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Milademetan Tosylate and Low-Dose Cytarabine With or Without Venetoclax in Treating Participants With Recurrent or Refractory Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT03634228
Recruitment Status : Recruiting
First Posted : August 16, 2018
Last Update Posted : June 2, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
This phase I/II trial studies the side effects and best dose of milademetan tosylate and to see how well it works with cytarabine with or without ventoclax in treating participants with acute myeloid leukemia that has come back (recurrent) or that does not respond to treatment (refractory). Milademetan tosylate and ventoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine, 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. It is not yet known if giving milademetan tosylate and low-dose cytarabine with or without ventoclax will work better in treating participants with recurrent or refractory acute myeloid leukemia.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Drug: Cytarabine Drug: Milademetan Tosylate Drug: Venetoclax Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability. (Phase 1) II. To determine the recommended phase II dose. (Phase I) III. To evaluate the efficacy (by International Working Group [IWG] criteria - Phase 2) of the MDM2 inhibitor, milademetan tosylate (DS-3032b), in combination with low dose cytarabine (LDAC), with or without the addition of venetoclax in both the frontline and in relapsed/refractory (non-TP53 mutant) patient population.

SECONDARY OBJECTIVES:

I. Evaluation of time to response variables including overall survival (OS), event-free survival (EFS) and duration of response (DOR).

II. Determine biomarkers that may be predictive of DS-3032b activity. III. Molecular profiling at screening, on study, and at relapse to determine genomic predictors of response and resistance.

OUTLINE: This is a phase I, dose escalation study of milademetan tosylate, followed by a phase II study. Patients are assigned to 1 of 2 arms.

ARM A: Patients receive low dose cytarabine subcutaneously (SC) twice daily (BID) on days 1-10 and milademetan tosylate orally (PO) once daily (QD) on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive low dose cytarabine SC BID on days 1-10, milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17, and venetoclax PO QD on days 1-14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment participants are followed up at 30 days.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 58 participants
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of the Oral MDM2 Inhibitor DS-3032b (Milademetan) in Combination With Low Dose Cytarabine (LDAC) in Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia (AML)
Actual Study Start Date : December 17, 2018
Estimated Primary Completion Date : May 1, 2021
Estimated Study Completion Date : May 1, 2022


Arm Intervention/treatment
Experimental: Arm A (low dose cytarabine, MDM2 inhibitor DS-3032b)
Patients receive low dose cytarabine SC BID on days 1-10 and milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Cytarabine
Given SC
Other Names:
  • .beta.-Cytosine arabinoside
  • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-.beta.-D-Arabinofuranosylcytosine
  • 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-Beta-D-arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
  • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
  • Alexan
  • Ara-C
  • ARA-cell
  • Arabine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • Aracytidine
  • Aracytin
  • Aracytine
  • Beta-cytosine Arabinoside
  • CHX-3311
  • Cytarabinum
  • Cytarbel
  • Cytosar
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Cytosine-beta-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453

Drug: Milademetan Tosylate
Given PO
Other Names:
  • DS-3032 Tosylate
  • DS-3032b
  • DS-3032b Tosylate

Experimental: Arm B (low dose cytarabine, MDM2 inhibitor DS-3032b)
Patients receive low dose cytarabine SC BID on days 1-10, milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17, and venetoclax PO QD on days 1-14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Cytarabine
Given SC
Other Names:
  • .beta.-Cytosine arabinoside
  • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-.beta.-D-Arabinofuranosylcytosine
  • 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-Beta-D-arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
  • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
  • Alexan
  • Ara-C
  • ARA-cell
  • Arabine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • Aracytidine
  • Aracytin
  • Aracytine
  • Beta-cytosine Arabinoside
  • CHX-3311
  • Cytarabinum
  • Cytarbel
  • Cytosar
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Cytosine-beta-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453

Drug: Milademetan Tosylate
Given PO
Other Names:
  • DS-3032 Tosylate
  • DS-3032b
  • DS-3032b Tosylate

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




Primary Outcome Measures :
  1. Incidence of adverse events (Phase I) [ Time Frame: Up to 1 year ]
    Graded according to Common Terminology Criteria for Adverse Events version 5.0.

  2. Maximum tolerated dose (MTD) (Phase I) [ Time Frame: Up to 28 days ]
    As determined by dose limiting toxicity (DLT). MTD is defined the highest dose at which no more than one patient out of 6 patients experience DLTs in the first cycle. A 3+3 algorithm will be applied for dose escalation or dose de-escalation.

  3. Overall response rate (Phase II) [ Time Frame: Up to cycle 2 (each cycle is 28 days) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • Diagnosis of acute myeloid leukemia (AML) by World Health Organization (WHO) 2016 criteria. Patients will be divided into 2 arms during the phase 2 portion:

    • Arm A: Subjects must have newly diagnosed AML
    • Arm B: Subjects must have refractory or relapsed AML
  • TP53 wild-type status on molecular testing performed within the last 3 months
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 3
  • Creatinine clearance >= 60 mL/min, as calculated using the modified Cockcroft-Gault equation OR creatinine =< 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN
  • Bilirubin =< 1.5 x ULN, unless resulting from hemolysis, Gilbert's disease or considered to be due to leukemic involvement
  • No gastrointestinal issues to interfere with oral medication absorption
  • No active uncontrolled infection or comorbidity that would interfere with therapy or place patient at increased risk
  • Subject (male and female) of childbearing/reproductive potential must agree to use double-barrier contraceptive measures or avoid intercourse during the study and for 90 days after the last dose of study drug
  • Subject must sign and date an Institutional Review Board-approved informed consent form (including Health Insurance Portability and Accountability Act authorization, if applicable) before performance of any study-specific procedures or tests
  • Able and willing to provide bone marrow biopsies/aspirates as requested by the protocol
  • Willing to undergo malignancy genotyping for TP53 mutation, insertion, or deletion at screening
  • Use of hydroxyurea is allowed prior to and during the first cycle of study treatment. 1‐2 doses of cytarabine are also permitted if needed for cytoreduction prior to initiating study treatment

Exclusion Criteria:

  • Patient with t(15;17) karyotypic abnormality or a diagnosis of acute promyelocytic leukemia
  • Patient with other malignancy that contains a non-synonymous mutation, insertion, or deletion in the TP53 gene determined previously or at screening
  • Prior treatment with an MDM2 inhibitor
  • Presence of central nervous system involvement of leukemia. History of prior leptomeningeal leukemia/disease that has fully resolved is eligible
  • A second concurrent primary malignancy that has required systemic anti‐neoplastic treatment within the previous 6 months, except for localized cancers that have apparently been cured, for example non‐melanoma skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast
  • Any condition that would preclude adequate absorption of DS-3032b, including refractory vomiting, malabsorption, biliary shunt, significant bowel resection, and/or graft-versus-host disease (GVHD) affecting the gut
  • Any active uncontrolled infection, known human immunodeficiency virus infection, or active hepatitis B or C infection
  • Any concomitant medical condition that would in the opinion of the investigator increase the risk of toxicity
  • Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5, grade =< 1 or baseline. Subjects with chronic grade 2 toxicities may be eligible per discretion of the investigator and sponsor (e.g., grade 2 chemotherapy-induced neuropathy)
  • Patient having received hematopoietic stem cell transplantation (HSCT) within 60 days of the first dose of DS-3032b, is on immuno-suppressive therapy post-HSCT at the time of screening, or has clinically significant GVHD (use of topical steroids for ongoing skin GVHD will be permitted)
  • Prolongation of corrected QT interval using Fridericia's method (QTcF) at rest, where the mean QTcF interval is >= 450 ms for males or >= 470 ms for females based on electrocardiograms (ECGs). Patients with right bundle branch block (RBBB) will be eligible after discussion with principal investigator (PI)
  • Pregnant or breastfeeding
  • Substance abuse or medical, psychological, or social conditions that, in the opinion of the investigator, may interfere with the subject's participation in the clinical study or evaluation of the clinical study results

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): NCT03634228


Contacts
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Contact: Kiran Naqvi 713-745-6877 knaqvi@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Kiran Naqvi    713-745-5073    knaqvi@mdanderson.org   
Principal Investigator: Kiran Naqvi         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Kiran Naqvi M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03634228    
Other Study ID Numbers: 2018-0333
NCI-2018-01612 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2018-0333 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: August 16, 2018    Key Record Dates
Last Update Posted: June 2, 2020
Last Verified: May 2020

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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
Cytarabine
Venetoclax
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs