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

Phase 1

Terminated

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

Interventions: Drug: Dexamethasone
Drug: Ponatinib Hydrochloride
Biological: Rituximab
Drug: Venetoclax

Registration Number: NCT03576547

Lead Sponsor: M.D. Anderson Cancer Center

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 9

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase I (400 mg Ponatinib) Treatment (ponatinib, venetoclax, dexamethasone, rituximab)	Dexamethasone	The regimen consists of 4 cycles of induction/consolidation followed by up to 2 years of maintenance therapy for responding patients.
Phase I (400 mg Ponatinib) Treatment (ponatinib, venetoclax, dexamethasone, rituximab)	Ponatinib Hydrochloride	The regimen consists of 4 cycles of induction/consolidation followed by up to 2 years of maintenance therapy for responding patients.
Phase I (400 mg Ponatinib) Treatment (ponatinib, venetoclax, dexamethasone, rituximab)	Rituximab	The regimen consists of 4 cycles of induction/consolidation followed by up to 2 years of maintenance therapy for responding patients.
Phase I (400 mg Ponatinib) Treatment (ponatinib, venetoclax, dexamethasone, rituximab)	Venetoclax	The regimen consists of 4 cycles of induction/consolidation followed by up to 2 years of maintenance therapy for responding patients.
Phase I (800 mg Ponatinib) Treatment (ponatinib, venetoclax, dexamethasone, rituximab)	Dexamethasone	The regimen consists of 4 cycles of induction/consolidation followed by up to 2 years of maintenance therapy for responding patients.
Phase I (800 mg Ponatinib) Treatment (ponatinib, venetoclax, dexamethasone, rituximab)	Ponatinib Hydrochloride	The regimen consists of 4 cycles of induction/consolidation followed by up to 2 years of maintenance therapy for responding patients.
Phase I (800 mg Ponatinib) Treatment (ponatinib, venetoclax, dexamethasone, rituximab)	Rituximab	The regimen consists of 4 cycles of induction/consolidation followed by up to 2 years of maintenance therapy for responding patients.
Phase I (800 mg Ponatinib) Treatment (ponatinib, venetoclax, dexamethasone, rituximab)	Venetoclax	The regimen consists of 4 cycles of induction/consolidation followed by up to 2 years of maintenance therapy for responding patients.
Phase II Ponatinib MDT	Dexamethasone	Participants in Phase II will receive the dose that was determined to be the Maximum Tolerated Dose (MDT) found in the Phase I portion of the study. The regimen consists of 4 cycles of induction/consolidation followed by up to 2 years of maintenance therapy for responding patients.
Phase II Ponatinib MDT	Ponatinib Hydrochloride	Participants in Phase II will receive the dose that was determined to be the Maximum Tolerated Dose (MDT) found in the Phase I portion of the study. The regimen consists of 4 cycles of induction/consolidation followed by up to 2 years of maintenance therapy for responding patients.
Phase II Ponatinib MDT	Rituximab	Participants in Phase II will receive the dose that was determined to be the Maximum Tolerated Dose (MDT) found in the Phase I portion of the study. The regimen consists of 4 cycles of induction/consolidation followed by up to 2 years of maintenance therapy for responding patients.
Phase II Ponatinib MDT	Venetoclax	Participants in Phase II will receive the dose that was determined to be the Maximum Tolerated Dose (MDT) found in the Phase I portion of the study. The regimen consists of 4 cycles of induction/consolidation followed by up to 2 years of maintenance therapy for responding patients.

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) of Venetoclax When Given in Combination With Ponatinib and Dexamethasone (Phase I)	Up to 1 year	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.
Number of Participants With a Response Complete Response (CR) + CR With Incomplete Count Recovery (CRi)	9 weeks	Overall response rate, defined as the rate or complete response (CR) + CR with incomplete count recovery (CRi). Complete Remission (CR): Normalization of the peripheral blood and bone marrow with 5% or less blasts in normocellular or hypercellular marrow with a granulocyte count of 1 x 10\^9/L or above, and platelet count of 100 x 10\^9/L. Complete resolution of all sites of extramedullary disease is required for CR. Complete remission without recovery of counts (CRi): Peripheral blood and marrow results as for CR, but with incomplete recover of counts (platelets \< 100 x 10\^9/L; neutrophils \< 1 x 10\^9/L).
Event Free Survival (EFS)	Monthly up to 5 years, 11 months and 7 days	Time from date of treatment start until the date of failure or death from any cause.

Secondary Outcome Measures

Name	Time	Method
Number of Participants Achieving Minimal Residual Disease Negativity	After 2 cycles of therapy	The proportion of patient achieving minimal residual disease negativity (as assessed by polymerase chain reaction PCR for BCR-ABL transcripts) after 2 cycles of therapy will be estimated.
Proportion of Patients Proceeding to Allogeneic Stem Cell Transplant (ASCT) a	Up to 1 year	All patients assessed for allogeneic stem cell transplant.
Overall Survival (OS)	From treatment initiation to death or last follow-up, up to 5 years, 11 months and 7 days	Time from date of treatment start until date of death due to any cause or last Follow-up.
Relapse-free Survival (RFS)	Monthly up to 5 years, 11 months and 7 days	Relapse-free survival is the time from documented CR/CRi until relapse or death. Complete Remission (CR): Normalization of the peripheral blood and bone marrow with 5% or less blasts in normocellular or hypercellular marrow with a granulocyte count of 1 x 10\^9/L or above, and platelet count of 100 x 10\^9/L. Complete resolution of all sites of extramedullary disease is required for CR. Complete remission without recovery of counts (CRi): Peripheral blood and marrow results as for CR, but with incomplete recover of counts (platelets \< 100 x 10\^9/L; neutrophils \< 1 x 10\^9/L).