Venetoclax Combined With Vyxeos (CPX-351) for Participants With Relapsed or Refractory Acute Leukemia

Study Overview
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Brief Summary
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This study evaluates the safety and tolerability of combining venetoclax with Vyxeos (CPX-351) in pediatric and young adult patients with acute leukemia that has come back or not responded to treatment.

Detailed Description
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This is a single-institution Phase I pilot study designed to test the safety and tolerability of combining venetoclax with Vyxeos (CPX-351, cytarabine and daunorubicin liposome) for the treatment of relapsed/refractory acute leukemia in young patients. Subjects will receive a single course of study therapy consisting of daily, oral venetoclax at an assigned dose level with a 3-day ramp-up to target dose and Vyxeos administered intravenously at the established dose on Days 1, 3, and 5. In addition to safety and tolerability, the overall response rate to these therapies will be estimated. Pharmacokinetic (PK) analysis will also be conducted to define the drug clearance of venetoclax in this combination.

Official Title
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A Phase I Study of Venetoclax Combined With Vyxeos (CPX-351) for Children, Adolescents and Young Adults With Relapsed or Refractory Acute Leukemia

Conditions
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Leukemia

Intervention / Treatment
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* Drug: Vyxeos
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 1-39 years Diagnosis of one of the following: Acute myeloid leukemia (AML) Acute undifferentiated leukemia (AUL) Mixed phenotype acute leukemia (MPAL) T-cell acute lymphoblastic leukemia (T ALL) Early thymocyte precursor (ETP) ALL KMT2A-rearranged ALL Disease status Relapsed/Refractory AML, MPAL and AUL Relapsed/Refractory KMT2A-rearranged ALL, T-cell ALL, ETP ALL Karnofsky/ Lanksy performance level score of greater than or equal to 50 percent Prior therapy requirements Fully recovered from acute toxicities of Hematopoietic Stem Cell Transplant (HSCT) or Anthracycline Exposure 14 days must have elapsed since the completion of systemic cytotoxic therapy other than hydroxyurea, decitabine or azacitidine 2 weeks must have elapsed for local palliative radiotherapy (RT); 6 months must have elapsed if prior craniospinal RT or if 50% radiation of pelvis, and at least 6 weeks must have elapsed if other substantial bone marrow radiation Adequate renal, liver, cardiac and central nervous system (CNS) function Exclusion Criteria: Diagnosis of one of the following: Acute Promyelocytic Leukemia (APML) Acute leukemia with CNS status 3 involvement Philadelphia chromosome positive leukemia (Ph+ ALL, MPAL, or AUL) Fanconi Anemia, Shwachman-Diamond syndrome, or any other bone marrow failure syndrome or DNA repair disorder Wilson's Disease or other copper-metabolism disorder Pregnant or breastfeeding Uncontrolled infection Received greater than 13.6 Gray (Gy) prior radiation to the mediastinum Unable to swallow tablets Receipt of growth factors within 7 days prior to enrollment Currently receiving another investigational drug Currently receiving anti-cancer agents (with the exception of intrathecal (IT) agents or hydroxyurea) Unable to comply with the safety monitoring requirements of the study

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 39 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 and Vyxeos combination<br>Venetoclax will be given orally on Days per the assigned dose level. A single course consisting of 3 doses of Vyxeos and 7-21 doses of venetoclax depending on the assigned dose level will be administered to participants in this study. Vyxeos will be administered by central venous catheter over 90 minutes on Day 1, 3, and 5. Venetoclax is given daily by mouth per assigned dose level. | Drug: Vyxeos<br>* Vyxeos Dose: daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 administered via intravenous infusion over 90 minutes on Days 1, 3, and 5.<br>* Other names: cytarabine and daunorubicin liposome, CPX-351;Drug: Venetoclax<br>* Venetoclax Dose: Dose Level 0 - weight based daily dosing for 21 days Dose Level -1 - weight based daily dosing for 14 days Dose Level -2- weight based daily dosing for 10 days Dose Level -3- weight based daily dosing for 7 days<br>* Other names: Venclexta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of combining venetoclax and Vyxeos (dose limiting toxicities) | If 2 or more participants have dose limiting toxicities at a given dose level, the maximum tolerated dose will have been exceeded. | 28 days | 
| Treatment related toxicities | Number of related adverse events | 60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease response | Estimate of overall response rate (ORR) defined as (CR/CRi/CRp). | 42 days | 
| Cancer therapeutics-related cardiac dysfunction (CTRCD) in patients who have previously received anthracyclines | Measured by echocardiogram (ECHO) | 60 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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relapsed, refractory, Vyxeos, Venetoclax, acute myeloid leukemia, acute myeloid leukemia, childhood, mixed-lineage leukemia (MLL), AML, CPX-351, Venclexta, Histone-lysine N-methyltransferase 2A (KmT2A)