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

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ClinicalTrials.gov Identifier: NCT03576547
Recruitment Status : Recruiting
First Posted : July 3, 2018
Last Update Posted : October 21, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE June 26, 2018
First Posted Date  ICMJE July 3, 2018
Last Update Posted Date October 21, 2019
Actual Study Start Date  ICMJE June 26, 2018
Estimated Primary Completion Date January 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 6, 2018)
  • Maximum tolerated dose (MTD) of venetoclax when given in combination with ponatinib and dexamethasone (Phase I) [ Time Frame: 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.
  • Overall response rate [ Time Frame: 9 weeks ]
    Overall response rate, defined as the rate or complete response (CR) + CR with incomplete count recovery (CRi)
Original Primary Outcome Measures  ICMJE
 (submitted: June 26, 2018)
  • Maximum Tolerated Dose (MTD) of Venetoclax When Given in Combination with Ponatinib and Dexamethasone [ Time Frame: Start of study drug combination up to day 49 ]
    MTD defined as the highest dose studied for which the observed incidence of dose limiting toxicity (DLT) is less than 33%. Toxicities tabulated according to the NCI Common Toxicity Criteria.
  • Overall response rate [ Time Frame: Start of study drug combination up to 5 weeks ]
    The primary objective is to determine the overall response rate, defined as the rate or CR + CRi occurring at the end of 2 cycles of treatment.
Change History Complete list of historical versions of study NCT03576547 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 6, 2018)
  • Rate of minimal residual disease negativity assessed by polymerase chain reaction (PCR) for BCR-ABL transcripts [ Time Frame: 9 weeks ]
  • Proportion of patients proceeding to allogeneic stem cell transplant (ASCT) a [ Time Frame: Up to 1 year ]
  • Overall survival (OS) [ Time Frame: From treatment initiation to death or last follow-up, assessed up to 1 year ]
    Kaplan-Meier curves will be used to estimate unadjusted OS distribution.
  • Relapse-free survival (RFS) [ Time Frame: Up to 1 year ]
    Kaplan-Meier curves will be used to estimate unadjusted RFS distribution.
  • Incidence of adverse events evaluated according to NCI Common Toxicity Criteria [ Time Frame: Up to 1 year ]
    Toxicity type, severity, and attribution will be summarized for each patient using frequency tables.
  • Median time to allogeneic stem cell transplant (ASCT) [ Time Frame: Up to 1 year ]
Original Secondary Outcome Measures  ICMJE
 (submitted: June 26, 2018)
  • Rate of Minimal residual disease negativity by polymerase chain reaction (PCR) for BCR-ABL1 transcripts [ Time Frame: Start of study drug combination up to 30 days after study drug combination stopped ]
  • Median Relapse-Free Survival (RFS) [ Time Frame: Start of study drug combination up to 30 days after study drug combination stopped ]
  • Median Overall Survival (OS) [ Time Frame: Start of study drug combination up to 30 days after study drug combination stopped ]
  • Proportion of Patients Proceeding to Allogeneic stem Cell Transplant (ASCT) [ Time Frame: Start of study drug combination up to 30 days after study drug combination stopped ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Venetoclax, Ponatinib, and Dexamethasone in Participants With Philadelphia Chromosome or BCR-ABL Positive Relapsed or Refractory Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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  ICMJE
  • Drug: Dexamethasone
    Given PO or IV
    Other Names:
    • 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
  • Drug: Ponatinib Hydrochloride
    Given PO
    Other Names:
    • AP24534 HCl
    • Iclusig
  • Biological: Rituximab
    Given IV
    Other Names:
    • 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
  • Drug: Venetoclax
    Given PO
    Other Names:
    • ABT-0199
    • ABT-199
    • ABT199
    • GDC-0199
    • RG7601
    • Venclexta
Study Arms  ICMJE Experimental: Treatment (ponatinib, venetoclax, dexamethasone, rituximab)
See Detailed Description
Interventions:
  • Drug: Dexamethasone
  • Drug: Ponatinib Hydrochloride
  • Biological: Rituximab
  • Drug: Venetoclax
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 26, 2018)
38
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 31, 2020
Estimated Primary Completion Date January 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Farhad Ravandi-Kashani 713-745-0394 fravandi@mdanderson.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03576547
Other Study ID Numbers  ICMJE 2017-0313
NCI-2018-01100 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2017-0313 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.D. Anderson Cancer Center
Study Sponsor  ICMJE M.D. Anderson Cancer Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Farhad Ravandi-Kashani M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP