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

NCT03576547 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 2017-0313NCI-2018-01100
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

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.

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)

Outcome Measures

Primary Outcomes (3)

• 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

• Number of Participants With a Response Complete Response (CR) + CR With Incomplete Count Recovery (CRi)

  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).

  9 weeks

• Event Free Survival (EFS)

  Time from date of treatment start until the date of failure or death from any cause.

  Monthly up to 5 years, 11 months and 7 days

Secondary Outcomes (4)

• Number of Participants Achieving Minimal Residual Disease Negativity

  After 2 cycles of therapy

• Proportion of Patients Proceeding to Allogeneic Stem Cell Transplant (ASCT) a

  Up to 1 year

• Overall Survival (OS)

  From treatment initiation to death or last follow-up, up to 5 years, 11 months and 7 days

• Relapse-free Survival (RFS)

  Monthly up to 5 years, 11 months and 7 days

Study Arms (3)

Phase I (400 mg Ponatinib) Treatment (ponatinib, venetoclax, dexamethasone, rituximab)

EXPERIMENTAL

The regimen consists of 4 cycles of induction/consolidation followed by up to 2 years of maintenance therapy for responding patients.

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

Phase I (800 mg Ponatinib) Treatment (ponatinib, venetoclax, dexamethasone, rituximab)

EXPERIMENTAL

The regimen consists of 4 cycles of induction/consolidation followed by up to 2 years of maintenance therapy for responding patients.

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

Phase II Ponatinib MDT

EXPERIMENTAL

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.

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

Interventions

Dexamethasone DRUG

Given PO or IV

Also known as: Aacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, 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

Phase I (400 mg Ponatinib) Treatment (ponatinib, venetoclax, dexamethasone, rituximab); Phase I (800 mg Ponatinib) Treatment (ponatinib, venetoclax, dexamethasone, rituximab); Phase II Ponatinib MDT

Ponatinib Hydrochloride DRUG

Given PO

Also known as: AP24534 HCl, Iclusig

Phase I (400 mg Ponatinib) Treatment (ponatinib, venetoclax, dexamethasone, rituximab); Phase I (800 mg Ponatinib) Treatment (ponatinib, venetoclax, dexamethasone, rituximab); Phase II Ponatinib MDT

Rituximab BIOLOGICAL

Given IV

Also known as: ABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, 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

Phase I (400 mg Ponatinib) Treatment (ponatinib, venetoclax, dexamethasone, rituximab); Phase I (800 mg Ponatinib) Treatment (ponatinib, venetoclax, dexamethasone, rituximab); Phase II Ponatinib MDT

Venetoclax DRUG

Given PO

Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta

Phase I (400 mg Ponatinib) Treatment (ponatinib, venetoclax, dexamethasone, rituximab); Phase I (800 mg Ponatinib) Treatment (ponatinib, venetoclax, dexamethasone, rituximab); Phase II Ponatinib MDT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Links

• MD Anderson Cancer Center Website

MeSH Terms

Conditions

Blast Crisis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Interventions

Dexamethasone; Calcium Dobesilate; auricularum; dexamethasone acetate; dexamethasone 21-phosphate; ponatinib; Rituximab; CT-P10; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Cell Transformation, Neoplastic; Carcinogenesis; Neoplastic Processes; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

This study was terminated early due to slow accrual. The trial did not move on to Phase II, therefore zero participants were registered on the Phase II Portion.

Results Point of Contact

• Title: Farhad Ravandi-Kashani, MD./Professor
• Organization: The University of Texas MD Anderson Cancer Center

fravandi@mdanderson.org

713-745-0394

Study Officials

• Farhad Ravandi-Kashani

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 26, 2018
• First Posted: July 3, 2018
• Study Start: June 26, 2018
• Primary Completion: June 19, 2024
• Study Completion: June 19, 2024
• Last Updated: May 8, 2025
• Results First Posted: May 8, 2025

Record last verified: 2025-05

Locations

US (1)