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Decitabine/Cedazuridine and Venetoclax in Combination With Ivosidenib or Enasidenib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT04774393
Recruitment Status : Recruiting
First Posted : March 1, 2021
Last Update Posted : July 6, 2021
Sponsor:
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
This phase Ib/II trials studies the side effects of decitabine/cedazuridine (ASTX727) and venetoclax in combination with ivosidenib or enasidenib, and how well they work in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). ASTX727 is the combination of a fixed dose of 2 drugs, cedazuridine and decitabine. Cedazuridine may slow down how fast decitabine is broken down by the body, and decitabine may block abnormal cells or cancer cells from growing. Venetoclax may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Enasidenib and ivosidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving decitabine/cedazuridine and venetoclax in combination with ivosidenib or enasidenib may help control acute myeloid leukemia.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Drug: Decitabine and Cedazuridine Drug: Enasidenib Drug: Ivosidenib Drug: Venetoclax Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVE:

I. To determine the safety and tolerability and recommended phase 2 dose (RP2D) of oral decitabine/cedazuridine (ASTX727) and venetoclax in combination with either ivosidenib (Arm A) or enasidenib (Arm B) for patients with acute myeloid leukemia. (Phase Ib) II. To determine the overall response rate (complete response [CR], complete remission with incomplete hematologic recovery [CRh], morphologic leukemia-free state [MLFS] and partial response [PR)] of oral decitabine/cedazuridine (ASTX727) and venetoclax in combination with either ivosidenib (Arm A) or enasidenib (Arm B) for patients with acute myeloid leukemia. (Phase 2)

SECONDARY OBJECTIVES:

I. To determine duration of response (DOR), event-free survival (EFS), and overall survival (OS).

II. To evaluate occurrence of minimal residual disease (MRD) negative status by multiparameter flow cytometry and molecular evaluation.

EXPLORATORY OBJECTIVE:

I. To investigate global gene expression profiles, deoxyribonucleic acid (DNA) methylation profiles, BH3 profiling and other potential prognostic markers to explore predictors of antitumor activity and/or resistance to treatment.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM A: Patients receive decitabine/cedazuridine orally (PO) daily on days 1-5, venetoclax PO daily on days 1-14, and ivosidenib PO daily on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive decitabine/cedazuridine PO daily on days 1-5, venetoclax PO daily on days 1-14, and enasidenib PO daily on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 84 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1b/2 Study of Oral Decitabine/Cedazuridine (ASTX727) and Venetoclax in Combination With the Targeted Mutant IDH1 Inhibitor Ivosidenib or the Targeted Mutant IDH2 Inhibitor Enasidenib
Actual Study Start Date : May 24, 2021
Estimated Primary Completion Date : November 29, 2024
Estimated Study Completion Date : November 29, 2024


Arm Intervention/treatment
Experimental: Arm A (decitabine/cedazuridine, venetoclax, ivosidenib)
Patients receive decitabine/cedazuridine PO daily on days 1-5, venetoclax PO daily on days 1-14, and ivosidenib PO daily on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Decitabine and Cedazuridine
Given PO
Other Names:
  • ASTX727
  • CDA Inhibitor E7727/Decitabine Combination Agent ASTX727
  • Cedazuridine/Decitabine Combination Agent ASTX727
  • Cedazuridine/Decitabine Tablet
  • Inqovi

Drug: Ivosidenib
Given PO
Other Names:
  • AG-120
  • Tibsovo

Drug: Venetoclax
Given PO
Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta
  • Venclyxto

Experimental: Arm B (decitabine/cedazuridine, venetoclax, enasidenib)
Patients receive decitabine/cedazuridine PO daily on days 1-5, venetoclax PO daily on days 1-14, and enasidenib PO daily on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Decitabine and Cedazuridine
Given PO
Other Names:
  • ASTX727
  • CDA Inhibitor E7727/Decitabine Combination Agent ASTX727
  • Cedazuridine/Decitabine Combination Agent ASTX727
  • Cedazuridine/Decitabine Tablet
  • Inqovi

Drug: Enasidenib
Given PO
Other Names:
  • AG-221
  • CC-90007 Free Base

Drug: Venetoclax
Given PO
Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta
  • Venclyxto




Primary Outcome Measures :
  1. Dose limiting toxicity (Phase Ib) [ Time Frame: Up to 1 cycle (1 cycle = 28 days) ]
    Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5 by organ system.

  2. Overall response rate (ORR) (Phase II) [ Time Frame: Within 4 months of treatment ]
    Defined as complete remission (CR), CR with incomplete hematologic recovery, CR with incomplete count recovery, partial response or marrow clearance of blasts. Will estimate the ORR for the combination treatmen1t, along with the Bayesian 95% credible interval.

  3. Incidence of adverse events (Phase II) [ Time Frame: Within 4 months of treatment ]
    Assessed using Common Toxicity Criteria version 5.0. Safety data will be summarized using frequency and percentage, by category and severity.


Secondary Outcome Measures :
  1. Event-free survival (EFS) [ Time Frame: Time interval between treatment start until disease progression, relapse/refractory, or death due to any cause, assessed up to 3 years ]
    The Kaplan-Meier method will be used to estimate the probabilities of EFS. Log-rank tests will be used to compare among subgroups of patients in terms of EFS.

  2. Overall survival (OS) [ Time Frame: Time interval between treatment start until death due to any cause, assessed up to 3 years ]
    The Kaplan-Meier method will be used to estimate the probabilities of OS. Log-rank tests will be used to compare among subgroups of patients in terms of OS.

  3. Duration of response [ Time Frame: Up to 3 years ]
    The Kaplan-Meier method will be used to estimate the probabilities and log-rank tests will be used to compare among subgroups of patients.

  4. Minimal residual disease negative status [ Time Frame: Up to 3 years ]
    Will be summarized graphically and with descriptive statistics. The association between molecular and cellular markers and overall response and/or resistance will be assessed through logistic regression analyses. Paired t-test or Wilcoxon signed rank test will be used to assess the marker change over time.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with a diagnosis of relapsed or refractory acute myeloid leukemia (AML) (including biphenotypic or bilineage leukemia including a myeloid component or isolated extramedullary AML); OR
  • Patients (> 60 year old) with newly diagnosed AML not eligible for intensive chemotherapy are also eligible
  • Age >= 18 years
  • Subjects must have documented IDH1 or IDH2 gene mutation
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Adequate renal function including creatinine < 2 unless related to the disease
  • Direct bilirubin < 2 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement
  • Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3 x ULN unless considered due to leukemic involvement, in which case direct bilirubin or AST and/or ALT < 5 x ULN will be considered eligible)
  • In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 7 days for cytotoxic or non-cytotoxic (immunotherapy agent(s). Oral hydroxyurea and/or cytarabine (up to 2 g/m^2) for patients with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the principle investigator (PI). Concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted
  • Male subjects who are sexually active with a women of childbearing potential (WOCBP) and who have not had vasectomies must be willing to use a barrier method of contraception and refrain from sperm donation from initial study drug until 90 days after last dose of study drug
  • Willing and able to provide informed consent

Exclusion Criteria:

  • Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British [FAB] class M3-AML)
  • Patients with any concurrent uncontrolled clinically significant medical condition including life-threatening severe infection, or psychiatric illness, which could place the patient at unacceptable risk of study treatment
  • Patients with active graft-versus-host-disease (GVHD) status post stem cell transplant (patients without active GVHD on chronic suppressive immunosuppression and/or phototherapy for chronic skin GVHD are permitted after discussion with the PI)
  • Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications
  • Corrected QT (QTc) interval using Fridericia's formula (QTcF) >= 450 msec. Bundle branch block and prolonged QTc interval are permitted after discussion with the PI
  • Known active hepatitis B (HBV) or hepatitis C (HCV) infection or known human immunodeficiency virus (HIV) infection
  • Subject has a white blood cell count > 25 x 10^9/L. (Note: Hydroxyurea is permitted to meet this criterion)
  • Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception

    • Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, intrauterine device (IUD), and double barrier methods (for example a condom in combination with a spermicide)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04774393


Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Courtney DiNardo    713-794-1141    cdinardo@mdanderson.org   
Principal Investigator: Courtney DiNardo         
Sponsors and Collaborators
M.D. Anderson Cancer Center
Investigators
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Principal Investigator: Courtney DiNardo M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT04774393    
Other Study ID Numbers: 2020-1220
NCI-2021-00893 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2020-1220 ( Other Identifier: M D Anderson Cancer Center )
First Posted: March 1, 2021    Key Record Dates
Last Update Posted: July 6, 2021
Last Verified: July 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Decitabine
Venetoclax
Ivosidenib
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors