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Venetoclax

Vincristine

Tubulin Modulators

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Patients receive venetoclax PO QD on days 1-42 of course 1 and days 43-70 of course 2. Patients also receive vincristine liposomal IV weekly for 4 weeks starting on day 14 of course 1.

Laboratory Biomarker Analysis

Vincristine Liposomal

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Nikolai A. Podoltsev

Shira N. Dinner

Hassan Alkhateeb

Dale G. Schaar

Jae Park

David F. Claxton

Noelle Frey

Neil D. Palmisiano

Ehab L. Atallah

Neil Palmisiano

This phase Ib/II clinical trial studies the side effects and best dose of venetoclax and how well it works when given together with vincristine liposomal in treating patients with T-cell or B-cell acute lymphoblastic leukemia that has come back or does not respond to treatment. Venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as vincristine liposomal, 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. Giving venetoclax together with vincristine liposomal may work better in treating patients with acute lymphoblastic leukemia.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of venetoclax in combination with vincristine liposomal (liposomal vincristine) in patients with relapsed or refractory T-cell and B-cell acute lymphoblastic leukemia (ALL). (Phase I) II. Safety assessment and toxicity characterization after treatment of venetoclax in combination with liposomal vincristine in patients with relapsed or refractory T-cell and B-cell ALL. (Phase I) III. To determine the preliminary efficacy of venetoclax in combination with liposomal vincristine to induce complete remission (CR) by day 70 in patients with relapsed or refractory T-cell and B-cell ALL. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the progression free survival, overall survival and toxicity after the combination treatment in patients with relapsed or refractory T-cell and B-cell ALL. (Phase II)

TERTIARY OBJECTIVES:

I. To determine if genetic signature as determined by next generation sequencing can predict response to combination. (Phase II) II. To determine if immunophenotype of ALL is associated with response to combination. (Phase II) III. To determine if the BH3 profile is associated with response to combination. (Phase II) IV. To determine if relative expression of BCL-2 measure by flow cytometry is associated with response to combination. (Phase II)

OUTLINE: This is a phase Ib, dose-escalation study of venetoclax, followed by a phase II study.

Patients receive venetoclax orally (PO) once daily (QD) on days 1-42 of course 1 and days 43-70 of course 2. Patients also receive vincristine liposomal intravenously (IV) weekly for 4 weeks starting on day 14 of course 1.

After completion of study treatment, patients are followed up every 6 months for 5 years.

Venetoclax and Vincristine Liposomal in Treating Patients With Relapsed or Refractory T-cell or B-cell Acute Lymphoblastic Leukemia

A Phase IB/II Study of Venetoclax (ABT-199) in Combination With Liposomal Vincristine in Patients With Relapsed or Refractory T-Cell or B-Cell Acute Lymphoblastic Leukemia

Will be assessed by next generation sequencing.

Logistic regression models will be used to investigate the association of the BCL-2 expression at baseline and immunophenotype with response (CR/CRi/PR vs. others by 70 days). Multivariable Cox PH modelling and logistic regression modelling will also be used to adjust for the effect of covariates that are possibly associated with these efficacy outcomes.

Will determine if the BH3 profile is associated with response to combination.

Will determine if relative expression of BCL-2 measure by flow cytometry is associated with response to combination.

Toxicities will be assessed and graded according to Common Terminology Criteria for Adverse Events version 5.0.

A 95% confidence interval will be computed.

Will be estimated using the Kaplan-Meier method, and the median PFS along with its corresponding 95% confidence interval will be reported.

Will be estimated using the Kaplan-Meier method, and the median OS along with its corresponding 95% confidence interval will be reported.

95% confidence interval will be computed.

Will be assessed by flow cytometry and dichotomized into two groups by the median (low vs. high). Univariate Cox proportional hazards (PH) models will be used to evaluate the association of the BCL-2 expression at baseline and immunophenotype (B-cell and T-cell acute lymphoblastic leukemia) with OS and PFS, separately. Logistic regression models will be used to investigate the association of the BCL-2 expression at baseline and immunophenotype with response (CR/CRi/partial remission \[PR\] versus \[vs.\] others by 70 days). Multivariable Cox PH modelling and logistic regression modelling will also be used to adjust for the effect of covariates that are possibly associated with these efficacy outcomes

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Venetoclax and Vincristine Liposomal in Treating Patients With Relapsed or Refractory T-cell or B-cell Acute Lymphoblastic Leukemia	NCT03504644	B Acute Lymphob... Lymphoblasts 5 ... Recurrent Adult... Recurrent Child... Refractory Acut... T Acute Lymphob...	Laboratory Biom... Venetoclax Vincristine Lip...	18 Years -	Eastern Cooperative Oncology Group
Venetoclax and Vincristine Liposomal in Treating Patients With Relapsed or Refractory T-cell or B-cell Acute Lymphoblastic Leukemia	NCT03504644	B Acute Lymphob... Lymphoblasts 5 ... Recurrent Adult... Recurrent Child... Refractory Acut... T Acute Lymphob...	Laboratory Biom... Venetoclax Vincristine Lip...	18 Years -	Eastern Cooperative Oncology Group

Spots Global Cancer Trial Database for lymphoblasts 5 percent or more of bone marrow nucleated cells