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.
Cabozantinib in Patients With Advanced Hepatocellular Carcinoma With Child Pugh Class B Cirrhosis After First-Line Therapy
The aim of this study is to determine the safety and efficacy of cabozantinib in the
management of unresectable or metastatic hepatocellular carcinoma (HCC) with underlying
Child-Pugh class B cirrhosis.
• Patients must have a radiologically consistent (early enhancement and delayed
enhancement washout) or pathologically confirmed diagnosis of hepatocellular carcinoma
that is not eligible for curative resection, transplantation, or ablative therapies.
• Prior radiation, liver directed therapy (including bland, chemo- or radioembolization,
or ablation), or hepatic resection are permitted if ≥4 weeks from start of therapy.
Extra-hepatic palliative radiation is permitted if completed ≥2 weeks prior to first
dose of study therapy and the patient has recovered to ≤ grade 1 toxicity.
• Patients must have radiographically measurable disease (RECIST1.1) in at least one
site not previously treated or with progression after radiation or liver directed
therapy (including bland, chemo- or radio-embolization, or ablation) either within the
liver or in a metastatic site.
• Patients must have either progressed or deemed intolerant of first-line systemic
therapy. More than one line of systemic therapy is not permitted. The last dose should
be at least 2 weeks from first dose of study therapy. Prior treatment may not contain
cabozantinib.
• Recovery to ≤ grade 1 from toxicities related to any prior treatments, unless the AEs
were clinically non-significant and/or stable on supportive therapy
• Must have a Child-Pugh score of B7 or B8
• Must have an ECOG performance status of 0-1.
• Ability to understand and willingness to sign IRB-approved informed consent.
• Willing to provide archived tissue, if available, from a previous diagnostic biopsy.
• Must be able to tolerate CT and/or MRI with contrast.
• Adequate organ function obtained ≤ 2 weeks prior to enrollment.
Exclusion Criteria:
• Must not have uncontrolled ascites (requiring paracentesis within 3 months of
screening) or hepatic encephalopathy requiring hospitalization (within 6 months of
screening)
• Must not have prior history of organ transplantation.
• No known brain metastasis unless adequately treated with radiotherapy and/or surgery
and stable for at least 4 weeks before registration. Eligible subjects must have been
without corticosteroid treatment at the time of registration.
• Must not have undergone a major surgery (e.g., GI surgery, removal or biopsy of brain
metastasis) within 8 weeks before first dose of study treatment. Complete wound
healing from major surgery must have occurred 1 month before first dose and from minor
surgery (e.g., simple excision, tooth extraction) at least 10 days before first dose.
Subjects with clinically relevant ongoing complications from prior surgery are not
eligible.
• Must not have an active second malignancy other than non-melanoma skin cancer or
cervical carcinoma in situ. Patients with history of malignancy are eligible provided
primary treatment of that cancer was completed > 1 year prior to enrollment and the
patient is free of clinical or radiologic evidence of recurrent or progressive
malignancy.
• Must not have uncontrolled, significant intercurrent or recent illness including, but
not limited to the following conditions:
• Cardiovascular disorders (Congestive heart failure or uncontrolled hypertension;
or stroke, myocardial infarction, or other ischemic or thromboembolic event
within 6 months before first dose)
• Gastrointestinal disorders, including those associated with a high risk of
perforation or fistula formation
• Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon of
red blood or other history of significant bleeding within 12 weeks before first
dose
• Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
manifestation
• Lesions invading or encasing any major blood vessels except thromboses of
portal/hepatic vasculature attributed to underlying liver disease and/or liver
tumor
• Other clinically significant disorders that would preclude safe study
participation (serious non-healing wound/ulcer/bone fracture;
uncompensated/symptomatic hypothyroidism; known HIV)
• Must not have untreated or incompletely treated varices with bleeding or high risk for
bleeding. Subjects treated with adequate endoscopic therapy (in accordance with
institutional standards) without any episodes of recurrent overt GI bleeding requiring
transfusion or hospitalization for at least 6 months prior to study entry are eligible
• Must not have a psychiatric illness, other significant medical illness, or social
situation (such as involuntary incarceration) which, in the investigator's opinion,
would limit compliance or ability to comply with study requirements
• Women must not be pregnant or breastfeeding since cabozantinib may harm the fetus or
child.
• Women of child-bearing potential (not surgically sterilized and between menarche and
1-year post menopause) and men must agree to use 2 methods of adequate contraception
(hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the
duration of study participation, and for 4 months following completion of study
therapy. Should a woman become pregnant or suspect she is pregnant while participating
in this study, she should inform her treating physician immediately.
• Prisoners or subjects who are involuntarily incarcerated, or compulsorily detained for
treatment of either a psychiatric or physical (e.g. infectious disease) illness would
be excluded.
• Concomitant treatment with strong inducers or inhibitors of CYP3A4 is not allowed.
Patients must discontinue the drug(s) at least 14 days prior to first study dose on
the study.
• Concomitant anticoagulation with oral anticoagulants (e.g. warfarin, direct thrombin
and factor Xa inhibitors), or platelet inhibitors (e.g. clopidogrel) is not allowed.
• Must not have corrected QT interval calculated by the Fridericia formula (QTcF) > 500
ms per electrocardiogram (ECG) within 28 days before first dose of study treatment.
Olanzapine Versus Megestrol Acetate for the Treatment of Loss of Appetite Among Advanced Cancer Patients
This phase III trial compares the effects of olanzapine versus megestrol acetate in treating
loss of appetite in patients with cancer that has spread to other places in the body
(advanced). Olanzapine may stimulate and increase appetite. This study aims to find out if
olanzapine is better than the usual approach (megestrol acetate) for stimulating appetite and
preventing weight loss.
• Women and men of reproductive potential should agree to use an appropriate method of
birth control throughout their participation in this study due to the teratogenic
potential of the therapy utilized in this trial. Appropriate methods of birth control
include abstinence, oral contraceptives, implantable hormonal contraceptives or double
barrier method (diaphragm plus condom)
• Diagnosis of advanced cancer
• Patient-reported 2-month weight loss of at least 5 pounds (2.3 kilograms) and/or
physician-estimated caloric intake of less than 20 calories/kilogram of body weight
per day
• The patient must perceive loss of appetite and/or weight as a problem; and have an
appetite score of 4 or worse on the "Please rate your appetite…." question that
requires a patient response on a 0-10 numeric rating scale
• Not receiving ongoing tube feedings or parenteral nutrition at the time of
registration
• Not currently using systemic adrenal steroids (with the exception of short-term
dexamethasone within 3 days of chemotherapy for control of chemotherapy side effects)
• No use of androgens, progesterone analogs, or other appetite stimulants within the
past month
• Patient should not have poorly controlled hypertension or congestive heart failure at
registration
• Patient should not have an obstruction of the alimentary canal, malabsorption, or
intractable vomiting (defined as vomiting more than 3 times per day over the preceding
week)
• Not currently using olanzapine for another medical condition or had previously used
olanzapine for chronic nausea or for any pre-existing psychotic disorder
• Patient should not have had a previous blood clot at any time in the past
• No history of poorly controlled diabetes
• No symptomatic leptomeningeal disease or known brain metastases as these patients may
have difficulty taking oral medications
• No history of hypersensitivity to olanzapine or megestrol acetate
• No COVID-19 infection in the past that, in the opinion of the treating physician, had
left patients with compromised taste, which has not resolved at the time of
registration
• Not pregnant and not nursing, because this study involves an investigational agent
whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn
are unknown. Therefore, for women of childbearing potential only, a negative urine or
serum pregnancy test done =< 14 days prior to registration is required
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
• Estimated life expectancy of 3 months or longer
• Serum creatinine =< 2.0 mg/dL
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3 x upper limit
of normal (ULN)
• Fasting glucose > 1410 mg/dl
• Granulocytes > 1000/hpf
• No treatment with another antipsychotic agent, such as risperidone, quetiapine,
clozapine, butyrophenone within 30 days of enrollment
• In order to complete the mandatory patient-completed measures, participants must be
able to speak and/or read English or Spanish. Sites seeking to enroll Spanish-speaking
patients should have access to Spanish speaking staff on site or through the use of a
translation service to be able to conduct the informed consent discussion in Spanish,
and to conduct the weekly phone calls
Exclusion Criteria:
• Psychiatric illness which would prevent the patient from giving informed consent
• Medical condition such as uncontrolled infection (including human immunodeficiency
virus [HIV]), uncontrolled diabetes mellitus or cardiac disease which, in the opinion
of the treating physician, would make this protocol unreasonably hazardous for the
patient
• Patients who cannot swallow oral formulations of the agents
• Patients with impaired decision-making capacity (such as with a diagnosis of dementia
or memory loss) are not eligible for this study
• No presence of a hormone-sensitive tumor, such as breast, endometrial, or prostate
cancer (this exclusion criterion is intended to circumvent any confounding
antineoplastic effects of megestrol acetate)
• life expectancy of less than 24 hours
• anoxic brain injury or an uncontrolled metabolic condition as primary cause of SE
• treatment of current SE episode with IV anesthetics
Drug: Ganaxolone, Drug: Placebo
Epilepsy, Status Epilepticus, Convulsive Status EPILEPTICUS, Non-Convulsive Status Epilepticus
The PATHway Study: Primary Care Based Depression Prevention in Adolescents (PATHway)
Prevention of depressive disorders has become a key priority for the NIMH, but the
investigators have no widely available public health strategy to reduce morbidity and
mortality. To address this need, the investigators developed and evaluated the primary care
based-technology "behavioral vaccine," Competent Adulthood Transition with
Cognitive-Behavioral Humanistic and Interpersonal Therapy (CATCH-IT). The investigators will
engage N=4 health systems representative of the United States health care system, and conduct
a factorial design study to optimize the intervention in preparation for an implementation
study and eventual dissemination.
• Adolescents ages 13 through 18 years, and
• Adolescents must be experiencing an elevated level of depressive symptoms (PHQ-9 =
5-18), and
• Adolescents will be included if they have had past depressive episode/s, but not if
they are in a current depressive episode.
Exclusion Criteria:
1. Outside age range:
1. 12 or younger
2. 19 or older
2. Adolescent is a non-English speaker/reader
3. On the PHQ-9 screening, depression symptom level is:
1. PHQ-9 = 4 or lower
2. PHQ-9 =19 or higher
4. As assessed by the MINI Kid, a current depressive episode
5. As assessed by the MINI Kid, adolescent meets DSM-5 criteria for a psychotic or
bipolar disorder.
6. Currently using medication therapy for depression, anxiety, or other internalizing
disorders.
7. Currently engaged in individual treatment for a mood disorder (assessed by BCC during
phone screen)
8. Currently engaged in a cognitive-behavioral group or therapy (assessed by BCC during
phone screen)
9. Any past psychiatric hospitalizations
10. Any past suicide attempt or incident of self-harm with moderate or greater lethality
11. Extreme, current drug/alcohol abuse (determined by clinician follow up following a
score of 3 or greater on the CRAFFT)
12. Current suicidal thoughts
1. Eligibility will be determined on a case-by-case basis during the baseline PhQ-9
and MINI Kid assessment process and after a consultation with a licensed mental
health clinician has taken place. If adolescent report suicidal ideation on the
baseline PhQ-9, and found ineligible, the MINI Kid assessment may not be
required.
2. Adolescents with current (within the past 6 months), active suicidal feelings
will be excluded.
3. Adolescents with passive thoughts of death or suicide but report to the mental
health clinician that they would never act on these thoughts may be admitted,
depending on the severity of the risk.
4. Adolescents with past (greater than 6 months ago) ideation who are determined to
be low risk will be admitted into the study if there has never been an attempt of
moderate or greater lethality.
13. Significant reading impairment (a minimum sixth-grade reading level based on parental
report) and/or significant intellectual or developmental disabilities
14. Not willing to comply with the study protocol
15. Did not complete phone assessment with MINI Kid by BCC
16. Not affiliated with any of the sites listed in Appendix A.
17. Parent/guardian does not speak English or Spanish
18. Parent/guardian has a cognitive or intellectual impairment
19. Participant Declined/Changed Mind/Uninterested in participating
Behavioral: Competent Adulthood Transition with Cognitive-Behavioral, Humanistic and Interpersonal Training
Depression, Mental Disorder in Adolescence
Adolescents Depression, Internet intervention, Cognitive-Behavioral Therapy, Prevention, MOST design
Study of CLR 131 in Select B-Cell Malignancies (CLOVER-1) and Pivotal Expansion in Waldenstrom Macroglobulinemia (CLOVER-WaM)
Part A of this study evaluates CLR 131 in patients with select B-cell malignancies (multiple
myeloma( MM), indolent chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL),
lymphoplasmacytic lymphoma (LPL)/Waldenstrom Macroglobulinemia (WM), marginal zone lymphoma
(MZL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and central nervous
system lymphoma (CNSL) who have been previously treated with standard therapy for their
underlying malignancy. Part B (CLOVER-WaM) is a pivotal efficacy study evaluating IV
administration of CLR 131 in patients with WM that have received at least two prior lines of
therapy.
All Patients
• Histologically or cytologically confirmed MM; Patients with primary or secondary CNSL
may be enrolled.
• ECOG performance status of 0 to 2
• 18 years of age or older
• Life expectancy of at least 6 months
• Platelets ≥ 75,000/µL (if full-dose anticoagulation therapy is used, platelets ≥
100,000/µL are required)
• WBC count ≥ 3000/µL
• Absolute neutrophil count ≥ 1500/µL
• Hemoglobin ≥ 9 g/dL (last transfusion, if any, must be at least 1 week prior to study
registration, and no transfusions are allowed between registration and dosing)
• Estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2
• Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 × upper
limit of normal (ULN)
• Bilirubin < 1.5 × ULN
• International normalized ratio (INR) < 2.5
• If patient is on full-dose anticoagulation therapy, the anticoagulation therapy must
be reversible and reversal of the anticoagulation therapy must not be
life-threatening, as judged by the Investigator
• Patients who have undergone stem cell transplant must be at least 100 days from
transplant
Patients with Multiple Myeloma
• At least 5 prior regimens, which must include at least 1 approved proteasome inhibitor
(bortezomib, carfilzomib, or ixazomib), at least 1 approved immunomodulatory agent
(thalidomide, lenalidomide, or pomalidomide), and at least 1 approved monoclonal
antibody (e.g., daratumumab or elotuzumab) with or without maintenance therapy, unless
patients are intolerable to such agents or ineligible to receive such agents.
• At least triple-class refractory (refractory to a proteasome inhibitor,
immunomodulatory agent, and a monoclonal antibody)
• Progressive disease defined by any of the following:
• 25% increase in serum M-protein from the lowest response value during (or after)
last therapy and/or absolute increase in serum M-protein of ≥ 0.5 g/dL
• 25% increase in urine M-protein from the lowest response value during (or after)
last therapy and/or absolute increase in urine M-protein of ≥ 200 mg/24 h
• 25% increase in bone marrow plasma cell percentage from the lowest response value
during (or after) last therapy. Absolute bone marrow plasma cell percentage must
be ≥ 10% unless prior CR when absolute bone marrow plasma cell percentage must be
≥ 5%.
• 25% increase in serum FLC level from the lowest response value during (or after)
last therapy; the absolute increase must be > 10 mg/dL
• New onset hypercalcemia > 11.5 mg/dL
• Failure to obtain a partial response or better to current treatment, or cannot
further improve their response to current treatment
• Appearance of new extramedullary disease
• Measurable disease defined by any of the following:
• Serum M-protein > 0.5 g/dL
• Urine M-protein > 200 mg/24 h
• Serum FLC assay: Involved FLC level ≥ 10 mg/dL provided serum FLC ratio is
abnormal.
[CLOSED] Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma,
Lymphoplasmacytic Lymphoma/Waldenstom Macroglobulinemia, or Marginal Zone Lymphoma
• Prior treatment with at least 2 prior regimens, which may include chemotherapy, an
approved anti-CD20 antibody with or without maintenance therapy, and an approved
targeted agent, unless patients are ineligible to receive such agents
• Patients with Helicobacter pylori+ mucosa-associated lymphoid tissue lymphoma must
have received 1 prior antibiotic regimen for H pylori
• At least 1 measurable nodal lesion with longest diameter > 15 mm or 1 measurable
extranodal lesion (eg, hepatic nodule) with longest diameter > 10 mm. Additional
parameters (e.g., measurable IgM for patients with Lymphoplasmacytic Lymphoma) may be
allowed if they meet current NCCN guidelines for symptomatic disease. Patients with
uptake by FDG-PET scan may be allowed with prior approval of Sponsor.
[CLOSED] Patients with Mantle Cell Lymphoma
• Prior treatment with at least 1 prior regimen
• At least 1 measurable nodal lesion with longest diameter > 15 mm or 1 measurable
extranodal lesion (eg, hepatic nodule) with longest diameter > 10 mm. Patients with
uptake by FDG-PET scan may be allowed with prior approval of Sponsor.
[CLOSED] Patients with Diffuse Large B-Cell Lymphoma
• Relapsed or refractory to combination chemotherapy for DLBCL that contains rituximab
and an anthracycline; or is intolerable to such agents. Relapsed disease is defined as
either recurrence of disease after a CR or PD after achieving a partial response (PR)
or SD. Refractory disease is defined as failure to achieve at least SD with any 1 line
of therapy or with PD ≤ 3 months of the most recent chemotherapy regimen.
• At least 1 measurable nodal lesion with longest diameter > 15 mm or 1 measurable
extranodal lesion (eg, hepatic nodule) with longest diameter > 10 mm. Patients with
uptake by FDG-PET scan may be allowed with prior approval of Sponsor.
Patients with CNS Lymphoma
• Must have biopsy-proven disease and must have received at least one prior intervention
for their disease.
• Must be at least two weeks from CNS biopsy before administration of CLR 131.
• Must have at least one lesion with enhancement on brain imaging.
• Stable (or decreasing) dose of corticosteroids or anti-convulsant medication for at
least 7 days prior to dosing
[CLOVER-1]
Exclusion Criteria:
• Ongoing Grade 2 or greater toxicities due to previous therapies. Stable, tolerable
Grade 2 AEs (eg, neuropathy) may be allowed.
• Prior external-beam RT resulting in greater than 20% of total bone marrow receiving
greater than 20 Gy.
• Prior total body or hemi-body irradiation. Patients who have received prior low-dose
total body or hemi-body irradiation may be allowed on a case-by-case basis after
discussion with Sponsor (considerations may include factors such as time since
irradiation, total lifetime accumulated dose, etc.)
• Extradural tumor in contact with the spinal cord or tumor located where swelling in
response to therapy may impinge upon the spinal cord
• For patients with CLL/SLL, LPL, or MZL, transformation to a more aggressive form of
NHL
• Ongoing chronic immunosuppressive therapy
• Clinically significant bleeding event within prior 6 months
• Ongoing anti-platelet therapy (except low-dose aspirin [eg, 81 mg daily] for
cardioprotection)
• Anti-cancer therapy within two weeks of initial CLR 131 infusion. Low dose
dexamethasone for symptom management is allowed
• Radiation therapy, chemotherapy, immunotherapy, or investigational therapy within 2
weeks of eligibility-defining bone marrow biopsy.
• For patients with primary or secondary CNSL, active bleeding in the tumor bed and/or
uncontrolled seizure activity
[CLOVER-WaM] Inclusion Criteria
• Histologically or cytologically confirmed WM. Patients with a diagnosis of LPL may be
enrolled with prior Sponsor approval.
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0
to 2 (Appendix C)
• Patient is 18 years of age or older
• Life expectancy of at least 6 months
• Received at least two prior lines of therapy for WM
• Measurable IgM (above upper limit of normal) OR at least one measurable nodal lesion
with longest diameter > 15 mm or one measurable extranodal lesion (e.g., hepatic
nodule) with longest diameter > 10 mm
[CLOVER-WaM] Exclusion Criteria
• Ongoing Grade 2 or greater toxicities due to previous therapies, excluding alopecia.
• Prior external-beam RT resulting in greater than 20% of total bone marrow receiving
greater than 20 Gy.
• Prior total body or hemi-body irradiation. Patients who have received prior low-dose
total body or hemi-body irradiation may be allowed on a case-by-case basis after
discussion with Sponsor (considerations may include factors such as time since
irradiation, total lifetime accumulated dose, etc.)
• Patients with second malignancies in addition to WM, if the second malignancy has
required therapy in the last 2 years or is not in remission; exceptions to this
criterion include successfully treated non-metastatic basal cell or squamous cell skin
carcinoma, or prostate cancer that does not require therapy
• Anti-cancer therapy within two weeks of initial CLR 131 infusion.
• Need for acute treatment of WM (e.g., those with hyperviscosity)
Multiple Myeloma, Waldenström Macroglobulinemia, Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Marginal Zone Lymphoma, Mantle Cell Lymphoma, Diffuse Large B Cell Lymphoma, Non-Hodgkins Lymphoma, Central Nervous System Lymphoma, Lymphoplasmacytic Lymphoma
Optimizing the Use of Ketamine to Reduce Chronic Postsurgical Pain (KALPAS)
The study utilizes a 3-arm placebo-controlled RCT to study the effectiveness of ketamine in
reducing chronic post-mastectomy pain. Participants randomized to the first arm will receive
a 0.35 mg/kg dose after induction, followed by a 0.25 mg/kg/hr infusion during surgery (up to
a maximum of 6 hours) and continued for 2 hours postoperatively. Participants in the second
arm will receive a single dose of 0.6 mg/kg of ketamine in the post-anesthesia care unit, and
the final group will serve as the control group and receive saline (no ketamine).
• Woman 18 years of age or older
• Undergoing elective breast surgery for oncologic indication as follows: unilateral or
bilateral mastectomy, prophylacticmastectomy, +/- lymph node dissection, +/- immediate
or delayed reconstruction.
• No distant metastases
Exclusion Criteria:
• History of cognitive impairment or clinical signs of altered mental status (AMS) that
may interfere with adherence to study procedures and/or participant safety. Clinical
signs of AMS may include but are not limited to: confusion, amnesia, disorientation,
fluctuating levels of alertness, etc.
• Past ketamine or phencyclidine misuse or abuse
• Schizophrenia or history of psychosis
• History of post-traumatic stress disorder
• Known sensitivity or allergy to ketamine
• Liver or renal insufficiency
• History of uncontrolled hypertension, chest pain, cardiac arrhythmia, stroke, head
trauma, intracranial mass or hemorrhage, glaucoma, porphyria, uncontrolled thyroid
disease, or other contraindication to ketamine
• Lamotrigine, alfentanil, physostigmine, or 4-aminopyridine use
• Currently Pregnant
• Body mass index (BMI) greater than 35
• Non-English or non-Spanish speaker
• Currently participating in another pain interventional trial
• Unwilling to comply with all study procedures and be available for the duration of the
study
• Patient is American Society of Anesthesiologists (ASA) physical status 4, 5, or 6
• Patient has started or undergone hormone therapy for gender transition into male.
• Patient scheduled for any bilateral (or greater) flap reconstruction
Effect on Body Movement and Mental Skills in Patients Who Received Gadolinium-based Contrast Media for Magnetic Resonance Examination Multiple Times Within 5 Years (ODYSSEY)
This study is a postmarketing requirement jointly carried out by four NDA holders (Bayer AG,
Bracco, GE Healthcare and Guerbet) and the CRO IQVIA.
The study aims to create detailed images of the organs and tissue of the human body during
x-ray, CT-scan or MRI investigations, doctors are using contrast media (a kind of dye) which
can be given to patients by injection into a blood vessel or by mouth.
In this study researchers want to find out whether so called gadolinium-based contrast agents
(GBCAs) have an effect on body movement and mental skills when given to participants multiple
times within 5 years.
The study plans to enroll about 2076 participants suffering from a condition for which they
are likely to have at least annually a MRI or another imaging examinations. Only adults up to
65 years will be considered to join this study. During the study duration of 5 years
participants will receive annually a MRI or other imaging tests (such as CT-scan, x-ray) and
will visit the study doctor at least 7 times for physical examinations, laboratory
investigations and tests on body movement and mental skills.
• Participant must be neurologically normal, defined as free of unstable neurologic and
psychiatric disease as confirmed by a normal neurologic examination at screening
• Participant (GBCA-exposed or controls) agrees to undergo unenhanced magnetic resonance
imaging (UE-MRI) of the brain at enrollment and at the end of the observation period
(5 years)
• Participants should have at least 1 of the following indications: a) Medium to high
risk for breast cancer or dense breasts undergoing breast cancer screening with MRI,
b) Elevated prostate-specific antigen (PSA) and under active diagnostic surveillance
for prostate cancer, c) Chronic liver disease (eg, liver cirrhosis limited to Child
class A, post-hepatitis chronic hepatopathy, or primary sclerosing cholangitis) for
surveillance of hepatocellular carcinoma development, d) Low-grade colorectal cancer
or neuroendocrine tumor undergoing screening for liver metastases or e) Branch-duct
intraductal papillary mucinous neoplasm (IPMN) of the pancreas (maximum size ≤2 cm)
undergoing imaging surveillance.
In addition, for participants in the GBCA Arms only:
• Each participant should be likely to undergo ≥5 GBCA-enhanced MR examinations with the
same GBCA at least annually throughout the 5-year study duration
• Prospective participants with up to 3 well documented GBCA administrations prior to
study screening are acceptable, provided that the imaging was performed with the same
GBCA as the one to be prospectively used in the study. If the GBCA used cannot be
identified, he/she cannot be enrolled.
For the Control Arm:
• Participants who never had and are not likely to receive any GBCA injection during the
course of the study
• Each control participant must be willing to undergo UE-MRI of the brain at baseline
and at Year 5. In Years 1 to 4, the control participants will undergo their clinically
indicated UE-MRIs, computed tomography (CT), ultrasound, or X-ray procedures
Exclusion Criteria:
• As evidenced by history or determined in the neurologic exam at screening, concurrent
neurological and/or psychiatric disease (or treatments) that could influence the
results of the study's motor and cognitive tests (e.g. Cerebrovascular disease,
Multiple sclerosis, Neurodegenerative disease, Malignant disease other than listed in
indications, Carcinoid tumors, Epilepsy, Prior neurosurgery, Psychotic disorders or
any prior psychotic episode not otherwise specified •any documented prior history of
chronic schizophrenia, Remittent or current medically confirmed major depressive
disorder or bipolar disorder, History of long-term major depression or bipolar
affective disorder with an active episode in the past 2 to 5 years, Neurodevelopmental
disorders (eg, trisomy 21), Uncontrolled severe migraine, Uncontrolled or controlled
anxiety or depression within 6 months before enrollment, Screening scores of ≤24 on
the MMSE and/or ≥11 on the Hospital Anxiety and Depression Scale (HADS)).
• Prior, planned, or ongoing chemotherapy or brain irradiation
• Use of concomitant medication(s) affecting neuro-cognitive or motor function
• Substance or alcohol abuse as determined by the investigator
• Alcoholic cirrhosis
• Renal disease, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73
m2
• History of environmental/occupational/other exposure to one or more chemicals that may
affect cognitive and/or motor function, including, but not limited to, heavy metals
(arsenic [As], cadmium [Cd], lead [Pb], manganese [Mn], and mercury [Hg]), pesticides,
solvents, or carbon monoxide.
• Clinical indications requiring >1 contrast enhanced magnetic resonance imaging
(CE-MRI) every 6 months
• Pregnant or nursing (lactating) women
• Presence of any metal-containing joint implants/prostheses
In addition, for participants in either of the GBCA Arms only:
•Receipt of a GBCA or generic prior to study entry other than the specific GBCA to be
administered during the course of the study.
For participants in the Control Arm only:
• Participants with any previous exposure to a GBCA.
• Participants with any contraindication to UE-MRI examinations.
Procedure: Motor Tests, Procedure: Cognitive Tests, Procedure: Unenhanced-MRI of the brain, Procedure: Gadolinium Measurements, Drug: Gadoxetate disodium, Drug: Gadobenate dimeglumine, Drug: Gadodiamide, Drug: Gadoterate meglumine, Drug: Gadobutrol, Drug: Gadoteridol
Breast - Female, Breast - Male, Colon, Liver, Other Endocrine System, Pancreas, Prostate, Rectum, Motor Function, Cognitive Function, Contrast Media
Motor function assessment, Cognitive function assessment, Magnetic Resonance Imaging (MRI), Gadolinium, Gadolinium-based contrast agent (GBCA), Gadolinium retention, Breast cancer, Prostate cancer, Hepatocellular carcinoma, Colorectal cancer, Neuroendocrine tumor, Branch-duct intraductal papillary mucinous neoplasm (IPMN) of the pancreas
A Study to Compare Early Use of Vinorelbine and Maintenance Therapy for Patients With High Risk Rhabdomyosarcoma
This phase III trial compares the safety and effect of adding vinorelbine to vincristine,
dactinomycin, and cyclophosphamide (VAC) for the treatment of patients with high risk
rhabdomyosarcoma (RMS). High risk refers to cancer that is likely to recur (come back) after
treatment or spread to other parts of the body. This study will also examine if adding
maintenance therapy after VAC therapy, with or without vinorelbine, will help get rid of the
cancer and/or lower the chance that the cancer comes back. Vinorelbine and vincristine are in
a class of medications called vinca alkaloids. They work by stopping cancer cells from
growing and dividing and may kill them. Dactinomycin is a type of antibiotic that is only
used in cancer chemotherapy. It works by damaging the cell's deoxyribonucleic acid (DNA) and
may kill cancer cells. Cyclophosphamide is in a class of medications called alkylating
agents. It works by damaging the cell's DNA and may kill cancer cells. It may also lower the
body's immune response. Vinorelbine, vincristine, dactinomycin and cyclophosphamide are
chemotherapy medications that 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. This trial may have the potential to eliminate rhabdomyosarcoma for a long time or
for the rest of patient's life.
• Patients must be =< 50 years of age at the time of enrollment
• Patients with newly diagnosed RMS of any subtype, except adult-type pleomorphic, based
upon institutional histopathologic classification are eligible to enroll on the study
based upon stage, group, and age, as below. FOXO1 fusion status must be determined by
week 4 (day 28) of therapy. RMS types included under embryonal RMS (ERMS) include
those classified in the 1995 International Classification of Rhabdomyosarcoma (ICR) as
ERMS (classic, spindle cell, and botryoid variants), which are reclassified in the
2020 World Health Organization (WHO) Classification as ERMS (classic, dense and
botryoid variants) and spindle cell/sclerosing RMS (encompassing the historical
spindle cell ERMS variant and the newly recognized sclerosing RMS variant).
Classification of alveolar RMS (ARMS) in the 2020 WHO Classification is the same as in
the ICR and includes classic and solid variants
• ERMS
• Stage 4, group IV, >= 10 years of age
• ARMS
• Stage 4, group IV Patients will be eligible to remain on protocol therapy
based upon stage, group, and age
• Bone marrow metastatic disease is based on morphologic evidence of RMS based on
hematoxylin and eosin (H&E) stains. In the absence of morphologic evidence of marrow
involvement on H&E, patients with bone marrow involvement detected ONLY by flow
cytometry, reverse transcriptase (RT)-polymerase chain reaction (PCR), fluorescence in
situ hybridization (FISH), or immunohistochemistry will NOT be considered to have
clinical bone marrow involvement for the purposes of this study
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows (must be
performed within 7 days prior to enrollment):
• Age; Maximum serum creatinine (mg/dL)
• 1 month to < 6 months; 0.4 mg/dL (male); 0.4 mg/dL (female)
• 6 months to < 1 year; 0.5 mg/dL (male); 0.5 mg/dL (female)
• 1 to < 2 years; 0.6 mg/dL (male); 0.6 mg/dL (female)
• 2 to < 6 years; 0.8 mg/dL (male); 0.8 mg/dL (female)
• 6 to < 10 years; 1 mg/dL (male); 1 mg/dL (female)
• 10 to < 13 years; 1.2 mg/dL (male); 1.2 mg/dL (female)
• 13 to < 16 years; 1.5 mg/dL (male); 1.4 mg/dL (female)
• >= 16 years; 1.7 mg/dL (male); 1.4 mg/dL (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (must be performed within
7 days prior to enrollment)
• If there is evidence of biliary obstruction by tumor, then total bilirubin must
be < 3 x ULN for age
• 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:
• Patients with evidence of uncontrolled infection are not eligible
• RMS that is considered a second malignancy and previous cancer(s) that were treated
with chemotherapy and/or radiation. Surgical resection alone of previous cancer(s) is
allowed
• Patients with central nervous system involvement of RMS as defined below:
• Malignant cells detected in cerebrospinal fluid
• Intra-parenchymal brain metastasis separate and distinct from primary tumor
(i.e., direct extension from parameningeal primary tumors is allowed).
• Diffuse leptomeningeal disease
• Patients who have received any chemotherapy (excluding steroids) and/or radiation
therapy for RMS prior to enrollment.
• Note: the following exception:
• Patients requiring emergency radiation therapy for RMS. These patients are
eligible, provided they are consented to ARST2031 prior to administration of
radiation
• Note: Patients who have received or are receiving chemotherapy or radiation for
non-malignant conditions (e.g. autoimmune diseases) are eligible. Patients must
discontinue chemotherapy for non-malignant conditions prior to starting protocol
therapy
• Vincristine and vinorelbine are sensitive substrates of CYP450 3A4 isozyme. Patients
must not have received drugs that are moderate to strong CYP3A4 inhibitors and
inducers within 7 days prior to study enrollment
• 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
Elucidating the Neurocircuitry of Irritability With High-Field Neuroimaging to Identify Novel Therapeutic Targets (UNIKET)
The study is investigating dysfunctions in neurocircuitry in regards to irritability with
healthy controls (HC) and individuals with Major Depressive Disorder (MDD) by performing
MRIs. The MDD group will also be randomized to receive ketamine or midazolam to investigate
changes post-treatment in neurocircuitry with regards to irritability.
1. Male or female subjects, 18-65 years of age and body weight less than or equal to 120
kg on baseline visit.
2. Participants must have a level of understanding of the English language sufficient to
agree to all tests and examinations required by the study and must be able to
participate fully in the informed consent process.
3. For Healthy Controls: Subjects must be free of any lifetime psychiatric condition
based on the Mini-International Neuropsychiatric Interview (MINI). For MDD: Subjects
must meet Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for
current unipolar depression [major depressive disorder (MDD) or persistent depressive
disorder (PDD) in a current major depressive episode (MDE)] based on MINI.
4. A woman of childbearing potential who is sexually active with a male must agree to use
an acceptable method of contraception [defined as either one highly effective
(permanent sterilization, intrauterine device or hormonal implant) or two other forms
of contraception (such as oral contraceptive pill and condom)] to avoid pregnancy
throughout the study. Throughout the study and for 90 days (one spermatogenesis cycle)
after receiving the last dose of study drug (ketamine/midazolam) man who is sexually
active with a woman of childbearing potential must use an acceptable method of
contraception (described above) with his female partner and must agree not to donate
sperm.
5. Subjects must either be free of psychotropic medications (including antidepressants,
antipsychotics, benzodiazepines, mood stabilizers, sedative/hypnotics, dopamine
agonists, stimulants, buspirone, and triptans) and certain anticonvulsants (topiramate
and levetiracetam) or be stable on these medications for four weeks prior to the
baseline visit [first magnetic resonance imaging (MRI) scan].
6. Subjects with MDD should be willing to participate in neuroimaging scans before and
after infusions, and be willing to undergo infusions with study drug.
Exclusion Criteria:
1. Lifetime diagnosis of schizophrenia or any psychotic disorder, bipolar disorder,
pervasive developmental disorder or intellectual development disorder.
2. Current diagnosis of obsessive-compulsive disorder, anorexia nervosa or bulimia.
Comorbid anxiety, stress and trauma-related disorders are permitted as long as
unipolar depression is the primary diagnosis.
3. Diagnosis of a moderate or severe substance use disorder within the past 6 months per
MINI; all subjects must have a negative urine toxicology test on the day of the MRI,
prior to the scan.
4. Female subjects who are pregnant, nursing, for may become pregnant. Women of
childbearing potential must have a negative urine pregnancy test on the day of the
fMRI, prior to scan, and on days of study drug infusion, prior to infusion.
5. Any unstable medical illnesses including hepatic, renal, gastroenterologic,
respiratory, cardiovascular (including ischemic heart disease), endocrinologic,
immunologic, or hematologic disease.
6. Inadequately treated obstructive sleep apnea (STOP-Bang score of 5-8 if untreated, if
using positive airway pressure device then past-month apnea hypopnea index ≥ 15 per
hour representing moderate or higher severity).
7. Presence of a significant neurological disease such as Parkinson's disease, primary or
secondary seizure disorders, intracranial tumors, or severe head trauma.
8. Presence of neurocognitive or dementing disorders.
9. Clinically significant abnormalities of laboratories, physical examination (including
unstable hypertension •systolic blood pressure >170, diastolic blood pressure >100),
or electrocardiogram at screening visit.
10. Subjects judged to be at serious and imminent suicidal or homicidal risk by the PI or
another study-affiliated psychiatrist.
11. Any contraindications to MRI, including pacemakers or metallic objects in the body.
12. Any claustrophobia or other conditions which may result in inability to lie still in
the MRI scanner for 1 hour or more.
13. Allergy to ketamine or midazolam in subjects with MDD.
14. Must not be on any prohibited concomitant medication.
The Synuclein-One Study will be evaluating α-synuclein in patients with Parkinson's disease,
Multiple System Atrophy, Dementia with Lewy bodies and Pure Autonomic Failure. Using a simple
diagnostic test will improve clinical accuracy in diagnosing, earlier diagnosis, and
distinguish between neurodegenerative diseases.
• Male and female between 40-99 years of age
• Prior clinical diagnosis of Parkinson's disease, Multiple System Atrophy, Dementia
with Lewy bodies or Pure Autonomic Failure
• Health Subjects, no history of clinical or symptoms suggestive with synucleinopathy
Exclusion Criteria:
• Clinical evidence of severe vascular disease (history of ulceration, poor wound
healing, vascular claudication)
• Clinically active coronary artery or cerebrovascular disease
• Current smoker or alcoholism
• History of allergic reaction to local anesthesia for skin biopsies
• Use of blood thinners (aspirin or Plavix alone is allowed)
• Significantly impaired wound healing or history of scarring or keloid formation
• Healthy individuals or individuals with synucleinopathy is disease may be explained by
other causes: recent history of encephalitis, Cortical dementia of Alzheimer's type,
Whipple's disease, toxin exposure, repeated head injury and stepwise disease
progression suggestive of vascular etiology
Diagnostic Test: Skin Biopsy
Multiple System Atrophy, Parkinson Disease, Pure Autonomic Failure, Brain and Nervous System, Dementia With Lewy Bodies
A Gene Transfer Therapy Study to Evaluate the Safety and Efficacy of SRP-9001 in Participants With Duchenne Muscular Dystrophy (DMD) (EMBARK)
The study will evaluate the safety and efficacy of gene transfer therapy in boys with DMD. It
is a randomized, double-blind, placebo-controlled study. The participants who are randomized
to the placebo arm will have an opportunity for treatment with gene transfer therapy at the
beginning of the second year.
• Is ambulatory and from 4 to under 8 years of age at time of randomization.
• Definitive diagnosis of DMD based on documented clinical findings and prior genetic
testing.
• Ability to cooperate with motor assessment testing.
• Stable daily dose of oral corticosteroids for at least 12 weeks prior to Screening,
and the dose is expected to remain constant throughout the study (except for
modifications to accommodate changes in weight).
• rAAVrh74 antibody titers are not elevated as per protocol-specified requirements.
Exclusion Criteria:
• Exposure to gene therapy, investigational medication, or any treatment designed to
increase dystrophin expression within protocol specified time limits.
• Abnormality in protocol-specified diagnostic evaluations or laboratory tests.
• Presence of any other clinically significant illness, medical condition, or
requirement for chronic drug treatment that in the opinion of the Investigator creates
unnecessary risk for gene transfer.
Other inclusion or exclusion criteria could apply.
Genetic: SRP-9001, Genetic: Placebo
Duchenne Muscular Dystrophy, Other
Muscular Dystrophies, Duchenne Muscular Dystrophy, DMD, North Star Ambulatory Assessment (NSAA), Ambulatory, Pediatric, Gene-Delivery
Contrast Ultrasound for Pediatric Trauma - Comparative Evaluation (CAPTURE Study)
This multicenter study aims to evaluate the accuracy of contrast-enhanced ultrasound (CEUS)
in diagnosing abdominal solid organ injuries in pediatric patients. Up to 130 subjects will
complete the study across approximately 5-10 sites in the US, with up to 30 patients in the
training phase (3 per site) and 100 patients in the treatment phase of the study. All
subjects will have had a CT scan as part of standard of care, confirming at least one solid
organ abdominal injury. The study procedure will occur within 48 hours from time of injury.
All subjects will have an abdominal ultrasound without contrast, followed by a
contrast-enhanced ultrasound using the contrast agent Lumason. Ultrasound and
contrast-enhanced ultrasound results will be compared to the CT scan results. The CT and
ultrasound scans will be read locally and will undergo central review.
1. Hemodynamically stable, as determined by the trauma team
2. Age 8 through 18 years (inclusive)
3. Interpretable CT of the abdomen and pelvis that demonstrates at least one solid organ
injury among the liver, spleen, pancreas, and kidneys
4. Plan for observation or admission to the hospital
5. Candidate for abdominal ultrasound based on body habitus, as determined by the
investigator
6. Glasgow Coma Score of 15
7. Able to complete the study procedures within 48 hours of injury
Exclusion Criteria:
1. Known cardiac abnormality
2. Pulmonary Hypertension
3. Known sensitivity to any Lumason components •including sulfur hexafluoride,
polyethylene glycol 4000, distearoylphosphatidylcholine (DSPC),
dipalmitoylphosphatidylglycerol sodium (DPPG-Na), or palmitic acid
4. Unable to be rolled onto side to allow lateral ultrasound windows if necessary
5. Unable to assent or consent
6. Pregnant
7. Lactating
8. CT images not available for transmission to central image repository
Drug: Lumason
Cardiovascular, Gall Bladder, Kidney, Liver, Pancreas, Soft Tissue, Abdominal Injury
A Study to Test if Fremanezumab is Effective in Preventing Chronic Migraine in Patients 6 to 17 Years of Age
The primary objective of the study is to evaluate the effectiveness of fremanezumab as
compared to placebo for the preventive treatment of chronic migraine (CM).
Secondary objectives are to further demonstrate the efficacy of Fremanezumab as compared to
placebo for the preventive treatment of CM, to evaluate the safety and tolerability of
Fremanezumab in the preventive treatment of CM and to evaluate the immunogenicity of
Fremanezumab and the impact of antidrug antibodies (ADAs) on clinical outcomes in
participants exposed to Fremanezumab
The total duration of the study is planned to be 48 months.
• The participant has a clinical history of recurrent headache consistent with the
diagnosis of migraine for at least 6 months before screening, consistent with ICHD-3
criteria (Headache Classification Committee of the IHS 2013), and a history of ≥15
headache days per month, of which ≥8 headache days were assessed as migraine days per
month in each of the 3 months prior to screening (visit 1).
• The participant or parent/caregiver maintain a prospectively collected headache diary
• The participant does not have chronic daily headache. For the purposes of this study,
chronic daily headache is operationally defined as <4 headache-free days during the
28-day baseline period.
NOTE: Additional criteria apply; please contact the investigator for more information.
Exclusion Criteria:
• The participant is using medications containing opioids (including codeine) or
barbiturates (including Fiorinal®, Fioricet®, or any other combination containing
butalbital) for the treatment of migraine during the 3 months prior to the day of the
screening visit.
• The participant has used an intervention/device (eg, scheduled nerve block or
transcranial magnetic stimulation) for the treatment of migraine or in the head or
neck area for any condition during the 2 months prior to the day of the screening
visit.
• The participant has a current history of a clinically significant psychiatric
condition, any prior history of a suicide attempt, or a history of suicidal ideation
with a specific plan within the past 2 years, at the discretion of the investigator.
• The participant has an ongoing infection or a known history of human immunodeficiency
virus infection, tuberculosis, Lyme disease, or chronic hepatitis B or C, or a known
active infection of coronavirus disease 2019 (COVID-19).
• The participant has a past or current history of cancer.
• The participant is pregnant, nursing.
• The participant has a history of hypersensitivity reactions to injected proteins,
including mAbs, or a history of Stevens-Johnson Syndrome or toxic epidermal necrolysis
syndrome, or the participant is concomitantly using lamotrigine.
• The participant received a live attenuated vaccine (eg, intranasal flu vaccine, and
measles, mumps, and rubella vaccine) within the 12-week period prior to screening.
Note: If a medical need arises during the study, the participant may receive a live
attenuated vaccine.
• The patient has a current or past medical history of hemiplegic migraine.
NOTE: Additional criteria apply; please contact the investigator for more information.
HERTHENA-Lung02: A Study of Patritumab Deruxtecan Versus Platinum-based Chemotherapy in Metastatic or Locally Advanced EGFRm NSCLC After Failure of EGFR TKI Therapy
Disease progression is typical for patients with epidermal growth factor receptor mutated
(EGFRm) non-small cell lung cancer (NSCLC). Standard platinum-based chemotherapy offers
limited efficacy and an unfavorable safety profile.There is an urgent need for more effective
and tolerable therapies for patients with EGFRm NSCLC who have exhausted available targeted
therapies. Clinical evidence suggest that patritumab deruxtecan constitutes a promising
investigational therapy for patients with EGFRm NSCLC.
1. Is a male or female subject aged ≥18 years (follow local regulatory requirements if
the legal age of consent for study participation is >18 years old).
2. Has histologically or cytologically documented metastatic or locally advanced
non-squamous NSCLC not amenable to curative surgery or radiation.
3. Has documentation of an EGFR-activating mutation detected from tumor tissue or blood
sample: exon 19 deletion or L858R at diagnosis or thereafter.
4. Received 1 or 2 prior line(s) of an approved EGFR TKI treatment in the metastatic or
locally advanced setting, which must include a third -generation EGFR TKI
5. May have received either neoadjuvant and/or adjuvant treatment if progression to
metastatic or locally advanced disease occurred at least 12 months after the last dose
of such therapy and subsequently experienced disease progression on or after
third-generation EGFR TKI treatment administered in the metastatic or locally advanced
setting.
6. Has not received any other prior systemic therapies in the metastatic or locally
advanced setting (including chemotherapy, immunotherapy etc) (even if administered in
combination with EGFR TKI).
7. Has documentation of radiographic disease progression while receiving or after
receiving a third generation EGFR TKI for metastatic or locally advanced disease.
8. Has at least 1 measurable lesion as per RECIST v1.1 by Investigator assessment.
9. Is willing to have a tumor biopsy or provide recently obtained tumor tissue.
10. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at
Screening.
11. Has adequate bone marrow reserve and organ function based on local laboratory
evaluation within 14 days prior to randomization:
• Platelet count: ≥100,000/mm^3 or ≥100 × 10^9/L
• Absolute neutrophil count: ≥1500/mm^3 or ≥1.5 × 10^9/L
• Hemoglobin (Hgb): ≥9.0 g/dL
• Creatine clearance (CrCl): CrCl ≥45 mL/min calculated by using the
Cockcroft-Gault equation or measured CrCl
• Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT): AST/ALT ≤3×
Upper limit of normal (ULN)
• Total bilirubin (TBL): TBL ≤1.5 × ULN
• Serum albumin: ≥2.5 g/dL
• Prothrombin time (PT) or Prothrombin time-International normalized ratio (PT-INR)
and activated partial thromboplastin time (aPTT)/partial thromboplastin time
(PTT): ≤1.5 × ULN, except for participants receiving coumarin-derivative
anticoagulants or other similar anticoagulant therapy who must have PT-INR within
therapeutic range as deemed appropriate by the Investigator
Exclusion Criteria:
1. Has any previous histologic or cytologic evidence of small cell OR combined small
cell/non-small cell disease in the archival tumor tissue or pretreatment tumor biopsy,
or squamous NSCLC histology
2. Has any history of interstitial lung disease (ILD) (including pulmonary fibrosis or
radiation pneumonitis), has current ILD, or is suspected to have such disease by
imaging during Screening
3. Has clinically severe respiratory compromise (based on the Investigator's assessment)
resulting from intercurrent pulmonary illnesses including, but not limited to the
following:
• Any underlying pulmonary disorder, restrictive lung disease, or pleural effusion
• Any autoimmune, connective tissue, or inflammatory disorders where there is
documented, or a suspicion of pulmonary involvement at the time of Screening
• OR prior complete pneumonectomy
4. Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or equivalent
anti-inflammatory activity or any form of immunosuppressive therapy prior to
randomization
5. Has evidence of any leptomeningeal disease
6. Has evidence of clinically active spinal cord compression or brain metastases, defined
as being symptomatic and untreated, or requiring therapy with corticosteroids or
anticonvulsants to control associated symptoms
7. Any prior treatment with any agent including an antibody drug conjugate (ADC)
containing a chemotherapeutic agent targeting topoisomerase I, human epidermal growth
factor receptor 3 (HER3) antibody, and any systemic therapies (other than EGFR TKIs)
in the metastatic/locally advanced setting, including chemotherapy or any other
systemic therapy in combination with an EGFR TKI
8. Has history of other active malignancy within 3 years prior to randomization, except
for adequately resected nonmelanoma skin cancer, adequately treated intraepithelial
carcinoma of the cervix, and any other curatively treated in situ disease
9. Has uncontrolled or significant cardiovascular disease prior to randomization
10. Has active hepatitis B and/or hepatitis C infection, such as those with serologic
evidence of active viral infection within 28 days of randomization
11. Has a known human immunodeficiency virus (HIV) infection that is not well controlled
12. Has clinically significant corneal disease
An International Prospective Open-label, Randomized, Phase III Study Comparing 177Lu-PSMA-617 in Combination With SoC, Versus SoC Alone, in Adult Male Patients With mHSPC (PSMAddition)
The purpose of this study is to evaluate the efficacy and safety of 177Lu-PSMA-617 in
combination with Standard of Care, versus Standard of Care alone, in adult male patients with
mHSPC. In this study, the SoC is defined as a combination of Androgen Receptor Directed
Therapy + Androgen Deprivation Therapy. Approximately 1126 patients will be randomized in
this study.
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study
2. Patients must be adults ≥18 years of age
3. Patients must have an ECOG performance status of 0 to 2
4. Patients must have a life expectancy >9 months as determined by the study investigator
5. Patients must have metastatic prostate cancer with histologically or cytologically
confirmed adenocarcinoma (current or prior biopsy of the prostate and/or metastatic
site)
6. Patients must have evidence of PSMA-positive disease as seen on a 68Ga-PSMA-11 PET/CT
scan, and eligible as determined by the sponsor's central reader
7. Patients must have at least one documented metastatic bone and/or soft tissue/visceral
lesion documented in the following manners within 28 days prior randomization:
1. Metastatic disease to the bone (in any distribution) visible on 99Tc-MDP bone
scintigraphy on either pre-ADT scans or baseline scans AND/OR
2. Lymph node metastases of any size or distribution. If lymph nodes are the only
site of metastasis, then at least one must be at least 1.5 cm in short axis AND
outside of the pelvis AND/OR
3. Visceral metastases of any size or distribution. If a participant has a history
of visceral metastases at any time prior to randomization, he should be coded as
having visceral metastases at baseline (i.e., patients with visceral metastases
prior to ADT that disappear at baseline will be counted as having visceral
metastases and would therefore have high volume disease for stratification
purposes).
8. Patients must have adequate organ function:
• Bone marrow reserve ANC ≥1.5 x 109/L Platelets ≥100 x 109/L Hemoglobin ≥9 g/dL
• Hepatic Total bilirubin ≤2 x the institutional upper limit of normal (ULN). For
patients with known Gilbert's Syndrome ≤3 x ULN is permitted Alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 x ULN OR ≤5.0 x
ULN for patients with liver metastases
• Renal eGFR ≥ 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease
(MDRD) equation
9. Albumin ≥2.5 g/dL
10. Human immunodeficiency virus (HIV)-infected patients who are healthy and have a low
risk of acquired immune deficiency syndrome (AIDS)-related outcomes can participate in
this trial
11. Patients must be:
Treatment naïve OR minimally treated with:
• Up to 45 days of luteinizing hormone-releasing hormone (LHRH) agonist /antagonists or
bilateral orchiectomy with or without first generation anti-androgen (e.g.
bicalutamide, flutamide) for metastatic prostate cancer is allowed prior to ICF
signature. If given, first generation anti-androgen must be discontinued prior to
start of study therapy or after 45 days whatever happens first.
• If received, prior LHRH agonist/antagonist with or without first generation
anti-androgen use in the adjuvant/neo-adjuvant setting must have been discontinued >
12 months prior to ICF signature AND must not have exceeded 24 months of therapy AND
must not have shown disease progression within 12 months of completing
adjuvant/neo-adjuvant therapy.
• Up to 45 days of CYP17 inhibitor or ARDT exposure for metastatic prostate cancer is
allowed prior to ICF signature. No CYP17 inhibitor or ARDT exposure for earlier stages
of prostate cancer is allowed.
Exclusion Criteria:
Participants meeting any of the following criteria are not eligible for inclusion in this
study.
1. Participants with rapidly progressing tumor that requires urgent exposure to
taxane-based chemotherapy
2. Any prior systemic anti-prostate cancer therapy (with the exception of the drugs
listed on inclusion criteria 11), including chemotherapy, Poly (adenosine
diphosphate-ribose) polymerase (PARP) inhibitors, immunotherapy or biological therapy
(including monoclonal antibodies).
3. Concurrent cytotoxicity chemotherapy, immunotherapy, radioligand therapy, PARP
inhibitor, biological therapy or investigational therapy
4. Previous treatment with any of the following within 6 months of randomization:
Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body
irradiation. Previous PSMA-targeted radioligand therapy is not allowed
5. Ongoing participation in any other clinical trial
6. Use of other investigational drugs within 30 days prior to day of randomization
7. Known hypersensitivity to any of the study treatments or its excipients or to drugs of
similar chemical classes
8. Transfusion for the sole purpose of making a participant eligible for study inclusion
9. Participants with CNS metastases that are neurologically unstable, symptomatic, or
receiving corticosteroids for the purpose of maintaining neurologic integrity.
Participants with epidural disease, canal disease and prior cord involvement are
allowed if those areas have been treated, are stable, and not neurologically impaired.
Participants with parenchymal CNS metastasis (or a history of CNS metastasis), that
have received prior therapy and are neurologically stable, asymptomatic and not
receiving steroids for CNS metastases, are allowed, baseline and subsequent
radiological imaging must include evaluation of the brain (magnetic resonance imaging
(MRI) preferred or CT with contrast).
10. Diagnosed with other malignancies that are expected to alter life expectancy or may
interfere with disease assessment. However, participants with a prior history of
malignancy that has been adequately treated and who have been disease free, treatment
free for more than 3 years prior to randomization, or participants with adequately
treated non-melanoma skin cancer, superficial bladder cancer are eligible.
11. Concurrent serious (as determined by the Principal Investigator) medical conditions,
including, but not limited to, uncontrolled infection, known active hepatitis B or C,
or other significant co-morbid conditions that in the opinion of the investigator
would impair study participation or cooperation. Participants with an active
documented COVID-19 infection (any grade of disease severity) at time of informed
consent may be included only when completely recovered (in accordance with local
guidance).
12. Active clinically significant cardiac disease defined as any of the following:
• NYHA class 3/4 congestive heart failure within 6 months prior to ICF signature
unless treated with improvement and echocardiogram or MUGA demonstrates EF > 45%
with improvement in symptoms to class < 3.
• History or current diagnosis of ECG abnormalities indicating significant risk of
safety for participants in the study such as: Concomitant clinically significant
cardiac arrhythmias, e.g. sustained ventricular tachycardia, complete left bundle
branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block,
Mobitz type II and third degree AV block)
• History of familial long QT syndrome or known family history of Torsades de
Pointes
• Cardiac or cardiac repolarization abnormality, including any of the following:
History of myocardial infarction (MI), angina pectoris, or coronary artery bypass
graft (CABG) within 6 months prior to ICF signature
13. History of somatic or psychiatric disease/condition that may interfere with the
objectives and assessments of the study
14. Symptomatic cord compression, or clinical or radiologic findings indicative of
impending cord compression
15. Any condition that precludes raised arms position
16. Unmanageable concurrent bladder outflow obstruction or urinary incontinence. Note:
participants with bladder outflow obstruction or urinary incontinence, which is
manageable and controlled with best available standard of care (incl. pads, drainage)
are allowed.
17. Sexually active males unwilling to use a condom during intercourse while taking study
treatment and for 14 weeks after stopping study treatment. A condom is required for
all sexually active male participants to prevent them from fathering a child AND to
prevent delivery of study treatment via seminal fluid to their partner. In addition,
male participants must not donate sperm for the time period specified above. If local
regulations deviate from the contraception methods listed above to prevent pregnancy,
local regulations apply and will be described in the ICF
Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity (STEP-HFpEF)
This study will look at how the participants daily life is affected by their heart failure.
The study will also look at the change in participants body weight from the start to the end
of the study.
This is to compare the effect on heart failure symptoms and on body weight in people taking
semaglutide (a new medicine) to people taking "dummy" medicine.
Participants will either get semaglutide or "dummy" medicine - which treatment participants
get is decided by chance.
Participants will need to take 1 injection once a week. The study medicine is injected with a
thin needle in a skin fold in the stomach area, thigh or upper arm.
During the study participants will have talks with the study staff about healthy lifestyle
choices including healthy food and physical activity.
The study will last for approximately 59 weeks. Participants will have 11 clinic visits and 1
phone call with the study doctor. Women: Women cannot take part if they are pregnant,
breast-feeding or plan to become pregnant during the study period.
• Male or female, age above or equal to 18 years at the time of signing informed
consent.
• Body mass index (BMI) greater than or equal to 30.0 kg/m^2
• New York Heart Association (NYHA) Class II-IV
• Left ventricular ejection fraction (LVEF) greater than or equal to 45 percentage at
screening
Exclusion Criteria:
• A self-reported change in body weight greater than 5 kg (11 lbs) within 90 days before
screening irrespective of medical records
• Haemoglobin A1c (HbA1c) greater than or equal to 6.5 percentage (48 mmol/mol) based on
latest available value from medical records, no older than 3 months or if unavailable
a local measurement at screening
Radiation Medication (Radium-223 Dichloride) Versus Radium-223 Dichloride Plus Radiation Enhancing Medication (M3814) Versus Radium-223 Dichloride Plus M3814 Plus Avelumab (a Type of Immunotherapy) for Advanced Prostate Cancer Not Responsive to Hormonal Therapy
This phase I/II trial studies the best dose of M3814 when given together with radium-223
dichloride or with radium-223 dichloride and avelumab and to see how well they work in
treating patients with castrate-resistant prostate cancer that had spread to other places in
the body (metastatic). M3814 may stop the growth of tumor cells by blocking some of the
enzymes needed for cell growth. Radioactive drugs, such as radium-223 dichloride, may carry
radiation directly to tumor cells and not harm normal cells. Immunotherapy with monoclonal
antibodies, such as avelumab, may help the body's immune system attack the cancer, and may
interfere with the ability of tumor cells to grow and spread. This study is being done to
find out the better treatment between radium-223 dichloride alone, radium-223 dichloride in
combination with M3814, or radium-223 dichloride in combination with both M3814 and avelumab,
to lower the chance of prostate cancer growing or spreading in the bone, and if this approach
is better or worse than the usual approach for advanced prostate cancer not responsive to
hormonal therapy.
• PHASE 1: Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky
>= 70%)
• PHASE 2: ECOG performance status =< 2 (Karnofsky >= 60%)
• Unless a patient has had orchiectomy by surgery, the patient is expected to be on
antiandrogen therapy (ADT) for "medical castration". ADT needs to be maintained
throughout the study. Testosterone level should be checked, and kept consistently
lower than 50 ng/dL, similar to that obtained with bilateral orchiectomy
• Progressive castration-resistant prostate cancer with two or more skeletal metastases
identified by 99mTC bone scintigraphy. One or more lymph node metastases allowed, but
not mandatory. Lymph node metastases in each individually must measure less than 3 cm
in the longest dimension. Visible visceral organ metastases are not allowed. A
diagnosis of prostate cancer must have been histologically confirmed at any time point
• Baseline prostatic specific antigen (PSA) level of 1 ng/mL or higher with evidence of
progressively increasing PSA values (two consecutive increases over the previous
reference value)
• Progression after at least one of the following: abiraterone, enzalutamide,
apalutamide, darolutamide, or taxane chemotherapy (docetaxel, cabazitaxel). There is
no maximum number of prior therapies. Prior immunotherapies (for example, Sipuleucel-T
or pembrolizumab) do not exclude the patient from participation
• Age >= 18 years. Castrate-resistant prostate cancer (CRPC) affects older adults and is
rarely encountered in children and adolescents
• Life expectancy >= 6 months
• Albumin > 2.5 mg/dL
• Hemoglobin > 9 mg/dL
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (with the exception
of < 3 mg/dL for patients with Gilbert's disease)
• Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional ULN
• Creatinine =< 1.5 x institutional ULN OR
• Glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy (with no medications prohibited by this protocol [e.g. drug-drug
interactions]) with undetectable viral load within 6 months are eligible for this
trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy (with no medications prohibited by
this protocol [e.g. drug-drug interactions]), if indicated
• 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 (with no medications prohibited
by this protocol [e.g. drug-drug interactions])
• Patients with a prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional classification. To be
eligible for this trial, patients should be class 2B or better
• Concomitant use of physiologic corticosteroids is allowed
• Concomitant use of bisphosphonates is allowed (use of bone health agents is mandatory
•either denosumab [preferred] or bisphosphonates)
• The effects of radium-223 dichloride, M3814, and avelumab on the developing human
fetus are unknown. Men treated or enrolled on this protocol must also agree to use
adequate contraception prior to the study, for the duration of study participation,
and 6 months after completion of Radium-223 dichloride, M3814, and avelumab
administration
• Ability to understand and the willingness to sign a written informed consent document.
Participants with impaired decision-making capacity (IDMC) who have a
legally-authorized representative (LAR) and/or family member available will also be
eligible
• Patients must be able to swallow orally administered medication
• Patients with asymptomatic, treated brain metastases are permitted if there is no
evidence of progression for at least 4 weeks after central nervous system
(CNS)-directed treatment, as ascertained by clinical examination and brain imaging
(magnetic resonance imaging [MRI] or computed tomography [CT] scan) during the
screening period
Exclusion Criteria:
• Active autoimmune conditions or patients on chronic immunosuppression due to
underlying autoimmune condition
• Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering
the study
• Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) with the exception of alopecia
• Prior therapy with radionuclides (e.g., strontium, samarium, rhenium, radium)
• Patients who are receiving any other investigational agents
• Patients who have had previous hemibody external radiation
• Patients who have had systemic radiotherapy with radioisotopes
• Patients who have imminent/established spinal cord compression, pathological fracture
in weight bearing bones or bone lesion with soft tissue component unless treated as
appropriate with radiation and/or surgery before starting on trial
• Patients who have a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to radium-223 dichloride, M3814, or avelumab
• Patients unable to discontinue medications or substances that are potent inhibitors,
inducers or sensitive substrates of CYP3A4/5 or CYP2C19 prior to study treatment are
ineligible.
• Medications or substances that are strong inhibitors of CYP3A4/5 or CYP2C19 must
be discontinued at least 1 week prior to first M3814 dose.
• Medications or substances that are strong inducers of CYP3A4/5 or CYP2C19 must be
stopped at least 3 weeks prior to the first M3814 dose.
• Drugs mainly metabolized by CYP3A with a narrow therapeutic index (as judged by
the Investigator or authorized designee) must be discontinued at least 1 day
prior to first M3814 dose.
• Note: Because the lists of these agents are constantly changing, it is important
to regularly consult a frequently- updated medical reference. As part of the
enrollment/informed consent procedures, the patient will be counseled on the risk
of interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the- counter medicine or
herbal product.
• Patients with uncontrolled intercurrent illness
• Patients with psychiatric illness/social situations that would limit compliance with
study requirements
• Patients must not have an active infection requiring systemic treatment
• Patients must not use immunosuppressive medication =< 7 days of registration, EXCEPT
for the following:
• Intranasal, inhaled, topical steroids, or local steroid injection (e.g.,
intra-articular injection)
• Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or
equivalent
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication)
• Patients who cannot discontinue concomitant H2 blockers or proton-pump inhibitors
(PPIs). Patients may confer with the study doctor to determine if such medications can
be discontinued. These must be discontinued >= 5 days prior to study treatment.
Patients do not need to discontinue calcium carbonate
• Patients receiving sorivudine or any chemically related analogues (such as brivudine)
are excluded
• Patients with a known history or present osteonecrosis of the jaw
Metastatic Prostate Carcinoma, Stage IV Prostate Cancer AJCC v8, Prostate, Metastatic Malignant Neoplasm in the Lymph Nodes, Castration-Resistant Prostate Carcinoma
Phase 2 Study With Minimal Residual Disease (MRD) Driven Adaptive Strategy in Treatment for Newly Diagnosed Multiple Myeloma (MM) With Upfront Daratumumab-based Therapy
This phase 2 trial will test whether the combination of DaraRd (daratumumab + lenalidomide +
dexamethasone) as induction therapy, followed by DRVd (daratumumab + lenalidomide +
bortezomib + dexamethasone) consolidation therapy, if needed, will result in more patients
achieving minimal residual disease (MRD)-negative status, relative to the standard of care.
Consolidation therapy will be administered only to those patients with MRD-positive status
after induction therapy.
This is a study based on adaptive design for decision making of treatment options. Duration
of therapy (daratumumab cycles) will depend on individual approach, response, evidence of
disease progression and tolerance.
INCLUSION
1. Participants ≥18 years of age or legal age of consent per local regulations (whichever
is greater).
2. Voluntary written consent must be given before performance of any study-related
procedure not part of standard medical care, with the understanding that consent may
be withdrawn by the participant at any time without prejudice to future medical care.
3. ECOG status (Appendix A) of ≤2 and able to tolerate all applicable treatments per
investigator's evaluation and standard institutional criteria.
4. Both transplant eligible and ineligible myeloma patients can be included in this
study. If applicable, participant should be able to tolerate all treatments per
investigator's evaluation, including high-dose chemotherapy and autologous stem cell
transplant (ASCT) based on standard criteria at the institution where this treatment
will be administered.
5. Participant must have a diagnosis of active MM according to International Myeloma
Working Group (IMWG) diagnostic criteria.
6. Participant must also have measurable disease per protocol.
7. Participant agrees to refrain from blood donations during therapy on study and for 12
weeks after therapy is completed.
8. Participant must be registered in and must comply with all requirements of REMSTM
program for lenalidomide.
9. Female participant who:
• Is post-menopausal for at least one year prior to study enrollment, OR
• Is surgically sterile, OR
• If of childbearing potential, must have a negative urine or serum pregnancy test
within 10-14 days prior to and again within 24 hours of starting lenalidomide.
They must also be willing to use TWO effective forms of contraception
simultaneously from the time of signing the study consent until 90 days following
the administration of the last dose of lenalidomide and 7 months following the
administration of the last dose of bortezomib, OR
• Agree to practice true abstinence if that is aligned with their lifestyle, which
does not include periodic abstinence or withdrawal.
10. Male participant, even if surgically sterilized, must agree to one of the following:
• Agree to practice effective barrier contraception during the entire study
treatment period and through 90 days after the last dose of lenalidomide and 4
months following the administration of the last dose of bortezomib, OR
• Agree to practice true abstinence if that is aligned with their lifestyle, which
does not include periodic abstinence or withdrawal.
EXCLUSION:
1. Diagnoses of smoldering MM (SMM), monoclonal gammopathy of undetermined significance
(MGUS), non-secretory MM, plasma cell leukemia, AL amyloidosis, Waldenstrom's.
macroglobulinemia, POEMS syndrome. History of SMM and/or MGUS is not excluded.
2. Known disease involvement of the CNS.
3. History of prior hematopoietic stem cell transplant of any type.
4. Received more than one cycle of anti-myeloma therapy prior to enrollment. Up to one
cycle of myeloma therapy is allowed. Concomitant treatment is allowed with low-dose
corticosteroids and bisphosphonates. The dose of corticosteroids for myeloma treatment
should not exceed the equivalent of 160 mg of dexamethasone over a two-week period
before initiation of protocol. Prednisone up to but no more than 10 mg po daily or its
equivalent is allowed, for symptom management and comorbid conditions.
5. Significant renal insufficiency, defined as creatinine clearance <30ml/min per
Cockcroft-Gault formula.
6. Hepatic impairment, defined as bilirubin >1.5 x institutional upper limit of normal
(ULN) or AST (SGOT), ALT (SGPT), or alkaline phosphatase > 3x institutional ULN.
7. Absolute neutrophil count (ANC) < 1000 cells/mm3 within 14 days of enrollment. Growth
factor may not be used to meet ANC eligibility criteria.
8. Hemoglobin (Hgb) < 8g/dL within 14 days of enrollment. Transfusion may not be used to
meet Hgb eligibility criteria.
9. Platelet count < 75,000 cells/mm3 within 14 days of enrollment. Transfusion may not be
used to meet platelet eligibility criteria.
10. Any condition, including laboratory abnormalities, that in the opinion of the
investigator places the subject at unacceptable risk if subject were to participate in
the study.
11. Major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from
complications of the surgery.
12. Clinically significant peripheral neuropathy not well controlled with treatment,
defined as symptoms limiting activities of daily living (basic ADLs).
13. Symptomatic uncontrolled cardiac disease including congestive heart failure with New
York Heart Association class III-IV symptoms, arrhythmia, unstable angina or
myocardial infarction within the past six months, or any other uncontrolled or severe
cardiovascular condition.
14. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in
1 second (FEV1) <50% of predicted normal.
15. Clinically uncontrolled asthma of any classification or known moderate or severe
persistent asthma within the past two years (see asthma guidelines.
https://www.nhlbi.nih.gov/files/docs/guidelines/asthma_qrg.pdf).
16. Serious intercurrent illness including but not limited to clinically relevant
cerebrovascular disease, uncontrolled diabetes mellitus, cirrhosis, pulmonary disease.
17. Active autoimmune process or other disease requiring systemic immunosuppressive,
monoclonal antibody, small molecule, or radiation therapy.
18. Participant is:
• Seropositive for HIV
• Seropositive for Hepatitis B (defined by a positive test for hepatitis B surface
antigen [HBsAg]
• Subjects with resolved infection (i.e., subjects who are HBsAg negative but
positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies
to hepatitis B surface antigen [anti-HBs]) must be screened using real-time
polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA
levels. Those who are PCR positive will be excluded.
• Participants with serologic findings suggestive of HBV vaccination (anti-HBs
positivity as the only serologic marker) AND a known history of prior HBV
vaccination, do not need to be tested for HBV DNA by PCR.
• Seropositive for Hepatitis C (except in the setting of a sustained virologic
response [SVR], defined as aviremia at least 12 weeks after completion of
antiviral therapy).
19. History of additional active malignancy in the past five years (not including squamous
cell or basal cell carcinoma of the skin or in situ cervical cancer). However,
malignancy treated with curative intent with <5% chance of disease relapse /
recurrence in the next two years is allowed.
20. Known drug allergy or intolerance to study medications (including steroids) or
appropriate prophylactic medications (e.g. acyclovir, aspirin, warfarin or
low-molecular weight heparin).
21. Women with a positive pregnancy test during the screening period prior to study
initiation or who are lactating.
22. Participation in other clinical trials, including those with other investigational
agents not included in this trial, within 30 days of the start of this trial and
throughout the duration of this trial.
23. Any significant history of non-compliance to medical regimens or unwilling or unable
to comply with the instructions given.
24. Participants using strong CYP3A4 inducers are excluded unless the inducer can be
switched to an alternative agent while receiving Bortezomib (per protocol).
A Study of Avapritinib in Pediatric Patients With Solid Tumors Dependent on KIT or PDGFRA Signaling
This is a Phase 1/2, multicenter, open-label trial of avapritinib in patients aged 2 to less
than 18 years of age with with relapsed/refractory (R/R) solid tumors with mutations
(including non-synonymous point mutations, insertions, and deletions) in KIT or PDGFRA, or
gliomas with the H3K27M mutation, and no available alternative treatment options. This is a
single-arm trial in which all patients will receive avapritinib. The study consists of 2
parts: dose confirmation, safety, and PK (Part 1) and initial efficacy, safety, and PK at the
Part 2 recommended dose (Part 2).
• Patient has confirmed diagnosis of a R/R solid or CNS tumor with a mutation in KIT or
PDGFRA (confirmed by local mutational testing of tumor sample) that has progressed
despite standard therapy and no alternative treatment option is available OR Confirmed
diagnosis of H3K27M mutant glioma that has failed standard therapy or for which no
standard therapy that may convey clinical benefit exists, as judged by the
Investigator.
• Patients with CNS disease should be on a stable dose (≤10% change) of corticosteroids
for at least 7 days prior to first dose of avapritinib, with no plans for dose
escalation.
• Disease extent
1. Part 1: All patients must have at least 1 measurable lesion as defined by RECIST
v1.1 or RANO (for CNS tumors). If radiation therapy has been administered, at
least
1 measurable lesion must not have been irradiated, or must have clearly
progressed since being irradiated.
2. Part 2: At least one measurable lesion as defined by RECIST v1.1 (RANO for CNS
tumors). If radiation therapy has been administered, at least 1 measurable lesion
must not have been irradiated within the previous 12 weeks, or must have clearly
progressed since being radiated (per RANO). For up to 5 patients with H3K27M
mutant gliomas where there is no standard therapy that may convey clinical
benefit as judged by the investigator, progression of disease of a measurable
lesion after irradiation is not required.
• A Lansky (≤16 years of age) or Karnofsky (>16 years of age) score of at least 50. If
the patient is unable to walk due to paralysis, but is mobile in a wheelchair, the
patient is considered ambulatory for the purpose of assessing their performance
status.
• Patient agrees to utilize contraception consistent with local regulations
Exclusion Criteria:
• Patient has any of the following within 14 days before the first dose of study
treatment:
1. Platelet count <75 × 109/L (<100 × 109/L if a CNS tumor).
2. Absolute neutrophil count (ANC) <1.0 × 109/L.
3. Hemoglobin <8.0 g/dL (RBC transfusion ≥14 days before test is permitted to meet
criterion).
4. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 × the upper
limit of normal (ULN) for age; except in patients with tumor involvement of the
liver who must not have AST and ALT >5 × ULN for age.
5. Total bilirubin >1.5 mg/dL for age; and in presence of Gilbert's syndrome, total
bilirubin.
> 3 × ULN or direct bilirubin > 1.5 × ULN.
6. Serum creatinine >1.5 × ULN for age.
7. International normalized ratio (INR) or prothrombin time (PT) >ULN (>1.5 × ULN if
on prophylactic reversible anticoagulants).
• Patient has a QT interval corrected using Fridericia's formula (QTcF) >470 msec.
Patient has a familial or personal history of prolonged QT syndrome or Torsades de
pointes.
• Patient has clinically significant, uncontrolled, cardiovascular disease including
congestive heart failure Grade III or IV according to the New York Heart Association
(NYHA) classification; myocardial infarction or unstable angina within the previous 6
months, uncontrolled hypertension (>99th percentile for age), or clinically
significant, uncontrolled arrhythmias, including bradyarrhythmias that may cause QT
prolongation (eg, Type II second degree heart block or third-degree heart block).
• Patient received the following systemic antineoplastic therapies:
1. Systemic antineoplastic therapy (including experimental therapy within 5
half-lives or 28 days [6 weeks if prior nitrosurea], whichever is shorter).
2. Focal external beam radiotherapy, including stereotactic radiosurgery, within 6
weeks prior to the first dose of avapritinib to either target or non-target
lesions. Systemic radiopharmaceuticals, including nonstereotactic radiosurgery,
within 2 weeks of the first dose of avapritinib (within 6 weeks for patients with
CNS tumors). Craniospinal irradiation within 12 weeks prior to the first dose of
avapritinib.
3. All AEs related to other antineoplastic therapies (eg, systemic antineoplastics,
radiotherapy) must have resolved to Grade ≤1 (Grade ≤2 for peripheral neuopathy
and/or ototoxicity) prior to the first dose of avapritinib.
• Patient has previously received treatment with avapritinib.
• Patient received autologous stem cell transplant (SCT) following myeloablative therapy
or chimeric antigen receptor T cell (CAR-T) therapy within 3 months prior to the first
dose of avapritinib or prior allogeneic SCT within 1 year and no evidence of Grade 1
or greater graft-versus-host disease and no immunosuppressants for graft-versus-host
disease (steroids for primary malignancy being permitted). Patients who received stem
cell reinfusion following nonmyeloablative therapy are eligible once they meet the
peripheral blood count criteria in Exclusion Criterion #1.
• Patient requires on going treatment or has received treatment within 28 days before
the start of avapritinib administration with drugs or foods that are strong CYP3A
inhibitors or inducers or EIAEDs (eg, carbamazepine, phenytoin, phenobarbital, and
primidone). Please refer to Appendix 1 for a list of these drugs and/or foods.
• Patient has had a major surgical procedure within 14 days of the first dose of study
treatment (procedures such as central venous catheter placement, tumor needle biopsy,
and feeding tube placement are not considered major surgical procedures).
• Patient has a history of another primary malignancy that has been diagnosed or
required therapy within 3 years before the first dose of avapritinib. The following
prior malignancies are not exclusionary: completely resected basal cell and squamous
cell skin cancer, curatively treated localized prostate cancer, and completely
resected carcinoma in situ of any site.
• Female subjects of childbearing potential who are unwilling, if not post-menopausal or
surgically sterile, to abstain from sexual intercourse or employ highly effective
contraception from the time of informed consent and for at least 6 weeks after the
last dose of study treatment. Male subjects who are unwilling, if not surgically
sterile, to abstain from sexual intercourse or employ highly effective contraception
from the time of informed consent and for at least 6 weeks after the last dose of
study treatment. Refer to Section 5.4.2 for acceptable methods of contraception.
• Patient is pregnant
• Patient is breastfeeding.
• Patient has prior or ongoing clinically significant illness, medical condition,
surgical history, physical finding, or laboratory abnormality that, in the
Investigator's opinion, could affect the safety of the patient; alter the absorption,
distribution, metabolism, or excretion of the study drug; or impair the assessment of
study results.
• History of thrombosis requiring treatment within the past 6 months.
• Patients who require anticoagulants, with the exception of stable doses of
prophylactic reversible anticoagulants.
• Patients who are unable to swallow tablets (in Part 1) or mini-tablets (in Part 2)
within the sprinkle capsules.
• Patients with a known risk of intracranial bleeding, such as a brain aneurysm that has
not been removed or repaired, or a history of intracranial bleeding within the past
year, or radiographic evidence of hemorrhage on Screening MRI. Exceptions are patients
with primary CNS tumors who are eligible unless CNS bleeding has occurred within 2
weeks of the first dose of avapritinib and patients with punctate hemorrhages <3 mm.
• History of a seizure disorder that is not well controlled on current antiepileptic
medications. EIAEDs carbamazepine, phenytoin, phenobarbital, and primidone are
prohibited.
• Patient is unwilling or unable to comply with scheduled visits, treatment
administration plan, laboratory tests, or other study procedures and study
restrictions
A Study of the Drug Selinexor With Radiation Therapy in Patients With Newly-Diagnosed Diffuse Intrinsic Pontine (DIPG) Glioma and High-Grade Glioma (HGG)
This phase I/II trial tests the safety, side effects, and best dose of selinexor given in
combination with standard radiation therapy in treating children and young adults with newly
diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG) with a genetic
change called H3 K27M mutation. It also tests whether combination of selinexor and standard
radiation therapy works to shrink tumors in this patient population. Glioma is a type of
cancer that occurs in the brain or spine. Glioma is considered high risk (or high-grade) when
it is growing and spreading quickly. The term, risk, refers to the chance of the cancer
coming back after treatment. DIPG is a subtype of HGG that grows in the pons (a part of the
brainstem that controls functions like breathing, swallowing, speaking, and eye movements).
This trial has two parts. The only difference in treatment between the two parts is that some
subjects treated in Part 1 may receive a different dose of selinexor than the subjects
treated in Part 2. In Part 1 (also called the Dose-Finding Phase), investigators want to
determine the dose of selinexor that can be given without causing side effects that are too
severe. This dose is called the maximum tolerated dose (MTD). In Part 2 (also called the
Efficacy Phase), investigators want to find out how effective the MTD of selinexor is against
HGG or DIPG. Selinexor blocks a protein called CRM1, which may help keep cancer cells from
growing and may kill them. It is a type of small molecule inhibitor called selective
inhibitors of nuclear export (SINE). Radiation therapy uses high energy to kill tumor cells
and shrink tumors. The combination of selinexor and radiation therapy may be effective in
treating patients with newly-diagnosed DIPG and H3 K27M-Mutant HGG.
• STEP 0: Patients must be >= 12 months and =< 21 years of age at the time of enrollment
on Step 0.
• Please note:
• This age range includes pre-screening for all HGG patients. Individual
treatment protocols may have different age criteria.
• Non-DIPG patients with tumors that do not harbor an H3K27M-mutation and are
>= 18 years of age will not be eligible to enroll on ACNS1821 (Step 1).
• STEP 0: Patient is suspected of having localized, newly diagnosed HGG, excluding
metastatic disease, OR patient has an institutional diagnosis of DIPG
• STEP 0:
• For patients with non-pontine tumors: Patient and/or their parents or legal
guardians have signed informed consent for eligibility screening on APEC14B1 Part
A.
• For patients with DIPG: Patient and/or their parents or legal guardians have
signed informed consent for ACNS1821.
• STEP 0:
• For patients with non-pontine tumors only, the specimens obtained at the time of
diagnostic biopsy or surgery must be submitted through APEC14B1 ASAP, preferably
within 5 calendar days of definitive surgery
• STEP 1: Patients must be >= 12 months and =< 21 years of age at the time of enrollment
• STEP 1: Patients must have newly-diagnosed DIPG or HGG (including DMG).
• STEP 1: Stratum DIPG
• Patients with newly-diagnosed typical DIPG, defined as tumors with a pontine
epicenter and diffuse involvement of at least 2/3 of the pons on at least 1 axial
T2 weighted image, are eligible. No histologic confirmation is required.
• Patients with pontine tumors that do not meet radiographic criteria for typical
DIPG (e.g., focal tumors or those involving less than 2/3 of the pontine
cross-sectional area with or without extrapontine extension) are eligible if the
tumors are biopsied and proven to be high-grade gliomas (such as anaplastic
astrocytoma, glioblastoma, high-grade glioma not otherwise specified [NOS],
and/or H3 K27M-mutant) by institutional diagnosis.
• STEP 1: Stratum DMG (with H3 K27M mutation)
• Patients must have newly-diagnosed non-pontine H3 K27M-mutant HGG without BRAF
V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular
Screening Reviews performed on APEC14B1
• Note: Patients need not have either measurable or evaluable disease, i.e., DMG
patients may have complete resection of their tumor prior to enrollment. Primary
spinal tumors are eligible for enrollment. For rare H3 K27M-mutant HGG in
non-midline structures (e.g., cerebral hemispheres), these patients will be
considered part of Stratum DMG.
• STEP 1: Stratum HGG (without H3 K27M mutation)
• Patients must have newly-diagnosed non-pontine H3 K27M-wild type HGG without BRAF
V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular
Screening Reviews performed on APEC14B1
• Please note:
• Patients who fall in this category and who are >= 18 years of age are not
eligible due to another standard-of-care regimen (radiation/temozolomide)
that is available
• Patients need not have either measurable or evaluable disease, i.e., HGG
patients may have complete resection of their tumor prior to enrollment.
Primary spinal tumors are eligible for enrollment
• STEP 1: 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. Patients who are unable to walk because
of paralysis, but who are up in a wheelchair, will be considered ambulatory for the
purpose of assessing the performance score.
• STEP 1: Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to
step 1 enrollment)
• STEP 1: Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to
step 1 enrollment)
• STEP 1: Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within
7 days prior to step 1 enrollment)
• STEP 1: Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 (within 7 days prior to step 1 enrollment) or
A serum creatinine based on age/gender as follows (within 7 days prior to step 1
enrollment):
• Age / Maximum Serum Creatinine (mg/dL)
• 1 to < 2 years / male: 0.6; female: 0.6
• 2 to < 6 years / male: 0.8; female: 0.8
• 6 to < 10 years / male: 1; female: 1
• 10 to < 13 years / male: 1.2; female: 1.2
• 13 to < 16 years / male: 1.5; female: 1.4
• >= 16 years / male: 1.7; female: 1.4
• STEP 1: Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• STEP 1: Serum glutamate pyruvate transaminase (SGPT) (alanine
aminotransferase [ALT]) =< 135 U/L. For the purpose of this study, the ULN
for SGPT is 45 U/L.
• STEP 1: Serum amylase =< 1.5 x ULN
• STEP 1: Serum lipase =< 1.5 x ULN
• STEP 1: No evidence of dyspnea at rest, no exercise intolerance, and a pulse
oximetry > 94% if there is clinical indication for determination.
• STEP 1: Patients with seizure disorder may be enrolled if on anticonvulsants
and well controlled.
• STEP 1: Patients must be enrolled and protocol therapy must begin no later
than 31 days after the date of radiographic diagnosis (in the case of
non-biopsied DIPG patients only) or definitive surgery, whichever is the
later date (Day 0).
For patients who have a biopsy followed by resection, the date of resection will be
considered the date of definitive diagnostic surgery. If a biopsy only was performed, the
biopsy date will be considered the date of definitive diagnostic surgery.
Exclusion Criteria:
• STEP 1: Patients must not have received any prior therapy for their central nervous
system (CNS) malignancy except for surgery and steroid medications.
• STEP 1: Patients who are currently receiving another investigational drug are not
eligible.
• STEP 1: Patients who are currently receiving other anti-cancer agents are not
eligible.
• STEP 1: Patients >=18 years of age who have H3 K27M-wild type HGG.
• STEP 1: Patients who have an uncontrolled infection.
• STEP 1: Patients who have received a prior solid organ transplantation.
• STEP 1: Patients with grade > 1 extrapyramidal movement disorder.
• STEP 1: Patients with known macular degeneration, uncontrolled glaucoma, or cataracts.
• STEP 1: Patients with metastatic disease are not eligible; MRI of spine with and
without contrast must be performed if metastatic disease is suspected by the treating
physician.
• STEP 1: Patients with gliomatosis cerebri type 1 or 2 are not eligible, with the
exception of H3 K27M-mutant bithalamic tumors.
• STEP 1: Patients who are not able to receive protocol specified radiation therapy.
• STEP 1:
• 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. It is not known whether selinexor is excreted in human milk.
• Female patients of childbearing potential are not eligible unless a negative
pregnancy test result has been obtained.
• Sexually active patients of reproductive potential are not eligible unless they
have agreed to use two effective methods of birth control (including a medically
accepted barrier method of contraception, e.g., male or female condom) for the
duration of their study participation and for 90 days after the last dose of
selinexor. Abstinence is an acceptable method of birth control.
A Trial to Assess the Efficacy and Safety of Octreotide Subcutaneous Depot in Patients With PLD (POSITANO)
The purpose of the trial is to compare the effectiveness and safety of 2 treatment regimens
of CAM2029 (given weekly or every 2 weeks) to placebo in participants with symptomatic PLD,
either isolated as in autosomal dominant PLD (ADPLD) or associated with autosomal dominant
polycystic kidney disease (ADPKD).
In the Treatment Period of the trial, participants will be allocated at random to 1 of the 3
treatment arms in a 1:1:1 ratio. After completing the Treatment Period (53 weeks)
participants may proceed to a 24-week open-label extension part of the trial and then only
receive the same CAM2029 treatment.
The active ingredient in CAM2029, octreotide, is administered as a subcutaneous depot using
Camurus' FluidCrystal® technology.
• Male or female patient, ≥18 years at screening
• Diagnosis of PLD (associated with ADPKD or isolated as in ADPLD) as defined by htTLV
≥2500 mL/m at screening
• Presence of at least 1 of the following PLD-related symptoms within 2 weeks before
screening: bloating, fullness in abdomen, lack of appetite, feeling full quickly after
beginning to eat, acid reflux, nausea, rib cage pain or pressure, pain in side,
abdominal pain, back pain, shortness of breath after physical exertion, limited in
mobility, concern about abdomen getting larger, dissatisfied by the size of abdomen
• Not a candidate for, or not willing to undergo, surgical intervention for hepatic
cysts during the trial
Exclusion Criteria:
• Surgical intervention for PLD within 3 months before screening
• Treatment with a somatostatin analogue (SSA) within 3 months before screening
• Non-responsive to previous treatment of PLD with an SSA as per the Investigator's
assessment
• Cholelithiasis within 3 months before screening or previous medical history of
cholelithiasis induced by SSAs unless treated with cholecystectomy
• Presence of extrahepatic cysts that, in the Investigator's opinion, may prevent the
patient from safely participating in the trial
• Severe kidney disease, as defined by eGFR <30 mL/min/1.73^m2
• Severe liver disease defined as liver cirrhosis of Child-Pugh class C
• Any other current or prior medical condition that may interfere with the conduct of
the trial or the evaluation of its results in the opinion of the Investigator
A Study to Assess the Safety, Tolerability, and Pharmacokinetics of Brensocatib Tablets in Adults With Cystic Fibrosis
The main objective of the study is to evaluate the pharmacokinetics of brensocatib in
participants with cystic fibrosis following once daily oral administration of study drug and
to evaluate the safety of brensocatib compared to placebo in participants with cystic
fibrosis (CF) over the 4-week treatment period.
• Participants must be ≥18 years of age at the time of signing the informed consent.
• Male or female participants with a confirmed diagnosis of CF related lung disease:
a. Stable CF treatment for at least 30 days and willing to remain on a stable regimen
throughout the treatment period.
• Has a body mass index ≥18 kg/m^2.
• Male and female participants must use contraceptives that are consistent with local
regulations regarding the methods of contraception for those participating in clinical
studies.
1. Male participants, who are not sterile, with female partners of childbearing
potential must be using effective contraception from Day 1 to at least 90 days
after the last dose.
2. Women must be postmenopausal (defined as no menses for 12 months without an
alternative medical cause), surgically sterile, or using highly effective
contraception methods (ie, methods that alone or in combination achieve <1%
unintended pregnancy rates per year when used consistently and correctly) from
Day 1 to at least 90 days after the last dose.
• Male participants with pregnant or nonpregnant women of childbearing potential
partners must use a condom.
Exclusion Criteria:
• Severe or unstable CF, per Investigator's judgement. .
• Currently being treated for allergic bronchopulmonary aspergillosis or nontuberculous
mycobacteria or tuberculosis.
• Active and current infection by severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2).
• History of malignancy in the past 5 years, except completely treated in situ carcinoma
of the cervix and completely treated non-metastatic squamous or basal cell carcinoma
of the skin.
• Established diagnosis of hepatitis B viral infection or positive for hepatitis B
surface antigen (HBsAg) at Screening.
• History of human immunodeficiency virus (HIV) infection.
• Acute upper or lower respiratory tract infection, pulmonary exacerbation, or changes
in therapy (including intravenous and oral antibiotics) for pulmonary disease within 4
weeks prior to Day 1 (administration of the first dose of study drug). Participants
meeting this criterion could be rescreened 4 weeks after resolution of symptoms.
• History of solid organ or hematological transplantation.
• Currently being treated for periodontal disease.
• Received any live attenuated vaccine within 4 weeks prior Screening.
• Ongoing participation in another therapeutic clinical study or prior participation in
an investigational drug study within 90 days prior to Screening.
• Known history of hypersensitivity to brensocatib or any of its excipients.
• Use of any immunomodulatory agents within 4 weeks before the Screening Visit is
prohibited during the study through end of study (including, but not limited to:
bortezomib, ixazomib, thalidomide, cyclophosphamide, mycophenolate, Janus kinase
inhibitors, interferon gamma (IFN-γ], and azathioprine).
• Continuous use of high-dose non-steroidal anti-inflammatory drugs (NSAIDs) is
prohibited during the study through end of study.
• History of alcohol, medication, or illicit drug abuse.
• Current smoker, as defined by Centers for Disease Control and Prevention: An adult who
has smoked 100 cigarettes in his or her lifetime and who currently smokes cigarettes.
Safety and Efficacy of HMI-103, a Gene Editing Development Candidate in Adults With Classical PKU Due to PAH Deficiency
This is an open-label, sequential ascending dose-escalation, Phase 1 study to evaluate the
safety and efficacy of a single intravenous (I.V.) administration of HMI-103, a gene editing
development candidate, in adult participants aged 18 to 55 years, inclusive, with classical
PKU due to PAH deficiency who have uncontrolled disease despite Phe restricted dietary
management.
• Adults 18-55 years of age at the time of informed consent
• Diagnosis of classical phenylketonuria (PKU) due to PAH deficiency
• Four baseline plasma Phe values with a concentration of ≥ 600 μmol/L and at least one
historical value ≥ 600 μmol/L in the preceding 24 months.
• Participants must have uncontrolled classical PKU disease (despite Phe-restricted
dietary management) in the judgment of the investigator and confirmed by the
independent DMC at the end of the Screening period.
• Participant has the ability and willingness to maintain their baseline diet, for the
duration of the trial, unless otherwise directed
Exclusion Criteria:
• Subjects with PKU that is not due to PAH deficiency
• Presence of anti-AAVHSC15 neutralizing antibodies
• Participants who are well controlled on a Phe-restricted diet.
• Hemoglobin A1c >6.5% or fasting glucose >126 mg/dL
• Liver function tests > ULN
• International normalized ratio (INR) > 1.2
• Hematology values outside of the normal range
• Previously received gene therapy for the treatment of any condition.
Drug: HMI-103
Other Endocrine System, Phenylketonurias, PAH Deficiency, Phenylketonuria
Testing Early Treatment for Patients With High-Risk Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Leukemia (SLL), EVOLVE CLL/SLL Study
This phase III trial compares early treatment with venetoclax and obinutuzumab versus delayed
treatment with venetoclax and obinutuzumab in patients with newly diagnosed high-risk chronic
lymphocytic leukemia or small lymphocytic lymphoma. Venetoclax is in a class of medications
called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by
blocking Bcl-2, a protein needed for cancer cell survival. Immunotherapy with monoclonal
antibodies, such as obinutuzumab, may help the body's immune system attack the cancer, and
may interfere with the ability of tumor cells to grow and spread. Starting treatment with the
venetoclax and obinutuzumab early (before patients have symptoms) may have better outcomes
for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma compared to
starting treatment with the venetoclax and obinutuzumab after patients show symptoms.
• Participants must have a confirmed diagnosis of chronic lymphocytic leukemia (CLL) or
small lymphocytic lymphoma (SLL) (collectively referred to as CLL throughout)
according to the 2018 International Workshop on CLL. Participants must have been
diagnosed within 12 months prior to registration
• Participants must have CLL-International Prognostic Index (CLL-IPI) score >= 4 and/or
complex cytogenetics (defined as 3+ chromosomal abnormalities)
• Cytogenetic AND/OR FISH analyses must be completed at a Clinical Laboratory
Improvement Act (CLIA)-approved (or laboratories accredited under Accreditation Canada
Diagnostics to conduct FISH analyses) laboratory within 12 months prior to
registration. FISH panel should use probes to detect for abnormalities in chromosomes
13q, 12, 11q, and 17p
• TP53 mutation status (if completed) must be obtained within 12 months prior to
registration
• Immunoglobulin heavy chain locus variable (IgVH) mutational status must be obtained
prior to registration (at any time prior to registration)
• Serum beta-2 microglobulin level must be obtained within 28 days prior to registration
• Treatment with high dose corticosteroids and/or intravenous immunoglobulin for
autoimmune complications of CLL must be complete at least 4 weeks prior to enrollment
• Steroids used for treatment of conditions other than CLL/SLL must be at a dose of at
most 20 mg/day of prednisone or equivalent corticosteroid at the time of registration
• Prior therapy with anti CD20 monoclonal antibodies is not allowed
• Participants must be >= 18 years of age
• Participants must have Eastern Cooperative Oncology Group (ECOG) performance status =<
2
• Platelet count >= 100,000/mm^3 within 28 days prior to registration
• Absolute neutrophil count (ANC) >= 1,000/mm^3 within 28 days prior to registration
• Creatinine clearance >= 30mL/min (by Cockcroft Gault) within 28 days prior to
registration
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x upper
limit of normal (ULN) within 28 days prior to registration
• Total bilirubin =< 2.0 x ULN (or 5.0 x ULN if the participant has a history of
Gilbert's disease), within 28 days prior to registration
• Participants must be able to take oral medications
• Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
• Participants with history of malignancy are allowed providing the cancer has not
required active treatment within 2 years prior to registration (hormonal therapy is
permissible). The following exceptions are permissible: basal cell, squamous cell
skin, or non-melanomatous skin cancer, in situ cervical cancer, superficial bladder
cancer not treated with intravesical chemotherapy or Bacillus Calmette-Guerin (BCG)
within 6 months, localized prostate cancer requiring no more than chronic hormonal
therapy, or localized breast cancer requiring no more than chronic hormonal therapy
• Obinutuzumab has been associated with hepatitis reactivation. Participants must not
have uncontrolled active infection with hepatitis B or C. Participants with latent
hepatitis B infection must agree to take prophylaxis during and for 6 months following
active protocol therapy with V-O.
• Active infection with hepatitis B or C:
• Active infection is defined as detectable hepatitis B deoxyribonucleic acid
(DNA) or hepatitis C ribonucleic acid (RNA) by quantitative polymerase chain
reaction (PCR).
• Latent infection with hepatitis B:
• Latent infection is defined as meeting all of the following criteria:
• Hepatitis B surface antigen positive
• Anti-hepatitis B total core antibody positive
• Anti-hepatitis IgM core antibody undetectable
• Hepatitis B PCR undetectable
• Participants with latent hepatitis B infection must agree to take
prophylaxis with anti-hepatitis agents during and for 6 months following
active protocol therapy with V-O.
• Participants who have received intravenous immunoglobulin (IVIG) therapy
within 6 months who are hepatitis B core total antibody positive but PCR
undetectable are not mandated to take prophylaxis
• Participants must agree to have specimens submitted for translational medicine (MRD)
and specimens must be submitted as outlined
• Participants must be offered participation in banking for future research. With
patient's consent, specimens must be submitted as outlined
• Participants who are able to complete patient reported outcome (PRO) forms in English,
Spanish, French, German, Russian or Mandarin must agree to participate in the quality
of life assessments. (Those participants who are unable to read and write in English,
Spanish, French, German, Russian or Mandarin may be registered to S1925 without
contributing to the quality of life portion of the study.)
• Participants must be informed of the investigational nature of this study and must
sign and give written informed consent in accordance with institutional and federal
guidelines
• NOTE: As a part of the Oncology Patient Enrollment Network (OPEN) registration process
the treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has been
entered in the system
Exclusion Criteria:
• Participants must not meet any of the IWCLL specified criteria for active CLL therapy
• Participants must not have received or be currently receiving any prior CLL-directed
therapy, including non-protocol-related therapy, anti-cancer immunotherapy,
experimental therapy (with exception of agents approved for emergency access use for
the prevention or treatment of COVID-19), or radiotherapy
• Participants must not be receiving or planning to receive any other investigational
agents before completing protocol therapy
• Participants must not have current, clinically significant gastrointestinal
malabsorption, in the opinion of treating doctor
• Participants must not have cirrhosis
• Participants must not have had major surgery within 30 days prior registration or
minor surgery within 7 days prior to registration. Examples of major surgery include
neurosurgical procedures, joint replacements, and surgeries that occur inside the
thoracic or abdomino-pelvic cavities. Examples of minor surgery include dental
surgery, insertion of a venous access device, skin biopsy, or aspiration of a joint.
If there is a question about whether a surgery is major or minor, this should be
discussed with the study chair
• Participants must not have known bleeding disorders (e.g., von Willebrand's disease or
hemophilia)
• Participants must not have a history of stroke or intracranial hemorrhage within 6
months prior to enrollment
• Participants must not require continued therapy with a strong inhibitor or inducer of
CYP3A4/5, as venetoclax is extensively metabolized by CYP3A4/5
• Participants must not have uncontrolled autoimmune hemolytic anemia or idiopathic
thrombocytopenia purpura
• Participants must not have any currently active, clinically significant cardiovascular
disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as
defined by the New York Heart Association Functional Classification
• Participants must not have a history of myocardial infarction, unstable angina, or
acute coronary syndrome within 6 months prior to enrollment
• Participants must not be pregnant or nursing, as there are no safety data available
for these drug regimens 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. 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
A Phase 1b/2 Trial of the Safety and Microbiological Activity of Bacteriophage Therapy in Cystic Fibrosis Subjects Colonized With Pseudomonas Aeruginosa
This is a phase 1b/2 study of a single dose of intravenous (IV) bacteriophage in males and
non-pregnant females, at least 18 years old, diagnosed with Cystic Fibrosis (CF). This
clinical trial is designed to assess the safety and microbiological activity of bacteriophage
product WRAIR-PAM-CF1, directed at Pseudomonas aeruginosa in clinically stable CF individuals
chronically colonized with P. aeruginosa. WRAIR-PAM-CF1 is a 4 component anti-pseudomonal
bacteriophage mixture containing between 4 x 10^7 and 4 x 10^9 Plaque Forming Units (PFU) of
bacteriophage. Enrollment will occur at up to 20 clinical sites in the United States. In
stage 1, two eligible subjects will be assigned to each of the three dosing arms receiving a
single dosage of the IV bacteriophage therapy (4 x 10^7 PFU, 4 x 10^8 PFU, and 4 x 10^9 PFU;
total of 6 sentinel subjects), followed by 30 ± 7 days observation period. If no SAEs
(related to the study product) are identified during the 96 hours after bacteriophage
administration for all Sentinel Subjects in Stage 1, the study will proceed to Stage 2. In
Stage 2a, 32 subjects will be enrolled into one of 4 arms (placebo IV, 4 x 10^7 PFU, 4 x 10^8
PFU, and 4 x 10^9 PFU) in a 1:1:1:1 allocation. An interim analysis will be performed after
all subjects have completed follow up visit 7 on Day 30 to select the IV bacteriophage dose
with the most favorable safety and microbiological activity profile. During Stage 2b,
subjects will be randomized into the bacteriophage (dose selected based on Interim Analysis
following Stage 2a) or placebo arm. The final sample size is expected to be up to 72 subjects
total with up to 25 subjects in the placebo arm and up to 25 subjects in the Stage 2b
bacteriophage dose.
Subjects must meet all the inclusion criteria to be eligible to participate in the study:
1. Adult (>/= 18 years) at the time of screening.
2. Confirmed CF diagnosis based on a compatible clinical syndrome confirmed by either an
abnormal sweat chloride testing or CFTR gene variations.*
*Can be obtained from documentation in medical records; actual test results not
necessary.
3. Likely able to produce at least 2 mL of sputum during a 30-minute sputum collection
following a hypertonic saline treatment or other approach to increase sputum
production.*
**Determined by investigator or their designee judgement. Approaches for obtaining
sputum may include, but are not limited to, inhaled hypertonic saline (e.g. 3%, 7%, or
10%), inhaled hypertonic bicarbonate, inhaled mannitol, or spontaneously expectorated
sputum. The same approach should be used for all sputum collections for a given
subject.
4. P. aeruginosa (regardless of Colony Forming Units (CFU)/mL) isolated from a sputum,
throat culture, or other respiratory specimen in the past 12 months.
5. Confirmed P. aeruginosa isolation from a sample of expectorated sputum at the
Screening Visit.
6. Capable of providing informed consent.
7. Capable and willing to complete all study visits and perform all procedures required
by the protocol.
Exclusion Criteria:
Subjects who meet any of the exclusion criteria will not be enrolled in the study:
1. Body weight < 30 kg.
2. Forced Expiratory Volume 1 second < 20% of predicted value at screening, using the
Hankinson equations.
3. Elevated LFTs obtained at screening.*
*a. Alanine aminotransferase (ALT) > 5 x the upper limit of normal (ULN) or aspartate
transaminase (AST) > 5 x ULN or total bilirubin > 3 x ULN, OR b. Total bilirubin > 1.5
x ULN combined with either ALT > 3 x ULN or AST > 3 x ULN. ULN reflects local
laboratory ranges.
4. Acute clinical illness requiring a new (oral, parenteral), or inhaled antibiotic(s)
45 years old and has gone at least
12 months without a spontaneous menstrual period without other known or suspected
cause.
3. Effective methods of contraception include (a) abstinence, (b) partner vasectomy,
(c) intrauterine devices, (d) hormonal implants (such as Implanon), or (e) other
hormonal methods (birth control pills, injections, patches, vaginal rings).
6. Active treatment of any mycobacterial or fungal organisms
This is a Phase 1b/2, randomized, double-blind, multi-center study to evaluate the safety,
tolerability, and preliminary clinical efficacy of STMC-103H in neonates and infants at risk
for developing allergic disease (Type 1 hypersensitivity). Subjects will be enrolled in a
three-part sequential approach. Participants in the safety-run portion of the study (Part A1:
1 year to <6 years of age and A2: 1 month to <12 months of age) will receive 28 days of
treatment with STMC-103H or placebo, followed by 28 days of follow-up. A Data and Safety
Monitoring Committee (DSMC) will review safety data after all patients in each part complete
28 days of therapy prior to enrolling the next part. After A2, Part B will enroll 224
patients for 336 days of treatment with STMC-103H or placebo, followed by 336 days of
follow-up. Stool, blood, and optional samples will be collected in Parts A2 and part B.
Primary safety endpoints are frequency, type and severity of Adverse Events (AEs) and Serious
Adverse Events (SAEs), as well as findings on physical exams, vitals, and safety
laboratories. The primary efficacy endpoint is incidence of physician-diagnosed atopic
dermatitis at day 336.
• All Parts (A1, A2, B)
1. Subject's parent(s)/legal representative(s) providing consent must be 18 years or
older
2. Biological mother and/or biological father and/or full sibling(s), have a history
of asthma, atopic dermatitis, food allergy, or allergic rhinitis as determined by
the screening questionnaire
3. Subject's parent(s)/legal representative(s) (if appropriate according to local
laws) is/are willing and able to give informed consent for participation in the
study
4. Subject's parent(s)/legal representative(s) (if appropriate according to local
laws) is/are willing and able, in the PI's opinion, to comply with all study
requirements
Part A1 Only
Inclusion criteria 1-4 for all parts plus:
5 (A1). Subject is between 1 year and < 6 years old at the time of enrollment
Part A2 Only
Inclusion criteria 1-4 for all parts plus:
5 (A2). Subject is between 28 days and < 12 months of life at the time of enrollment 6
(A2). Subject's parent(s)/legal representative(s) do not plan to give probiotics (including
infant formula that contain probiotics) to the subject during the trial
Part B Only
Inclusion criteria 1-4 for all parts plus:
5 (B). Subject is ≤ 14 days of life at the time of enrollment. Sites should make every
effort to enroll newborns as soon as possible after birth.
6 (B). Subject has a birthweight ≥ 2.5 kg and ≤ 4.5 kg 7 (B). Subject's parent(s)/legal
representative(s) do not plan to give probiotics (including infant formula that contain
probiotics) to the subject from the time of birth to the end of the trial.
Exclusion Criteria:
• All Parts (A1, A2, B)
1. Subject's twin (or higher order multiple) is enrolled in STMC-103H-102
2. Subject has any congenital abnormalities or condition, significant disease,
illness, physical exam finding, or disorder that, in the opinion of the PI, may
put the subject at safety risk or is likely to hinder feeding or affect
metabolism that may influence the results of the study. (Neonatal
hyperbilirubinemia (jaundice), including jaundice that requires phototherapy,
should not be considered exclusionary).
3. Subject is acutely ill or on systemic antibiotics at the time of enrollment
4. Subject is participating in another interventional clinical study involving
investigational medication, formula, probiotic, or prebiotic use within 30 days
(or five half-lives, whichever is longer) of this study
5. Subject has evidence of immune deficiency/immune compromise in the judgment of
the investigator
Part B Only
Exclusion Criteria 1-5 for all parts plus:
6 (B). Subject was born at < 35 weeks' gestation 7 (B). Biological maternal medical
condition during the pregnancy that, in the opinion of the PI, may put the subject at risk
because of participation in the study. (Maternal antibiotics during the time of delivery
should not be considered exclusionary.)
Study of ONO-4685 in Patients With Relapsed or Refractory T Cell Lymphoma
This study will investigate the safety, tolerability, pharmacokinetics, and preliminary
efficacy of ONO-4685 in patients with relapsed or refractory T cell Lymphoma
Inclusion Criteria
1. Patients aged ≥ 18 years at time of screening
2. Written informed consent by the patient or the patients' legally authorized
representative prior to screening
3. Patients with histologically or cytologically confirmed diagnosis of one of the
following subtypes of T-cell lymphoma:
1. Peripheral T-cell lymphoma (PTCL): Angioimmunoblastic T-cell lymphoma (AITL),
PTCL, not otherwise specified (PTCL-NOS), nodal PTCL with T-follicular helper
(TFH) and follicular T-cell lymphoma (FTCL)
2. Cutaneous T-cell lymphoma (CTCL) (stages II-B, III, and IV): Mycosis fungoides
(MF) and Sezary syndrome (SS)
4. Patients must have received at least 2 prior systemic therapies.
5. Patients with PTCL must have at least 1 measurable lesion
6. Patients with CTCL must have assessable disease by response criteria for CTCL (Olsen
EA, 2011)
7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 0-2
8. Life expectancy of at least 3 months
9. Adequate bone marrow, renal and hepatic functions
Exclusion Criteria:
1. Patients with central nervous system (CNS) involvement
2. Patients with Adult T-cell leukemia/lymphoma (ATLL)
3. Prior allogeneic stem cell transplant
4. Prior treatment with ONO-4685, anti-PD-1, anti-PD-L1, anticytotoxic T lymphocyte
associated protein 4 (CTLA-4) antibody, or any other antibody or drug specifically
targeting T-cell co-stimulation or checkpoint pathways
5. Patients with malignancies (other than T-cell lymphoma) except for completely resected
basal cell carcinoma, stage I squamous cell carcinoma, carcinoma in situ, or any other
malignancies that has not relapsed for at least 2 years
6. History of severe allergy or hypersensitivity to any monoclonal antibodies, other
therapeutic proteins or corticosteroid (e.g., dexamethasone)
7. History of infection with Mycobacterium tuberculosis within 2 years prior to the first
dose of study treatment
8. Patients with systemic and active infection including human immunodeficiency virus
(HIV), hepatitis B or C virus infection
9. Patients not recovered to Grade 1 or stabilized from the adverse effects (excluding
alopecia) of any prior therapy for their malignancies
10. Women who are pregnant or lactating
Drug: ONO-4685
Lymphoid Leukemia, Relapsed or Refractory T Cell Lymphoma
ONO-4685, PD-1, CD3, Bispecific antibody, PTCL, AITL, PTCL-NOS, nodal PTCL with TFH, FTCL, CTCL, MF, SS
A Study to Assess the Efficacy, Safety, and Tolerability of Oral LPCN 1148 in Male Subjects With Cirrhosis of the Liver and Sarcopenia
This is a randomized, double-blind, placebo-controlled study to assess the efficacy, safety,
and tolerability of LPCN 1148 in men with cirrhosis of the liver and sarcopenia.
1. Male ≥ 18 years old
2. Currently listed, on the liver transplant waitlist for cirrhosis secondary to
Hepatitis B or C infection, Alcoholic Liver Disease (ALD), or Non-Alcoholic
Steatohepatitis (NASH)
3. Evidence of sarcopenia with appropriate cutoff recommended by clinical guidance
Exclusion Criteria:
1. Suspected or proven hepatocellular carcinoma (HCC)
2. History of current or suspected prostate or breast cancer
3. History of malignancies other than prostate, breast, or HCC, unless successfully
treated with curative intent and believed to be cured (defined as complete remission
lasting at least 5 years)
4. History of uncontrolled or recurrent portal hypertensive bleeding, including
uncontrolled or recurrent bleeding from varices, gastropathy, colopathy, or
hemorrhoidal bleeding.
5. History or current thrombosis (including portal vein thrombosis), thromboembolism, or
treatment for portal vein thrombosis
6. History of hemochromatosis
7. History of hypercoagulable state (e.g. Factor V Leiden deficiency, protein C
deficiency, protein S deficiency, anti-thrombin III deficiency, or the presence of
lupus anticoagulant)
8. Prior history of complications of ascites including:
1. Spontaneous bacterial peritonitis
2. Hepatic hydrothorax
9. MELD score > 25
10. Abnormal lab value in serum chemistry, hematology, or urinalysis that the PI considers
clinically significant, including but not limited to:
1. PSA > 4 ng/mL
2. Polycythemia (Hematocrit >54%) or history of polycythemia
3. ALT or AST > 5x ULN
4. ALP > 1.5x ULN
5. Platelet count < 30,000/mL
6. EGFR < 60 mL/min/1.73 m2
7. Total bilirubin > 3.0 mg/dL
8. Serum albumin < 2.8 g/dL
9. INR > 2.3 or PT prolongation > 6.0 seconds
11. Subjects with PSA between 2.5 ng/mL and 4 ng/mL are excluded only if any of the below
criteria are met at baseline:
1. Hematocrit > 48%
2. I-PSS > 19
3. Any irregularity found on digital rectal examination of the prostate
12. Subjects with PSA > 3 ng/mL are excluded only if any of the below criteria are met at
baseline:
1. Subject is African American
2. Subject has a first-degree relative who has a history of prostate cancer
3. Hematocrit > 48%
4. I-PSS > 19
5. Any irregularity found on digital rectal examination of the prostate
13. Clinically significant abnormal prostate digital rectal examination (DRE) in the
opinion of the PI, with DRE screening initiated at International Prostate Symptom
Score (I-PSS) > 19
14. History of bariatric surgery
15. History of stroke or myocardial infarction within the past 5 years
16. Known positivity for Human Immunodeficiency Virus (HIV) infection
17. Acute liver failure as the indication for addition to the liver transplant waitlist
18. Estimated life expectancy less than 3 months or expected to undergo liver transplant
within 3 months
19. Known heart failure of New York Heart Association class III or IV
20. Evidence of severe encephalopathy or encephalopathy that is not controlled despite
adequate medical therapy
21. History of prior organ transplant
22. History of Fontan physiology
23. History of pulmonary embolus
24. Porto-pulmonary hypertension
25. Hepatopulmonary syndrome
26. Uncontrolled epilepsy or migraine
27. Active substance abuse or dependency extending to within the previous 6 months
28. History of significant sensitivity or allergy to testosterone, or product excipients.
29. Use of known strong inhibitors (e.g., ketoconazole) or inducers (e.g., dexamethasone,
phenytoin, rifampin, carbamazepine) of cytochrome P450 3A (CYP3A) within 30 days prior
to study drug administration and through the end of the study
30. Subjects who are currently receiving any androgens (testosterone or other androgens or
androgen-containing supplements) and are unwilling to washout prior to screening
a. Washout: 12 weeks following long-acting intramuscular androgen injections; 4 weeks
following topical or buccal androgens; 3 weeks following oral androgens
31. Uncontrolled hypertension (>160/90 mmHg despite treatment)
32. Uncontrolled obstructive sleep apnea
33. Use of any investigational drug within 5 half-lives of the last dose or in the past 6
months prior to Study Day -2 without medical monitor and/or Sponsor approval
34. Subject who is not willing to use adequate contraception for the duration of the study
35. Any other condition, which in the opinion of the investigator would impede compliance
to the study protocol (including diet, exercise, and alcohol abstinence) or hinder
completion of the study
36. Failure to give informed consent
A Study of Intravesical Enfortumab Vedotin For Treatment of Patients With Non-muscle Invasive Bladder Cancer (NMIBC)
This study will test a drug called enfortumab vedotin in participants with a type of bladder
cancer called non-muscle invasive bladder cancer (NMIBC).
This study will also evaluate what the side effects are and if the drug works to treat NMIBC.
A side effect is anything a drug does to your body besides treating your disease.
In this study enfortumab vedotin will be put into the bladder using a catheter. A catheter is
a thin tube that can be put into your bladder.
• Histologically confirmed, non-muscle invasive urothelial carcinoma with carcinoma in
situ (CIS) (with or without papillary disease)
• Predominant histologic component (>50 percent) must be urothelial (transitional cell)
carcinoma
• Participants must have high-risk Bacillus Calmette-Guerin (BCG) •unresponsive
disease, defined as (where adequate BCG therapy is defined as one of the following: 5
of 6 doses of an initial induction course + at least 2 of 3 doses maintenance therapy
or 5 of 6 doses of an initial induction course + at least 2 of 6 doses of a second
induction course):
• Persistent or recurrent CIS alone or with recurrent Ta/T1 (noninvasive papillary
disease/tumor invades the subepithelial connective tissue) disease within 12
months of completion of adequate BCG therapy.
• Recurrent high-grade Ta/T1 disease within 6 months of completion of adequate BCG
therapy, or
• T1 high-grade disease at the first evaluation following an induction BCG course
(at least 5 or 6 doses)
• Participant must be ineligible for or refusing a radical cystectomy
• All visible papillary Ta/T1 tumors must be completely resected within 60 days prior to
enrollment.
• Eastern Cooperative Oncology Group Performance Status score of 0, 1, or 2.
Exclusion Criteria:
• Current or prior history of muscle-invasive urothelial carcinoma or metastatic
disease.
• Nodal or metastatic disease as noted on computed tomography (CT) or magnetic resonance
imaging (MRI) within 3 months prior to study treatment
• Concomitant upper tract urothelial carcinoma as noted on CT or MRI urogram performed
within 3 months prior to study treatment
• Prior or concomitant urothelial carcinoma of the prostatic urethra within 6 months
prior to study treatment
• Participants with tumor-related hydronephrosis
• Participant has received other systemic anticancer therapy including chemotherapy,
biologic therapy, immunotherapy, targeted therapy, endocrine therapy, and/or
investigational agent within 4 weeks or intravesical therapy within 6 weeks of first
dose of study treatment
• Participant has had any prior radiation to the bladder for urothelial cancer
A Study to Evaluate the Safety and Efficacy of JCAR017 in Pediatric Subjects With Relapsed/Refractory (r/r) B-cell Acute Lymphoblastic Leukemia (B-ALL) and B-cell Non-Hodgkin Lymphoma (B-NHL)
This is a Phase 1/2, open-label, single arm, multicohort study to evaluate the safety and
efficacy of JCAR017 in pediatric subjects aged ≤ 25 years with CD19+ r/r B-ALL and B-NHL.
Phase 1 will identify a recommended Phase 2 dose (RP2D). Phase 2 will evaluate the efficacy
of JCAR017 RP2D in the following three disease cohorts: Cohort 1 (r/r B-ALL), Cohort 2 (MRD+
B-ALL) and Cohort 3 (r/r B-NHL, [DLBCL, BL, or PMBCL]). A Simon's Optimal two-stage study
design will be applied to Cohort 1 and 2 in Phase 2.
Subjects must satisfy the following criteria to be enrolled in the study:
1. Phase 1: Subject < 18 years of age and weighs ≥ 6 kg at the time of signing the
informed consent form (ICF)/informed assent form (IAF).
Phase 2: Subject ≤ 25 years of age and weighs ≥ 6 kg at the time of signing the
ICF/IAF.
2. Subject (when applicable, parental/legal representative) must understand and
voluntarily provide permission to the ICF/IAF prior to conducting any study-related
assessments/procedures.
3. Subject is willing and able to adhere to the study visit schedule and other protocol
requirements.
4. Investigator considers the subject is appropriate for adoptive T cell therapy.
5. Evidence of CD19 expression via flow cytometry (peripheral blood or bone marrow) or
immunohistochemistry (bone marrow biopsy)
6. Subject has a Karnofsky score of ≥ 50 (subjects ≥ 16 years of age) or a Lansky score ≥
50 (subjects < 16 years of age).
7. Diagnosis of B-cell ALL or B-cell NHL as defined below:
Phase 1: Subjects with r/r B-ALL, defined as morphological evidence of disease in BM
(5% or greater lymphoblast by morphology) and either of the following:
• First or greater marrow relapse, or
• Any marrow relapse after allogeneic HSCT, or
• Primary refractory defined as not achieving a CR or a CRi after 2 or more
separate induction regimens (or chemo-refractory as not achieving CR/CRi after 1
cycle of standard chemotherapy for relapsed leukemia), or
• Ineligible for allogeneic HSCT Note: Subjects will be included regardless of MRD
status.
Phase 2: Subjects with one of the following:
• Cohort 1: r/r B-ALL, defined as morphological evidence of disease in BM (5% or
greater lymphoblast by morphology) and either:
• First or greater marrow relapse, or
• Any marrow relapse after allogeneic HSCT, or
• Primary refractory defined as not achieving a CR or a CRi after 2 or more
separate induction regimens (or chemo-refractory as not achieving CR/CRi
after 1 cycle of standard chemotherapy for relapsed leukemia), or
• Ineligible for allogeneic HSCT.
• Cohort 2: MRD+ B-ALL, defined as:
• < 5% lymphoblasts by morphology with,
• MRD detected by a validated assay at a frequency of 1 x10-4 or greater in BM
cells. Subjects eligible for enrollment in Cohort 2 are those with MRD
positive morphologic CR2 after re-induction when these subjects had
previously experienced an early relapse (< 36 months) after first-line
chemotherapy. Subjects who are in MRD+ morphologic CR3 and later, regardless
of time to relapse in earlier lines, are also eligible. Subjects who are in
morphologic relapse at screening (r/r B-ALL) and become MRD+ after bridging
chemotherapy are also eligible for treatment in Cohort 2.
• Cohort 3: r/r B-NHL (DLBCL, BL or PMBCL), defined as measurable disease after 1
or more lines of chemotherapy and/or having failed HSCT or being ineligible for
HSCT.
Note: B-NHL subjects with secondary CNS lymphoma involvement are eligible however
subject selection must consider clinical risk factors for severe neurological AEs and
alternative treatment options. Subjects should only be enrolled if the Investigator
considers the potential benefit outweighs the risk for the subject.
8. Subjects with Philadelphia chromosome positive ALL are eligible if they are intolerant
to or have failed one or more lines of tyrosine-kinase inhibitor (TKI) therapy or if
TKI therapy is contraindicated.
9. Adequate organ function, defined as:
• Adequate BM function to receive LD chemotherapy as assessed by the Investigator.
• Subject with adequate renal function, which is defined as:
Serum creatinine based on age/gender as described below. Subjects that do not meet the
criteria but who have a creatinine clearance or radioisotope glomerular filtration
rate (GFR) > 70 mL/min/1.73 m2 are eligible.• Alanine aminotransferase (ALT) ≤ 5 x
upper limit of normal (ULN) and total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for
subjects with Gilbert's syndrome or leukemic/lymphomatous infiltration of the liver).
• Adequate pulmonary function, defined as ≤ Grade 1 dyspnea according to Common
Toxicity Criteria for Adverse Events (CTCAE) and oxygen saturation (SaO2) ≥ 92%
on room air.
• Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥
40% as assessed by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA)
within 4 weeks prior to leukapheresis.
10. Adequate vascular access for leukapheresis procedure.
11. Participants must agree to use effective contraception
Exclusion Criteria:
The presence of any of the following will exclude a subject from enrollment:
1. Subject has any significant medical condition, laboratory abnormality, or psychiatric
illness that would prevent the subject from participating in the study.
2. Subject has any condition including the presence of laboratory abnormalities, which
places the subject at unacceptable risk if he/she were to participate in the study.
3. Subject has any condition that confounds the ability to interpret data from the study.
4. Subject with a history of another primary malignancy that has not been in remission
for at least 2 years prior to enrollment.
5. Subjects who have received previous CD19-targeted therapy must have CD19-positive
disease confirmed since completing the prior CD19-targeted therapy.
6. Prior CAR T cell or other genetically-modified T cell therapy.
7. Subject with a previous history of or active hepatitis B, hepatitis C, or human
immunodeficiency virus (HIV) infection.
8. Subjects with uncontrolled systemic fungal, bacterial, viral or other infection
(including tuberculosis) despite appropriate antibiotics or other treatment at the
time of leukapheresis or JCAR017 infusion.
9. Subject has presence of acute or chronic graft-versus-host disease (GVHD).
10. Subject with active autoimmune disease requiring immunosuppressive therapy.
11. Subject has cardiac disorders (CTCAE version 4.03 Grade 3 or 4) within the past 6
months.
12. Subject with a concomitant genetic syndrome, with the exception of Down's syndrome.
13. Subject with active CNS disease and significant neurological deterioration. Subjects
with CNS-2 or CNS-3 involvement are eligible provided they are asymptomatic and do not
have significant neurological deterioration and, in the opinion of the study
investigator, the CNS disease burden can be controlled until JCAR017 infusion.
14. Subject with a history or presence of clinically relevant CNS pathology such as
epilepsy, seizure, paresis, aphasia, stroke, cerebral edema, severe brain injuries,
dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or
psychosis.
15. Subject is pregnant or nursing.
16. Subject has used the following:
• Therapeutic doses of corticosteroids (defined as > 0.4 mg/kg maximum 20 mg/day
prednisone or equivalent) within 7 days prior to leukapheresis or 72 hours prior
to JCAR017 infusion. Physiologic replacement, topical, and inhaled steroids are
permitted.
• Low-dose chemotherapy (eg, vincristine, rituximab, cyclophosphamide ≤ 300 mg/m2)
given after leukapheresis to maintain disease control must be stopped ≥ 7 days
prior to LD chemotherapy.
• Cytotoxic chemotherapeutic agents that are not considered lymphotoxic within 1
week prior to leukapheresis. Oral anticancer agents are allowed if at least 3
half-lives have elapsed prior to leukapheresis.
• Lymphotoxic chemotherapeutic agents (eg, cyclophosphamide, ifosfamide,
bendamustine) within 2 weeks prior to leukapheresis.
• Experimental agents within 4 weeks prior to leukapheresis unless no response or
PD is documented on the experimental therapy and at least 3 half-lives have
elapsed prior to leukapheresis.
• Immunosuppressive therapies within 4 weeks prior to leukapheresis and JCAR017
infusion (eg, calcineurin inhibitors, methotrexate or other chemotherapeutics,
mycophenolate, rapamycin, thalidomide, immunosuppressive antibodies such as
antitumor necrosis factor [TNF], anti-IL-6, or anti-IL-6R).
• Donor lymphocyte infusions (DLI) within 6 weeks prior to JCAR017 infusion.
• Radiation within 6 weeks prior to leukapheresis. Subjects must have PD in
irradiated lesions or have additional non-irradiated lesions to be eligible.
Radiation to a single lesion, if additional non-irradiated, measurable lesions
are present, is allowed up to 2 weeks prior to leukapheresis.
• Allogeneic HSCT within 90 days prior to leukapheresis.
17. Tumor invasion of venous or arterial vessels (B-NHL subjects only).
18. Deep Venous Thrombosis (DVT) or Pulmonary Embolism (PE) within 3 months prior to
leukapheresis. Subjects with DVT or PE that occurred longer than 3 months prior to
leukapheresis, who still require ongoing therapeutic levels of anti-coagulation
therapy, are also excluded.
19. Existence of CD19-negative clone(s) of leukemia cells