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Venetoclax and ASTX727 for the Treatment of Relapsed, Refractory, or Newly Diagnosed Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT04746235
Recruitment Status : Recruiting
First Posted : February 9, 2021
Last Update Posted : December 9, 2022
Sponsor:
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Study Description
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Brief Summary:
This phase II trial studies the possible benefits of venetoclax and ASTX727 in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory), or elderly patients with newly diagnosed acute myeloid leukemia who are not candidates for intensive chemotherapy. Venetoclax may help block the formation of growths that may become cancer. 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. Giving venetoclax and ASTX727 may help to control the disease.

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

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the overall response rate (ORR) of decitabine and cedazuridine (ASTX727) in combination with venetoclax in patients with refractory/relapsed acute myeloid leukemia (AML).

II. To determine the overall response rate (ORR) of ASTX727 in combination with venetoclax in elderly (> 60 year old) patients with newly diagnosed acute myeloid leukemia (AML) not eligible for intensive chemotherapy.

SECONDARY OBJECTIVES:

I. To determine the duration of response, disease-free survival (DFS), and overall survival (OS) of patients with refractory/relapsed AML treated with this combination.

II. To determine similar outcomes for newly diagnosed patients with AML who are not candidates for intensive chemotherapy.

III. To determine the safety of venetoclax in combination with ASTX727 in patients with refractory/ relapsed AML, and newly diagnosed patients with AML not candidates for intensive chemotherapy.

IV. To determine the number of relapsed patients able to proceed to stem cell transplantation upon achieving response with the combination venetoclax/ASTX727 regimen.

EXPLORATORY OBJECTIVE:

I. To characterize the pharmacokinetic (PK) profiles of ASTX727 when combined with venetoclax.

OUTLINE:

Patients receive decitabine and cedazuridine orally (PO) daily on days 1-5 and venetoclax PO daily on days 1-28 of the first cycle and on days 1-21 of subsequent cycles. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients with an objective response are followed every 3-6 months for up to 5 years.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Venetoclax in Combination With ASTX727 in Patients With Relapsed/Refractory Acute Myeloid Leukemia, and Newly Diagnosed Elderly Patients With AML Who Are Not Candidates for Intensive Chemotherapy
Actual Study Start Date : February 22, 2021
Estimated Primary Completion Date : October 15, 2023
Estimated Study Completion Date : October 15, 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Treatment (decitabine and cedazuridine, venetoclax)
Patients receive decitabine and cedazuridine PO daily on days 1-5 and venetoclax PO daily on days 1-28 of the first cycle and on days 1-21 of subsequent cycles. Treatment repeats every 28 days for up to 24 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: Venetoclax
Given PO
Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta
  • Venclyxto


Outcome Measures
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Primary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: Within 3 months of treatment initiation ]
    Will be 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 acute myeloid leukemia (AML). Response criteria will be modified from the International Working Group for AML. Will estimate the ORR for the combination treatments for each cohort, along with the 90% credible intervals. The association between ORR and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.

  2. Overall incidence and severity of all adverse events [ Time Frame: Up to 5 years post treatment ]
    Will be assessed by Common Toxicity Criteria version 5.0.


Secondary Outcome Measures :
  1. Disease free survival [ Time Frame: Up to 5 years post treatment ]
    Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.

  2. Overall survival [ Time Frame: Up to 5 years post treatment ]
    Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests.


Eligibility Criteria
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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 AML by the World Health Organization (WHO) classification who have failed prior therapy, refractory to it or relapsed after prior response. Patients with isolated extramedullary AML are eligible (cohort 1)
  • Age >= 18 years
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2

  • For cohort 2 (frontline elderly or unfit AML AML), the following inclusion criteria:

    • Confirmed newly diagnosed AML

    • Ineligible for induction therapy defined as

      • Either age >= 75 years
      • Or 18-74 years of age with at least one comorbidity (chronic heart failure [CHF] requiring therapy or eject fraction [EF] =< 50%, carbon monoxide diffusing capability [DLCO] =< 65% or forced expiratory volume in 1 second [FEV1] =< 65%, or ECOG 2 or 3)
  • Creatinine < 2 x upper limit of normal unless related to the disease (e.g. infiltration)
  • Total bilirubin < 2 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement
  • Alanine aminotransferase (ALT) < 3 x ULN unless considered due to leukemic involvement (by biopsy or imaging)
  • Able to give 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 hydroxyurea 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:

  • Acute promyelocytic leukemia
  • Prior therapy with a BCL2 inhibitor
  • Symptomatic or uncontrolled 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
  • 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
Contacts and Locations
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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): NCT04746235


Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Farhad Ravandi-Kashani    713-745-0394    fravandi@mdanderson.org   
Principal Investigator: Farhad Ravandi-Kashani         
Sponsors and Collaborators
M.D. Anderson Cancer Center
Investigators
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Principal Investigator: Farhad Ravandi-Kashani M.D. Anderson Cancer Center
More Information
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT04746235    
Other Study ID Numbers: 2020-1007
NCI-2021-00112 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2020-1007 ( Other Identifier: M D Anderson Cancer Center )
First Posted: February 9, 2021    Key Record Dates
Last Update Posted: December 9, 2022
Last Verified: December 2022

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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
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors