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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Philadelphia Chromosome Positive; Recurrent Acute Lymphoblastic Leukemia; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Acute Lymphoblastic Leukemia; Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive; t(9;22)
• Intervention / Treatment: Drug: Venetoclax; Drug: Dexamethasone; Biological: Rituximab; Drug: Ponatinib Hydrochloride

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.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (ponatinib, venetoclax, dexamethasone, rituximab); See Detailed Description

Drug: Venetoclax; Given PO; Other Names: Venclexta; ABT-0199; ABT-199; ABT199; GDC-0199; RG7601; Drug: Dexamethasone; Given PO or IV; Other Names: Decadron; Aacidexam; Adexone; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Amplidermis; Anemul mono; Auricularum; Auxiloson; Baycuten; Baycuten N; Cortidexason; Cortisumman; Decacort; Decadrol; Decalix; Decameth; Decasone R.p.; Dectancyl; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Dinormon; Fluorodelta; Fortecortin; Gammacorten; Hexadecadrol; Hexadrol; Lokalison-F; Loverine; Methylfluorprednisolone; Millicorten; Mymethasone; Orgadrone; Spersadex; Visumetazone; Biological: Rituximab; Given IV; Other Names: Rituxan; MabThera; ABP 798; BI 695500; C2B8 Monoclonal Antibody; Chimeric Anti-CD20 Antibody; CT-P10; IDEC-102; IDEC-C2B8; IDEC-C2B8 Monoclonal Antibody; Monoclonal Antibody IDEC-C2B8; PF-05280586; Rituximab Biosimilar ABP 798; Rituximab Biosimilar BI 695500; Rituximab Biosimilar CT-P10; Rituximab Biosimilar GB241; Rituximab Biosimilar IBI301; Rituximab Biosimilar PF-05280586; Rituximab Biosimilar RTXM83; Rituximab Biosimilar SAIT101; RTXM83; Drug: Ponatinib Hydrochloride; Given PO; Other Names: AP24534 HCl; Iclusig

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Farhad Ravandi-Kashani, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• MD Anderson Cancer Center Website

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2018
• Primary Completion (Estimated): August 31, 2024
• Study Completion (Estimated): August 31, 2024

Study Registration Dates

• First Submitted: June 26, 2018
• First Submitted That Met QC Criteria: June 26, 2018
• First Posted (Actual): July 3, 2018

Study Record Updates

• Last Update Posted (Actual): May 2, 2024
• Last Update Submitted That Met QC Criteria: May 1, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Neoplastic Processes; Cell Transformation, Neoplastic; Carcinogenesis; Chromosome Aberrations; Translocation, Genetic; Chronic Disease; Leukemia; Leukemia, Myeloid; Recurrence; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Blast Crisis; Philadelphia Chromosome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Dexamethasone; Dexamethasone acetate; BB 1101; Antibodies; Immunoglobulins; Venetoclax; Rituximab; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Ponatinib
• Other Study ID Numbers: 2017-0313 (Other Identifier: M D Anderson Cancer Center); NCI-2018-01100 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No