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Venetoclax in Combination With Decitabine in r/r AML

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ClinicalTrials.gov Identifier: NCT03404193
Recruitment Status : Recruiting
First Posted : January 19, 2018
Last Update Posted : May 31, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE January 11, 2018
First Posted Date  ICMJE January 19, 2018
Last Update Posted Date May 31, 2019
Actual Study Start Date  ICMJE January 16, 2018
Estimated Primary Completion Date December 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 12, 2018)
Overall response rate (ORR) of venetoclax in combination with 10-day decitabine [ Time Frame: 3 months ]
ORR defined as the proportion of patients who had CR (complete remission), CRp (complete remission with incomplete platelet recovery), CRi (complete remission with incomplete count recovery), PR (partial response) or marrow clearance of blasts within 3 months of treatment initiation among adult patients with AML; and complete remission (CR), partial remission (PR) or marrow CR† (mCR) lasting at least 4 weeks for patients with MDS.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03404193 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 29, 2019)
  • Duration of Response of patients with refractory/relapsed AML treated with this combination. [ Time Frame: 1 year ]
  • Disease-Free Survival (DFS) of patients with refractory/relapsed AML treated with this combination. [ Time Frame: 1 year ]
  • Overall Survival (OS) of patients with refractory/relapsed AML treated with this combination. [ Time Frame: 1 year ]
  • Determination of the number of patients who achieve a hematologic improvement (HI) in platelets, hemoglobin, or absolute neutrophil count (ANC) and the number of patients who achieve > 50% reduction in blasts on therapy with venetoclax/10-day decitabine. [ Time Frame: 1 year ]
  • Safety of venetoclax in combination with 10-day decitabine in patients with refractory/ relapsed AML. [ Time Frame: Baseline up to 30 days after last dose of study drug ]
    The overall incidence and severity of all reported adverse events using Common Toxicity Criteria v 4.0.
  • Determination of the number of patients who transition towards stem cell transplantation upon achieving response with the combination venetoclax/10-day decitabine regimen. [ Time Frame: 3 months ]
    Response assessed based by Modified IWG Response Criteria for MDS (Cheson et al, 2006).
  • Determine the incidence of infections complications per cycle with the Venetoclax in combination with 10-day Decitabine. [ Time Frame: 1 year ]
Original Secondary Outcome Measures  ICMJE
 (submitted: January 12, 2018)
  • Duration of Response of patients with refractory/relapsed AML treated with this combination. [ Time Frame: 1 year ]
  • Disease-Free Survival (DFS) of patients with refractory/relapsed AML treated with this combination. [ Time Frame: 1 year ]
  • Overall Survival (OS) of patients with refractory/relapsed AML treated with this combination. [ Time Frame: 1 year ]
  • Determination of the number of patients who achieve a hematologic improvement (HI) in platelets, hemoglobin, or ANC and the number of patients who achieve > 50% reduction in blasts on therapy with venetoclax/10-day decitabine. [ Time Frame: 1 year ]
  • Safety of venetoclax in combination with 10-day decitabine in patients with refractory/ relapsed AML. [ Time Frame: Baseline up to 30 days after last dose of study drug ]
    The overall incidence and severity of all reported adverse events using Common Toxicity Criteria v 4.0.
  • Determination of the number of patients who transition towards stem cell transplantation upon achieving response with the combination venetoclax/10-day decitabine regimen. [ Time Frame: 3 months ]
    Response assessed based by Modified IWG Response Criteria for MDS (Cheson et al, 2006).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Venetoclax in Combination With Decitabine in r/r AML
Official Title  ICMJE A Phase II Study of Venetoclax in Combination With 10-Day Decitabine in Newly Diagnosed Elderly or Relapsed/Refractory Acute Myeloid Leukemia and Relapsed High-Risk Myelodysplastic Syndrome
Brief Summary

The goal of this clinical research study is to learn if venetoclax in combination with decitabine can help to control acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS) in newly diagnosed elderly patients or in patients with disease that has relapsed (come back after treatment). The safety of this drug combination will also be studied.

This is an investigational study. Venetoclax and decitabine are FDA approved and commercially available. Venetoclax is FDA approved and commercially available for the treatment of chronic lymphocytic leukemia. Decitabine is FDA approved and commercially available for the treatment of MDS. It is considered investigational to use venetoclax in combination with decitabine to treat AML or HR-MDS.

The study doctor can explain how the study drugs are designed to work.

Up to 280 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed Description

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive decitabine by vein over about 1 hour on Days 1-10 of each 28-day study cycle. Note that the start of future cycles may be delayed if you have side effects to the study drug.

You will take venetoclax by mouth on Days 1-28 of the first cycle and Days 1-21 of all other cycles. Each dose should be taken within 30 minutes after eating a meal (preferably breakfast) with about a cup (8 ounces) of water. If the study doctor thinks it is needed based on any side effects you may be having (such as low blood cell counts and/or infections), your dose(s) of venetoclax may be delayed until it is thought to be safe for you to receive it.

If venetoclax is not available at the start of treatment for any reason (insurance, financial, transportation, and so on), you can begin receiving decitabine and venetoclax can be added when it is available.

During Cycle 1, you will be admitted into the hospital as an inpatient for at least the first 3 days of combination therapy. During this time, you will also be given drugs to prevent tumor lysis syndrome (TLS). TLS happens when breakdown products of the cancer cells entering the blood stream, causing possible weakness, low blood pressure, muscle cramps, kidney damage, and/or other organ damage. You may be given fluids (either by mouth or by vein) and treatment with allopurinol or rasburicase. After Day 3, if there is If no evidence of TLS, you may be discharged. You will then receive the rest of the study drug doses as an outpatient.

If the study doctor thinks it is in your best interest, you may be able to also receive standard of care therapies (such as sorafenib, midostaurin, imatinib, dasatinib, ponatinib, and so on) while you are on study. The study doctor will discuss these treatments with you, as well as their risks and benefits.

If the study doctor thinks it is needed for your safety, you may also receive cytarabine to help prevent central nervous system side effects. Cytarabine will be given intrathecally (through a spinal tap) on either Day 21 of Cycle 1 or Day 14 of Cycle 2.

Length of Study:

You may continue taking the study drugs for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

Study Visits:

On Day 1 of each cycle (+/- 4 days), you will have a physical exam.

One (1) time every week during Cycles 1, 2 and 3, and then on Day 1 of each cycle after that (+/- 4 days):

  • Blood (about 1 tablespoon) will be drawn for routine tests.
  • You will have a bone marrow biopsy and aspirate to check the status of the disease, and for biomarker and cytogenetic testing (Day 21 [+/- 3 days]). If the study doctor thinks it is needed, this will be repeated on Day 28. Additionally, you will have a bone marrow biopsy and aspirate to check the status of the disease, for biomarker and for cytogenetic testing at the end of Cycles 2 and 4, then every 1-3 cycles after that, then at any time that the disease appears to get worse.

Additional Research Tests:

Blood (about 3 tablespoons) will be drawn for biomarker testing at the following time points (within 24 hours). Biomarkers, which may include genetic biomarkers, are found in the blood and tissue and may be related to your reaction to the study drug:

  • Baseline (before the first decitabine dose), about Day 3 of Cycle 1, and between Days 21 to 28 of Cycle 1
  • At the end of Cycles 2 and 4
  • At any point that the disease appears to get worse

You will have a "cheek scrape" at the end of Cycle 1. These cells will be used to compare to cancer cells to look for effects of the study drug. For this test, a small sample of cells from the inside of your mouth will be collected by scraping a special brush against the inside of your cheek a few times, until enough cells are collected.

End-of-Study Visit:

Within 30 days after your last dose of study drug(s):

  • You will have a physical exam.
  • Blood (about 1 tablespoon) will be drawn for routine tests.
  • You will have a bone marrow aspirate/biopsy to check the status of the disease and for biomarker and cytogenetic testing.

Follow-up:

If the disease responded to the study treatment, you will then be called every 3 to 6 months for up to 5 years and asked about how you are doing. Each call should last about 15-30 minutes.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myeloid Leukemia
  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • Blasts 10 Percent or More of Bone Marrow Nucleated Cells
  • Blasts 10-20 Percent of Bone Marrow Nucleated Cells
  • Chronic Myelomonocytic Leukemia
  • High Risk Chronic Myelomonocytic Leukemia
  • High Risk Myelodysplastic Syndrome
  • Myelodysplastic Syndrome
  • Recurrent Acute Biphenotypic Leukemia
  • Recurrent Acute Myeloid Leukemia
  • Recurrent Chronic Myelomonocytic Leukemia
  • Recurrent High Risk Myelodysplastic Syndrome
  • Recurrent Mixed Phenotype Acute Leukemia
  • Refractory Acute Myeloid Leukemia
  • Refractory Chronic Myelomonocytic Leukemia
  • Refractory High Risk Myelodysplastic Syndrome
  • Refractory Mixed Phenotype Acute Leukemia
  • TP53 Gene Deletion
  • TP53 Gene Mutation
Intervention  ICMJE
  • Drug: Decitabine
    20 mg/m2 by vein over approximately 1 hour daily x 10 days on days 1-10 of each treatment cycle.
    Other Names:
    • 5-Aza-2'-deoxycytidine
    • Aza-TdC
    • Dacogen
    • Decitabine for Injection
    • Deoxyazacytidine
    • Dezocitidine
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Venetoclax
    400 mg by mouth on Days 1-28 of the first cycle and Days 1-21 of all other cycles.
    Other Names:
    • ABT-0199
    • ABT-199
    • ABT199
    • GDC-0199
    • RG7601
    • Venclexta
Study Arms  ICMJE Experimental: Treatment (decitabine, venetoclax)
Participants receive decitabine by vein over 1 hour on days 1-10 and may also receive decitabine on days 1-5 after achieving complete remission/complete remission with incomplete count recovery during consolidation/maintenance. Participants also receive venetoclax PO daily on days 1-28 of cycle 1 and on days 1-21 of subsequent cycles. Treatment repeat every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: Decitabine
  • Other: Laboratory Biomarker Analysis
  • 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: April 17, 2019)
280
Original Estimated Enrollment  ICMJE
 (submitted: January 12, 2018)
160
Estimated Study Completion Date  ICMJE December 30, 2021
Estimated Primary Completion Date December 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with AML, biphenotypic or bilineage leukemia (including a myeloid component) or mixed phenotype acute leukemia (MPAL) who have failed prior therapy; patients with AML should have failed prior therapy or have relapsed after prior therapy; patients with isolated extramedullary AML are eligible
  • Elderly (> 60 year old) patients with newly diagnosed AML or mixed phenotype acute leukemia (MPAL) not eligible for intensive chemotherapy
  • Patients with newly diagnosed AML with poor risk complex karyotype and/or TP53 deletions/mutations equal or younger than 60 year old
  • AML patients with prior history of MDS or CMML who received any therapy or no therapy for the MDS or CMML and progressed to AML, are eligible at the time of diagnosis of AML regardless of any prior therapy for MDS; the World Health Organization (WHO) classification will be used for AML
  • Patients with high-risk MDS with bone marrow blasts between 10% and 20%, relapsed or refractory to prior hypomethylating agent (HMA) therapy, defined as prior receipt of 4 cycles of HMA therapy with failure to attain a response, or relapse after prior response to HMA therapy; patients with high risk chronic myelomonocytic leukemia (CMML) with bone marrow blasts >= 10% regardless of prior therapy
  • Age>/=18 years old
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 3
  • White blood cell count =< 10,000
  • Adequate renal function including creatinine < 2 unless related to the disease
  • Adequate hepatic function including total bilirubin < 2 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement
  • Provision of written informed consent
  • Oral hydroxyurea and/or one dose of cytarabine (up to 2 g/m^2) for patients with rapidly proliferative disease is allowed before the start of study therapy and while the patient is on active study treatment through cycle 1, as needed, for clinical benefit and after discussion with the principal investigator (PI); concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted
  • Females must be surgically or biologically sterile or postmenopausal (amenorrheic for at least 12 months) or if of childbearing potential, must have a negative serum or urine pregnancy test within 72 hours before the start of the treatment
  • Women of childbearing potential must agree to use an adequate method of contraception during the study and until 3 months after the last treatment; males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study until 3 months after the last treatment

Exclusion Criteria:

  • Patients having received any prior BCL2 inhibitor therapy
  • Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British [FAB] class M3-AML)
  • Patients with symptomatic CNS leukemia or patients with poorly controlled CNS leukemia
  • Active and uncontrolled comorbidities including active uncontrolled infection, uncontrolled hypertension despite adequate medical therapy, active and uncontrolled congestive heart failure New York Heart Association (NYHA) class III/IV, clinically significant and uncontrolled arrhythmia as judged by the treating physician
  • Patients with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C
  • Any other medical, psychological, or social condition that may interfere with study participation or compliance, or compromise patient safety in the opinion of the investigator
  • Pregnant or breastfeeding
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: Marina Konopleva, MD, PHD 713-794-1628 mkonople@mdanderson.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03404193
Other Study ID Numbers  ICMJE 2017-0912
NCI-2018-00752 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2017-0912 ( 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: Marina Konopleva M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date May 2019

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