A Study of Venetoclax in Combination With Navitoclax and Chemotherapy in Subjects With Relapsed/Refractory Acute Lymphoblastic Leukemia or Relapsed/Refractory Lymphoblastic Lymphoma

Study Overview
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Brief Summary
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This dose-escalating study is to determine the safety, pharmacokinetics, and preliminary efficacy of venetoclax in combination with navitoclax and chemotherapy in adult and pediatric participants with relapsed/refractory acute lymphoblastic leukemia (ALL) or relapsed/refractory lymphoblastic lymphoma. A safety expansion cohort of approximately 20 patients may be enrolled in addition to the 50 participants in dose-escalation cohort.

Official Title
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A Phase 1 Dose Escalation, Open-Label Study of Venetoclax in Combination With Navitoclax and Chemotherapy in Subjects With Relapsed/Refractory Acute Lymphoblastic Leukemia or Relapsed/Refractory Lymphoblastic Lymphoma

Conditions
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Acute Lymphoblastic Leukemia (ALL), Lymphoblastic Lymphoma

Intervention / Treatment
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* Drug: Navitoclax
* Drug: Chemotherapy
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have relapsed or refractory acute lymphoblastic leukemia (ALL) or relapsed or refractory lymphoblastic lymphoma (LL). Refractory is defined as persistent disease after at least 2 courses of chemotherapy. Participants with ALL with Philadelphia chromosome or with an ABL class targetable fusion are eligible. Participants with LL must have radiographic evidence of disease Participants <= 18 years of age who do not have a standard of care treatment option available. Must weigh greater than or equal to 20 kg. Must be able to swallow pills. Must have adequate hepatic and kidney function. Must have adequate performance status: Participants less than or equal to 16 years of age: Lansky greater than or equal to 50 Participants greater than 16 years of age: Karnofsky greater than or equal to 50 or Eastern Cooperative Oncology Group (ECOG) less than 3. Exclusion Criteria: Participant has central nervous system (CNS) disease with cranial involvement that requires radiation. Participants who are less than 100 days post-transplant, or greater than 100 days post-transplant with active graft versus host disease (GVHD), or are still continuing post-transplant immunosuppressant therapy within 7 days prior to the first dose of study drug. Participants who have received any of the following prior to the first dose of study drug: Inotuzumab within 30 days (if participant received inotuzumab > 30 days prior to Day 1, must have ALT, AST and bilirubin < ULN). A biologic agent (i.e., monoclonal antibodies) for anti-neoplastic intent within 30 days CAR-T infusion or other cellular therapy within 30 days Any anti-cancer therapy including blinatumomab, chemotherapy, radiation therapy targeted small molecule agents or investigational agents within 14 days, or 5 half-lives, whichever is shorter Exception: Philadelphia Chromosome (Ph)+ ALL subjects on TKIs at Screening may enroll and remain on Tyrosine Kinase Inhibitor (TKI) therapy to control disease. Participants on venetoclax at screening may enroll and remain on venetoclax. Steroid therapy for anti-neoplastic intent within 5 days Hydroxyurea that is ongoing (hydroxyurea is permitted up to the first dose) A strong or moderate CYP3A inhibitor or inducer within 7 days Aspirin within 7 days, or 5 half-lives, whichever is longer An excluded antiplatelet/anticoagulant drug or a herbal supplement that affects platelet function within 7 days, or 5 half-lives, whichever is longer Participants with malabsorption syndrome or any other condition that precludes enteral administration.

Ages Eligible for Study
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Minimum Age: 4 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 + Navitoclax + Chemotherapy<br>Venetoclax weight-adjusted doses administered orally every day (QD) starting on Day 1 + navitoclax various, weight-adjusted doses administered orally QD starting on Day 3 + chemotherapy (peg-asparaginase [or any other forms of asparaginase], vincristine, dexamethasone) and tyrosine kinase inhibitor [TKI, if applicable]). This regimen and any of its components may be delayed, reduced or omitted at the discretion of the Investigator. | Drug: Navitoclax<br>* tablet<br>* Other names: ABT-263;Drug: Chemotherapy<br>* peg-asparaginase (or other form of asparaginase, per local standard of care (intravenous) + vincristine (intravenous) + dexamethasone (oral) + tyrosine kinase inhibitor (TKI) (if applicable, oral)<br>Drug: Venetoclax<br>* tablet<br>* Other names: ABT-199 GDC-0199;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of Venetoclax + Navitoclax | Maximum observed plasma concentration (Cmax) of venetoclax + navitoclax | Up to approximately 9 months | 
| AUC of Venetoclax + Navitoclax | Area under the plasma concentration-time curve (AUC) of venetoclax + navitoclax | Up to approximately 9 months | 
| Tmax of Venetoclax + Navitoclax | Time to Cmax (Tmax) of Venetoclax + Navitoclax | Up to approximately 9 months | 
| CL/F of Venetoclax + Navitoclax | Apparent oral clearance (CL/F) of venetoclax + navitoclax | Up to approximately 9 months | 
| Number of participants with dose-limiting toxicities (DLT) | A DLT is any Grade 3 or higher non-hematologic adverse event (AE) with exceptions outlined in the protocol. AEs and toxicities that occur beyond the DLT assessment period will also be evaluated by the investigator and AbbVie and may be considered as dose-limiting. | Up to approximately 28 days after initial dose of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | PFS is defined as the number of days from the date of enrollment to the date of earliest disease progression or death. | Up to 9 months after the last subject has enrolled into the study | 
| Partial Response (PR) rate | PR defined as no peripheral blasts or peripheral blood absolute blast count decreased by ≥ 50% from baseline, bone marrow with 5 - 25% blasts and at least a 50% decrease in bone marrow blast percent from baseline, no evidence of extramedullary disease. | Up to 9 months after the last subject has enrolled into the study | 
| Number of Participant who Proceed to Stem Cell Transplantation or Chimeric antigen receptor T-cell (CAR-T) Therapy | Determine the number of participants who proceed to stem cell transplantation or CAR-T therapy. | Up to 9 months after the last subject has enrolled into the study | 
| Overall survival (OS) | OS is defined as the number of days from the date of enrollment to the date of death. | Up to 9 months after the last subject has enrolled into the study | 
| Objective response rate (ORR) | The proportion of subjects with objective response rate (complete response [CR] + CR incomplete recovery [CRi] + CR without platelet recovery [CRp]) for ALL subjects and (CR+PR) for LL subjects. | Up to 9 months after the last subject has enrolled into the study | 
| Complete Response (CR) rate | CR defined as hematologic recovery (absolute neutrophil count [ANC] greater than or equal to 500/μL; platelet counts greater than or equal to 75,000/μL), evidence of trilineage hematopoiesis in the bone marrow and less than 5% blasts in the bone marrow, absence of circulating blasts, and no evidence of extramedullary disease. | Up to 9 months after the last subject has enrolled into the study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed of Refractory Acute Lymphoblastic Leukemia, Cancer, Venetoclax, Navitoclax