Venetoclax, Ponatinib, and Dexamethasone in Participants With Philadelphia Chromosome or BCR-ABL Positive Relapsed or Refractory Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia

Study Overview
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Brief Summary
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This phase I/II trial studies the best dose of venetoclax when given together with ponatinib and dexamethasone and to see how well they work in treating participants with Philadelphia chromosome or BCR-ABL positive acute lymphoblastic leukemia or chronic myelogenous leukemia that has come back or does not respond to treatment. Drugs used in chemotherapy, such as venetoclax and dexamethasone, 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. Ponatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving venetoclax, ponatinib, and dexamethasone may work better in treating participants with acute lymphoblastic leukemia or chronic myelogenous leukemia.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of venetoclax, ponatinib, and dexamethasone in patients with relapsed/refractory Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) or lymphoid blastic phase (BP)-chronic myelogenous leukemia (CML). (Phase I) II. To determine the efficacy of the regimen, as defined by the rate of complete remission (CR) or CR with incomplete count recovery (CRi). (Phase II) SECONDARY OBJECTIVES: I. To determine efficacy outcomes, including rate of minimal residual disease negativity by polymerase chain reaction (PCR) for BCR-ABL1 transcripts, median relapse-free survival (RFS), and median overall survival (OS). II. To determine the proportion of patients proceeding to allogeneic stem cell transplant (ASCT). III. To preliminarily determine the safety of the combination regimen. EXPLORATORY OBJECTIVES: I. To evaluate the effect of single-agent ponatinib on apoptotic proteins and Bcl-2 dependency. II. To correlate apoptotic protein expression and Bcl-2 dependency on response and resistance to the combination regimen. III. To assess impact of baseline genomics on outcomes with the combination regimen. OUTLINE: This is a phase I, dose-escalation study of venetoclax followed by a phase II study. INDUCTION (COURSE 1): Participants who have not received ponatinib within 2 weeks of the anticipated start date receive ponatinib orally (PO) daily on days 1-35, venetoclax PO daily on days 8-35, and dexamethasone PO or intravenously (IV) over 15 minutes on days 8-11. Participants who have received ponatinib within 2 weeks of the anticipated start date receive ponatinib PO and venetoclax PO daily on days 1-28 and dexamethasone PO or IV over 15 minutes on days 1-4. Participants with CD20 expression receive rituximab IV over 2-6 hours on days 14 and 21 at the discretion of the treating physician after the maximum dose of venetoclax has been reached. CONSOLIDATION (COURSES 2-4): Participants receive ponatinib PO and venetoclax PO daily on days 1-28 and dexamethasone PO or IV over 15 minutes on days 1-4. Participants with CD20 expression receive rituximab IV over 2-6 hours for up to 2 doses each course at the discretion of the treating physician after the maximum dose of venetoclax has been reached. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE (COURSES 5+): Participants receive ponatinib PO and venetoclax PO daily on days 1-28 and dexamethasone PO or IV over 15 minutes on days 1-4. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Participants achieving remission undergo ASCT at the discretion of the treating physician. After completion of study treatment, participants are followed up at 30 days.

Official Title
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A Phase I/II Study of the Combination of Venetoclax, Ponatinib and Corticosteroids in Patients With Relapsed or Refractory Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia and Lymphoid Blast Phase Chronic Myelogenous Leukemia

Conditions
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Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Refractory Acute Lymphoblastic Leukemia, Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive, t(9;22), Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Philadelphia Chromosome Positive, Recurrent Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Dexamethasone
* Drug: Ponatinib Hydrochloride
* Biological: Rituximab
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with relapsed/refractory Ph-positive ALL or lymphoid blast phase CML (either t(9;22) and/or BCR-ABL1 positive by fluorescent in situ hybridization or polymerase chain reaction), including prior therapy with at least one Bcr-Abl tyrosine kinase inhibitor Performance status =< 3 Eastern Cooperative Oncology Group (ECOG scale) Total serum bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome, hemolysis or the underlying leukemia approved by the principal investigator (PI) Alanine aminotransferase (ALT) =< 1.5 x ULN, unless due to the underlying leukemia approved by the PI Aspartate aminotransferase (AST) =< 1.5 x ULN unless due to the underlying leukemia approved by the PI Creatinine clearance >= 30 mL/min Serum lipase and amylase =< 1.5 x ULN Ability to swallow Signed informed consent Exclusion Criteria: Prior history of treatment with venetoclax. Prior ponatinib is allowed Active serious infection not controlled by oral or intravenous antibiotics (e.g. persistent fever or lack of improvement despite antimicrobial treatment) History of acute pancreatitis within 1 year of study or history of chronic pancreatitis Uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL) Active secondary malignancy that in the investigator's opinion will shorten survival to less than 1 year Active grade III-V cardiac failure as defined by the New York Heart Association criteria Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: any history of myocardial infarction (MI), stroke, revascularization, unstable angina or transient ischemic attack prior to enrollment; left ventricular ejection fraction (LVEF) less than lower limit of normal per local institutional standards prior to enrollment; diagnosed or suspected congenital long QT syndrome; any history of clinically significant atrial or ventricular arrhythmias (such as uncontrolled atrial fibrillation, ventricular tachycardia, ventricular fibrillation, or Torsades de pointes) as determined by the treating physician; prolonged corrected QT interval (QTc) interval on pre-entry electrocardiogram (> 480 msec) unless corrected after electrolyte replacement; history of venous thromboembolism including deep venous thrombosis or pulmonary embolism within the past 3 months; uncontrolled hypertension (diastolic blood pressure > 100 mmHg; systolic > 150 mmHg) Patients currently taking drugs that are generally accepted to have a high risk of causing Torsades de Pointes (unless these can be changed to acceptable alternatives) Received strong or moderate CYP3A inhibitors or inducers within 3 days of study entry Consumed grapefruit, grapefruit products, Seville oranges, or star fruit within 3 days prior to starting venetoclax Treatment with any investigational antileukemic agents or chemotherapy agents in the last 7 days before study entry, unless full recovery from side effects has occurred or patient has rapidly progressive disease judged to be life-threatening by the investigator. Prior recent treatment with corticosteroids and hydroxyurea is permitted Pregnant and lactating women will not be eligible; women of childbearing potential should have a negative pregnancy test prior to entering on the study and be willing to practice methods of contraception throughout the study period. Women do not have childbearing potential if they have had a hysterectomy or are postmenopausal without menses for 12 months. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control. Appropriate birth control will be determined by the treating physician

Ages Eligible for Study
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Minimum Age: 18 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: Treatment (ponatinib, venetoclax, dexamethasone, rituximab)<br>See Detailed Description | Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: Visumetazone;Drug: Ponatinib Hydrochloride<br>* Given PO<br>* Other names: Iclusig;Biological: Rituximab<br>* Given IV<br>* Other names: RTXM83;Drug: Venetoclax<br>* Given PO<br>* Other names: Venclexta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of venetoclax when given in combination with ponatinib and dexamethasone (Phase I) | MTD is defined as the highest dose level where a dose limiting toxicity (DLT) occurs within at most one out of six patients treated. The MTD is defined as the highest dose studied for which the observed incidence of DLT is less than 33%. Frequencies of toxicities will be tabulated according to the National Cancer Institute (NCI) Common Toxicity Criteria. Patients will be continued to be followed for one year for evidence of late toxicity. | Up to 1 year | 
| Overall response rate | Overall response rate, defined as the rate or complete response (CR) + CR with incomplete count recovery (CRi) | 9 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of minimal residual disease negativity assessed by polymerase chain reaction (PCR) for BCR-ABL transcripts |  | 9 weeks | 
| Proportion of patients proceeding to allogeneic stem cell transplant (ASCT) a |  | Up to 1 year | 
| Overall survival (OS) | Kaplan-Meier curves will be used to estimate unadjusted OS distribution. | From treatment initiation to death or last follow-up, assessed up to 1 year | 
| Relapse-free survival (RFS) | Kaplan-Meier curves will be used to estimate unadjusted RFS distribution. | Up to 1 year | 
| Incidence of adverse events evaluated according to NCI Common Toxicity Criteria | Toxicity type, severity, and attribution will be summarized for each patient using frequency tables. | Up to 1 year | 
| Median time to allogeneic stem cell transplant (ASCT) |  | Up to 1 year |