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.
DExterous Hand Control Through Fascicular Targeting (DEFT) - (Human Subjects)
Our goal is to temporarily implant the following groups for 540 +/- 30 days:
1. Forearm FAST electrodes
1. Five human partial hand amputees (amputated at the level of the hand) with 2 FAST
electrodes in the ulnar nerve and 2-5 FAST electrodes in the median nerve.
2. Five human hand and forearm amputees (amputated at the level of the forearm) with 2
FAST electrodes in the ulnar nerve and 2-5 FAST electrodes in the median nerve .
2. Arm FAST electrodes
1. Five human partial hand amputees (amputated at the level of the hand) with 2 FAST
electrodes in the ulnar nerve and 2-5 FAST electrodes in the median nerve.
2. Five human hand and forearm amputees (amputated at the level of the forearm) with 2
FAST electrodes in the ulnar nerve and 2-5 FAST electrodes in the median nerve.
3. Five human hand, forearm and arm amputees (amputated at the level of the arm) with
2 FAST electrodes in the ulnar nerve and 2-5 FAST electrodes in the median nerve.
Criteria for Inclusion of Subjects:
Hand, forearm and arm amputees:
1. Male or female, age 18 and older, of any race or ethnicity
2. Able and willing to sign Consent
3. Able and willing to participate in all study activities including implantation,
testing and explantation of the study device.
4. Able to communicate effectively in English without an interpreter
After preliminary screening subjects will be assessed for the following inclusion criteria:
Overall and phantom pain are well-controlled and not incapacitating
Criteria for Exclusion of Subjects:
1. If MR neurogram and EMG/NCS study show nerve or muscle dysfunction/injury at a higher
level than anticipated based on the appearance of the physical amputation stump, the
subject may be excluded from the study due to adverse neuromuscular anatomy which
would preclude use of the proposed experimental electrode implants. The radiographs
will be used to confirm suitability of the amputation stump configuration. If the bony
anatomy of the amputation stump is found to be unsuitable, the patient may be excluded
from the study.
2. Subjects who have a history of cardiac arrhythmia will be excluded from the study.
Other: Fast electrode
Amputation, Traumatic, Hand, Brain and Nervous System
peripheral nerve, intraneural electrode, hand amputation, forearm amputation
Phase 1 Dose-escalating Study of MM-398 (Irinotecan Sucrosofate Liposome Injection) Plus Intravenous Cyclophosphamide in Recurrent or Refractory Pediatric Solid Tumors
This is a Phase 1 study of the combination of two drugs: MM-398 and Cyclophosphamide. The
goal is to find the highest dose of MM-398 that can be given safely when it is used together
with the chemotherapy drug Cyclophosphamide.
• Histologically or cytologically-confirmed Ewing sarcoma, rhabdomyosarcoma,
neuroblastoma, or osteosarcoma
• Disease progression after prior therapy in locally advanced or metastatic setting
• Measurable or evaluable disease based on the Response Evaluation Criteria in Solid
Tumors (RECIST v1.1) criteria
• Age 12 months to <21 years
• Adequate bone marrow reserves, hepatic function, and renal function
• Recovered from effects of any prior surgery or cancer therapy
• Patients 18 years or older will provide written consent. A parent or legal guardian of
a patient <18 years of age will provide informed consent and patients 11 to 18 years
of age will provide written assent or as per participating institutional policy.
Exclusion Criteria:
• Clinically significant gastrointestinal disorders
• NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled
blood pressure
• Active infection or unexplained fever
• Known hypersensitivity to any of the components of MM-398 or other liposomal products
• Recent Investigational therapy
• Pregnant or breast feeding; females of child-bearing potential must test negative for
pregnancy at the time of enrollment
Drug: MM-398 (Irinotecan Sucrosofate Liposome Injection) plus cyclophosphamide
Neuroblastoma, Sarcoma, Ewing Sarcoma, Mycosis Fungoides, Rhabdomyosarcoma, Osteosarcoma, Recurrent or Refractory Solid Tumors, Brain and Nervous System, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Ear, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Nose, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Uterine (Endometrial), Vulva, Hodgkins Lymphoma, Kaposis sarcoma, Other Hematopoietic, Small Intestine, Soft Tissue
TransMedics (OCS) Liver Trial: Preserving and Assessing Donor Livers for Transplantation (Liver PROTECT)
A prospective, phased-pivotal, international randomized trial to evaluate the effectiveness
of the OCS™ Liver to preserve and assess donor livers intended for transplantation.
• Registered male or female primary Liver transplant candidate
• Age ≥18 years old
• Signed: 1) written informed consent document and 2) authorization to use and disclose
protected health information
Exclusion Criteria:
• Acute, fulminant liver failure
• Prior solid organ or bone marrow transplant
• Chronic use of hemodialysis or diagnosis of chronic renal failure, defined as chronic
serum creatinine of >3 mg/dl for >2 weeks and/or requiring hemodialysis
• Multi-organ transplant
• Ventilator dependent
• Dependent on > 1 IV inotrope to maintain hemodynamics
Device: OCS™ Liver System, Other: Control
Liver Transplantation, Liver Preservation for Transplant
Study of Biomarker-Based Treatment of Acute Myeloid Leukemia
This screening and multi-sub-study Phase 1b/2 trial will establish a method for genomic
screening followed by assigning and accruing simultaneously to a multi-study "Master Protocol
(BAML-16-001-M1)." The specific subtype of acute myeloid leukemia will determine which
sub-study, within this protocol, a participant will be assigned to evaluate investigational
therapies or combinations with the ultimate goal of advancing new targeted therapies for
approval. The study also includes a marker negative sub-study which will include all screened
patients not eligible for any of the biomarker-driven sub-studies.
• Adults, age 60 years or older at the time of diagnosis
• Subjects or their legal representative must be able to understand and provide written
informed consent
• Cohort Inclusion Criteria •Group A: Subjects must have previously untreated acute
myeloid leukemia (AML) according to the WHO classification with no prior treatment
other than hydroxyurea. Prior therapy for myelodysplastic syndrome (MDS),
myeloproliferative syndromes (MPD), or aplastic anemia is permitted but not with
hypomethylating agents.
• Cohort Inclusion Criteria •Group B: Subjects must have relapsed or refractory AML
according to the WHO classification. For study purposes, refractory AML is defined as
failure to ever achieve CR or recurrence of AML within 6 months of achieving CR;
relapsed AML is defined as all others with disease after prior remission. (Group B is
not currently recruiting. Expected to begin recruiting in 3rd quarter 2017.)
Exclusion Criteria:
• Isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement with
AML to enter the study)
• Acute promyelocytic leukemia
• Symptomatic central nervous system (CNS) involvement by AML
• Signs of leukostasis requiring urgent therapy
• Disseminated intravascular coagulopathy with active bleeding or signs of thrombosis
• Patients with psychological, familial, social, or geographic factors that otherwise
preclude them from giving informed consent, following the protocol, or potentially
hamper compliance with study treatment and follow-up
• Any other significant medical condition, including psychiatric illness or laboratory
abnormality, that would preclude the patient participating in the trial or would
confound the interpretation of the results of the trial
This is a multi-center, randomized, double-masked, placebo-controlled clinical trial of
suppressive valacyclovir for one year in immunocompetent study participants with an episode
of dendriform epithelial keratitis, stromal keratitis, endothelial keratitis, and/or iritis
due to Herpes Zoster Ophthalmicus (HZO) in the year prior to enrollment.
PARTICIPANT INCLUSION CRITERIA
To be eligible for study participation, an individual must meet all of the following
criteria:
1. Ability to understand, and willingness and ability to read and sign, the informed
consent form.
2. Ability to understand and follow instructions and study procedures.
3. Willingness to comply with all study procedures and be available for the duration of
the study.
4. Ability to take oral medication, and are willing to adhere to study medication
regimen.
5. Age 18 years or older.
6. Diagnosed with HZO in one eye based on both of these criteria:
1. History of characteristic unilateral vesicular rash in the dermatomal
distribution of cranial nerve V1.
2. Medical record documentation of an episode of active dendriform epithelial
keratitis, stromal keratitis, endothelial keratitis, and/or iritis due to HZO
within the preceding year. This episode of active anterior segment ocular disease
may be due to HZO of recent onset (within the preceding 6 months); or chronic HZO
(with onset six or more months ago); may be new, worsening, or recurrent disease
after a period of inactivity; and may occur after medication was reduced.
i. Study participants with chronic HZO must be on a stable treatment regimen and off
antivirals for at least 30 days before enrollment. Study participants with chronic HZO
who do not meet this criterion may be rescreened, if they are able to meet this
criterion within 3 months after the study visit. (This is not a requirement for study
participants with recent onset HZO, who may be enrolled at any time, preferably after
completing recommended acute antiviral treatment, if prescribed, is completed).
7. For females with reproductive potential, willingness to use highly effective
contraception (e.g., hormonal contraception, barrier contraception, intrauterine
device, or abstinence).
PARTICIPANT EXCLUSION CRITERIA
An individual who meets any of the following criteria will be excluded from participation
in this study:
1. History of immunocompromised status as defined by current CDC contraindications for
the vaccine against zoster (44).
1. Study participants who are diagnosed with leukemia, lymphomas or other malignant
neoplasms affecting bone marrow or lymphatic system, unless leukemia in remission
and off chemotherapy for at least 3 months.
2. Study participants who are diagnosed with Acquired Immune Deficiency Syndrome
(AIDS) or presents with other clinical manifestations of Human Immunodeficiency
virus (HIV) including CD4 count of ≤ 200 cells/ml.
3. Study participants on immunosuppressive therapy including:
i. High-dose corticosteroids (greater than equivalent of prednisone 20 mg/day within 1
month) ii. Chemotherapy, other than low dose used for treatment of immune-mediated
diseases within 3 months iii. Study participants receiving recombinant human immune
mediators and immune modulators, especially antitumor necrosis agents, within 1 month
prior to enrollment d. Study participants with unspecified cellular immunodeficiency.
e. Study participants with history of hematopoietic stem cell transplantation.
2. Medical history of a systemic disease and thought likely to meet one of the exclusion
criteria listed in exclusion criterion #1 during the 18-month study period.
3. Renal insufficiency:
1. Requires dialysis or has history of renal transplant or
2. eGFR less than 45, determined within 30 days preceding enrollment.
4. Allergy or adverse reaction to valacyclovir or acyclovir.
5. History of vaccination against zoster within one month prior to enrollment. Study
participants who meet this exclusion criterion may be rescreened.
6. Keratoplasty or keratorefractive surgery of the involved eye with zoster.
7. On systemic antivirals with activity against herpes within the past 30 days, including
acyclovir, valacyclovir, or famciclovir, for any reason except for treatment of acute
HZO, including investigational drug trial.
8. History of another condition that may require treatment with one of these three
antivirals listed above in exclusion criterion #7, during the course of the study;
study participants who require chronic suppressive antiviral treatment with these
medications will be excluded.
9. Sexually active women who are pregnant, nursing, or in their reproductive years who do
not agree to use contraception during the 1-year treatment period.
10. Incarceration
11. Any condition or circumstance that in the opinion of the study investigator, would
place the study participant in increased risk or affect his/her full compliance or
completion of the study.
12. Participation in a clinical study testing a drug, biologic, device or other
intervention within the last 30 days from enrollment visit. Study participants who
meet this criterion may be rescreened.
A Study of Therapeutic Iobenguane (131-I) and Vorinostat for Recurrent or Progressive High-Risk Neuroblastoma Subjects (OPTIMUM)
The purpose of this study is to evaluate the efficacy and safety of 131I-MIBG in combination
with Vorinostat in patients with Recurrent or Progressive neuroblastoma
1. Subjects with a diagnosis of iobenguane avid, high-risk neuroblastoma based on Revised
INRC criteria at the time of study enrollment with recurrent or progressive disease at
any time prior to enrollment, regardless of overall response to frontline therapy,
where frontline therapy includes a minimum of 4 cycles of induction therapy at any
time prior to enrollment.
2. May have had prior 131I-MIBG therapy, provided:
1. It has been at least 6 months from the date of last 131I-MIBG ;
2. Response was other than progressive disease on first restaging after 131I-MIBG ;
3. Prior 131I-MIBG was given as monotherapy and not in combination with systemic
anticancer agents;
4. Cumulative lifetime dose of 131I-MIBG at enrollment does not exceed 18 mCi/kg.
3. All soft tissue lesions identified on CT/MRI scans must be iobenguane avid lesions on
an (123I)-iobenguane scan, or
1. any progressive non-iobenguane avid lesion is proven by biopsy to be a
non-neuroblastoma lesion.
2. any other non-avid lesion is comprised of a fibrotic or scarred mass as shown by
routine imaging and confirmed by the investigator.
4. Adequate cryopreserved autologous peripheral blood stem cells or bone marrow (at least
2 aliquots of 2.0 × 10exp6 CD34/kg at the time of study enrollment).
5. If a male, must agree to use an adequate contraception method as deemed appropriate by
the Investigator (e.g., vasectomy, condoms) or partner using effective contraception
and to not donate sperm during the study and for 90 days after receiving the last dose
of study drug.
6. If a female of childbearing potential, have a negative serum pregnancy test result
prior to each dosing and, if sexually active, be practicing an effective method of
birth control [e.g., intrauterine device, double-barrier method (i.e., diaphragm, or a
cervical cap) with intravaginal spermicidal foam, cream or gel], or male partner
sterilization throughout the study.
7. Age at study entry ≥1 year.
8. Previous platelet transfusions are permitted, as long as the subject has a platelet
count ≥50,000/μL without transfusion support for at least 1 week.
9. Subjects must have a minimum pulse oximetry measurement of at least 94% at baseline.
10. An absolute neutrophil count ≥750/μL without growth factor for 5 days.
11. Liver function parameter results: total bilirubin ≤2 × upper limit of normal for age,
and Serum alanine aminotransferase (glutamic-pyruvic transaminase) and serum aspartate
aminotransferase (glutamic-oxaloacetic transaminase) ≤ 10 times the upper limit of
normal (for all sites, the upper limit of normal for alanine aminotransferase is
defined as 45 U/L).
12. Normal thyroid function as measured by T4 or TSH or have abnormal results that are not
considered clinically important by the Investigator or may be receiving levothyroxine.
13. Cardiac Function: shortening fraction of ≥ 27% by echocardiogram or ejection fraction
≥ 50% documented by echocardiogram or radionuclide angiogram within 1 month prior to
Visit 1 (Baseline).
14. Karnofsky Performance Status (for subjects >16 years of age) or the Lansky Performance
Status Performance Status (for subjects 1 to 16 years of age) ≥50%.
15. Full recovery from the toxic effects of any prior therapy.
16. Coagulation Function:
1. International Normalized Ratio (INR) < 1.5
2. Partial thromboplastin time (PTT) < 1.5 times upper limit of normal.
Exclusion Criteria:
1. Subjects within 5 half-lives after any antibody-based immunotherapy, or have not
recovered from effects of any biologic therapy.
2. Subjects <12 weeks after myeloablative therapy with autologous stem cell transplant.
3. Subjects who have had an allogeneic stem cell treatment less than 4 months from Visit
1 are excluded. Those who have received allogeneic stem cell treatment more than 4
months from Visit 1 must have recovered and have no active graft versus host disease
(GVHD) to be eligible.
4. Subjects must not have received radiation for a minimum of 2 weeks prior to study
enrollment. Subjects whose only site(s) of disease have been radiated are eligible as
long as the subject has MIBG avidity 2 weeks after completion of radiation. A minimum
of 12 weeks prior to study enrollment is required following prior large field
radiation therapy (ie, craniospinal, whole abdominal, total lung, > 50% marrow space)
5. History of total body irradiation.
6. Subjects do not have adequate renal function defined as GFR ≥ 70 mL/min/1.73 m2 either
by creatinine clearance or radioisotope direct measurement or by calculation with the
Schwartz formula
7. Subjects who are on hemodialysis.
8. Pregnancy or breastfeeding.
9. Significant active infections including active hepatitis B, or hepatitis C infection,
or known infection with human immunodeficiency virus (HIV) (testing for HIV is not
required prior to study entry).
10. Clinically important cardiac, pulmonary, and hepatic impairment.
11. Vorinostat treatment exclusion criteria (subjects, who meet any one of these criteria
and otherwise meet eligibility criteria, are still eligible for 131I-MIBG monotherapy)
1. Since valproic acid has HDAC inhibitory activity, patients must not have received
valproic acid within 30 days of study entry.
2. Since vorinostat may prolong the QT interval, patients must not be receiving
other medications known to prolong the QT interval at the time of study entry .
Pentamidine must not have been received within 1 week of study enrollment.
3. Patients with a history of deep venous thrombosis that was not associated with
the presence of a central venous catheter.
4. Patients who are receiving Coumadin.
Drug: 131I-MIBG, Drug: 131-MIBG + Vorinostat
Neuroblastoma, Neoplasms, Neuroectodermal Tumors, Brain and Nervous System
A Study of Galcanezumab (LY2951742) in Participants 6 to 17 Years of Age With Episodic Migraine (REBUILD-1)
The main purpose of this study is to evaulate the efficacy and safety of galcanezumab in
participants 6 to 17 years of age for the preventive treatment of episodic migraine. The
primary objective is to demonstrate the superiority of galcanezumab versus placebo in the
reduction of monthly migraine headache days across the 3-month double-blind treatment period.
• Have a diagnosis of migraine with or without aura as defined by the IHS ICHD-3
guidelines (1.1 or 1.2 according to ICHD-3 [2018]), with a history of migraine
headaches of at least 6 months prior to screening.
Exclusion Criteria:
• Participants who are taking, or are expected to take, therapeutic antibodies during
the course of the study (adalimumab, infliximab, trastuzumab, bevacizumab, etc.).
Prior use of therapeutic antibodies is allowed if that use was more than 12 months
prior to baseline.
• Known hypersensitivity to monoclonal antibodies or other therapeutic proteins, or to
galcanezumab or its excipients.
• Current use or prior exposure to galcanezumab, another CGRP antibody, or CGRP receptor
antibody, including those who have previously completed or withdrawn from this study
or any other study investigating a CGRP antibody.
• History of IHS ICHD-3 diagnosis of new daily persistent headache, cluster headache or
migraine subtypes including hemiplegic (sporadic or familial) migraine and migraine
with brainstem aura (previously basilar-type migraine).
• History of significant head or neck injury within 6 months prior to screening; or
traumatic head injury at any time that is associated with significant change in the
quality or frequency of their headaches, including new onset of migraine following
traumatic head injury.
• Participants with a known history of intracranial tumors or developmental
malformations including Chiari malformations.
1. Must have given written informed consent (signed and dated)
2. Participated in a PBC study with seladelpar
3. Females of reproductive potential must use at least one barrier contraceptive and a
second effective birth control method during the study and for at least 90 days after
the last dose. Male subjects who are sexually active with female partners of
reproductive potential must use barrier contraception and their female partners must
use a second effective birth control method during the study and for at least 90 days
after the last dose
Exclusion Criteria:
Exclusion criteria are only applicable for subjects with a seladelpar interruption greater
than 4 weeks prior to Day 1 of this study and for subjects who participated in CB8025-21838
irrespective of seladelpar interruption.
1. Treatment-related adverse event (AE) leading to seladelpar discontinuation in a
previous PBC study with seladelpar (MBX-8025)
2. A medical condition, other than PBC, that in the investigator's opinion would preclude
full participation in the study or confound its results (e.g., cancer)
3. AST or ALT above 3 × the upper limit of normal (ULN)
4. Total bilirubin above 2 × ULN
5. MELD score ≥ 12. For subjects on anticoagulation medication, evaluation of the
baseline INR, in concert with any current dose adjustments in anti-coagulant
medications, will be taken into account when calculating this score. This will be done
in consultation with the medical monitor.
6. Evidence of advanced PBC as defined by the Rotterdam criteria: albumin below 1× the
lower limit of normal (LLN) AND total bilirubin above 1 × ULN)
7. eGFR ≤45 mL/min/1.73 m2 (calculated by MDRD formula)
8. Auto-immune hepatitis
9. Primary sclerosing cholangitis
10. Known history of alpha-1-antitrypsin deficiency
11. Known history of chronic viral hepatitis
12. For females, pregnancy or breast-feeding
13. Use of colchicine, methotrexate, azathioprine, or long-term use of systemic steroids
(e.g. prednisone, prednisolone, budesonide) (>2 weeks) within 2 months prior to
Screening
14. Current use of fibrates or use of fibrates within 3 months prior to Screening
15. Current use of obeticholic acid or use of obeticholic acid within 3 months prior to
Screening
16. Use of an experimental or unapproved treatment for PBC within 3 months prior to
Screening
17. History of malignancy diagnosed or treated, actively or within 2 years, or active
evaluation for malignancy; localized treatment of squamous or non-invasive basal cell
skin cancers and cervical carcinoma in-situ is allowed if appropriately treated prior
to Screening
18. Treatment with any other investigational therapy or medical device within 30 days or
within 5 half-lives, whatever is longer, prior to Screening
19. Any other condition(s) that would compromise the safety of the subject or compromise
the quality of the clinical study, as judged by the Investigator
20. Immunosuppressant therapies (e.g., cyclosporine, tacrolimus, anti-TNF or other
immunosuppressive biologics)
21. Other medications that effect liver or GI functions such as absorption of medications
or the roux-en-y gastric bypass procedure may be prohibited and should be discussed
with the medical monitor on a case-by-case basis
22. Positive for:
1. Hepatitis B, defined as the presence of hepatitis B surface antigen
2. Hepatitis C, defined as the presence of hepatitis C virus ribonucleic acid (RNA)
3. Human immunodeficiency virus (HIV) antibody
23. Active COVID-19 infection during screening
CAN-Stim Compared to SNS in Treatment of Urinary Urgency Incontinence With Wireless Neuromodulation Technology (PROTECT)
This is a prospective, randomized, controlled, multi-center, study in which 150 evaluable
subjects will be randomized 1:1 to receive either a Protect CAN-Stim or SNS InterStim®
system. Subjects from both groups will immediately start with therapy. The primary endpoint
is a ≥ 50% reduction in number of incontinence episodes associated with urgency at the
3-month visit, with additional measurements assessed at 14 days, 1, 6, 9 and 12-months.
• Diagnosis of overactive bladder with urgency urinary incontinence or mixed
incontinence (urge and stress) with predominate urge, as confirmed by the MESA
questionnaire;
• Women and men ≥ 18 years of age;
• Women of child-bearing age willing to practice birth control;
• At least 4 incontinent episodes associated with urgency on a 3-day voiding diary;
• At least 10 voids per day;
• Average urgency score of at least 2 as measured with IUSS on a 3-day voiding diary;
• Self-reported bladder symptoms present > 6 months;
• Documented failure of an adequate trial of first and second line therapy;
• Off all antimuscarinics and beta-3 adrenergic agonists for at least 2 weeks prior to
enrollment;
• If on Tricyclic antidepressants, dosage must be stabilized for at least 3 months;
• Have no active urethral obstruction/stricture, bladder calculi or bladder tumor based
on medical history;
• Normal upper urinary tract function based on medical history;
• Based on the medical opinion of the Investigator, there is no evidence of anatomic
abnormalities that could jeopardize the placement of the device or pose a hazard to
the subject;
• Based on the medical opinion of the Investigator, subject is willing and able to
operate the patient programmer, recharging equipment, diary and has the ability to
undergo study assessments and provide accurate responses;
• Based on the medical opinion of the Investigator, subject is a good surgical subject
for the implant procedure;
• Capable of giving informed consent;
• Capable and willing to follow all study related procedures.
Exclusion Criteria:
• An active implantable electronic device regardless of whether stimulation is ON or
OFF;
• Pregnant as confirmed by a urine pregnancy test or plan to become pregnant during the
following 12 months period;
• Primary complaint of stress urinary incontinence;
• Less than 1 year post-partum and/or are breast-feeding;
• Neurogenic bladder (i.e. Multiple sclerosis, Parkinson's, Spinal Cord Injury);
• Patients with spinal hardware that would limit access to the sacrum;
• Botox use in bladder or pelvic floor muscles in the past nine months;
• Have a post-void residual urine volume >150 cc at baseline;
• Current urinary tract infection (UTI);
• Previous treatment with sacral neuromodulation;
• Previous treatment with percutaneous tibial nerve stimulation, pelvic floor muscle
stimulation, or biofeedback within the past 60 days;
• Conditions requiring Magnetic Resonance Imaging (MRI) evaluation or diathermy
procedures;
• Inability to operate the CAN-Stim System or InterStim System;
• Diabetes with peripheral nerve compromise or severe uncontrolled diabetes (HbA1C 8.5
or greater);
• History of coagulopathy or bleeding disorder;
• History of pelvic pain as primary diagnosis (VAS score of > 4) at baseline;
• Anatomical restrictions such that device placement is not possible;
• Are currently participating or have participated within the past 30 days in any
clinical investigation involving or impacting urinary or renal function;
• Have a life expectancy of less than 1 year;
• Cannot independently comprehend and complete the questionnaires and diaries;
• Deemed unsuitable for enrollment by the investigator based on history or physical
examination (including bleeding disorders or anticoagulant medications, and peripheral
neuropathy);
• Dependent on wearable, transcutaneous, or other therapeutic medical device (examples:
glucose monitor, TENS) for treatment of a disease or disorder.
A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001) (LIBRETTO-001)
This is an open-label, first-in-human study designed to evaluate the safety, tolerability,
pharmacokinetics (PK) and preliminary anti-tumor activity of selpercatinib (also known as
LOXO-292) administered orally to participants with advanced solid tumors, including
rearranged during transfection (RET)-fusion-positive solid tumors, medullary thyroid cancer
(MTC) and other tumors with RET activation.
For Phase 1:
• Participants with a locally advanced or metastatic solid tumor that:
• Has progressed on or is intolerant to standard therapy, or
• For which no standard therapy exists, or in the opinion of the Investigator, are not
candidates for or would be unlikely to tolerate or derive significant clinical benefit
from standard therapy, or
• Decline standard therapy
• Prior multikinase inhibitors (MKIs) with anti-RET activity are allowed
• A RET gene alteration is not required initially. Once adequate PK exposure is
achieved, evidence of RET gene alteration in tumor and/or blood is required as
identified through molecular assays, as performed for clinical evaluation
• Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as
appropriate to tumor type
• Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 or Lansky Performance
Score (LPS) greater than or equal to (≥) 40 percent (%) (age less than [<] 16 years)
with no sudden deterioration 2 weeks prior to the first dose of study treatment
• Adequate hematologic, hepatic and renal function
• Life expectancy of at least 3 months
For Phase 2: As for phase 1 with the following modifications:
• For Cohort 1: Participants must have received prior standard therapy appropriate for
their tumor type and stage of disease, or in the opinion of the Investigator, would be
unlikely to tolerate or derive clinical benefit from appropriate standard of care
therapy
• Cohorts 1 and 2:
• Enrollment will be restricted to participants with evidence of a RET gene
alteration in tumor
• At least one measurable lesion as defined by RECIST 1.1 or RANO, as appropriate
to tumor type and not previously irradiated
• Cohorts 3 and 4: Enrollment closed
• Cohort 5:
• Cohorts 1-4 without measurable disease
• MCT not meeting the requirements for Cohorts 3 or 4
• MTC syndrome spectrum cancers (e.g., MTC, pheochromocytoma), cancers with
neuroendocrine features/differentiation, or poorly differentiated thyroid cancers
with other RET alteration/activation may be allowed with prior Sponsor approval
• cfDNA positive for a RET gene alteration not known to be present in a tumor
sample
• Cohort 6: Participants who otherwise are eligible for Cohorts 1, 2 or 5 who
discontinued another RET inhibitor may be eligible with prior Sponsor approval
• Cohort 7: Participants with a histologically confirmed stage IB-IIIA NSCLC and a RET
fusion; determined to be medically operable and tumor deemed resectable by a thoracic
surgical oncologist, without prior systemic treatment for NSCLC
Key Exclusion Criteria (Phase 1 and Phase 2):
• Phase 2 Cohorts 1 and 2: an additional known oncogenic driver
• Cohorts 3 and 4: Enrollment closed
• Cohorts 1, 2 and 5: prior treatment with a selective RET inhibitor Notes: Participants
otherwise eligible for Cohorts 1, 2, and 5 who discontinued another selective RET
inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval
• Investigational agent or anticancer therapy (including chemotherapy, biologic therapy,
immunotherapy, anticancer Chinese medicine or other anticancer herbal remedy) within 5
half-lives or 2 weeks (whichever is shorter) prior to planned start of LOXO-292
(selpercatinib). In addition, no concurrent investigational anti-cancer therapy is
permitted Note: Potential exception for this exclusion criterion will require a valid
scientific justification and approval from the Sponsor
• Major surgery (excluding placement of vascular access) within 2 weeks prior to planned
start of LOXO-292 (selpercatinib)
• Radiotherapy with a limited field of radiation for palliation within 1 week of planned
start of LOXO-292 (selpercatinib), with the exception of participants receiving
radiation to more than 30% of the bone marrow or with a wide field of radiation, which
must be completed at least 4 weeks prior to the first dose of study treatment
• Any unresolved toxicities from prior therapy greater than Common Terminology Criteria
for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment with the
exception of alopecia and Grade 2, prior platinum-therapy related neuropathy
• Symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis, or untreated
spinal cord compression. Participants are eligible if neurological symptoms and CNS
imaging are stable and steroid dose is stable for 14 days prior to the first dose of
LOXO-292 (selpercatinib) and no CNS surgery or radiation has been performed for 28
days, 14 days if stereotactic radiosurgery (SRS)
• Clinically significant active cardiovascular disease or history of myocardial
infarction within 6 months prior to planned start of LOXO-292 (selpercatinib) or
prolongation of the QT interval corrected (QTcF) greater than (>) 470 milliseconds
(msec)
• Participants with implanted pacemakers may enter the study without meeting QTc
criteria due to nonevaluable measurement if it is possible to monitor for QT
changes.
• Participants with bundle branch block may be considered for study entry if QTc is
appropriate by a formula other than Fridericia's and if it is possible to monitor
for QT changes.
• Required treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or
inducers and certain prohibited concomitant medications
• Phase 2 Cohort 7 (neoadjuvant treatment): Participant must not have received prior
systemic therapy for NSCLC.
Drug: LOXO-292
Lymphoma, Non-Small Cell Lung Cancer, Colon Cancer, Medullary Thyroid Cancer, Any Solid Tumor, Brain and Nervous System, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Esophagus, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Stomach, Thyroid, Urinary Bladder, Hodgkins Lymphoma, Small Intestine, Soft Tissue
LOXO-292, KIF5B-RET, M918T, CCDC6-RET, RET-PTC1, NCOA4-RET, RET-PTC, RET-PTC3, RET-PTC4, PRKAR1A-RET, RET-PTC2, GOLGA5-RET, RET-PTC5, ERC1-RET, KTN1-RET, RET-PTC8, HOOK3-RET, PCM1-RET, TRIM24-RET, RET-PTC6, TRIM27-RET, TRIM33-RET, RET-PTC7, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1-RET, BCR-RET, FGRF1OP-RET, RFG8-RET, RET-PTC9, ACBD5-RET, MYH13-RET, CUX1-RET, KIAA1468-RET, FRMD4A-RET, SQSTM1-RET, AFAP1L2-RET, PPFIBP2-RET, EML4-RET, PARD3-RET, G533C, C609F, C609G, C609R, C609S, C609Y, C611F, C611G, C611S, C611Y, C611W, C618F, C618R, C618S, C620F, C620R, C620S, C630R, C630Y, D631Y, C634F, C634G, C634R, C634S, C634W, C634Y, K666E, E768D, L790F, V804L, V804M, A883F, S891A, R912P, CLIP1-RET, Y806C, RET fusion, RET alteration, RET mutation, RET rearrangement, RET translocation, Neoplasms by Site, Neoplasms, Non-Small Cell Lung Cancer, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Cancer of Lung, Cancer of the Lung, Lung Cancer, Neoplasms, Lung, Neoplasms, Pulmonary, Pulmonary Cancer, Pulmonary Neoplasms, Respiratory Tract Neoplasms, Lung Diseases, Respiratory Tract Diseases, Carcinoma, Bronchogenic, Bronchial Neoplasms, Medullary Thyroid Cancer, Papillary Thyroid Cancer, Thyroid Diseases, Thyroid Neoplasms, Cancer of the Thyroid, Cancer of Thyroid, Neoplasms, Thyroid, Thyroid Ademona, Thyroid Cancer, Thyroid Carcinoma, Endocrine System Diseases, Endocrine Gland Neoplasms, Head and Neck Neoplasms, Thoracic Neoplasms, CNS tumor, Primary CNS tumor, Cancer of Colon, Cancer of the Colon, Colon Cancer, Colon Neoplasms, Colonic Cancer, Neoplasms, Colonic, Malignant tumor of Breast, Mammary Cancer, Mammary Carcinoma, Human, Mammary Neoplasm, Human, Neoplasms, Breast, Tumors, Breast, Human Mammary Carcinoma, Malignant Neoplasm of Breast, Breast Carcinoma, Breast Tumors, Cancer of the Breast, Breast Neoplasms, Breast Cancer, RET Inhibitor, MTC, NSCLC, selpercatinib, neo-adjuvant treatment in early stage NSCLC
Main Study Up to 100 subjects, both non-CF volunteers and Cystic Fibrosis (CF) patients, will
participate in a single study visit that will include a DEXA scan, micro CT, and blood
collection.
Denosumab (Prolia) Sub study Approximately 10 adult subjects with CF who participated in the
main study and have results indicating bone disease will receive treatment with Denosumab for
up to 5 years. They will be asked to return annually for repeat DEXA scans, micro CT, and
blood collection.
• Must have CF diagnosis confirmed by sweat test or genotype analysis
• Subjects (and parents/legal guardians as applicable) must have the ability to read and
write in English
Sub-study
Exclusion Criteria:
• No CF diagnosis
• Men or women without osteoporosis
• Less than 18 years of age
• Unwilling to return annually for study visits for up to 5 years
• Unwilling and/or medically unable to take denosumab
• Stratum I
• Patients must be less than 18 years of age at the time of diagnosis.
• Patients must have histological verification of the diagnosis of Langerhans cell
histiocytosis according to the criteria described in Section 6.1
• Signed informed consent form
• Stratum II
• Patients of Stratum I who have:
• Progressive disease (AD worse) in non-risk organs after 6 weeks (Initial Course
• AD intermediate or worse in non-risk organs or AD better in risk organs after 12
weeks (Initial Course 2)
• Disease progression (AD worse) in non-risk organs at any time during continuation
treatment
• Active disease at the end of Stratum I treatment
• Disease reactivation in non-risk organs at any time after completion of Stratum I
treatment
• Stratum III
• Patients from Stratum I who fulfill the following criteria:
• AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD
intermediate in risk organs after week 12 (after Initial Course 2).
• Presence of unequivocally severe organ dysfunction at the above mentioned
evaluation points (hematological dysfunction, liver dysfunction, or both of them)
as
• Hb <70 g/L (<7.0 g/dl) and/or transfusion dependency
• PLT <20 x109/L (20,000/μL) and/or transfusion dependency (both criteria have
to be fulfilled) AND/OR
• Liver dysfunction (or digestive involvement with protein loss)
• Total protein <55 g/L or substitution dependency
• Albumin <25 g/L or substitution dependency (at least one of the two criteria
to be fulfilled)
• Stratum IV
• Patients from Stratum I or Stratum III who fulfill the following criteria:
• AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD
intermediate in risk organs after week 12 (after Initial Course 2) of Stratum I
OR
• AD worse after the 2nd and 3rd 2-CdA/Ara-C course, and those AD worse or AD
intermediate after the 4th 2-CdA/Ara-C course of Stratum III AND
• Presence of unequivocally severe organ dysfunction at the above mentioned
evaluation points (hematological dysfunction, liver dysfunction, or both of them)
as defined in Table XI (see Section 10.3.1).
• Informed consent: All patients or their legal guardians (if the patient is <18
years of age) must sign an Ethics or institutional Review Board approved consent
form indicating their awareness of the investigational nature and the risks of
this study. When appropriate, younger patients will be included in all
discussions in order to obtain assent.
• Adequate organ function: Patients should have adequate hepatic, renal, cardiac
and pulmonary function to undergo reduced intensity HCT based upon local
institutional guidelines, or at a minimum meet requirements noted in eligibility
checklist Appendix A-VIII_1. However, significant hepatic and pulmonary
dysfunction, if secondary to underlying LCH disease activity, will not exclude
patients from protocol enrollment and should be discussed with the National PI
Coordinator and the Coordinating Principal Investigator.
• Stratum V
• All patients with verified diagnosis of LCH and MRI findings consistent with
ND-CNSLCH irrespective of previous treatments (also those not registered to other
Strata ofLCH-IV).
• Patients with isolated tumorous CNS-LCH (including isolated DI with mass lesion
in the hypothalamus-pituitary axis). In patients with already established
diagnosis of LCH and radiologic finding of CNS lesions compatible with LCH, a
biopsy of the lesion is not obligatory. In all other cases a biopsy of the lesion
is needed for inclusion into the study
• Stratum VI
-- Patients with newly diagnosed SS-LCH and localization other than "multifocal
bone",isolated tumorous CNS lesion, or isolated "CNS-risk" lesion.
• Stratum VII -- All patients registered in LCH IV (regardless of treatment) as long as
consent for longterm follow-up has not been withheld.
Exclusion Criteria:
• Stratum I
• Pregnancy (patients of child-bearing age must be appropriately tested before
chemotherapy)
• LCH-related permanent consequences (e.g. vertebra plana, sclerosing cholangitis,
lung fibrosis, etc.) in the absence of active disease
• Prior systemic therapy
• Stratum II
• Patients with progressive disease in risk organs
• Permanent consequences (e.g. sclerosing cholangitis, lung fibrosis, etc.) without
evidence of active LCH in the same organ or in any other locations
• No written consent of the patient or his/her parents or legal guardian
• Stratum III
• The presence of any of the following criteria will exclude the patient from the
study:
• Isolated sclerosing cholangitis without evidence of active hepatic LCH as the
only evidence of risk organ involvement.
• Inadequate renal function as defined by serum creatinine > 3x normal for age
• Stratum IV
• Pulmonary failure (requiring mechanical ventilation) not due to active LCH.
• Isolated liver sclerosis or pulmonary fibrosis, without active LCH.
• Uncontrolled active life-threatening infection.
• Decreased renal function with a GFR of less than 50ml/1.73m2/min.
• Pregnancy or active breast feeding
• Failure to provide signed informed consent
• Stratum VI
• Patients with SS-LCH who have an isolated tumorous CNS lesion (they are eligible
for Stratum V),
• Patients with isolated "CNS-risk" or multifocal bone lesions (they are eligible
for Stratum I, Group 2)
Safety and Efficacy Study of IMSA101 in Refractory Malignancies
Open-label, dose escalation (Phase I) and dose expansion (Phase IIA) study of patients
receiving intra-tumoral IMSA101 alone or in combination with an immune checkpoint inhibitor
(ICI) (Phase I and II)
1. Signed informed consent and mental capability to understand the informed consent
2. Male or female patients > 18 years of age
3. Histologically or cytologically documented locally advanced or metastatic solid tumor
malignancies refractory to or otherwise ineligible for treatment with standard-of-care
agents/regimens, including but not limited to:
• Malignant melanoma
• Hormone receptor negative breast cancer
• Gastro-esophageal cancer
• Non-small cell lung cancer
• Head and neck cancer
• Hepatoma
• Renal cell carcinoma
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
5. Evaluable or measurable disease as follows:
• A minimum of 3 RECIST-evaluable lesions: one that is suitable for injection and
biopsied; one non-injected that will be biopsied for abscopal effect; and one
measurable lesion that will be followed for response only.
• Injectable tumors shall be accessed by intralesional (cutaneous) or percutaneous
injection only, including those lesions that are visible, palpable, or detectable
by standard radiographic or ultrasound methods. Neither surgical procedures nor
endoscopically-guided injections including those to endobronchial, endoluminal,
or endosinusial spaces shall be allowed. While no anatomic locations are required
or disallowed, lesions selected for intratumoral injection must, in the opinion
of the investigator:
• Not be immediately adjacent to blood vasculature or other physiologic landmarks
in such a way that will accrue undue safety risk to the patient
• Have longest diameter ≥ 10 mm and ≤ 50 mm
• Be fully efficacy evaluable per RECIST v1.1 criteria
6. Life expectancy > 3 months (Phase I) and > 6 months (Phase IIA)
7. ECG without evidence of clinically meaningful conduction abnormalities or active
ischemia as determined by the investigator
8. Acceptable organ and marrow function as defined below:
• Absolute neutrophil count > 1,500 cells/μL
• Platelets > 50,000 cells/μL
• Total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine transaminase (ALT) ≤ 2.5 times ULN. If
liver metastases are present, AST/ALT < 5 times ULN
• Serum creatinine < 1.5 mg/dL and a measured creatinine clearance ≥ 50 mL/min
using the Cockcroft-Gault formula
• Prothrombin time (PT)/partial thromboplastin time (PTT) ≤ 1.5 times ULN
9. Women of child-bearing potential (defined as a female who has experienced menarche and
who has not undergone successful surgical sterilization (hysterectomy, bilateral
salpingectomy, or bilateral oophorectomy) or is not postmenopausal (defined as
amenorrhea for at least 12 consecutive months with an appropriate clinical profile at
the appropriate age, e.g., greater than 45 years) must have a negative serum pregnancy
test prior to first dose of study drug
10. Male and female patients with reproductive potential must agree to use two forms of
highly effective contraception throughout the study
11. Phase I combination only: Demonstrated RECIST stable disease through ≥ 4 consecutive
cycles of an approved PD-1 or PD-L1 targeted ICI with no Grade ≥ 3 CTCAE events
considered by the investigator to be drug-related.
Exclusion Criteria:
1. Anti-cancer therapy within 4 weeks or < 5 half-lives of the first dose of study drug.
2. Failure to recover to Grade 1 or less from clinically significant AEs due to prior
anti-cancer therapy.
3. Known untreated brain metastases or treated brain metastases that have not been stable
(scan showing no worsening of central nervous system (CNS) lesion[s] and no
requirement of corticosteroids) ≥ 4 weeks prior to study enrollment
4. Baseline prolongation of QT/QTc interval (QTc interval > 470)
5. Uncontrolled intercurrent illness (including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations) that in opinion of the
investigator would limit compliance with study requirements
6. Women who are pregnant or breastfeeding
7. Phase I combination only: Prior tumor progression through PD-1 or PD-L1 targeted ICI
therapy.
Best Available Therapy Versus Autologous Hematopoetic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS) (BEAT-MS)
This is a multi-center prospective rater-masked (blinded) randomized controlled trial of 156
participants, comparing the treatment strategy of Autologous Hematopoietic Stem Cell
Transplantation (AHSCT) to the treatment strategy of Best Available Therapy (BAT) for
treatment-resistant relapsing multiple sclerosis (MS). Participants will be randomized at a 1
to 1 (1:1) ratio.
All participants will be followed for 72 months after randomization (Day 0, Visit 0).
Participant(s) must meet all of the following criteria to be eligible for this study:
1. Diagnosis of Multiple Sclerosis (MS) according to the 2017 McDonald Criteria
2. (Kurtzke) Expanded Disability Status Scale (EDSS) ≤ 6.0 at the time of randomization
(Day 0)
3. T2 abnormalities on brain Magnetic Resonance Imaging (MRI) that fulfill the 2017
McDonald MRI criteria for dissemination in space
--A detailed MRI report or MRI images must be available for review by the site
neurology investigator.
4. Highly active treatment-resistant relapsing MS, defined as ≥ 2 episodes of disease
activity in the 36 months prior to the screening visit (Visit -2). The two disease
activity episodes will be a clinical MS relapse or MRI evidence of MS disease activity
and must meet all the criteria as described below:
1. At least one episode of disease activity must occur following ≥ 1 month of
treatment with an oral DMT approved by the FDA or MHRA for the treatment of
relapsing MS, or a monoclonal antibody, specifically: dimethyl fumarate
(Tecfidera®), diroximel fumarate, teriflunomide (Aubagio®), cladribine
(Mavenclad®), daclizumab (Zinbryta®), siponimod (Mayzent®), ozanimod, fingolimod
(Gilenya®), rituximab (Rituxan®), ocrelizumab (Ocrevus®), natalizumab (Tysabri®),
alemtuzumab (Campath®, Lemtrada®), or ofatumumab (Arzerra®), and
2. At least one episode of disease activity must have occurred within the 12 months
prior to the screening visit (Visit -2), and
3. At least one episode of disease activity must be a clinical MS relapse (see item
c.i. below). The other episode(s) must occur at least one month before or after
the onset of the clinical MS relapse, and must be either another clinical
MS relapse or MRI evidence of disease activity (see item d.ii. below):
i. Clinical MS relapse must be confirmed by a neurologist's assessment and documented
contemporaneously in the medical record. If the clinical MS relapse is not documented
in the medical record, it must be approved by the study adjudication committee, and
ii. MRI evidence of disease activity must include ≥ 2 unique active lesions on a brain
or spinal cord MRI. A detailed MRI report or MRI images must be available for review
by the site neurology investigator. A unique active lesion is defined as either of the
following:
• A gadolinium-enhancing lesion, or
• A new non-enhancing T2 lesion compared to a reference scan obtained not more than
24 months prior to the screening visit (Visit -2).
5. Candidacy for treatment with at least one of the following high efficacy DMTs:
Cladribine, natalizumab, alemtuzumab, ocrelizumab, rituximab, and ofatumumab (after
approval by the FDA for relapsing MS). Candidacy for treatment for each DMT is defined
as meeting all of the following:
• No prior disease activity with the candidate DMT, and
• No contraindication to the candidate DMT, and
• No treatment with the candidate DMT in the 12 months prior to screening.
6. Completion of SARS-CoV-2 vaccination series ≥ 14 days prior to randomization (Day 0).
7. Positive for VZV antibodies, or completion of at least one dose of the varicella
zoster glycoprotein E (gE) Shingrix vaccine at least 4 weeks prior to randomization
(Day 0).
8. Insurance or public funding approval for MS treatment with at least one candidate DMT,
and
9. Ability to comply with study procedures and provide informed consent, in the opinion
of the investigator.
Exclusion Criteria:
Subject(s) who meet any of the following criteria will not be eligible for this study:
1. Diagnosis of primary progressive Multiple Sclerosis (MS) according to the 2017
McDonald criteria
2. History of neuromyelitis optica or anti-myelin oligodendrocyte glycoprotein (anti-MOG)
antibodies associated encephalomyelitis
3. Prior treatment with an investigational agent within 3 months or 5 half-lives,
whichever is longer. Agents authorized by the FDA or MHRA for prevention or treatment
of SARS-CoV-2 are not considered investigational.
4. Either of the following within one month prior to randomization (Day 0):
1. Onset of acute MS relapse, or
2. Treatment with intravenous methylprednisolone 1000 mg/day for 3 days or
equivalent.
5. Initiation of natalizumab, alemtuzumab, ocrelizumab, or rituximab between screening
visit (Visit -2) and randomization (Day 0)
6. Brain MRI or Cerebrospinal fluid (CSF) examination indicating a diagnosis of
progressive multifocal leukoencephalopathy (PML)
7. History of cytopenia consistent with the diagnosis of myelodysplastic syndrome (MDS)
8. Presence of unexplained cytopenia, polycythemia, thrombocythemia or leukocytosis
9. History of sickle cell anemia or other hemoglobinopathy
10. Evidence of past or current hepatitis B or hepatitis C infection, including treated
hepatitis B or hepatitis C
-Note: Hepatitis B surface antibody following hepatitis B immunization is not
considered to be evidence of past infection.
11. Presence or history of mild to severe cirrhosis
12. Hepatic disease with the presence of either of the following:
1. Total bilirubin ≥ 1.5 times the upper limit of normal (ULN) or total bilirubin
• 3.0 times the ULN in the presence of Gilbert's syndrome, or
2. Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) ≥ 2.0 times
the ULN.
13. Positive SARS-CoV-2 PCR test, or alternative nucleic acid amplification test (NAAT)
per institutional standards, within 14 days prior to randomization (Day 0).
14. Evidence of HIV infection
15. Positive QuantiFERON •TB Gold, TB Gold Plus, or T-SPOT®.TB test results (e.g., blood
test results. Purified Protein Derivative (PPD) tuberculin test may be substituted for
QuantiFERON •TB Gold, TB Gold Plus, or T-SPOT®.TB test results.
16. Active viral, bacterial, endoparasitic, or opportunistic infections
17. Active invasive fungal infection
18. Hospitalization for treatment of infections or parenteral (IV or IM) antibacterials,
antivirals, antifungals, or antiparasitic agents within the 30 days prior to
randomization (Day 0) unless clearance is obtained from an Infectious Disease
specialist
19. Receipt of live or live-attenuated vaccines within 6 weeks of randomization (Day 0)
20. Presence or history of clinically significant cardiac disease including:
1. Arrhythmia requiring treatment with any antiarrhythmia therapy, with the
exception of low dose beta blocker for intermittent premature ventricular
contractions
2. Coronary artery disease with a documented diagnosis of either:
• Chronic exertional angina, or
• Signs or symptoms of congestive heart failure.
3. Evidence of heart valve disease, including any of the following:
• Moderate to severe valve stenosis or insufficiency,
• Symptomatic mitral valve prolapse, or
• Presence of prosthetic mitral or aortic valve.
21. Left ventricular ejection fraction (LVEF) < 50%
22. Impaired renal function defined as Estimated glomerular filtration rate (eGFR) < 60
mL/min/1.73 m^2 according to the Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) formula
23. Forced expiratory volume in one second (FEV1) <70% predicted (no bronchodilator)
24. Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for Hgb) < 70%
predicted
25. Poorly controlled diabetes mellitus, defined as HbA1c >8%
26. History of malignancy, with the exception of adequately treated localized basal cell
or squamous skin cancer, or carcinoma in situ of the cervix.
-Note:Malignancies for which the participant is judged to be cured prior to
randomization (Day 0) will be considered on an individual basis by the study
adjudication committee.
27. Presence or history of any moderate to severe rheumatologic autoimmune disease
requiring treatment, including but not limited to the following:
• systemic lupus erythematous
• systemic sclerosis
• rheumatoid arthritis
• Sjögren's syndrome
• polymyositis
• dermatomyositis
• mixed connective tissue disease
• polymyalgia rheumatica
• polychondritis
• sarcoidosis
• vasculitis syndromes, or
• unspecified collagen vascular disease.
28. Presence of active peptic ulcer disease, defined as endoscopic or radiologic diagnosis
of gastric or duodenal ulcer
29. Prior history of AHSCT
30. Prior history of solid organ transplantation
31. Positive pregnancy test or breast-feeding
32. Inability or unwillingness to use effective means of birth control
33. Failure to willingly accept or comprehend irreversible sterility as a side effect of
therapy
34. Psychiatric illness, mental deficiency, or cognitive dysfunction severe enough to
interfere with compliance or informed consent
35. History of hypersensitivity to mouse, rabbit, or Escherichia coli-derived proteins
36. Any metallic material or electronic device in the body, or condition that precludes
the participant from undergoing MRI with gadolinium administration
37. Presence or history of ischemic cerebrovascular disorders, including but not limited
to transient ischemic attack, subarachnoid hemorrhage, cerebral thrombosis, cerebral
embolism, or cerebral hemorrhage
38. Presence or history of other neurological disorders, including but not limited to:
• central nervous system (CNS) or spinal cord tumor
• metabolic or infectious cause of myelopathy
• genetically-inherited progressive CNS disorder
• CNS sarcoidosis, or
• systemic autoimmune disorders potentially causing progressive neurologic disease
or affecting ability to perform the study assessments.
39. Presence of any medical comorbidity that the investigator determines will
significantly increase the risk of treatment mortality, or
40. Presence of any other concomitant medical condition that the investigator deems
incompatible with trial participation.
Procedure: Autologous Hematopoietic Stem Cell Transplantation, Biological: Best Available Therapy (BAT)
Durvalumab vs Placebo Following Stereotactic Body Radiation Therapy in Early Stage Non-small Cell Lung Cancer Patients (PACIFIC-4)
This is a Phase III, randomized, placebo-controlled, double-blind, multi-center study
assessing the efficacy and safety of durvalumab versus placebo following SoC SBRT in patients
with unresected clinical Stage I/II lymph node-negative (T1 to T3N0M0) NSCLC.
1. Age ≥18 years
2. Histologically or cytologically documented Stage I to II NSCLC, with clinical Stage
I/II lymph node-negative (T1 to T3N0M0) disease and planned to receive definitive
treatment with SBRT. Patients may be medically inoperable or are medically operable
and refusing surgery or choosing to have SBRT (Stereotactic Body Radiation Therapy) as
definitive therapy
3. Completion of SoC SBRT as definitive treatment prior to randomization
4. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) PS of 0, 1,
or 2
5. Life expectancy of at least 12 weeks
6. Body weight >30 kg
7. Tumor sample required
8. Adequate organ and marrow function required
9. Patients with central or peripheral lesions are eligible
10. Staging studies must be done within 8 weeks before randomization
Key
Exclusion Criteria:
1. Mixed small cell and non-small cell cancer histology
2. History of allogeneic organ transplantation
3. History of another primary malignancy with exceptions
4. History of active primary immunodeficiency
5. Any unresolved toxicity National Cancer Institute (NCI) CTCAE Grade ≥2 from SBRT
(Stereotactic Body Radiation Therapy)
Drug: Durvalumab, Other: Placebo
Carcinoma, Non-Small-Cell Lung, Lung/Thoracic
NSCLC, Double- Blind, PD-L1, MEDI4736, Durvalumab, PFS, OS
UT Southwestern; Parkland Health & Hospital System
The primary objective of the Phase 1 part of the study is to determine the recommended dose
of APVO436 administered intravenously to patients with AML or MDS. The primary objective of
the Phase 1b part of the study is to evaluate the clinical activity of APVO436 in patients
with AML or MDS.
APVO436 is being studied in this Phase 1b, open-label, multi-center, two-part
dose-escalation/dose expansion study to evaluate the safety, pharmacokinetic/pharmacodynamic
(PK/PD), and clinical activity of APVO436 in patients with AML and MDS. The study will be
conducted in 2 parts. The first part of this Phase 1B study is an open-label, multiple dose
ascending dose escalation phase to determine the recommended dose (RP2D) level of APVO436 for
future Phase 2 studies. The goal of the dose expansion phase of the study (Part 2) is to (i)
evaluate the safety and tolerability of APVO436 at the RP2D level when it is used as an
adjunct to the standard of care and (ii) obtain a preliminary assessment of the anti-leukemia
activity of APVO436-containing experimental monotherapy and combination therapy modalities.
Study Objectives for Dose Escalation Phase
- Primary Objectives are to:
1. Determine the RP2D level of APVO436 administered intravenously (IV) in patients
with AML or MDS, and
2. Evaluate the safety and tolerability of APVO436 at the RP2D level when it is used
as an adjunct to the standard of care and obtain a preliminary assessment of the
anti-leukemia activity of APVO436-containing experimental monotherapy and
combination therapy modalities.
- Secondary Objectives are to:
1. Define the safety profile and immunogenicity of APVO436; to determine the PK/PD of
APVO436; to evaluate the clinical activity of APVO436 in AML and MDS patients.
2. Further evaluate the safety profile and immunogenicity of APVO436 and the PK/PD of
APVO436 and the relationship between PK/PD and clinical response.
Study Objectives for Dose Expansion Phase
- Primary Objective is to evaluate the safety and tolerability of APVO436 at the RP2D
level when it is used as an adjunct to the standard of care.
- Secondary Objective is to obtain a preliminary assessment of the anti-leukemia activity
of APVO436-containing experimental monotherapy and combination therapy modalities.
Inclusion Criteria for Part 1: Dose Escalation Phase:
All patients must meet the following criteria prior to the first dose of study drug:
1. Signed informed consent. Consent must be obtained prior to any study-related
procedure.
2. Age ≥ 18 years
3. Histologically confirmed AML or MDS:
1. AML •relapsed or refractory AML and refuses or is not a candidate for intensive
chemotherapy (due to prior failure or not eligible due to expected intolerance)
or allogeneic transplant
2. MDS •relapsed or refractory MDS with > 5% blasts in the marrow or any blasts in
the peripheral blood. Patients must have failed prior treatment with an HMA
(azacitidine, decitabine, or other HMA agent); failure is defined as intolerance
to HMA, lack of response (no CR by at least 6 cycles), or have IWG-defined
progressive disease during or after treatment with an HMA.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
5. Life expectancy of > 2 months in the Investigator's opinion
6. White blood cells (WBC) ≤ 25,000 cells/mm3 (may receive hydroxyurea to bring WBC count
down prior to and during the first cycle of treatment with study drug if necessary)
7. Creatinine ≤ 2 × upper limit of normal (ULN)
8. Adequate liver test parameters: total bilirubin < 2.5 × ULN (if disease related or
secondary to Gilbert's disease, then total bilirubin < 3.5 mg/dL), aspartate
aminotransferase (AST), and alanine aminotransferase (ALT) < 3 × ULN
9. Prothrombin time (PT) / international normalized ratio (INR) and partial
thromboplastin time (PTT) < 1.5 × ULN
10. Patients and partners of childbearing potential must be willing to use adequate
contraception during the study and for 2 months after last study drug administration.
Adequate contraception means less than 1% chance of pregnancy may occur with proper
use of the method(s).
Exclusion Criteria for Part 1: Dose Escalation Phase:
A patient is not eligible to enroll into the study if they have any of the following:
1. Any CNS (cerebral/meningeal) disease related to underlying malignancy
2. History of seizures
3. Acute promyelocytic leukemia
4. Prior anti-CD123 therapy outside of this study
5. Any clinically significant graft-versus-host disease (GVHD) secondary to prior
allogenic transplant. Patients must be > 90 days from transplant and have been on no
immunosuppressive therapy for > 30 days. Topical corticosteroids for minor skin rash
(<5% body surface area) is acceptable. Prior solid organ transplant is acceptable
provided the patient is on no immunosuppressive therapy.
6. Any therapy or experimental treatment for MDS or AML within 7 days of the first dose
of study drug. Must have recovered to Grade ≤ 1 from any Grade 2 to 4 toxicity from
previous treatment. The use of hydroxyurea is acceptable and does not exclude the
patient.
7. Active, uncontrolled infection requiring systemic therapy. If the infection is
controlled or has resolved, maintenance and/or prophylactic systemic antimicrobials
are permitted.
8. Major surgery within 3 weeks prior to first dose of study drug
9. Known to be positive for HIV, hepatitis B virus surface antigen (HBsAg), hepatitis B
core antibody (HBcAb), or hepatitis C virus (HCV)
10. Pregnant or breast feeding
11. Any other active systemic malignancies. Exceptions: noninvasive non-melanoma skin
cancer, in situ carcinoma, cervical intraepithelial neoplasia, and breast or prostate
cancer that is well controlled with anti-hormonal therapy
12. Any current autoimmune disorder requiring immunosuppressive therapy
13. Requires more than a replacement dose of corticosteroids (i.e., > 10 mg/day of
prednisone or equivalent)
14. Any uncontrolled medical condition, including but not limited to:
1. Symptomatic congestive heart failure ≥ Class III (New York Heart Association
Functional Classification)
2. Uncontrolled hypertension
3. Unstable angina
4. Myocardial infarction within previous 6 months
5. Clinically significant arrhythmias not controlled by medication
6. Uncontrolled metabolic disorders such as hypercalcemia
15. Substance use disorder, psychiatric, cognitive, or any other condition that, in the
opinion of the Investigator, would pose a risk to the patient's safety, may compromise
the patient's ability to understand and comply with the protocol or provide informed
consent, or interfere with the study evaluation
16. Any difficulty complying with protocol requirements that may increase the risk
associated with study participation or study drug administration, or may cause a
safety concern for the patient
Inclusion Criteria for Part 2: Dose Expansion Phase
Individuals eligible to participate in this study must meet all of the following:
All patients must meet the following criteria prior to the first dose of study drug:
1. Signed informed consent. Consent must be obtained prior to any study-related
procedure.
2. Age: >18 years
3. Histologically confirmed AML: Subjects must have de novo (primary) AML (any WHO 2016
classification excluding acute promyelocytic leukemia, AML with myelodysplasia-related
features, and Therapy-related secondary AML (except in Cohort 1 or Cohort 2)
4. Cohort 1: Fit primary or secondary AML patients (Age: >18 years) in 1st or 2nd relapse
with last CR <1 year or primary refractory disease; Relapsed patients must have
relapsed a maximum of two times after standard induction therapy for AML;
5. Cohort 2: Poor prognostic but fit primary or secondary AML patients who are
treatment-naïve or in 1st relapse; patients in relapse must have relapsed only once
after induction/consolidation therapy for AML, i.e., they must be in 1st relapse
6. Cohort 3: Fit primary AML patients with FLT3-negative intermediate or adverse risk AML
(including but not limited to: TP53, RUNX1 and ASXL1 mutations and/or complex
cytogenetics) who are treatment-naïve or in 1st relapse with a duration of CR1<1 year
7. Cohort 3: Patients are required to be either not in CR or be in CR is MRD positive
(≥01% level) by MFC (Central Laboratory) post induction/consolidation to be eligible
for APVO436 treatments.
8. Cohort 4: MRD+ (at ≥0.1% level by multicolor-multiparameter flow cytometry [MFC] in
Central Lab) high-risk 1st remission AML patients
9. Cohort 4: Patients must be newly diagnosed AML patients in 1st remission who achieved
their first remission after standard chemotherapy with a standard induction regimen
with or without post-induction consolidation.
10. Cohort 5: Patients must be AML patients who were in 1st relapse and achieved a 2nd
remission after standard chemotherapy with a standard induction regimen with or
without post-induction consolidation.
11. Cohorts 1-5: If patient was treated with Cytarabine-containing induction or
consolidation regimen, a minimum of 21 days must have passed since the last Cytarabine
dose to allow for resolution of the side effects
12. Cohorts 1-3: Patients must have CD123-positive AML as confirmed by flow cytometry in
Central Laboratory
13. Cohorts 4 and 5: Patients archived bone marrow or peripheral blood leukemic blast
cells must be CD123-positive •local laboratory results are acceptable. If cells are
available, the positivity should be confirmed by Central Laboratory.
14. Patients with precedent MDS are not eligible
15. MRD+ AML patients in Cohort 4 or Cohort 5 must be in CR (CR/CRi) for no more than 6
months and be MRD+, as determined by central hematopathology laboratory
16. MRD+ AML patients in Cohort 4 or Cohort 5 must first have an evaluable screening bone
marrow sample confirmed as MRD+ by central hematopathology laboratory
17. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
18. Life expectancy of > 2 months in the Investigator's opinion
19. Creatinine ≤ 2 × upper limit of normal (ULN)
20. Adequate liver test parameters: total bilirubin < 2.5 × ULN (if disease related or
secondary to Gilbert's disease, then total bilirubin < 3.5 mg/dL), aspartate
aminotransferase (AST), and alanine aminotransferase (ALT) < 3 × ULN
21. Prothrombin time (PT) / international normalized ratio (INR) and partial
thromboplastin time (PTT) < 1.5 × ULN
22. Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically
sterile) may participate, provided they meet the following conditions:
1. Must agree to use physician-approved contraceptive methods (e.g., abstinence,
intrauterine device, oral contraceptive, double barrier device) throughout the
study and for 3 months following the last dose of APVO436; and
2. Must have a negative serum or urine pregnancy test within 7 days prior to
beginning treatment on this study.
23. Males with female partners of child-bearing potential must agree to use
physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy)
throughout the study and should avoid conceiving children for 3 months following the
last dose of APVO436
Exclusion Criteria for Part 2: Dose Expansion Phase
Subjects with any of the following will not be eligible for study participation:
1. Acute promyelocytic leukemia (APL) with t(15;17) translocation
2. Absolute peripheral blood myeloblast count greater than 20,000/mm3 •may receive
hydroxyurea to reduce and control the myeloblast count down prior to and during the
first week of the first cycle of treatment with study drug if necessary if deemed
medically necessary and appropriate by the treating physician
3. Patients with active central nervous system (CNS) involvement by AML will be excluded.
A lumbar puncture does not need to be performed unless there is clinical suspicion of
CNS involvement per investigator judgement. Concurrent therapy for CNS prophylaxis or
continuation of therapy for controlled CNS AML is allowed with the approval of the
sponsor.
4. History of seizures
5. Prior anti-CD123 therapy with APVO436; prior anti-CD123 therapy with bispecific
antibodies, recombinant fusion proteins or antibody-drug conjugates is allowed.
6. Prior allogeneic, unrelated or autologous hematopoietic stem cell transplantation is
allowed only in Cohort 5. The transplant must have been performed more than 100 days
before the date of dosing on this study without any Grade ≥2 graft-versus-host disease
(GVHD) secondary to prior allogenic transplant. Patients must be > 100 days from
transplant and have been on no immunosuppressive therapy for > 30 days. Topical
corticosteroids for minor skin rash (<5% body surface area) is acceptable.
7. Prior allogeneic, unrelated or autologous hematopoietic stem cell transplantation is
not allowed for Cohorts 1 to 4
8. Prior solid organ transplant is acceptable provided the patient is on no
immunosuppressive therapy.
9. Any therapy or experimental treatment for AML within 7 days of the first dose of study
drug. Must have recovered to Grade ≤ 1 from any Grade 2 to 4 toxicity from previous
treatment. The use of hydroxyurea is acceptable and does not exclude the patient.
10. Active, uncontrolled infection requiring systemic therapy. If the infection is
controlled or has resolved, maintenance and/or prophylactic systemic antimicrobials
are permitted.
11. Major surgery within 3 weeks prior to first dose of study drug
12. Known to be positive for HIV, hepatitis B virus surface antigen (HBsAg), hepatitis B
core antibody (HBcAb), or hepatitis C virus (HCV)
13. Uncontrolled hypertension, defined as blood pressure ≥ 140/90 mm Hg despite maximum
medical intervention
14. History of congenital long QT syndrome or torsades de pointes
15. Pathologic bradycardia or heart block (excluding first degree heart block)
16. Prolonged baseline QTc, defined as QTcF (Fredericia correction) interval >480 msec
(including subjects with a bundle branch block)
17. History of ventricular arrhythmia (excluding PVCs)
18. Major surgery within 28 days prior to informed consent
19. Unstable angina pectoris within 28 days
20. Myocardial infarction and/or new ST elevation or depression or new Q wave on ECG
within 6 months
21. Any history of stroke
22. Symptomatic congestive heart failure Class III or greater (New York Heart Association
Functional Classification)
23. On full dose anti-coagulation defined as warfarin intended to raise the INR to 2-3
24. Major hemorrhagic event within 28 days requiring transfusion of packed red blood cells
25. Prior history of hypertensive crisis or hypertensive encephalopathy
26. Clinical evidence suggestive of central nervous system (CNS) involvement with leukemia
unless a lumbar puncture was performed to confirm the absence of leukemic blasts in
the cerebrospinal fluid (CSF)
27. Systemic fungal, bacterial, viral, or other infection not controlled (defined as
exhibiting ongoing signs/symptoms related to the infection and without improvement,
despite appropriate antibiotics or other treatment)
28. Any open wound
29. Pregnant and nursing subjects are excluded because the effects of APVO436 on a fetus
or nursing child are unknown
30. Treatment with any anticancer therapy (standard or investigational) within the
previous 14 days prior to the first dose of study drug. In addition, subjects must
have fully recovered (NCI CTCAE Grade 1) from the clinically significant toxic effects
of that treatment. The use of hydroxyurea in subjects with rapidly proliferating
disease is allowed only during Cycle 1. Hydroxyurea is allowed prior to starting the
study, and may be used for two weeks after dosing in Cycle 1 (e.g., Days 1-14 dosed
with hydroxyurea)
31. Substance use disorder, psychiatric, cognitive, or any other condition that, in the
opinion of the Investigator, would pose a risk to the patient's safety, may compromise
the patient's ability to understand and comply with the protocol or provide informed
consent, or interfere with the study evaluation, study participation, or follow-up
32. Any difficulty complying with protocol requirements that may increase the risk
associated with study participation or study drug administration, or may cause a
safety concern for the patient
33. Any uncontrolled medical condition, including but not limited to:
1. Uncontrolled hypertension
2. Unstable angina
3. Clinically significant arrhythmias not controlled by medication
4. Uncontrolled metabolic disorders such as hypercalcemia
34. Any other active systemic malignancies. Exceptions: noninvasive non-melanoma skin
cancer, in situ carcinoma, cervical intraepithelial neoplasia, and breast or prostate
cancer that is well controlled with anti-hormonal therapy
35. Any current autoimmune disorder requiring immunosuppressive therapy with more than a
replacement dose of corticosteroids (i.e., > 10 mg/day of prednisone or equivalent)
Dabrafenib Combined With Trametinib After Radiation Therapy in Treating Patients With Newly-Diagnosed High-Grade Glioma
This phase II trial studies how well the combination of dabrafenib and trametinib works after
radiation therapy in children and young adults with high grade glioma who have a genetic
change called BRAF V600 mutation. Radiation therapy uses high energy rays to kill tumor cells
and reduce the size of tumors. Dabrafenib and trametinib may stop the growth of tumor cells
by blocking BRAF and MEK, respectively, which are enzymes that tumor cells need for their
growth. Giving dabrafenib with trametinib after radiation therapy may work better than
treatments used in the past in patients with newly-diagnosed BRAF V600-mutant high-grade
glioma.
• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patients must be >= 12 months and =< 21
years of age at the time of enrollment on Step 0
• Note: This age range encompasses pre-screening for all HGG patients. Individual
treatment protocols may have different age criteria.
• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patient is suspected of having
localized newly-diagnosed HGG, excluding metastatic disease.
• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patient and/or their parents or legal
guardians have signed informed consent for eligibility screening on APEC14B1 Part A.
• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): The specimens obtained at the time of
diagnostic biopsy or surgery must be submitted through APEC14B1 as soon as possible
(ASAP), preferably within 5 calendar days of the procedure.
• Please note: See the APEC14B1 Manual of Procedures for a full list of detailed
instructions for submitting required materials and for shipping details.
• Patients must be >= 3 years and =< 21 years of age at the time of enrollment.
• Patients must have eligibility confirmed by Rapid Central Pathology and Molecular
Screening Reviews performed on APEC14B1
• Newly diagnosed high-grade glioma with BRAF^V600-mutation
• Results for H3 K27M by immunohistochemistry (IHC) or sequencing
• Histologically confirmed high-grade glioma (World Health Organization [WHO] grade
III or IV) including but not limited to: anaplastic astrocytoma (AA), anaplastic
pleomorphic xanthoastrocytoma (aPXA), anaplastic gangliogliomas (aGG),
glioblastoma (GB), and high-grade astrocytoma, not otherwise specified (NOS).
• Patients must have had histologic verification of a high-grade glioma diagnosis. CSF
cytology by lumbar puncture must be done if clinically indicated and determined to be
safe prior to study enrollment. If cytology proves positive, the patient would be
considered to have metastatic disease and would, therefore, be ineligible.
• A pre- and post-operative brain MRI with and without contrast and a baseline spine MRI
with contrast must be obtained prior to enrollment. The requirement for a
post-operative MRI is waived for patients who undergo biopsy only. If the spine MRI is
positive, the patient would be considered to have metastatic disease and would be
ineligible.
• Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age.
• Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to
enrollment).
• Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to
enrollment).
• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days
prior to enrollment).
• 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):
• Age 3 to < 6 years (Male 0.8 mg/dL, Female 0.8 mg/dL)
• Age 6 to < 10 years (Male 1 mg/dL, Female 1 mg/dL)
• Age 10 to < 13 years (Male 1.2 mg/dL, Female 1.2 mg/dL)
• Age 13 to < 16 years (Male 1.5 mg/dL, Female 1.4 mg/dL)
• Age >= 16 years (Male 1.7 mg/dL, Female 1.4 mg/dL)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to
enrollment), and
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135
U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN for
SGPT is 45 U/L.
• Patients with a seizure disorder may be enrolled if their seizures are well controlled
while on non-enzyme inducing anticonvulsants permitted on this study.
• All patients and/or their parents or legal guardians must sign a written informed
consent
• Patients must be enrolled and protocol therapy must be projected to begin no later
than 31 days after definitive surgery (day 0). If a biopsy only was performed, the
biopsy date will be considered the date of definitive surgery. For patients who have a
biopsy or incomplete resection at diagnosis followed by additional surgery, the date
of the last resection will be considered the date of definitive surgery.
Exclusion Criteria:
• Patients with intrinsic brainstem or primary spinal cord tumors will be excluded.
• Patients with metastatic disease (defined as neuraxis dissemination either by imaging
or by cytology) will be excluded.
• Patients must not have received any prior tumor-directed therapy including
chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant for the
treatment of HGG other than surgical intervention and/or corticosteroids.
• Previous treatment with dabrafenib or another RAF inhibitor, trametinib or another MEK
inhibitor, or an ERK inhibitor.
• Patients with a history of a malignancy with confirmed activating RAS mutation.
• History of allergic reactions attributed to compounds of similar chemical or biologic
composition to dabrafenib, trametinib, and their excipients.
• Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease,
or uncontrolled infection), psychological, familial, sociological, or geographical
conditions that do not permit compliance with the protocol; or unwillingness or
inability to follow the procedures required in the protocol.
• Presence of active gastrointestinal (GI) disease or other condition (e.g., small bowel
or large bowel resection) that will interfere significantly with the absorption of
drugs.
• History of hepatitis B virus, or hepatitis C virus infection (patients with laboratory
evidence of cleared hepatitis B virus and/or hepatitis C virus may be enrolled).
• History or current diagnosis of cardiac disease indicating significant risk of safety
for patients participating in the study such as uncontrolled or significant cardiac
disease, including any of the following:
• Recent myocardial infarction (within the last 6 months);
• Uncontrolled congestive heart failure;
• Unstable angina (within last 6 months);
• Clinically significant (symptomatic) or known, uncontrolled cardiac arrhythmias
(e.g., sustained ventricular tachycardia, and clinically significant second or
third degree atrioventricular [AV] block without a pacemaker) except sinus
arrhythmia within the past 24 weeks prior to the first dose of study treatment;
• Coronary angioplasty or stenting (within last 6 months);
• Intra-cardiac defibrillators;
• Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram.
• Patients with a history or current evidence of retinal vein occlusion (RVO) or central
serous retinopathy (CSR), or predisposing factors to RVO or CSR (e.g., uncontrolled
glaucoma or ocular hypertension).
• Patients with presence of interstitial lung disease or pneumonitis.
• Female patients who are pregnant are ineligible since there is yet no available
information regarding human fetal or teratogenic toxicities.
• Lactating females are not eligible unless they have agreed not to breastfeed their
infants for the duration of the study and for 4 months following discontinuation of
study therapy.
• Female patients of childbearing potential are not eligible unless a negative pregnancy
test result has been obtained.
• Sexually active patients of reproductive potential (male or female) are not eligible
unless they have agreed to use an effective contraceptive method for the duration of
their study participation and for 4 months following discontinuation of study therapy.
Male patients (including those who have had a vasectomy) taking dabrafenib and
trametinib combination therapy must use a condom during intercourse while on study and
for 16 weeks after stopping treatment, and should not father a child during these
periods. Women of childbearing potential should use effective non-hormonal
contraception during therapy and for 4 weeks following discontinuation of dabrafenib
and at least 4 months following the last dose of trametinib in patients taking
combination therapy. Women should be advised that dabrafenib may decrease the efficacy
of hormonal contraceptives and an alternate method of contraception, such as barrier
methods, should be used.
Study of Adjuvant Cemiplimab Versus Placebo After Surgery and Radiation Therapy in Patients With High Risk Cutaneous Squamous Cell Carcinoma
The primary objective of the study is to compare disease-free survival (DFS) of patients with
high-risk cutaneous squamous cell carcinoma (CSCC) treated with adjuvant cemiplimab, versus
those treated with placebo, after surgery and radiation therapy (RT).
The secondary objectives of the study are:
- To compare the overall survival (OS) of high-risk CSCC patients treated with adjuvant
cemiplimab, versus those treated with placebo, after surgery and RT
- To compare the effect of adjuvant cemiplimab with that of placebo on patients' freedom
from locoregional recurrence (FFLRR) after surgery and RT
- To compare the effect of adjuvant cemiplimab with that of placebo on patients' freedom
from distant recurrence (FFDR) after surgery and RT
- To compare the effect of adjuvant cemiplimab with that of placebo on the cumulative
incidence of second primary CSCC tumors (SPTs) after surgery and RT
- To evaluate the safety of adjuvant cemiplimab and that of placebo in high-risk CSCC
patients after surgery and RT
- To assess cemiplimab pharmacokinetics and immunogenicity in human serum
• For Japan only, men and women ≥21 years old
• Patient with resection of pathologically confirmed CSCC (primary CSCC lesion only, or
primary CSCC with nodal involvement, or CSCC nodal metastasis with known primary CSCC
lesion previously treated within the draining lymph node echelon), with macroscopic
gross resection of all disease
• High risk CSCC, as defined in the protocol
• Completion of curative intent post-operative radiation therapy (RT) within 2 to 10
weeks of randomization
• Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1
• Adequate hepatic, renal, and bone marrow function as defined in the protocol
Key
Exclusion Criteria:
• Squamous cell carcinomas (SCCs) arising in non-cutaneous sites as defined in the
protocol
• Concurrent malignancy other than localized CSCC and/or history of malignancy other
than localized CSCC within 3 years of date of randomization as defined in the protocol
• Patients with hematologic malignancies (note: patients with chronic lymphocytic
leukemia (CLL) are not excluded if they have not required systemic therapy for CLL
within 6 months of enrollment)
• Patients with history of distantly metastatic CSCC (visceral or distant nodal), unless
the disease-free interval is at least 3 years (regional nodal involvement of disease
in draining lymph node basin that was resected and radiated prior to enrollment will
not be exclusionary)
• Ongoing or recent (within 5 years of randomization date) evidence of significant
autoimmune disease that required treatment with systemic immunosuppressive treatments,
which may suggest risk for immune-related adverse events (irAEs). The following are
not exclusionary: vitiligo, childhood asthma that has resolved, type 1 diabetes,
residual hypothyroidism that required only hormone replacement, or psoriasis that does
not require systemic treatment.
• Has had prior systemic anti-cancer immunotherapy for CSCC
Note: Other protocol defined Inclusion/Exclusion criteria apply
A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1)
Phase 1 dose escalation will determine the first cycle dose-limiting toxicities (DLTs), the
maximum tolerated dose (MTD), the biologically effective dose and recommended Phase 2 dose
(RP2D) of repotrectinib given to adult subjects with advanced solid malignancies harboring an
ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
Midazolam DDI substudy will examine effect of of repotrectinib on CYP3A induction.
Phase 2 will determine the confirmed Overall Response Rate (ORR) as assessed by Blinded
Independent Central Review (BICR) of repotrectinib in each subject population expansion
cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene
rearrangement. The secondary objective will include the duration of response (DOR), time to
response (TTR), progression-free survival (PFS), overall survival (OS) and clinical benefit
rate (CBR) of repotrectinib in each expansion cohort of advanced solid tumors that harbor a
ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic
solid tumor (including primary CNS tumors) (Stage IV, American Joint Committee on
Cancer v.7) that harbors an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement by
protocol specified tests.
2. ECOG PS 0-1.
3. Age ≥18 (or age ≥ 20 of age as required by local regulation).
4. Capability to swallow capsules intact (without chewing, crushing, or opening).
5. At least 1 measurable target lesion according to RECIST version 1.1. CNS-only
measurable disease as defined by RECIST version 1.1 is allowed.
6. Prior cytotoxic chemotherapy is allowed.
7. Prior immunotherapy is allowed.
8. Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer
therapy to National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE) Version 4.03 Grade less than or equal to 1.
9. Patients with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic
leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol
specified criteria.
10. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils
count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L);
Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine
clearance Within normal limits or > 40 mL/min; Total serum bilirubin < 1.5 × ULN;
Liver transaminases (ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present
Alkaline phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are
present; Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or
without supplementation
11. Life expectancy ≥ 3 months.
PHASE 2 Key Inclusion Criteria
1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic
solid tumor (including primary CNS tumors) that harbors a ROS1, or NTRK1-3 gene
fusion.
2. Subject must have a documented ROS1 or NTRK1-3 gene fusion determined by tissue-based
local testing using either:
1. a next-generation sequencing (NGS) or quantitative polymerase chain reaction
(qPCR) test will be accepted to determine molecular eligibility.
• Adequate tumor tissue needs to be sent to the Sponsor designated central
diagnostic laboratory for retrospective confirmation by a central diagnostic
laboratory test selected by the Sponsor.
OR
2. a fluorescence in situ hybridization (FISH) test AND prospective confirmation of
fusion status by a central diagnostic laboratory test selected by the Sponsor
PRIOR to enrollment will be accepted to determine molecular eligibility.
• Adequate tumor tissue must be sent to the Sponsor designated central
diagnostic laboratory for prospective confirmation by a central diagnostic
laboratory test selected by the Sponsor PRIOR to enrollment.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
4. Age ≥12 (or age ≥ 20 as required by local regulation).
5. Willing and able to provide written institutional review board (IRB)/institutional
ethics committee-approved Informed Consent or an Assent signed by a parent or legal
guardian for subjects age 12 to 17.
6. At least 1 measurable target lesion according to RECIST (v1.1) prospectively confirmed
by Blinded Independent Central Radiology Review (BICR), selected by Sponsor, PRIOR to
enrollment. Subjects with CNS-only measurable disease ≥10 mm as defined by RECIST
(v1.1) are eligible.
7. Subjects with advanced solid tumors harboring ROS1, NTRK1, NTRK2, or NTRK3
rearrangement will be assigned into 6 distinct expansion (EXP) cohorts provided all
inclusion and exclusion criteria are met.
i. EXP-1: ROS1 TKI-naïve ROS1+ NSCLC ii. EXP-2: 1 Prior ROS1 TKI and 1 Platinum based
chemo ROS1+ NSCLC iii. EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (No Chemo or IO) iv.
EXP-4: 1 Prior ROS1 TKI ROS1+ NSCLC (No Chemo or IO) v. EXP-5: TRK TKI-naïve NTRK+
solid tumors vi. EXP-6: TRK TKI-pretreated NTRK+ solid tumors
8. Subjects with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic
leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol
specified criteria.
9. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils
count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L);
Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine
clearance > 40 mL/min; Total serum bilirubin < 1.5 × ULN; Liver transaminases
(ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present Alkaline
phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are present;
Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or without
supplementation
10. Life expectancy ≥ 3 months.
Key Exclusion Criteria PHASE 1 and PHASE 2
1. Concurrent participation in another therapeutic clinical trial.
2. Symptomatic brain metastases or leptomeningeal involvement.
3. History of previous cancer, except for squamous cell or basal-cell carcinoma of the
skin, or any in situ carcinoma that has been completely resected, requiring therapy
within the previous 2 years.
4. Major surgery within 4 weeks of start of repotrectinib treatment. Radiation therapy
(except palliative to relieve bone pain) within 2 weeks of study entry. Palliative
radiation (≤10 fractions) must have been completed at least 48 hours prior to study
entry
5. Clinically significant cardiovascular disease (either active or within 6 months prior
to enrollment): myocardial infarction, unstable angina, coronary/peripheral artery
bypass graft, symptomatic congestive heart failure (New York Heart Association
Classification Class ≥ II), cerebrovascular accident or transient ischemic attack,
symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac
dysrhythmias of NCI CTCAE grade ≥2
6. Any of the following cardiac criteria:
Mean resting corrected QT interval (ECG interval measured from the onset of the QRS
complex to the end of the T wave) for heart rate (QTcF) > 470 msec obtained from 3
ECGs, using the screening clinic ECG machine-derived QTc value Any clinically
important abnormalities in rhythm, conduction or morphology of resting ECG (e.g.,
complete left bundle branch block, third degree heart block, second degree heart
block, PR interval > 250 msec) Any factors that increase the risk of QTc prolongation
or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT
syndrome, family history of long QT syndrome, or any concomitant medication known to
prolong the QT interval.
7. Known active infections (bacterial, fungal, viral including HIV positivity).
8. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut
syndrome) or other malabsorption syndromes that would impact drug absorption.
9. Peripheral neuropathy of CTCAE ≥grade 2.
10. History of extensive, disseminated, bilateral, or presence of CTCAE grade 3 or 4
interstitial fibrosis or interstitial lung disease including a history of pneumonitis,
hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease,
obliterative bronchiolitis, and pulmonary fibrosis. Subjects with history of prior
radiation pneumonitis are not excluded.
The Role of 68Gallium PSMA-11 in Enhancing Diagnosis of Primary and Metastatic Prostate Cancer
To goal of this research is to assess the ability of Gallium-68 (68Ga) Prostate-Specific
Membrane Antigen-11 (PSMA-11) positron emission tomography/computed tomography (PET/CT) to
increase diagnostic accuracy in localizing primary and metastatic lesions in patients with
suspected prostate cancer and elevated Prostate Imaging Reporting and Data System (PI-RADS)
scores and Prostate-Specific Antigen (PSA).
• Patients with suspected prostate cancer (e.g., abnormal digital rectal exam, elevated
and/or rising PSA) as determined by referring physician
• Patients must have had a diagnostic, standard of care mpMRI of the prostate with at
least one lesion with a PI-RADS v2.1 score ≥ 4
• In men with PI-RADS v2.1 score 4, PSA should be ≥ 10 ng/mL. In men with at least one
PI-RADS v2.1 score 5 lesion, there is no restriction on PSA level.
• Patients must be scheduled for biopsy or radical prostatectomy
• Patients should not have had any type of curative or palliative therapy for prostate
cancer before enrolling in the study
• Patients must be medically stable as judged by the patient's physician
• Patients must be able to lie still for a total of 60 minutes for the PET/CT scans
• Ability to understand and the willingness to sign a written informed consent
Exclusion Criteria:
• Patients who have had a prior prostatectomy or radiotherapy for prostate cancer cannot
participate in the study
• Patients who have had a prior biopsy for prostate cancer cannot participate in the
study
• Patients who have been treated for cancers other than skin cancers
• Subjects may not be receiving any other investigational agents for the treatment of
the cancer under study
• Patients may not weigh more than the maximum weight limit for the PET/CT scanner table
(>200 kilograms or 440 pounds)
• History of allergic reactions attributed to compounds of similar chemical or biologic
composition to 68Ga PSMA-11 or other agents used in the study such as gadolinium-based
intravenous contrast agent used during the mpMRI
• Prior TURP/BPH procedures, including steam/laser therapies
Noninvasive Brain Stimulation on Memory in Individuals With Mild Cognitive Impairment and History of Brain Injury
The study will examine the efficacy of high definition transcranial direct current
stimulation (HD-tDCS) and its influence on episodic memory in patients with amnestic mild
cognitive impairment and a history of Traumatic brain injury. Ten sessions of HD-tDCS to the
dorsal anterior cingulate region is expected to result in improvements in episodic memory
measures immediately following the last session and at a 3-month follow-up.
• Age 50 and older
• Native English speakers
• 12 years of education or higher
• Active diagnosis of aMCI
• History of TBI based on VA/DOD criteria
Exclusion Criteria:
• TBI within the past 2 years
• Lifetime history of stroke, transient ischemic attack, heart attack, or congestive
heart failure
• Lifetime history of epilepsy
• Major psychiatric disorders (i.e., posttraumatic stress disorder, bipolar disorder,
schizophrenia)
• Substance use disorder
• Has metal fragments in head
• Taking medications that may interact with the HD-tDCS effect (i.e., amphetamines,
L-dopa, carbamazepine, sulpiride, pergolide, lorazepam, dextromethorphan,
D-cycloserine, flunarizine, or ropinirole)
Device: High Definition Transcranial Direct Current Stimulation, Device: Sham HD-tDCS
Traumatic Brain Injury, Amnestic Mild Cognitive Impairment, Mild Traumatic Brain Injury, Brain and Nervous System
UT Southwestern; Parkland Health & Hospital System
A Study to Compare Standard Chemotherapy to Therapy With CPX-351 and/or Gilteritinib for Patients With Newly Diagnosed AML With or Without FLT3 Mutations
This phase III trial compares standard chemotherapy to therapy with liposome-encapsulated
daunorubicin-cytarabine (CPX-351) and/or gilteritinib for patients with newly diagnosed acute
myeloid leukemia with or without FLT3 mutations. Drugs used in chemotherapy, such as
daunorubicin, cytarabine, and gemtuzumab ozogamicin, work in different ways to stop the
growth of cancer cells, either by killing the cells, by stopping them from dividing, or by
stopping them from spreading. CPX-351 is made up of daunorubicin and cytarabine and is made
in a way that makes the drugs stay in the bone marrow longer and could be less likely to
cause heart problems than traditional anthracycline drugs, a common class of chemotherapy
drug. Some acute myeloid leukemia patients have an abnormality in the structure of a gene
called FLT3. Genes are pieces of DNA (molecules that carry instructions for development,
functioning, growth and reproduction) inside each cell that tell the cell what to do and when
to grow and divide. FLT3 plays an important role in the normal making of blood cells. This
gene can have permanent changes that cause it to function abnormally by making cancer cells
grow. Gilteritinib may block the abnormal function of the FLT3 gene that makes cancer cells
grow. The overall goals of this study are, 1) to compare the effects, good and/or bad, of
CPX-351 with daunorubicin and cytarabine on people with newly diagnosed AML to find out which
is better, 2) to study the effects, good and/or bad, of adding gilteritinib to AML therapy
for patients with high amounts of FLT3/ITD or other FLT3 mutations and 3) to study changes in
heart function during and after treatment for AML. Giving CPX-351 and/or gilteritinib with
standard chemotherapy may work better in treating patients with acute myeloid leukemia
compared to standard chemotherapy alone.
• All patients must be enrolled on APEC14B1 and consented to Eligibility Screening (Part
A) prior to enrollment and treatment on AAML1831. Submission of diagnostic specimens
must be done according to the Manual of Procedures
• Patients must be less than 22 years of age at the time of study enrollment
• Patient must be newly diagnosed with de novo AML according to the 2016 World Health
Organization (WHO) classification with or without extramedullary disease
• Patient must have 1 of the following:
• >= 20% bone marrow blasts (obtained within 14 days prior to enrollment)
• In cases where extensive fibrosis may result in a dry tap, blast count
can be obtained from touch imprints or estimated from an adequate bone
marrow core biopsy
• < 20% bone marrow blasts with one or more of the genetic abnormalities
associated with childhood/young adult AML as provided in the protocol
(sample obtained within 14 days prior to enrollment)
• A complete blood count (CBC) documenting the presence of at least 1,000/uL
(i.e., a white blood cell [WBC] count >= 10,000/uL with >= 10% blasts or a
WBC count of >= 5,000/uL with >= 20% blasts) circulating leukemic cells
(blasts) if a bone marrow aspirate or biopsy cannot be performed (performed
within 7 days prior to enrollment)
• ARM C: Patient must be >= 2 years of age at the time of Late Callback
• ARM C: Patient must have FLT3/ITD allelic ratio > 0.1 as reported by Molecular
Oncology
• ARM C: Patient does not have any congenital long QT syndrome or congenital heart block
• ARM C: Females of reproductive potential must agree to use effective contraception
during treatment and for at least 6 months after the last dose of gilteritinib
• ARM C: Lactating women must agree not to breastfeed during treatment with gilteritinib
and for 2 months after the last dose of gilteritinib
• ARM C: Males of reproductive potential must agree to use effective contraception
during treatment and for at least 4 months after the last dose of gilteritinib
• ARM D: Patient must be >= 2 years of age at the time of Late Callback
• ARM D: Patient must have one of the clinically relevant non-ITD FLT3 activating
mutations as reported by Foundation Medicine
• ARM D: Females of reproductive potential must agree to use effective contraception
during treatment and for at least 6 months after the last dose of gilteritinib
• ARM D: Lactating women must agree not to breastfeed during treatment with gilteritinib
and for 2 months after the last dose of gilteritinib
• ARM D: Males of reproductive potential must agree to use effective contraception
during treatment and for at least 4 months after the last dose of gilteritinib
• NEUROPSYCHOLOGICAL TESTING: Patient must be enrolled on Arm A or Arm B. Patients who
transfer to Arm C or Arm D are not eligible
• NEUROPSYCHOLOGICAL TESTING: Patient must be 5 years or older at the time of enrollment
• NEUROPSYCHOLOGICAL TESTING: English-, French- or Spanish-speaking
• NEUROPSYCHOLOGICAL TESTING: No known history of neurodevelopmental disorder prior to
diagnosis of AML (e.g., Down syndrome, fragile X, William syndrome, mental
retardation)
• NEUROPSYCHOLOGICAL TESTING: No significant visual or motor impairment that would
prevent computer use or recognition of visual test stimuli
• 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.
Exclusion Criteria:
• Fanconi anemia
• Shwachman Diamond syndrome
• Patients with constitutional trisomy 21 or with constitutional mosaicism of trisomy 21
• Telomere disorders
• Germline predispositions known, or suspected by the treating physician to increase
risk of toxicity with AML therapy
• Any concurrent malignancy
• Juvenile myelomonocytic leukemia (JMML)
• Philadelphia chromosome positive AML
• Mixed phenotype acute leukemia
• Acute promyelocytic leukemia
• Acute myeloid leukemia arising from myelodysplasia
• Therapy-related myeloid neoplasms
• Patients with persistent cardiac dysfunction prior to enrollment, defined as ejection
fraction (EF) < 50% (preferred method Biplane Simpson's EF) or if EF unavailable,
shortening fraction (SF) < 24%. *Note: if clinically safe and feasible, repeat
echocardiogram is strongly advised in order to confirm cardiac dysfunction following
clinical stabilization, particularly if occurring in the setting of sepsis or other
transient physiologic stressor. If the repeat echocardiogram demonstrates an EF >=
50%, the patient is eligible to enroll and may receive an anthracycline-containing
Induction regimen
• Administration of prior anti-cancer therapy except as outlined below:
• Hydroxyurea
• All-trans retinoic acid (ATRA)
• Corticosteroids (any route)
• Intrathecal therapy given at diagnosis
• In particular, strong inducers of CYP3A4 and/or P-glycoprotein (P-gp) should be
avoided from the time of enrollment until it is determined whether the patient
will receive gilteritinib. Patients receiving gilteritinib will be required to
avoid strong CYP3A4 inducers and/or strong P-gp inducers for the duration of the
study treatment
• 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 their study participation
• ARM D: Patient does not have any congenital long QT syndrome or congenital heart block
1. Participant is able and willing to provide informed consent (≥18 years), or informed
consent is obtained by the parent or legal guardian for minor participants, with the
minor providing age appropriate assent, according to local law and regulations;
2. Life expectancy ≥ 12 weeks;
3. Known high-risk neuroblastoma OR previously intermediate-risk neuroblastoma that has
relapsed or progressed to high-risk, with failure to achieve complete response with
standard therapy (defined as at least 4 cycles of aggressive multi-drug induction
chemotherapy with or without radiation and surgery, or according to a standard
high-risk treatment/neuroblastoma protocol), OR who are medically ineligible to
receive standard treatment OR who are intolerant to standard treatment;
4. Adequate recovery from acute toxic effects of any prior therapy, as deemed by the
Investigator or treating Sub-Investigator;
5. Adequate liver function as defined by the following laboratory values obtained within
28 days prior to administration of 64Cu-SARTATE: Aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) < 3.0 x upper limit of normal (ULN);
6. Adequate renal function;
7. Adequate laboratory parameters: Absolute neutrophil count > 1.0 x 10 9/L; Platelet
count > 50 x 10 9/L; Total bilirubin <1.5 x ULN;
8. Karnofsky or Lansky performance status ≥50;
9. All participants must have a hematopoietic stem cell product available (minimum CD34+
cell dose is ≥2 x 10 6 cells/kg);
10. Sexually active participants of reproductive potential must practice an effective
method of birth control while participating on this study, to avoid possible damage to
the fetus. Abstinence is considered acceptable;
11. 64Cu-SARTATE uptake on the 4 hour scan (SUVmax) of any lesion equal to or higher than
that of the liver in order to move on to the therapy phase of the study.
Exclusion Criteria:
1. Participants with disease of any major organ system that would compromise their
ability to tolerate therapy, as deemed by the Investigator or treating
Sub-Investigator;
2. Any other active malignancy, or a history of prior malignancy within the past 3 years;
3. History of cardiac failure as evidenced by: dyspnea at rest, exercise intolerance,
oxygen requirement, clinically significant cardiac dysfunction;
4. Planned administration of chemotherapy, anti-cancer cytokine therapy, immunotherapy or
radiotherapy within 2 weeks prior to the administration of 64Cu-SARTATE;
5. Administration of therapeutic dose of 131I-MIBG within 8 weeks prior to the
administration of 64Cu-SARTATE;
6. External beam radiation therapy (EBRT) to both kidneys or a single functioning kidney
within 12 months prior to the administration of 64Cu-SARTATE;
7. Administration of any investigational agents within 21 days prior to administration of
64Cu-SARTATE;
8. Treatment with long acting somatostatin analogues (administered within 28 days prior
to the administration of 64Cu-SARTATE), or short acting somatostatin analogues
(administered within 24 hours prior to the administration of 64Cu-SARTATE);
9. Known sensitivity or allergy to somatostatin analogues;
10. Previous peptide receptor radionuclide therapy (PRRT);
11. Female participants who are pregnant or lactating;
12. Participants who are on hemodialysis;
13. QTc interval ≥ 0.45 seconds as measured by Screening ECG;
14. Participants with uncontrolled infection(s);
15. Any medical condition which the Investigator feels may interfere with the procedures
or evaluations of the study;
16. Participants 12 months and younger will be excluded from cohorts where the planned
single or cumulative administered activity is modelled to deliver a radiation dose to
the marrow that exceeds 2 Gy.
A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Advanced Liver Cancers (Morpheus-Liver)
This is a Phase Ib/II, open-label, multicenter, randomized umbrella study in participants
with advanced liver cancers. The study is designed with the flexibility to open new treatment
arms as new treatments become available, close existing treatment arms that demonstrate
minimal clinical activity or unacceptable toxicity, modify the participant population, or
introduce additional cohorts of participants with other types of advanced primary liver
cancer.
Cohort 1 will enroll participants with locally advanced or metastatic hepatocellular
carcinoma (HCC) who have not received prior systemic therapy for their disease. Eligible
participants will initially be randomly assigned to one of several treatment arms (Stage 1).
Participants who experience loss of clinical benefit or unacceptable toxicity during Stage 1
may be eligible to receive treatment with a different treatment combination (Stage 2). When a
Stage 2 treatment combination is available, this will be introduced by amending the protocol.
Stage 1
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 within 7 days
prior to randomization
• Locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC) with
diagnosis confirmed by histology/cytology or clinically by American Association for
the Study of
• Liver Diseases criteria in cirrhotic patients
• Child-Pugh class A within 7 days prior to randomization
• Disease that is not amenable to curative surgical and/or locoregional therapies
• No prior systemic treatment for HCC
• Life expectancy >= 3 months
• Availability of a representative tumor specimen that is suitable for determination of
PD-L1 and/or additional biomarker status via central testing
Stage 1 and Stage 2
• Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1
• Adequate hematologic and end-organ function within 7 days prior to initiation of study
treatment
• Documented virology status of hepatitis, as confirmed by screening tests for hepatitis
B virus •(HBV) and hepatitis C virus (HCV)
• Negative HIV test at screening
• For women of childbearing potential: agreement to remain abstinent or use
contraception and for men: agreement to remain abstinent or use contraception, and
agreement to refrain from donating sperm
Stage 2
• ECOG Performance Status of 0, 1, or 2
• Ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable
toxicity not related to atezolizumab or RO7247669 or loss of clinical benefit as
determined by the investigator while receiving Stage 1 treatment
• Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage
1 (if deemed clinically feasible)
Exclusion Criteria:
Stage 1
• Prior treatment with CD137 agonists or immune checkpoint inhibitors
• Treatment with investigational therapy within 28 days prior to initiation of study
• Treatment with locoregional therapy to liver within 28 days prior to initiation of
study, or non-recovery from side effects of any such procedure
• Untreated or incompletely treated esophageal and/or gastric varices with bleeding or
at high risk for bleeding
• Prior bleeding event due to esophageal and/or gastric varices within 6 months prior to
initiation of study
• AEs from prior anti-cancer therapy that have not resolved to Grade <= 1 or better,
with the exception of alopecia of any grade
• Inadequately controlled hypertension
• History of hypertensive crisis or hypertensive encephalopathy
• Significant vascular disease
• History of hemoptysis within 1 month prior to initiation of study
• Evidence of bleeding diathesis or significant coagulopathy
• Current or recent use of asprin (>325 mg/day) or treatment with clopidogrel,
dipyramidole, ticlopidine, or cilostazol
• Current or recent use of full-dose oral or parenteral anticoagulants or thrombolytic
agents for therapeutic (as opposed to prophylactic) purpose
• Core biopsy or other minor surgical procedure within 3 days prior to initiation of
study
• History of abdominal or tracheoesophageal fistula, GI perforation, or intra-abdominal
abscess, intestinal obstruction and/or clinical signs/symptoms of GI obstruction
• Evidence of abdominal free air not explained by paracentesis or recent surgery
• Serious, non-healing/dehiscing wound, active ulcer, or untreated bone fracture
• Grade >=2 proteinuria
• Metastatic disease involving major airways/blood vessels, or centrally located
mediastinal tumor masses of large volume
• History of intra-abdominal inflammatory process
• Radiotherapy within 28 days or abdominal/pelvic radiotherapy within 60 days prior to
initiation of study with the exception of palliative radiotherapy to bone lesions
within 7 days prior to initiation of study
• Major surgery, open biopsy, or significant traumatic injury within 28 days prior to
initiation of study; or abdominal surgery, abdominal interventions or significant
abdominal traumatic injury within 60 days prior to initiation of study; or
anticipation of need for major surgery during study or non-recovery from side effects
of any such procedure
• Chronic daily treatment with NSAID
• Eligible only for control arm
Stage 1 and 2
• Fibrolamellar or sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
• History of hepatic encephalopathy
• Moderate or severe ascites
• HBV and HCV coinfection
• Symptomatic, untreated, or actively progressing CNS metastases
• History of leptomeningeal disease
• Uncontrolled tumor-related pain
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures
• Uncontrolled or symptomatic hypercalcemia
• Active or history of autoimmune disease or immune deficiency
• History of IPF, organizing pneumonia, drug-induced or idiopathic pneumonitis, or
evidence of active pneumonitis on screening chest CT scan
• Active TB
• Significant CV disease within 3 months prior to initiation of study, unstable
arrhythmia, or unstable angina
• Major surgery, other than for diagnosis, within 4 weeks prior to initiation of study,
or anticipated major surgery during study
• History of malignancy other than HCC within 5 years prior to screening
• Severe infection within 4 weeks prior to initiation of study
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
of study
• Prior allogeneic stem cell or solid organ transplantation
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study,
or anticipation of need for such a vaccine during atezolizumab treatment or within 5
months after the final dose of atezolizumab
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
or fusion proteins
• Known allergy or hypersensitivity to any of the study drugs or any of their excipients
Treatment with systemic immunostimulatory, immunosuppressive agents within 4 weeks or
5 drug-elimination half-lives (whichever is longer) prior to initiation of study
• Treatment with systemic immunosuppressive medication within 2 weeks prior to
initiation of study
• Patients entering Stage 2: immunotherapy-related adverse events that have not resolved
to Grade 1 or better or to baseline at time of consent
This is a Phase 3, randomized, masked, active-controlled, multicenter trial designed to
determine whether early intratracheal administration of a combination of budesonide with
surfactant, as compared to surfactant alone, will reduce the incidence of physiologic
bronchopulmonary dysplasia (BPD) or death by 36 weeks' post-menstrual age in extremely
preterm infants.
• Liveborn infants 22 0/7 •28 6/7 weeks gestation or 401 •1000 grams (inclusive) birth
weight
• Clinical decision to give surfactant
• Less than or equal to 48 hours postnatal age
Exclusion Criteria:
• Terminal illness (heart rate < 100 beats per minute, unresponsiveness to
resuscitation) or unlikely to survive as judged by the clinician
• Decision to redirect or limit support
• Use of surfactant before enrollment (first dose of surfactant must be study drug)
• Infant received systemic steroids prior to enrollment
• Use of indomethacin, either received by the mother within 24 hours prior to
delivery,received by the infant prior to enrollment, or intent to administer to the
infant for IVH prophylaxis or PDA management from enrollment up to 7 days of final
dose of study drug
• Serious chromosomal abnormalities or major malformations
• Known congenital infections including, but not limited to, confirmed sepsis,
congenital CMV, etc.
• Infants with a permanent neuromuscular condition that affects respiration
• Enrollment in a conflicting clinical trial
Circulating Tumor DNA Testing in Predicting Treatment for Patients With Stage IIA Colon Cancer After Surgery
This phase II/III trial studies how well circulating tumor deoxyribonucleic acid (ctDNA)
testing in the blood works in predicting treatment for patients with stage IIA colon cancer
after surgery. ctDNA are circulating tumor cells that are shed by tumors into the blood.
Finding ctDNA in the blood means that there is very likely some small amounts of cancer that
remain after surgery. However, this cancer, if detected, cannot be found on other tests
usually used to find cancer, as it is too small. Testing for ctDNA levels may help identify
patients with colon cancer after surgery who do benefit, and those who do not benefit, from
receiving chemotherapy.
• The patient must have signed and dated an Institutional Review Board (IRB)-approved
consent form that conforms to federal and institutional guidelines.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Histologically/pathologically confirmed stage IIA adenocarcinoma of the colon (T3, N0,
M0) with at least 12 lymph nodes examined at the time of surgical resection.
• Appropriate for active surveillance (i.e., no adjuvant chemotherapy) at the discretion
of and as documented by the evaluating oncologist based on current practice patterns.
• The distal extent of the tumor must be >= 12 cm from the anal verge on pre-surgical
endoscopy (i.e., excluding rectal adenocarcinomas warranting treatment with
chemoradiation). If the patient did not undergo a pre-surgical endoscopy, then the
distal extent of the tumor must be >= 12 cm from the anal verge as determined by
surgical examination or pre-operative imaging.
• The patient must have had an en bloc complete gross resection of tumor (curative
resection) as definitive surgical cancer treatment within 14 to 60 days of study
randomization. Patients who have had a two-stage surgical procedure to first provide a
decompressive colostomy and then, in a later procedure, to have the definitive
surgical resection, are eligible.
• Availability and provision of adequate surgical tumor tissue for molecular diagnostics
and confirmatory profiling.
• Absolute neutrophil count (ANC) must be >= 1200/mm^3 (within 28 days before
randomization).
• Platelet count must be >= 100,000/mm^3 (within 28 days before randomization); and
• Hemoglobin must be >= 9 g/dL (within 28 days before randomization).
• Total bilirubin must be =< ULN (upper limit of normal) for the lab (within 28 days
before randomization) unless the patient has a chronic grade 1 bilirubin elevation due
to Gilbert?s disease or similar syndrome involving slow conjugation of bilirubin; and
• Alkaline phosphatase must be < 2.5 x ULN for the lab (within 28 days before
randomization); and
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be < 1.5 x
ULN for the lab (within 28 days before randomization).
• Serum creatinine =< 1.5 x ULN for the lab or measured or calculated creatinine
clearance >= 50 mL/min using the Cockcroft-Gault formula for patients with creatinine
levels > 1.5 x ULN for the lab (within 28 days before randomization).
• Pregnancy test (urine or serum according to institutional standard) done within 14
days before randomization must be negative (for women of childbearing potential only).
• Patients receiving a coumarin-derivative anticoagulant must agree to weekly monitoring
of international normalized ratio (INR) if they are randomized to Arm 2 and receive
capecitabine.
Exclusion Criteria:
• Colon cancer histology other than adenocarcinoma (i.e., neuroendocrine carcinoma,
sarcoma, lymphoma, squamous cell carcinoma, etc.).
• Pathologic, clinical, or radiologic evidence of overt metastatic disease. This
includes isolated, distant, or non-contiguous intra-abdominal metastases, even if
resected (including the presence of satellite nodules constituting N1c disease in the
absence of lymph node involvement).
• Tumor-related bowel perforation.
• History of prior invasive colon malignancy, regardless of disease-free interval.
• History of organ transplantation.
• Any prior systemic chemotherapy, targeted therapy, or immunotherapy; or radiation
therapy administered as treatment for colorectal cancer (e.g., primary rectal
adenocarcinomas for which treatment with neoadjuvant chemoradiation is warranted are
not permitted).
• Other invasive malignancy within 5 years before randomization. Exceptions are colonic
polyps, non-melanoma skin cancer or carcinoma-in-situ including those of the cervix
and breast (DCIS).
• Synchronous primary rectal and/or colon cancers.
• Antineoplastic therapy (e.g., chemotherapy, targeted therapy, or immunotherapy) within
5 years before randomization. (For the purposes of this study, hormonal therapy is not
considered chemotherapy.).
• Uncontrolled cardiac disease, in the opinion of the treating medical oncologist, that
would preclude the use of any of the drugs included in the GI005 treatment regimen.
This includes but is not limited to:
• Clinically unstable cardiac disease, including unstable atrial fibrillation,
symptomatic bradycardia, unstable congestive heart failure, active myocardial
ischemia, or indwelling temporary pacemaker.
• Ventricular tachycardia or supraventricular tachycardia that requires treatment
with class Ia antiarrhythmic drugs (e.g., quinidine, procainamide, disopyramide)
or class III antiarrhythmic drug (e.g., sotalol, amiodarone, dofetilide). Use of
other antiarrhythmic drugs is permitted.
• Second- or third-degree atrioventricular (AV) block unless treated with a
permanent pacemaker.
• Complete left bundle branch block (LBBB) unless treated with a permanent
pacemaker.
• Sensory or motor neuropathy >= grade 2, according to Common Terminology Criteria for
Adverse Events (CTCAE) version (v) 5.0.
• Active seizure disorder uncontrolled by medication.
• Active or chronic infection requiring systemic therapy.
• Known homozygous DPD (dihydropyrimidine dehydrogenase) deficiency.
• Pregnancy or lactation at the time of randomization.
• Co-morbid illnesses or other concurrent disease that, in the judgement of the
clinician obtaining informed consent, would make the patient inappropriate for entry
into this study (i.e., unable to tolerate 6 months of combination chemotherapy or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens or prevent required follow-up).
• Prior testing with any available ctDNA test as part of the management of colon cancer,
is not permitted.
Trial of Encapsulated Rapamycin (eRapa) for Bladder Cancer Prevention
eRapa (encapsulated rapamycin) will be investigated for secondary prevention in patients with
diagnosed non-muscle invasive bladder cancer (NMIBC) through a phase II double-blind
randomized controlled trial of long-term (one year) prevention with eRapa versus placebo. The
primary hypothesis is that eRapa decreases the risk of cancer relapse for patients with
NMIBC. Secondary hypotheses are that eRapa can improve certain immune parameters and improve
cognition and physical function without adversely affecting patient-reported outcomes and
quality of life.
• Pathologically (histologically) proven diagnosis of non-muscle invasive (Ta, Tis, or
T1) bladder cancer within 90 days prior to enrollment
• Able to give informed consent
• 18 years or older
• Patients must not be taking oral glucocorticoids at the time of registration
• Not have active, uncontrolled infections
• No other prior non-bladder malignancy is allowed except for the following: adequately
treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately
treated Stage I or II cancer from which the patient is currently in complete
remission, or any other cancer from which the patient has been disease free for five
years.
• Patients with localized prostate cancer who are being followed by an active
survelillance program are also eligible.
• Patients must not be pregnant or nursing, as the use of Intravesical BCG is not
recommended during pregnancy. Women/ men of reproductive potential must have agreed to
use an effective contraceptive method. A woman is considered to be of "reproductive
potential" if she has had menses at any time in the preceding 12 consecutive months.
Examples of effective contraception include hormonal contraception, double barrier
method (condom with spermicidal cream, diaphragms with spermicidal cream, or condoms
with diaphragms), Intrauterine device, and/or partner vasectomy. In addition to
routine contraceptive methods, "effective contraception" also includes heterosexual
celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy
prevention) defined as a hysterectomy, bilateral oophorectomy, or bilateral tubal
ligation. However, if at any point a previously celibate patient chooses to become
heterosexually active during the time period for use of contraceptive measures
outlined in the protocol, he/she is responsible for beginning contraceptive measures.
Both male and female patients will be required to disclose contraception method during
screening and agree to continue to use that contraception method through the end of
their participation in the study.
• Patients must have had all grossly visible papillary tumors removed within 90 days
prior to registration or cystoscopy confirming no grossly visible papillary tumors
within 90 days prior to registration.
• Patients with T1 disease must have cross-sectional imaging of abdomen/pelvis
demonstrating no evidence of nodal involvement or metastatic disease (MRI or CT scan)
within 90 days prior to registration. Patients with T1 disease must have re-resection
confirming ≤ T1 disease within 90 days prior to registration.
• Patients must no have received prior intravesical BCG
Exclusion Criteria:
• Have muscle-invasive or higher (≥T2) bladder cancer
• Unable to give informed consent
• Age 17 or younger
• Taking oral glucocorticoids at the time of registration
• Another cancer requiring active treatment (except basal cell carcinoma or squamous
cell carcinoma of the skin)
• Patients at risk of pregnancy that are unwilling or unable to take effective
contraception during the study period, or patients that are nursing during the study
period. Women/ Men of reproductive potential must have agreed to use an effective
contraceptive method or will be considered ineligible for study participation.
• Evidence of nodal involvement or metastatic disease (MRI or CT scan) within 90 days
prior to registration
• History of prior intravesical BCG
• History of prior Rapamycin treatment
Drug: eRapa, Drug: Placebos
Urinary Bladder, Non-muscle Invasive Bladder Cancer
Ketamine Versus Midazolam for Recurrence of Suicidality in Adolescents
This project aims to examine the efficacy of ketamine, a rapidly acting medication shown to
decrease suicidality in adults in as short as hours or days, as opposed to weeks.
The study design is a double-blind, randomized, active-control trial of adolescents (ages
13-18 years) with recent suicidal behaviors (suicide attempt or increased suicidal ideation).
All participants must be receiving standard of care treatment which may range broadly from
both outpatient and inpatient programs which include clinically indicated psychosocial and/or
psychopharmacological treatments. Ketamine/midazolam treatment will occur twice weekly during
the first two weeks of the study, followed by weekly assessments through week 12.
Inclusion Criteria
Study participants must:
1. Be adolescents (aged 13-18 years);
2. Have had a recent suicidal event (suicide attempt or significant suicidal ideation
with a plan or intent warranting emergency evaluation or inpatient hospitalization
within the past 30 days);
3. Receiving standard of care treatment that includes clinically indicated psychosocial
and/or psychopharmacological treatment;
4. Have a current primary diagnosis of a depressive disorder based on the MINI-KID (other
psychiatric disorders are acceptable, but must not be primary);
5. Both participants and their designated caregiver must be able to complete assessments
in English, as the rating scales vital to study efficacy and safety evaluations have
not been validated in Spanish. (NOTE: Most potential participants ages 13 to 18 years
old, as well as most of their parents, have a good working knowledge of English);
6. Use effective method of contraception during and for 90 days following the end of
treatment for female and male participants. Recommended methods of birth control are
namely, consistent use of an approved hormonal birth control (pill/patches, rings), an
intrauterine device (IUD), contraceptive injection, double barrier methods, sexual
abstinence, or sterilization;
Exclusion Criteria
Study participants must not:
1. Have lifetime schizophrenia, psychotic disorder, pervasive developmental disorder, or
mental retardation;
2. Have current mania, hypomania, mixed episode, or obsessive-compulsive disorder;
3. Have a primary diagnosis other than a depressive disorder;
4. Have moderate to severe alcohol or substance use disorder within the past six months
(based on MINI-KID); If there is a positive urine drug screen at screening, the urine
drug screen will be repeated at each infusion visit. Positive urine drug screen will
be reviewed by study physician and infusion will proceed as long as no safety risk was
identified;
5. If female, be pregnant, lactating, or nursing; Women of childbearing potential must
have a negative urine pregnancy test prior to all infusions;
6. Have unstable medical conditions (stable for less than 3 months) or with clinically
significant laboratory values or an electrocardiogram (ECG) that would pose
significant risk;
7. Be at serious suicidal risk that cannot be managed in the outpatient setting;
8. Have prior treatment for depression with or contraindications to ketamine, esketamine,
or, midazolam;
9. Treatment with medications that may alter pharmacokinetics of ketamine, including
moderate-to-strong inhibitors or inducers of CYP3A4 and CYP2B6, is exclusionary.
Regarding pharmacodynamic interactions, medications that may increase heart rate or
blood pressure such as the ADHD stimulant medications will be permitted with last dose
at least 24 hours prior to infusion. All concomitant medications will be evaluated by
the study physician to determine if the type and dose of concomitant medication
requires discontinuation and will be excluded if the concomitant medication could
substantially increase the risk of study infusion. A complete list of medications that
are Not Allowed is available in Appendix D of the protocol. The study team will not
ask the participant to discontinue any treatment (except for not taking ADHD
medications for 24 hours before study treatment) just for the sake of taking part in
this study;
10. Weigh >120 kilograms at baseline. If participants are enrolled but exceed 120
kilograms at any time during the treatment period, they will be removed from the
treatment portion of the study.
Testing Immunotherapy Versus Observation in Patients With HPV Throat Cancer
This phase III trials studies whether maintenance immunotherapy (nivolumab) following
definitive treatment with radiation and chemotherapy (cisplatin) result in significant
improvement in overall survival (time being alive) and progression-free survival (time being
alive without cancer) for patients with intermediate risk human papillomavirus (HPV) positive
oropharynx cancer (throat cancer) that has spread to nearby tissue or lymph nodes. Drugs used
in chemotherapy such as 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. Radiation therapy uses high energy rays to kill tumor cells and shrink tumors.
Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune
system attack the cancer, and may interfere with the ability of tumor cells to grow and
spread. It is not yet known whether chemotherapy and radiation therapy followed by
maintenance nivolumab therapy works better than chemotherapy and radiation therapy alone in
treating patients with HPV positive oropharyngeal cancer.
• STEP 1: Age >= 18 years
• STEP 1: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• STEP 1: Patients must have oropharynx cancer (American Joint Committee on Cancer
[AJCC] 8) that is p16-positive by immunohistochemistry OR p16 equivocal by IHC and HPV
positive by in situ hybridization with the following criteria: >= 10 pack-years, stage
T1-2N2-N3 or T3-4N0-3 (less than 10 pack-years is considered a non-smoker) OR < 10
pack-years, stage T4N0-N3 or T1-3N2-3
• STEP 1: Patients must not have known hypersensitivity to nivolumab or compounds of
similar chemical or biologic composition.
• STEP 1: Patients with a history of allergic reactions attributed to platinum-based
chemotherapy agents are excluded.
• STEP 1: Patients must not have had prior systemic therapy, radiation treatment or
surgery for p16 positive oropharyngeal squamous cell carcinoma (OPSCC).
• NOTE: Patients who had resection of T1 or T2 carcinoma with no radiation or
chemotherapy are eligible if surgery was done 5 years prior to enrollment
• STEP 1: Patients must not have received previous irradiation for head and neck tumor,
skull base, or brain tumors.
• STEP 1: Patients must not receive investigational agents within 4 weeks of enrollment
or at any time while on study.
• STEP 1: Patients with evidence of distant metastases or leptomeningeal disease (LMD)
are excluded.
• STEP 1: Patients with uncontrolled inter-current illnesses which in the opinion of the
investigator will interfere with the ability to undergo therapy including chemotherapy
are excluded.
• STEP 1: Patients with a history of prior or second malignancy are excluded, with the
exception of curatively treated non-melanoma skin cancer, or curatively treated
cervical cancer; additionally, patients curatively treated for malignancy who remain
disease-free at > 2 years of follow up, are not excluded.
• STEP 1: Absolute neutrophil count (ANC) >= 1500/mm^3 (must be obtained =< 2 weeks
prior to randomization).
• STEP 1: Hemoglobin (Hgb) >= 8.0 g/dL (must be obtained =< 2 weeks prior to
randomization).
• STEP 1: Platelet count >= 100,000/mm^3 (must be obtained =< 2 weeks prior to
randomization).
• STEP 1: Creatinine clearance of >= 60 ml/min (must be obtained =< 2 weeks prior to
randomization). Creatinine clearance may be measured or calculated. If calculating,
creatinine clearance, use the Cockcroft-Gault formula.
• STEP 1: Total bilirubin within 1.5 times the normal limits (must be obtained =< 2
weeks prior to randomization).
• STEP 1: Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase
[AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase
[ALT]) within 2.0 times the normal limits (must be obtained =< 2 weeks prior to
randomization).
• STEP 1: Alkaline phosphatase within 2.0 times the normal limits (must be obtained =< 2
weeks prior to randomization).
• STEP 1: Patients must not be pregnant or breast-feeding as chemotherapy, radiation,
and immunotherapy may have possible teratogenicity effects; in addition, complications
from pregnancy may interfere with the ability of patients to have an uninterrupted
therapy. All patients of childbearing potential must have a blood test or urine study
within 2 weeks prior to randomization to rule out pregnancy. A patient of childbearing
potential is any female, regardless of sexual orientation or whether they have
undergone tubal ligation, who meets the following criteria: 1) has achieved menarche
at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has
not been naturally postmenopausal (amenorrhea following cancer therapy does not rule
out childbearing potential) for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months).
• STEP 1: Patients of childbearing potential must use an accepted and effective method
of contraception or abstain from sexual intercourse for at least one week prior to the
start of treatment, and continue for 5 months after the last dose of protocol
treatment. Patients must also not donate ova during this same time period.
• STEP 1: Patients must have measurable disease
• STEP 1: Patients must have tumor measurements with CT of neck and CT of chest (or CT
of neck and FDG PET/CT if standard of care) within 4 weeks prior to Step 1
randomization.
• STEP 1: Patients with active autoimmune disease or history of autoimmune disease that
might recur, which may affect vital organ function or require immune suppressive
treatment including systemic corticosteroids, should be excluded. These include but
are not limited to patients with a history of immune related neurologic disease,
multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome,
myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus
(SLE), connective tissue disease, scleroderma, inflammatory bowel disease (IBD),
Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal
necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be
excluded because of the risk of recurrence or exacerbation of disease. Patients with
vitiligo, endocrine deficiencies including thyroiditis managed with replacement
hormones including physiologic corticosteroids are eligible. Patients with rheumatoid
arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with
topical medication and patients with positive serology, such as antinuclear antibodies
(ANA), anti-thyroid antibodies should be evaluated for the presence of target organ
involvement and potential need for systemic treatment but should otherwise be
eligible.
• STEP 1: Patients are permitted to enroll if they have vitiligo, type I diabetes
mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone
replacement, psoriasis not requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger (precipitating event).
• STEP 1: Patients must not have a condition requiring systemic treatment with either
corticosteroids (> 10 mg/day prednisone equivalents) or other immunosuppressive
medications which are expected to continue during nivolumab administration. Inhaled or
topical steroids and adrenal replacement doses > 10 mg/day prednisone equivalents are
permitted in the absence of active autoimmune disease
• STEP 1: Patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy, if indicated
• STEP 1: Patients with a history of hepatitis C virus (HCV) infection must have been
treated and cured. For patients with HCV infection who are currently on treatment,
they are eligible if they have an undetectable HCV viral load
• STEP 1: Patients with a known history of testing positive for human immunodeficiency
virus (HIV) or known acquired immunodeficiency syndrome (AIDS) must have no detectable
viral load on a stable antiviral regimen
• STEP 1: Patients must not be receiving any other investigational agents.
• STEP 1: Patient must not have a baseline clinically significant hearing loss, which in
the opinion of the investigator would preclude the use of cisplatin
• STEP 2: Patients must have progression per RECIST criteria AND tissue-proven
progression on Arm B treatment within 12 months after completion of radiation therapy.
• STEP 2: ECOG performance status of 0 or 1.
• STEP 2: Patients must not have known hypersensitivity to nivolumab or compounds of
similar chemical or biologic composition.
• STEP 2: Patients must not have received non-protocol anti-cancer therapy after
completion of radiation and chemotherapy.
• STEP 2: ANC >= 1500/mm^3 (must be obtained =< 2 weeks prior to registration).
• STEP 2: Hgb >= 8.0 g/dL (must be obtained =< 2 weeks prior to registration).
• STEP 2: Platelet count >= 100,000/mm^3 (must be obtained =< 2 weeks prior to
registration).
• STEP 2: Creatinine within institutional limits of normal (must be obtained =< 2 weeks
prior to registration)
• STEP 2: Total bilirubin within 1.5 times the normal limits (must be obtained =< 2
weeks prior to registration).
• STEP 2: SGOT (AST) or SGPT (ALT) within 2.0 times the normal limits (must be obtained
=< 2 weeks prior to registration).
• STEP 2: Alkaline phosphatase within 1.5 times the normal limits (must be obtained =< 2
weeks prior to registration).
• STEP 2: Patients must not be pregnant or breast-feeding as chemotherapy, radiation,
and immunotherapy may have possible teratogenicity effects; in addition, complications
from pregnancy may interfere with the ability of patients to have an uninterrupted
therapy. All women of childbearing potential must have a blood test or urine study
within 2 weeks prior to registration to rule out pregnancy. A women of childbearing
potential is any female, regardless of sexual orientation or whether they have
undergone tubal ligation, who meets the following criteria: 1) has achieved menarche
at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has
not been naturally postmenopausal (amenorrhea following cancer therapy does not rule
out childbearing potential) for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months).
• STEP 2: Patients of childbearing potential must use an accepted and effective method
of contraception or abstain from sexual intercourse for at least one week prior to the
start of treatment, and continue for 5 months after the last dose of protocol
treatment. Patients must also not donate ova during this same time period.
• STEP 2: Patients must have measurable disease at the time of documented progression
• NOTE: For patients that have undergone salvage surgery for disease recurrence,
measurable disease is not required at the time of registration to Step 2
• STEP 2: Patients must have tumor measurements with CT of neck and CT of chest (or CT
of neck and FDG PET/CT if standard of care) within 4 weeks prior to Step 2
registration
• NOTE: Patients that have undergone salvage surgery for disease recurrence prior
to Step 2 are not required to have measurable disease post-resection, but must
have CT of neck and CT of chest (or CT of neck and FDG PET/CT if standard of
care) after salvage surgery and within 4 weeks prior to step 2 registration to
establish a baseline prior to nivolumab
Focal Salvage HDR Brachytherapy for Locally Recurrent Prostate Cancer in Patients Treated With Prior Radiotherapy (F-Sharp)
This purpose of this study is to evaluate the safety and effectiveness of a technique called
focal high-dose-rate (HDR) brachytherapy as treatment for prostate cancer that has come back
in the prostate after prior radiotherapy. The study will examine the safety and efficacy of
the treatment. The type of radiation that participants in this research will receive is
targeted directly at the areas of the prostate where recurrent disease is evident, while
avoiding treatment of the normal appearing prostate. This involves the placement of a
radioactive material in the affected area of the prostate temporarily, where it remains for a
short period of time, and then is subsequently removed using a minimally invasive technique
called HDR Brachytherapy.
• Biopsy proven locally recurrent adenocarcinoma of the prostate after the completion of
definitive radiation therapy for initially diagnosed prostate cancer.
• Biopsy must be performed within 182 days of trial registration
• Biopsy should be a standard sextant biopsy AND either a targeted MR/ultrasound
guided biopsy or saturation biopsy or both.
• Initial cancer diagnosis that fits these specific criteria:
• Stages T1-T3a
• Nx or N0
• Mx or M0
• Eligible initial definitive radiotherapy modalities include:
• External beam radiotherapy, with photon or proton beam therapy
• Conventional or moderately hypofractionated radiotherapy
• Extremely hypofractionated external beam radiotherapy (Stereotactic body
radiation therapy)
• Definitive Brachytherapy:
• Low-dose rate
• High-dose rate
• Locally recurrent disease confined to the prostate +/- seminal vesicles and
immediately adjacent tissue, as evaluated by the following:
• History/Physical examination
• Radiographically node negative disease (N0), as defined by CT or MR of pelvis +/-
abdomen within 6 months of registration.
• No evidence of bone metastases (M0) on bone scan within 6 months of registration.
• Fluciclovine-PET is encouraged, but not required
• Patients receiving ADT are eligible as long as they meet the other eligibility
criteria. However, the duration of all ADT must be documented.
• Current ECOG Performance status Scale 0-2
• Current International Prostate Symptom Score (IPSS) < 20
• The patient must be medically suitable to receive general anesthesia.
• The patient must be able and willing to sign a study-specific written informed consent
form before study entry.
Exclusion Criteria:
• Preregistration GI or GU toxicity (for any reason) grade ≥ 3 as defined in CTCAE
version 4.03. That is, grade ≥ 3 GU or GI toxicity after first course of radiotherapy
• Patients receiving any other investigational agents.
• Uncontrolled inter-current illness including, but not limited to, ongoing or active
infection, severely symptomatic congestive heart failure, cardiac arrhythmia, recent
myocardial infarction in last 6 months, or psychiatric illness/social situations that
could limit compliance with study requirements.
• Patients who have received chemotherapy or immunotherapy within one month prior to
study enrollment, other than ADT