A Study of the Safety and Pharmacokinetics of Venetoclax in Pediatric and Young Adult Patients With Relapsed or Refractory Malignancies

Study Overview
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Brief Summary
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An open-label, global, multi-center study to evaluate the safety and pharmacokinetics of venetoclax monotherapy, to determine the dose limiting toxicity (DLT) and the recommended Phase 2 dose (RPTD), and to assess the preliminary efficacy of venetoclax in pediatric and young adult participants with relapsed or refractory malignancies.

Official Title
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A Phase 1 Study of the Safety and Pharmacokinetics of Venetoclax in Pediatric and Young Adult Patients With Relapsed or Refractory Malignancies

Conditions
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Malignancies, Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Non-Hodgkin's Lymphoma, Neuroblastoma

Intervention / Treatment
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* Drug: chemotherapy
* Drug: venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have relapsed or refractory cancer. Participants must have adequate hepatic and kidney function. Participants less than or equal to 16 years of age must have performance status of Lansky greater than or equal to 50% and participants greater than 16 years of age must have performance status of Karnofsky greater than or equal to 50%. Participants with solid tumors (with the exception of neuroblastoma) must have adequate bone marrow function in Part 1. For the fifth cohort during Part 2 Cohort Expansion, participants with solid tumors must have evidence of BCL-2 expression (except participants with TCF3-HLF ALL). Exclusion Criteria: Participants with primary brain tumors or disease metastatic to the brain. Participants who have central nervous system (CNS) disease with cranial involvement that requires radiation. Participants who have received any of the following within the listed time frame, prior to the first dose of study drug Inotuzumab ozogamicin or gemtuzumab ozogamicin within 30 days Biologic agent (i.e., antibodies) for anti-neoplastic intent within 30 days or 5 half-lives whichever is shorter. CAR-T infusion or other cellular therapy within 30 days Anticancer therapy including chemotherapy, radiation therapy, targeted small molecule agents, investigational agents within 14 days or 5 half-lives, whichever is shorter (Exceptions: Ph+ALL participants on Tyrosine Kinase Inhibitor (TKI) at Screening may enroll and remain on TKI therapy to control disease and TCF3-HLF ALL participants are allowed to have received chemotherapy within 14 days or 5 half-lives, whichever is shorter). Steroid therapy for anti-neoplastic intent within 5 days (with the exception of TCF3-HLF ALL participants). Requires ongoing hydroxyurea (hydroxyurea permitted up to first dose) Participants who are less than 100 days post-transplant, or greater than or equal to 100 days post-transplant with active graft versus host disease (GVHD), or are receiving immunosuppressant therapy within 7 days prior to first dose of study drug. Participants who are less than 6 weeks post-131 I-metaiodobenzylguanidine (mIBG) therapy. Participants who have received the following within 7 days prior to the first dose of study drug: Strong and moderate Cytochrome P450 3A (CYP3A) inhibitors (Part 1 Dose Determination); Strong and moderate CYP3A inducers (Part 1 Dose Determination and Part 2 Cohort Expansion). Participants who have not recovered from clinically significant adverse effect(s)/toxicity(s) of the previous therapy (Exception: Chemotherapy induced side effects that are expected to return to baseline in TCF3-HLF ALL participants). Participants who have active, uncontrolled infections. Participants with malabsorption syndrome or any other condition that precludes enteral administration. Participants with recent positive test for SARS-CoV-2 (COVID-19) and no follow up test with negative result cannot be enrolled. Participants with contact to persons with COVID-19 and participants with signs and symptoms for COVID-19 infection must be tested before enrolling.

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Venetoclax with or without chemotherapy<br>Venetoclax administered orally once daily (QD) with various doses and dosing regimens with or without chemotherapy at the discretion of the investigator. Allowed chemotherapy regimens as outlined in the study protocol. | Drug: chemotherapy<br>* Dexamethasone and/or vincristine and/or pegasparaginase OR cytarabine and/or etoposide and/or pegasparaginase; tyrosine kinase inhibitor; cytarabine OR azacitidine OR decitabine; rituximab and/or dexamethasone and/or vincristine; cyclophosphamide and/or topotecan<br>Drug: venetoclax<br>* Oral tablet for participants; Tablet for oral suspension (participants who cannot swallow a tablet)<br>* Other names: Venclexta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Adverse Events | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study. | Up to 9 months | 
| Number of Participants With Dose Limiting Toxicities (DLT) of Venetoclax Monotherapy | A DLT is any Grade 3 or higher non-hematologic adverse event (AE) with exceptions outlined in the protocol. | First 21 days venetoclax monotherapy | 
| Recommended Phase 2 dose (RPTD) of Venetoclax | Venetoclax RPTD is the dose determined based on adverse event reporting and dose-limiting toxicity information from all participants. | First 21 days venetoclax monotherapy | 
| Cmax of Venetoclax | Maximum plasma concentration (Cmax) of venetoclax. | Up to approximately 2 weeks | 
| Tmax of venetoclax | Time to maximum plasma concentration (Tmax) of venetoclax. | Up to approximately 2 weeks | 
| AUC0-24 Post-Dose of Venetoclax | Area under the plasma concentration-time curve from 0 to 24 hours (AUC24) post-dose of venetoclax. | Up to approximately 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as the proportion of participants who achieved a response according to established criteria described in detail in the study protocol. | Up to 9 months | 
| Partial Response (PR) Rate | PR is defined according to established criteria for each tumor type and is described in detail within the study protocol. | Up to 9 months | 
| Complete Response (CR) Rate | CR is defined according to established criteria for each tumor type and is described in detail within the study protocol. | Up to 9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, Venetoclax, pediatric, relapsed or refractory, Venclexta