84 days prior to
surgery; Note: this imaging data (diagnostic pre-operative scan showing gross
disease) is to be submitted in DICOM format via TRIAD. The report is to be
uploaded into Rave.
• Chest CT scan (with or without contrast) or PET/CT that includes the chest (with
or without contrast) either within 84 days prior to surgery or within 120 days
prior to registration; Note: If the PET/CT with or without contrast is done
within 84 days prior to surgery, it fulfills the chest imaging requirement
• PHASE III: Zubrod performance status of 0-1 within 14 days prior to registration
• PHASE III: Leukocytes >= 2,500 cells/mm^3 (obtained within 14 days prior to
registration on study)
• PHASE III: Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (obtained within 14
days prior to registration on study)
• PHASE III: Platelets >= 100,000 cells/mm^3 (obtained within 14 days prior to
registration on study)
• PHASE III: Hemoglobin >= 8.0 g/dL (Note: The use of transfusion or other intervention
to achieve Hgb >= 8.0 g/dL is acceptable) (obtained within 14 days prior to
registration on study)
• PHASE III: Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
(however, patients with known Gilbert disease who have serum bilirubin level =< 3 x
institutional ULN may be enrolled) (within 14 days prior to registration)
• PHASE III: AST or ALT =< 3 x institutional ULN (within 14 days prior to registration)
• PHASE III: Alkaline phosphatase =< 2.5 x institutional ULN (within 14 days prior to
registration)
• PHASE III: Creatinine clearance (CrCl) >= 50 mL/min within 14 days prior to
registration determined by 24-hour collection or estimated by Cockcroft-Gault formula
• PHASE III: Patients with feeding tubes are eligible for the study
• PHASE III: Negative urine or serum pregnancy test within 14 days prior to registration
for women of childbearing potential
• PHASE III: All patients must provide study specific informed consent prior to study
entry
• PHASE III: Patients positive for human immunodeficiency virus (HIV) are allowed on
study, but HIV-positive patients must have:
• A stable regimen of highly active anti-retroviral therapy (HAART);
• No requirement for concurrent antibiotics or antifungal agents for the prevention
of opportunistic infections;
• A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
polymerase chain reaction (PCR)-based tests
Exclusion Criteria:
• PHASE II EXCLUSION CRITERIA (COMPLETE AS OF 20-MAR-2020)
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 1095 days (3 years); noninvasive cancers (for example, carcinoma in
situ of the breast, oral cavity, or cervix are all permissible) are permitted even if
diagnosed and treated < 3 years ago
• Patients with simultaneous primaries or bilateral tumors are excluded, with the
exception of patients with bilateral tonsil cancers or patients with T1-2, N0, M0
resected differentiated thyroid carcinoma, who are eligible
• Prior systemic chemotherapy or anti-epidermal growth factor (EGF) therapy for the
study cancer; note that prior chemotherapy for a different cancer is allowable
• Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation therapy fields
• Severe, active co-morbidity, defined as follows:
• Unstable angina and/or congestive heart failure requiring hospitalization within
6 months prior to registration
• Transmural myocardial infarction within 6 months prior to registration
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of registration
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of registration
• Idiopathic pulmonary fibrosis or other severe interstitial lung disease that
requires oxygen therapy or is thought to require oxygen therapy within 1
year prior to registration
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;
note, however, that laboratory tests for coagulation parameters are not required
for entry into this protocol
• Acquired immune deficiency syndrome (AIDS) based upon current Centers for
Disease and Control and Prevention (CDC) definition; note: human
immunodeficiency virus (HIV) testing is not required for entry into this
protocol; the need to exclude patients with AIDS from this protocol is
necessary because the treatments involved in this protocol may be
significantly immunosuppressive; protocol-specific requirements may also
exclude immuno-compromised patients.
• Grade 3-4 electrolyte abnormalities (Common Terminology Criteria for Adverse Events
[CTCAE], version [v.] 4):
• Serum calcium (ionized or adjusted for albumin) < 7 mg/dl (1.75 mmol/L) or > 12.5
mg/dl (> 3.1 mmol/L) despite intervention to normalize levels
• Glucose < 40 mg/dl (< 2.2 mmol/L) or > 250 mg/dl (> 14 mmol/L)
• Magnesium < 0.9 mg/dl (< 0.4 mmol/L) or > 3 mg/dl (> 1.23 mmol/L) despite intervention
to normalize levels
• Potassium < 3.0 mmol/L or > 6 mmol/L despite intervention to normalize levels
• Sodium < 130 mmol/L or > 155 mmol/L despite intervention to normalize levels
• Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception; this exclusion is
necessary because the treatment involved in this study may be significantly
teratogenic
• Prior allergic reaction to cetuximab
• PHASE III: Prior invasive malignancy (except non-melanomatous skin cancer) unless
disease free for a minimum of 1095 days (3 years) with the following exceptions: T1-2,
N0, M0 resected differentiated thyroid carcinoma; Note that noninvasive cancers (For
example, carcinoma in situ of the breast, oral cavity, or cervix) are permitted even
if diagnosed and treated < 3 years ago
• PHASE III: Patients with simultaneous primaries or bilateral tumors are excluded, with
the exception of patients with bilateral tonsil cancers or patients with T1-2, N0, M0
resected differentiated thyroid carcinoma, who are eligible
• PHASE III: Prior systemic therapy, including cytotoxic chemotherapy, biologic/targeted
therapy (such as anti-EGF therapy), or immune therapy for the study cancer; note that
prior chemotherapy for a different cancer is allowable, however, a prior anti-PD-1,
anti-PD-L1, or anti-PD-L2 agent is not permitted
• PHASE III: Prior radiotherapy to the region of the study cancer that would result in
overlap of radiation therapy fields
• PHASE III: Severe, active co-morbidity, defined as follows:
• Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of
cardiac function using the New York Heart Association Functional Classification;
to be eligible for this trial, patients should be class 2B or better within 6
months prior to registration
• Transmural myocardial infarction within 6 months prior to registration;
• Severe infections within 4 weeks prior to registration including, but not limited
to, hospitalization for complications of infection, bacteremia, or severe
pneumonia;
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of registration; Note: Patients receiving prophylactic antibiotics (e.g., for
prevention of a urinary tract infection or chronic obstructive pulmonary disease
exacerbation) are eligible.
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of
registration;
• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
tomography (CT) scan. History of radiation pneumonitis in a prior radiation field
(fibrosis) is permitted, provided that field does not overlap with the planned
radiation field for the study cancer;
• Patients with active tuberculosis (TB) are excluded;
• Known clinically significant liver disease, including active viral, alcoholic, or
other hepatitis; cirrhosis; fatty liver; and inherited liver disease;
• Patients with past or resolved hepatitis B infection (defined as having a
negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
[antibody to hepatitis B core antigen] antibody test) are eligible.
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction (PCR) is negative for HCV RNA.
• History of allogeneic bone marrow transplantation or solid organ transplantation.
• A diagnosis of immunodeficiency:
• Acquired immune deficiency syndrome (AIDS) based upon current CDC
definition; note: HIV testing is not required for entry into this protocol;
the need to exclude patients with AIDS from this protocol is necessary
because the treatments involved in this protocol may be significantly
immunosuppressive.
• Is receiving treatment with systemic immunosuppressive medications (including,
but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate,
thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks
prior to registration.
• Note: Patients who have received acute, low dose, systemic immunosuppressant
medications (e.g., a one-time dose of dexamethasone for nausea) may be
enrolled.
• Note: The use of inhaled corticosteroids and mineralocorticoids (e.g.,
fludrocortisone) for patients with orthostatic hypotension or adrenocortical
insufficiency is allowed.
• History or risk of autoimmune disease, including, but not limited to, systemic
lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular
thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis,
Sjogren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or
glomerulonephritis.
• Patients with a history of autoimmune hypothyroidism who are asymptomatic
and/or are on a stable dose of thyroid replacement hormone are eligible.
• Patients with controlled Type 1 diabetes mellitus on a stable insulin
regimen are eligible.
• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis
would be excluded) are permitted provided that they meet the following
conditions:
• Patients with psoriasis must have a baseline ophthalmologic exam to rule out
ocular manifestations
• Rash must cover less than 10% of body surface area (BSA)
• Disease is well controlled at baseline and only requiring low potency
topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)
• No acute exacerbations of underlying condition within the last 12 months
(not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,
retinoids, biologic agents, oral calcineurin inhibitors; high potency or
oral steroids)
• PHASE III: Grade 3-4 electrolyte abnormalities (CTCAE, v. 4) within 14 days prior to
registration:
• Serum calcium (ionized or adjusted for albumin) < 7 mg/dL (1.75 mmol/L) or > 12.5
mg/dL (> 3.1 mmol/L) despite intervention to normalize levels;
• Glucose < 40 mg/dL (< 2.2 mmol/L) or > 250 mg/dL (> 14 mmol/L);
• Magnesium < 0.9 mg/dL (< 0.4 mmol/L) or > 3 mg/dL (> 1.23 mmol/L) despite
intervention to normalize levels;
• Potassium < 3.0 mmol/L or > 6 mmol/L despite intervention to normalize levels;
• Sodium < 130 mmol/L or > 155 mmol/L despite intervention to normalize levels.
• PHASE III: Pregnancy or women of childbearing potential and men who are sexually
active and not willing/able to use medically acceptable forms of contraception for up
to 5 months from last study treatment; this exclusion is necessary because the
treatment involved in this study may be significantly teratogenic. Women who are
breastfeeding and unwilling to discontinue are also excluded
• PHASE III: History of severe allergic, anaphylactic, or other hypersensitivity
reactions to chimeric or humanized antibodies or fusion proteins
• PHASE III: Patients taking bisphosphonate therapy for symptomatic hypercalcemia. Use
of bisphosphonate therapy for other non-oncologic reasons (e.g., osteoporosis) is
allowed
• PHASE III: Patients requiring treatment with a RANKL inhibitor (e.g. denosumab) for
non-oncologic reasons who cannot discontinue it before registration
• PHASE III: Patients with known distant metastatic disease are excluded
• PHASE III: Known hypersensitivity to Chinese hamster ovary cell products or other
recombinant human antibodies
• PHASE III: Major surgical procedure within 28 days prior to registration or
anticipation of need for a major surgical procedure during the course of the study
• PHASE III: Administration of a live, attenuated vaccine within 4 weeks prior to
registration or anticipation that such a live, attenuated vaccine will be required
during the study and for patients receiving atezolizumab, up to 5 months after the
last dose of atezolizumab.
• Influenza vaccination should be given during influenza season only (approximately
October to March). Patients must not r
Accelerated v's Standard BEP Chemotherapy for Patients With Intermediate and Poor-risk Metastatic Germ Cell Tumours (P3BEP)
The purpose of this study is to determine whether accelerated BEP chemotherapy is more
effective than standard BEP chemotherapy in males with intermediate and poor-risk metastatic
germ cell tumours.
1. Age ≥ 11 years and ≤ 45 years on the date of randomisation
2. Histologically or cytologically confirmed germ cell tumour (non-seminoma or seminoma);
or Exceptionally raised tumour markers (AFP ≥ 1000ng/mL and/or HCG ≥ 5000 IU/L)
without histologic or cytologic confirmation in the rare case where pattern of
metastases consistent with GCT, high tumour burden, and a need to start therapy
urgently
3. Primary arising in testis, ovary, retro-peritoneum, or mediastinum
4. Metastatic disease or non-testicular primary
5. Intermediate or poor prognosis as defined by IGCCC classification3 (modified with
different LDH criteria for intermediate risk non-seminoma, and inclusion of ovarian
primaries). (See protocol for more information).
6. Adequate bone marrow function with ANC ≥1.0 x 10^9/L, Platelet count ≥100 x 10^9/L
7. Adequate liver function where bilirubin must be ≤1.5 x ULN, except participants with
Gilbert's Syndrome where bilirubin must be ≤2.0 x ULN; ALT and AST must be ≤2.5 x ULN,
except if the elevations are due to hepatic metastases, in which case ALT and AST must
be ≤ 5 x ULN
8. Adequate renal function with estimated creatinine clearance of ≥60 ml/min according to
the Cockcroft-Gault formula, unless calculated to be < 60 ml/min or borderline in
which case GFR should be formally measured, eg. with EDTA scan
9. ECOG Performance Status of 0, 1, 2, or 3
10. Study treatment both planned and able to start within 14 days of randomisation.
11. Willing and able to comply with all study requirements, including treatment, timing
and nature of required assessments
12. Able to provide signed, written informed consent
Exclusion Criteria:
1. Other primary malignancy (EXCEPT adequately treated non-melanomatous carcinoma of the
skin, germ cell tumour, or other malignancy treated at least 5 years previously with
no evidence of recurrence)
2. Previous chemotherapy or radiotherapy, except if patient has pure seminoma relapsing
after adjuvant radiotherapy or adjuvant chemotherapy with 1-2 doses of single agent
carboplatin or if patient has non-seminoma and poor prognosis by IGCCC criteria in the
rare case where low-dose induction chemotherapy is given prior to registration because
patient is not fit enough to receive protocol chemotherapy (eg. organ failure, vena
cava obstruction, overwhelming burden of disease). In these instances acceptable
regimens include cisplatin 20 mg/m^2 days 1-2 and etoposide 100 mg/m^2 days 1-2;
carboplatin AUC 3 days 1-2 and etoposide 100 mg/m^2 days 1-2; or baby-BOP. Patients
must meet all other inclusion and exclusion criteria at the time of registration.
Additionally participants who need to start therapy urgently prior to completing
study-specific baseline investigations may commence study chemotherapy prior to
registration and randomisation. Such patients must be discussed with the coordinating
centre prior to registration, and must be registered within 10 days of commencing
study chemotherapy.
3. Significant cardiac disease resulting in inability to tolerate IV fluid hydration for
cisplatin
4. Significant co-morbid respiratory disease that contraindicates the use of bleomycin
5. Peripheral neuropathy ≥ grade 2 or clinically significant sensorineural hearing loss
or tinnitus
6. Concurrent illness, including severe infection that may jeopardize the ability of the
participant to undergo the procedures outlined in this protocol with reasonable safety
7. Inadequate contraception. Men must use 2 effective methods of contraception, including
use of a condom, during chemotherapy and for a year after completing chemotherapy.
8. Known allergy or hypersensitivity to any of the study drugs
9. Presence of any psychological, familial, sociological or geographical condition that
in the opinion of the investigator would hamper compliance with the study protocol and
follow-up schedule, including alcohol dependence or drug abuse
The above inclusion and exclusion criteria will apply to stage 1 (n=150) and stage 2 (n=500
including stage 1) of the study. All sites will participate in both stages of the study
with the exception of the Children's Oncology Group who will be participate in stage 1
only.
A Neurosteroid Intervention for Menopausal and Perimenopausal Depression
HYPOTHESIS:
Pregnenolone administration will be associated with greater reduction in depressive symptom
severity than placebo in women with current mMDD.
STUDY AIMS:
Primary Aim: Determine if pregnenolone is associated with greater reduction in depressive
symptom severity than placebo in women with mMDD, as measured by MADRS.
Secondary Aims:
1. Determine if pregnenolone is associated with greater reduction in anxiety symptom
severity than placebo in women with mMDD.
2. Determine if pregnenolone is associated with greater improvement in cognition than
placebo in women with mMDD.
3. Determine if pregnenolone is associated with greater improvement in quality of life than
placebo in women with mMDD.
4. Determine if pregnenolone is associated with greater improvement in vasomotor symptoms
of menopause than placebo.
Mechanistic Aims:
1. Determine whether changes in neurosteroid levels with pregnenolone mediate clinical
response.
2. Determine if baseline neurosteroid levels predict pregnenolone response.
3. Determine whether depressive symptoms, anxiety, sleep or vasomotor symptoms improve
first. A crossed-lagged panel model will explore serial correlations between changes in
outcome measures.
The participants must meet the following criteria:
• Women aged 40-62 years who are perimenopausal or early postmenopausal (within 5 years
of the last menstrual period if not surgically postmenopausal), including:
• Women who have experienced changes in menstrual cycle frequency or duration, and/or
physical symptoms indicative of menopausal transition, as determined by clinician
• Women who are using hormonal IUDs (i.e. brands Mirena and Skyla), with FSH level > 20
mIU/m (as menstrual periods are irregular with IUDs that utilize hormones, making
irregular/absent periods difficult to assess as related to the menopausal transition).
• Women with significant menopause-related physical symptoms, indicated by any of the
following criteria:
• Greene Climacteric Scale total scores > 20
• Greene Climacteric Scale sub-score for vasomotor symptoms >3
• 5 or more bothersome hot flashes per week (self-reported)
• Women meeting DSM-5 criteria for current major depressive disorder (assessed by the
SCID)
• Baseline HRSD score of ≥ 18
• Subject agrees to abstain from disallowed medications for the duration of the trial
Exclusion Criteria:
The participants must not meet any of the following criteria:
• Vulnerable populations (e.g. pregnant/nursing, severe cognitive or intellectual
impairment, incarcerated)
• Pregnancy (determined by urine pregnancy test), intending pregnancy or breast feeding
• Psychiatric disorder other than MDD that is acute and the primary focus of symptom
burden or treatment.
• History of bipolar disorder or psychotic disorder
• Current substance use disorder
• Positive baseline urine drug screen of an illicit substance (in this study: opioids
and cocaine,) with the exception of a medication used with a prescription (use of a
detected substance that is used with a prescription, such as an opioid pain
medication, is not necessarily exclusionary and will be based upon judgment of the PI,
particularly in the cases of chronic opioid use). Participants who screen positive for
marijuana will be offered a rescreen for eligibility at a later date.
• Current eating disorder
• Treatment resistant depression (failure of 2 adequate antidepressant trials or
electroconvulsive therapy (ECT) during current episode; adequate antidepressant trials
are defined as within the US FDA approved dosage for the medication and used for at
least 6 weeks, with failure described by the patient as <50% improvement based on her
subjective experience).
• High risk for suicidal acts including active suicidal ideation with plan and intent or
> 2 suicide attempts in lifetime or any attempt in the past 6 months
• Use of selective estrogen-receptor modulators (SERMs), hormone replacement therapy,
hormonal contraceptives (hormonal IUDs allowed), episodic sleep medications (chronic,
regular, stable-dose benzodiazepines and hypnotics such as zolpidem, Sonata
(Zaleplon), and Lunesta (Eszopiclone) OR sleep-seating antihistamines such as Unisom
(Doxylamine succinate) or diphenhydramine allowed) within 2 weeks of the baseline
visit and randomization. Antidepressants will be allowed for those participants who
have been taking the antidepressant for 6 weeks with a stable dose for at least 4
weeks.
• Use of natural menopause and depression supplements, phytoestrogens, soy-based
medications, steroids within 2 weeks of baseline visit and randomization.
• Use of any disallowed medications (specified in the Excluded Concomitant Medication
section below).
• Women who have received a gonadal hormonal intervention within 1 month prior to study
entry (stable thyroid medications are allowed).
• Not using a medically approved method of birth control, if sexually active and not 12
or more months since last menstrual period IUDs, condoms, abstinence are acceptable
forms of contraception in this study; due to the possible interactions with the study
medication, oral contraceptive pills will be prohibited.
• Uncontrolled hypertension (>160/95mmHg)
• Active coronary artery disease, atrial fibrillation, stroke, deep vein thrombosis,
pulmonary embolism or blood clotting disorder
• Any severe, life threatening or unstable medical condition that, based on
clinician-judgment, would make participation in the study unsafe or inappropriate
• Personal or first degree family history of known hormone sensitive tumors
• History of allergic reaction or side effects with prior pregnenolone use
• Clinically significant laboratory or physical examination findings
• Concurrent enrollment in another clinical trial
Exclusion of Concomitant Medications:
• Selective estrogen-receptor modulators (SERMs)
• Hormone replacement therapy
• Hormonal contraceptives, excluding Mirena IUD or other IUD with localized progesterone
• Natural menopause or antidepressant supplements
• Episodic sleep medications (chronic, regular, stable-dose benzodiazepines and
hypnotics such as zolpidem, Sonata (Zaleplon), and Lunesta (Eszopiclone) OR
sleep-sedating antihistamines such as Unisom (Doxylamine succinate) or diphenhydramine
allowed)
• Sub-therapeutic dosages of antidepressants used for other indications will be
permissible with the exclusion of SSRIs, SNRIs, and Wellbutrin.
• Phytoestrogens
• Soy-based medications or supplements
Drug: Pregnenolone, Drug: Placebo
Major Depressive Disorder, Menopause, Perimenopause
Combination Chemotherapy, Bevacizumab, and/or Atezolizumab in Treating Patients With Deficient DNA Mismatch Repair Metastatic Colorectal Cancer, the COMMIT Study
This phase III trial studies how well combination chemotherapy, bevacizumab, and/or
atezolizumab work in treating patients with deficient deoxyribonucleic acid (DNA) mismatch
repair colorectal cancer that has spread to other places in the body (metastatic).
Chemotherapy drugs, such as fluorouracil, oxaliplatin, and leucovorin calcium, work in
different ways to stop the growth of tumor cells, either by killing the cells, by stopping
them from dividing, or by stopping them from spreading. Bevacizumab may stop or slow
colorectal cancer by blocking the growth of new blood vessels necessary for tumor growth.
Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune
system attack the cancer, and may interfere with the ability of tumor cells to grow and
spread. Giving combination chemotherapy, bevacizumab, and atezolizumab may work better in
treating patients with colorectal cancer.
• The patient must have signed and dated an Institutional Review Board (IRB)-approved
consent form that conforms to federal and institutional guidelines
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
• Diagnosis of metastatic adenocarcinoma of colon or rectum without previous
chemotherapy or any other systemic therapy for metastatic colorectal cancer except for
one cycle of FOLFOX or capecitabine and oxaliplatin (CAPOX), either with or without
bevacizumab prior to enrollment. Upon enrollment, the preceding single cycle of FOLFOX
or FOLFOX + bevacizumab, if the patient received one, will not count towards patients'
assessments per protocol. Cycle 1 day 1 (C1D1) of atezolizumab or C1D1 of
mFOLFOX6/bevacizumab + atezolizumab will correspond to the first day the patient
received therapy on trial
• Tumor determined to be mismatch-repair deficient (dMMR) by Clinical Laboratory
Improvement Act (CLIA)-certified immunohistochemical (IHC) assay with a panel of all
four IHC markers, including MLH1, MSH2, PMS2, and MSH6; alternatively, MSI-H diagnosed
by polymerase chain reaction (PCR)-based assessment of microsatellite alterations
(either Bethesda markers or Pentaplex panel) or by next-generation sequencing (NGS)
are eligible
• Documentation by PET/CT scan, CT scan, or MRI that the patient has measurable
metastatic disease per RECIST 1.1
• No immediate need for surgical intervention for the primary tumor or palliative
diversion/bypass
• Absolute neutrophil count (ANC) must be >= 1500/mm^3 (obtained within 28 days prior
randomization)
• Platelet count must be >= 100,000/mm^3 (obtained within 28 days prior randomization)
• Hemoglobin must be >= 8 g/dL (obtained within 28 days prior randomization)
• Total bilirubin must be =< 4 x ULN (upper limit of normal) (obtained within 28 days
prior randomization); and
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be =< 3 x ULN
for the lab with the following exception: for patients with documented liver
metastases, AST and ALT must be =< 5 x ULN (obtained within 28 days prior
randomization)
• Calculated creatinine clearance >= 30 mL/min (obtained within 28 days prior
randomization)
• A urine sample tested for proteinuria by either the dipstick method, urinalysis (UA),
or a urine protein creatinine (UPC) ratio:
• The dipstick method must indicate 0-1+ protein; if dipstick reading is >= 2+, a
24-hour urine must be done and it must demonstrate < 1.0 g of protein per 24
hours or a UPC ratio < 1.0
• A urine protein creatinine (UPC) ratio must be < 1.0; if the UPC ratio is >= 1.0
a 24-hour urine must be done and it must demonstrate < 1.0 g of protein per 24
hours
• Urinalysis must indicate < 30 mg/dl. If urinalysis >= 30 mg/dl, a 24-hour urine
must be done and it must demonstrate < 1.0 g of protein per 24 hours or a UPC
ratio < 1.0
• International normalized ratio of prothrombin time (INR) and prothrombin time (PT)
must be =< 1.5 x ULN for the lab within 28 days before randomization; patients who are
therapeutically treated with an agent such as warfarin may participate if they are on
a stable dose and no underlying abnormality in coagulation parameters exists per
medical history, regardless of PT/INR results
• Pregnancy test done within 28 days prior randomization must be negative (for women of
childbearing potential only); pregnancy testing should be performed according to
institutional standards; administration of atezolizumab or
mFOLFOX6/bevacizumab/atezolizumab may have an adverse effect on pregnancy and poses a
risk to the human fetus, including embryo-lethality; should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately
• Women of child-bearing potential and men must agree to use adequate contraception
methods that result in a failure rate of < 1% per year during the treatment period
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for 5 months (150 days) after the last dose
of atezolizumab, 6 months after the last dose of bevacizumab, and 6 months after the
last dose of mFOLFOX6; a woman is considered to be of childbearing potential if she is
not postmenopausal, has not reached a postmenopausal state (>= 12 continuous months of
amenorrhea with no identified cause other than menopause), and has not undergone
surgical sterilization (removal of ovaries and/or uterus); examples of contraceptive
methods with a failure rate of < 1% per year include: bilateral tubal ligation; male
partner sterilization; intrauterine devices; the reliability of sexual abstinence
should be evaluated in relation to the duration of the clinical study and the
preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar,
ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable
methods of contraception; men must refrain from donating sperm during this same period
Exclusion Criteria:
• Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies, fluoropyrimidines, folic acid derivatives or oxaliplatin
• Uncontrolled high blood pressure defined as systolic blood pressure (BP) > 150 mmHg or
diastolic BP > 100 mmHg with or without anti-hypertensive medication; patients with
initial BP elevations are eligible if initiation or adjustment of BP medication lowers
pressure to meet entry criteria
• Documented New York Heart Association (NYHA) class III or IV congestive heart failure
• Serious or non-healing wound, skin ulcer, or bone fracture
• History of inherited bleeding diathesis, gastrointestinal (GI) perforation,
significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
recent arterial thrombosis or symptomatic peripheral ischemia, transient ischemic
attack [TIA], cerebrovascular accident [CVA] or arterial thrombotic event), abdominal
fistula, intra-abdominal abscess, or active GI bleeding (with cause not addressed)
within 6 months prior to randomization, or other medical condition in the opinion of
the treating oncologist that makes the risk of cardiovascular or bleeding
complications with bevacizumab use unacceptably high
• Other malignancies are excluded unless the patient has completed therapy for the
malignancy >= 12 months prior to randomization and is considered disease-free;
patients with the following cancers are eligible if diagnosed and treated within the
past 12 months: in situ carcinomas or basal cell and squamous cell carcinoma of the
skin
• Known DPD (dihydro pyrimidine dehydrogenase) deficiency
• Symptomatic peripheral sensory neuropathy >= grade 2 (Common Terminology Criteria for
Adverse Events [CTCAE] version [v] 5.0)
• Prior treatment with oxaliplatin chemotherapy within 6 months prior to randomization
• History of grade 2 hemoptysis (defined as 2.5 mL of bright red blood per episode)
within 1 month prior to screening
• Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or
pathway-targeting agents; patients who have received prior treatment with anti-CTLA-4
may be enrolled provided the following requirements are met:
• Minimum of 12 weeks from the first dose of anti-CTLA-4 and > 6 weeks from the
last dose to randomization
• No history of severe immune-related adverse effects (CTCAE grade 3 and 4) from
anti-CTLA-4
• Treatment with systemic immunosuppressive medications (including, but not limited to,
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor [anti-TNF] agents) within 14 days prior to randomization; however,
• Patients who have received acute, low dose, systemic immunosuppressant
medications (e.g., a one-time dose of dexamethasone for nausea; or chronic daily
treatment with corticosteroids with a dose of =< 10 mg/day methylprednisolone
equivalent) may be enrolled
• The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)
for patients with orthostatic hypotension or adrenocortical insufficiency is
allowed
• Known clinically significant liver disease, including active viral, alcoholic, or
other hepatitis; cirrhosis; fatty liver; and inherited liver disease; however,
• Patients with past or resolved hepatitis B infection (defined as having a
negative hepatitis B surface antigen [HbsAg] test and a positive anti-HBc
[antibody to hepatitis B core antigen] antibody test) are eligible if polymerase
chain reaction (PCR) for hepatits B virus (HBV) ribonucleic acid (RNA) is
negative per local guidelines
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction (PCR) is negative for HCV RNA per local guidelines
• History or risk of autoimmune disease, including, but not limited to, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune
thyroid disease, vasculitis, or glomerulonephritis; however,
• Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
replacement hormone may be eligible
• Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may
be eligible
• Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis would
be excluded) are permitted provided that they meet the following conditions:
• Patients with psoriasis must have a baseline ophthalmologic exam to rule out
ocular manifestations
• Rash must cover less than 10% of body surface area (BSA)
• Disease is well controlled at baseline and only requiring low potency
topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
• No acute exacerbations of underlying condition within the last 12 months
(not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,
retinoids, biologic agents, oral calcineurin inhibitors; high potency or
oral steroids)
• History of idiopathic pulmonary fibrosis, organizing pneumonia (i.e., bronchiolitis
obliterans, cryptogenic organizing pneumonia, etc.), or active or recently active
(within 90 days of randomization) pneumonitis (including drug induced) that required
systemic immunosuppressive therapy (i.e. corticosteroids, etc.). History of radiation
pneumonitis in the radiation field (fibrosis) is permitted
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins
• Patients with known active tuberculosis (TB) are excluded
• Severe infections within 28 days prior to randomization, including but not limited to,
hospitalization for complications of infection, bacteremia, or severe pneumonia
• Signs or symptoms of infection within 14 days prior to randomization
• Received oral or intravenous (IV) antibiotics within 14 days prior to randomization;
patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract
infection or chronic obstructive pulmonary disease) are eligible
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to randomization or anticipation of need for a major surgical procedure during
the course of the study
• The administration of a live, attenuated vaccine within 28 days prior to randomization
• Pregnant women are excluded from this study because atezolizumab is an agent with the
potential for teratogenic or abortifacient effects; because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with atezolizumab, breastfeeding should be discontinued if the mother is
treated with atezolizumab; these potential risks may also apply to other agents used
in this study; (Note: pregnancy testing should be performed within 28 days prior to
randomization according to institutional standards for women of childbearing
potential)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
• Patients with prior allogeneic bone marrow transplantation or prior solid organ
transplantation
Phase 2 Study of TVB-2640 in KRAS Non-Small Cell Lung Carcinomas
This is a prospective one-arm, two-stage phase 2 trial of TVB-2640 in KRAS mutant NSCLC
patients. 13 patients will be treated with a minimum of 1 cycle of TVB-2640 therapy over 8
weeks.
Inclusion:
1. Metastatic or advanced stage, histologically or cytologically confirmed NSCLC and
molecular identification of oncogenic KRAS mutation.
• KRAS mutant NSCLC must be refractory, relapsed, and/or intolerant (including
contraindications to) of combination platinum-doublet chemotherapy and immune
checkpoint inhibitor therapy
• Molecular characterization (tissue- or blood-based [ie, cell-free/circulating
tumor DNA]) must have been performed and must have demonstrated an oncogenic KRAS
mutation (e.g., exon 12, 13, 61, or 117 mutation detected by sequencing) by a
CLIA-certified assay (source documentation required). KRAS mutations at other
codons require review and approval by Study Chair.
2. Subjects' EGFR mutation and ALK gene rearrangement status must be known prior to study
entry. Subjects with EGFR mutation or ALK gene rearrangement must have progressed
after appropriate FDA-approved targeted therapy options prior to eligibility.
3. Patient has evidence of disease progression on most recent line of therapy.
4. Patient has measurable disease by RECIST v1.1 (Eisenhauer, 2009).
5. Age ≥ 18 years.
6. ECOG performance status of 0 or 1.
7. Predicted life expectancy of >3 months.
8. Adequate organ and marrow function as defined below:
• absolute neutrophil count ≥ 1,500/mcL
• platelets ≥ 75,000/mcL
• total bilirubin <2X institutional upper limit of normal
• AST and ALT ≤5X institutional upper limit of normal
• serum creatinine <1.5X institutional upper limit of normal
• LVEF >50%
• QTcF <470msec
9. Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for 90 days following completion of therapy.
Should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately.
• A female of child-bearing potential is any woman (regardless of sexual
orientation, having undergone a tubal ligation, or remaining celibate by choice)
who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months
(i.e., has had menses at any time in the preceding 12 consecutive months).
10. No significant ischemic heart disease or myocardial infarction within 6 months of
first dose of TVB-2640 and with current adequate cardiac function as in 3.1.8.
11. Ability to understand and the willingness to sign a written informed consent.
Exclusion:
1. Patient is unable to swallow oral medications or has impairment of GI function or GI
disease that may significantly alter drug absorption such as active inflammatory bowel
disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome.
2. Patient has a history of risk factors for torsade de pointes such as uncontrolled
heart failure, severe hypokalemia with potassium less than 3mM/L, history of long QT
syndrome or require use during study participation of concomitant medications known to
prolong QT/QTc interval.
3. Patients who require use of strong CYP3A4/5 agonists or inhibitors during study
participation.
4. Patient has uncontrolled or severe intercurrent medical condition including
uncontrolled brain metastases. Patients with stable brain metastases either treated or
untreated, on a stable dose of steroids/anticonvulsants, with no dose increase within
4 weeks before the first dose of TVB-2640, and no anticipated dose change, are
allowed.
5. Patient underwent major surgery within 4 weeks before the first dose of TVB-2640 or
received cancer-directed therapy either chemotherapy, radiotherapy, hormonal therapy,
biologic or immunotherapy, etc. or an investigational drug or device within 2 weeks (6
weeks for mitomycin C and nitrosoureas) or 5 half-lives of that agent, whichever is
shorter before the first dose of TVB-2640. In addition, any drug- related toxicity,
with the exception of alopecia, an endocrinopathy controlled with replacement therapy,
or a clinically stable toxicity not expected to increase from study therapy (eg,
cisplatin-associated ototoxicity) should have recovered to
Exploring the Effects of Corticosteroids on the Human Hippocampus
Chronic corticosteroid (CS) exposure is associated with changes in memory and the hippocampus
in both humans and in animal models. The hippocampus has a high concentration of
glucocorticoid receptors (GCRs), and the pre-clinical literature demonstrates shortening of
apical dendrites in the CA3 region of the hippocampus and decreased neurogenesis in the
dentate gyrus (DG) following CS administration. In humans, both stress and CS exposure are
associated with a decline in declarative memory performance (a process mediated by the
hippocampus). Impairment in declarative memory and hippocampal atrophy are reported in
patients with excessive CS release due to Cushing's disease, and, by our group, in patients
receiving prescription CS therapy. These findings have important implications for patients
with mood disorders, as a large subset of people with major depressive disorder (MDD) show
evidence of HPA axis activation, elevated cortisol and, importantly, resistance to the
effects of CSs on both the HPA axis and on declarative memory. Thus, resistance to
corticosteroids appears to be a consequence of MDD.
this study will examine changes in declarative memory, as well as use state-of-the-art
high-resolution multimodal neuroimaging, including structural and functional (i.e.,
task-based and resting state) MRI, in both men and women healthy controls, and, as an
exploratory aim, a depressed group, given 3-day exposures to hydrocortisone (160 mg/day) or
placebo. The study will translate preclinical findings to humans, provide valuable data on
possible sex differences in the response to cortisol and, for the first time, identify
specific hippocampal subfields (e.g., CA3/DG) in humans that are most sensitive to acute CS
effects. Using resting state fMRI data and whole brain connectomics using graph theoretical
approaches, we will determine the effects of cortisol exposure on functional brain networks.
Furthermore, this will be the first study to use neuroimaging to compare the brain's response
to CSs in people with depression vs. controls, and determine whether depressed people
demonstrate glucocorticoid resistance within the hippocampus. We hypothesize that hippocampal
response to acute CSs will be greatest in the CA3/DG subfield, greater in women than in men,
and that depressed people will show a blunted hippocampal response to CSs compared to
controls. A multidisciplinary research team with extensive experience in CS effects on the
brain and hippocampal subfield neuroimaging, and a prior history of research collaboration,
will conduct the project.
• Men and women age 18-40 years with vision corrected to at least 20-40 (needed for fMRI
tasks)
• Education of ≥ 12 years
• Baseline RAVLT total words recalled T-score ≥ 40 (normal range)
• BMI between 18.5-35.0 (neither underweight nor severely obese)
• Baseline QIDS-C ≤ 5 (virtual absence of depressive symptoms) for "healthy controls"
and for the "depressed" group a QIDS-C between 11-20 (≥ moderate depressive symptoms
but < very severe depressive symptoms)
Exclusion Criteria:
• History of major psychiatric illness other than MDD for the depressed group, defined
as bipolar disorder, posttraumatic stress disorder, schizoaffective disorder,
schizophrenia, eating disorders, or MDD with psychotic features. For the control
group, a past episode of MDD (per SCID) is also exclusionary
• History of drug or alcohol use disorder
• History of neurological disorders including seizures, brain surgery, multiple
sclerosis, Parkinson's disease
• Taking CNS-acting medications (e.g., antidepressants, antipsychotics, lithium,
anticonvulsants, sedative/hypnotic/anxiolytics). Thus, the depressed group will be
medication free.
• History of allergic reaction or medical contraindication to hydrocortisone
• Metal implants, claustrophobia, or other contraindications to MRI
• Significant medical conditions (e.g., cancer, heart disease, diabetes)
• Vulnerable population including pregnant or nursing women, prisoners, and people with
intellectual disability, history of special education classes, dementia, or other
severe cognitive disorders
• Current suicidal ideation, a suicide attempt in the past 12 months or more than one
lifetime attempt
• History of systemic CS use in the past 12 months, lifetime cumulative use of more than
12 weeks, or recent (defined as past 28 days) inhaled CS use
• Women who are using estrogen containing oral contraceptive agents (other
contraceptives are acceptable, see Protection of Human Subjects section for a list of
acceptable birth control methods) or who are post- or peri-menopausal or with
irregular menstrual cycles (i.e., inconsistent menstruation patterns)
Evaluation of [18F]FLT PET/CT as an Early Predictor of Outcome in Pediatric Solid Tumors
The experimental [18F]FLT-PET/CT will be completed before initiation of chemotherapy at
either diagnosis or initiation of salvage chemotherapy at relapse and prior to the third
cycle (or month) of chemotherapy. Laboratory analysis and correlative radiology, as directed
per clinical care based on the primary diagnosis, are required within 30 days of the baseline
[18F]FLT PET/CT. Follow-up will comprise 24 months of standard practice treatment and follow
up.
• Patients with histologically confirmed solid tumor malignancies with residual tumors
present that require standard of care chemotherapy for a minimum number of cycles. All
anatomical sites and all tumor histologies are eligible including central nervous
system tumors. Both newly diagnosed and/or newly relapsed patients are eligible.
• Patients ages 8 •25 years
• In the opinion of the investigator, patients must be thought to be able to lie still
for imaging without sedation for 20 •30 minutes.
• Patients must have a performance status of > 50% (Lansky or Karnofsky).
• Patients of childbearing potential must have a negative urine or serum pregnancy test
as per institution's standard of care within 7 days prior to [18F]FLT PET/CT imaging.
• Ability to understand and the willingness to sign a written informed consent/assent.
Exclusion Criteria:
• Patients with known allergic or hypersensitivity reactions to previously administered
radiopharmaceuticals of similar chemical or biologic composition to [18F]FLT
• Newly diagnosed subjects who had prior chemotherapy or radiotherapy before enrollment
in the study. Relapsed patients are eligible prior to starting their relapsed
chemotherapy regimen if they meet the other eligibility criteria.
• Subjects for whom chemotherapy is not a standard of care primary therapy option.
• Patients who are pregnant or breast-feeding.
• Patients with no residual tumor (i.e. complete resection at diagnosis or relapse).
Drug: [18F]FLT-PET/CT
Sarcoma, Solid Tumor, Brain and Nervous System, Eye and Orbit, Anus, Breast - Female, Breast - Male, Carcinoid Tumor, Cervix, Colon, Corpus Uteri, Ear, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Nose, Ovary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Uterine (Endometrial), Vulva, Small Intestine, Soft Tissue
A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors (LIBRETTO-121)
This is an open-label, multi-center Phase 1/2 study of oral LOXO-292 in pediatric
participants with an activating rearranged during transfection (RET) alteration and an
advanced solid or primary CNS tumor.
• Advanced or metastatic solid or primary CNS tumor which has failed standard of care
therapies
• Evidence of an activating RET gene alteration in the tumor and/or blood
• Measurable or non-measurable disease
• Karnofsky (participants 16 years and older) or Lansky (participants younger than 16)
performance score of at least 50
• Participant with primary CNS tumors or cerebral metastases must be neurologically
stable for 7 days prior and must not have required increasing doses of steroids within
the last 7 days
• Adequate hematologic, hepatic and renal function.
• Ability to receive study drug therapy orally or via gastric access
• Willingness of men and women of reproductive potential to observe conventional and
effective birth control
Exclusion Criteria:
• Major surgery within two weeks prior to planned start of LOXO-292
• Clinically significant, uncontrolled cardiac, cardiovascular disease or history of
myocardial infarction within 6 months prior to planned start of LOXO-292
• Active uncontrolled systemic bacterial, viral, fungal or parasitic infection
• Clinically significant active malabsorption syndrome
• Pregnancy or lactation
• Uncontrolled symptomatic hyperthyroidism or hypothyroidism (i.e. the participant
required a modification to current thyroid medication in the 7 days before start of
LOXO-292)
• Uncontrolled symptomatic hypercalcemia or hypocalcemia
• Known hypersensitivity to any of the components of the investigational agent, LOXO-292
or Ora-Sweet® SF and OraPlus®, for participants who will receive LOXO-292 suspension
• Prior treatment with a selective RET inhibitor(s) (including investigational selective
RET inhibitor[s])
Lung-MAP: A Master Screening Protocol for Previously-Treated Non-Small Cell Lung Cancer
This screening and multi-sub-study randomized phase II/III trial will establish a method for
genomic screening of similar large cancer populations followed by assigning and accruing
simultaneously to a multi-sub-study hybrid Master Protocol (Lung-MAP). The type of cancer
trait (biomarker) will determine to which sub-study, within this protocol, a participant will
be assigned to compare new targeted cancer therapy, designed to block the growth and spread
of cancer, or combinations to standard of care therapy with the ultimate goal of being able
to approve new targeted therapies in this setting. In addition, the protocol includes
non-match sub-studies which will include all screened patients not eligible for any of the
biomarker-driven sub-studies.
5.1 Registration
Step 0:
1. Patients who need the fresh biopsy must also submit whole blood for ctDNA testing (see
Section 15.3). These patients must be registered to Step 0 to obtain a patient ID
number for the submission.
Patients registered to Step 0 are not registered to the LUNGMAP protocol. To
participate in LUNGMAP, patients must be registered to Step 1 after evaluation of
patient eligibility, including tumor tissue adequacy, per protocol Section 5.1, Step
1.
Patients registered at Step 0 must use the same SWOG patient ID for registration at
Step 1.
Step 1:
2. Patients must have pathologically proven non-small cell lung cancer (all histologic
types) confirmed by tumor biopsy and/or fine-needle aspiration. Disease must be Stage
IV as defined in Section 4.0, or recurrent. The primary diagnosis of non-small cell
lung cancer should be established using the current WHO/IASLC-classification of
Thoracic Malignancies. All histologies, including mixed, are allowed.
3. Patients must either be eligible to be screened at progression on prior treatment or
to be pre-screened prior to progression on current treatment.
These criteria are:
1. Screening at progression on prior treatment:
To be eligible for screening at progression, patients must have received at least
one line of systemic therapy for any stage of disease (Stages I-IV) and must have
progressed during or following their most recent line of therapy.
• For patients whose prior systemic therapy was for Stage I-III disease only
(i.e. patient has not received any treatment for Stage IV or recurrent
disease), disease progression on platinum-based chemotherapy must have
occurred within one year from the last date that patient received that
therapy. For patients treated with consolidation anti-PD-1 or anti-PD-L1
therapy for Stage III disease, disease progression on consolidation
anti-PD-1 or anti-PD-L1 therapy must have occurred within one year from the
date or initiation of such therapy.
• For patients whose prior therapy was for Stage IV or recurrent disease, the
patient must have received at least one line of a platinum-based
chemotherapy regimen or anti-PD-1/PD-L1 therapy, alone or in combination
(e.g. Nivolumab or Pembrolizumab).
2. Pre-Screening prior to progression on current treatment:
To be eligible for pre-screening, current treatment must be for Stage IV or recurrent
disease and patient must have received at least one dose of the current regimen.
Patients must have previously received or currently be receiving a platinum-based
chemotherapy regimen or anti-PD-1/PD-L1 therapy, alone or in combination (e.g.
Nivolumab or Pembrolizumab). Patients on first-line treatment are eligible upon
receiving Cycle 1, Day 1 infusion. Note: Patients will not receive their sub-study
assignment until they progress and the LUNGMAP Notice of Progression is submitted.
4. Patients must have adequate tumor tissue available, defined as ≥ 20% tumor cells and ≥
0.2 mm3 tumor volume.
• The local interpreting pathologist must review the specimen.
• The pathologist must sign the LUNGMAP Local Pathology Review Form confirming
tissue adequacy prior to Step 1 registration.
Patients must agree to have this tissue submitted to Foundation Medicine for common
broad platform CLIA biomarker profiling, PD-L1, and c-MET IHC (see Section 15.2). If
archival tumor material is exhausted, then a new fresh tumor biopsy that is
formalin-fixed and paraffin-embedded (FFPE) must be obtained. Patients who need the
fresh biopsy must also submit whole peripheral blood for ctDNA testing. A tumor block
or FFPE slides 4-5 microns thick must be submitted. Bone biopsies are not allowed. If
FFPE slides are to be submitted, at least 12 unstained slides plus an H&E stained
slide, or 13 unstained slides must be submitted. However, it is strongly recommended
that 20 FFPE slides be submitted. Note: Previous next-generation DNA sequencing (NGS)
will be repeated if done outside this study for sub-study assignment.
Patients must agree to have any tissue that remains after testing retained for the use
of sub-study Translational Medicine (TM) studies at the time of consent the patient is
enrolled in.
5. Patients with known EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion,
ROS 1 gene rearrangement, or BRAF V600E mutation are not eligible unless they have
progressed following all standard of care targeted therapy. EGFR/ALK/ROS/BRAF testing
is not required prior to Step 1 registration, as it is included in the Foundation One
testing for screening/pre-screening.
6. Patients must have Zubrod performance status 0-1 (see Section 10.2) documented within
28 days prior to Step 1 registration.
7. Patients must be ≥ 18 years of age.
8. Patients must also be offered participation in banking for future use of specimens as
described in Section 15.0.
9. Patients must be willing to provide prior smoking history as required on the LUNGMAP
Onstudy Form.
10. As a part of the OPEN registration process (see Section 13.4 for OPEN access
instructions) the treating institution's identity is provided in order to ensure that
the current (within 365 days) date of institutional review board approval for this
study has been entered in the system.
11. Patients must be informed of the investigational nature of this study and must sign
and give written informed consent in accordance with institutional and federal
guidelines.
12. U.S. patients who can complete the survey and the interview by telephone or email in
English must be offered participation in the S1400GEN Survey Ancillary Study if local
institution's policies allow participants to receive the Amazon gift card (see
Sections 15.7 and 18.5). Patients at institutions that cannot offer the survey must
still participate in the main study.
Mechanisms of Exercise Intolerance in Heart Failure With Preserved Ejection Fraction
The global objective of this study is to determine the mechanisms of exercise intolerance and
dyspnea on exertion (DOE) in patients with HFpEF and based on this pathophysiology, test
whether specific exercise training programs (whole body vs single leg) will result in
improved exercise tolerance.
Stopping Tyrosine Kinase Inhibitors in Affecting Treatment-Free Remission in Patients With Chronic Phase Chronic Myeloid Leukemia
This phase II trial studies how stopping tyrosine kinase inhibitors will affect
treatment-free remission in patients with chronic myeloid leukemia in chronic phase. When the
level of disease is very low, it's called molecular remission. TKIs are a type of medication
that help keep this level low. However, after being in molecular remission for a specific
amount of time, it may not be necessary to take tyrosine kinase inhibitors. It is not yet
known whether stopping tyrosine kinase inhibitors will help patients with chronic myeloid
leukemia in chronic phase continue or re-achieve molecular remission.
• Patient must have been diagnosed with CML-CP at < 18 years of age.
• Patient must have histologic verification of CML-CP at original diagnosis
• Patient must be in molecular remission (MR) with a BCR-ABL1 level of =< 0.01% BCR-ABL1
as measured using the International Scale (IS) by RQ-PCR for >= 2 consecutive years at
the time of enrollment
• Please note: The lab evaluating disease status and molecular response for this
study must be College of American Pathology (CAP) and/or Clinical Laboratory
Improvement Amendments (CLIA) certified (United States [US] only), sites in other
countries must be certified by their accredited authorities. All labs must use
the International Scale guidelines with a sensitivity of detection assay =< 0.01%
BCR-ABL1 and be able to report results in =< 2 weeks
• Patient must have received any TKI for a minimum of 3 consecutive years at time of
enrollment
• Patient agrees to discontinue TKI therapy
• REGULATORY REQUIREMENTS
• All patients and/or their parents or legal guardians must sign a written informed
consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met
• ELIGIBILITY FOR PATIENT-REPORTED OUTCOMES (PROs):
• Age >= 8 years at the time of enrollment
• Ability to understand English or Spanish
• Cognitive ability to complete instruments according to the primary team
• ELIGIBILITY FOR AAML18P1 NEUROCOGNITIVE STUDY:
• Patient must be 5 years or older at the time of enrollment
• English-, French- or Spanish-speaking
• No known history of neurodevelopmental disorder prior to diagnosis of CML (e.g., Down
syndrome, Fragile X, William syndrome, mental retardation)
• No significant visual or motor impairment that would prevent computer use or
recognition of visual test stimuli
Exclusion Criteria:
• Known T3151 mutation
• Additional clonal chromosomal abnormalities in Philadelphia chromosome (Ph) positive
(+) cells at any time prior to enrollment that include "major route" abnormalities
(second Ph, trisomy 8, isochromosome 17q, trisomy 19), complex karyotype or
abnormalities of 3q26.2
• History of accelerated phase or blast crisis CML
• Female patients who are pregnant
• Lactating females are not eligible unless they have agreed not to breastfeed their
infants
• Female patients of childbearing potential are not eligible unless a negative pregnancy
test result has been obtained