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

NCT03634228 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 2018-0333NCI-2018-01612
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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.

Conditions

Acute Myeloid Leukemia; Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD) (Phase I)

  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.

  Up to 28 days

• Participants With a Response

  Response is Complete Response (CR) + Complete Response with Incomplete Blood Count Recovery (CRi) + Partial Response (PR) + Morphologic Leukemia -Free State (MLFS: CR is Bone marrow blasts \< 5%; absence of circulating blasts and blasts with Auer rods; absence of extra-medullary disease; ANC \>/= 1.0 x 10\^9/L; platelet count \>/= 100 x 10\^9/L. CRi is CR except for ANC \< 1.0 x 10\^9 or platelet count , 100 x 10\^9/L. PR is decreased bone marrow blast % by at least 50% to a value of 5% to 25% and ANC \>/= 1.0 x 10\^9/L; platelet count \>/= 100 x 10\^9/L. MLFS is Bone marrow blasts \< 5%; abcence of blasts with Auer rods; absence of extra-medullary disease; no hematologic recovery required.

  Up to 3 years, 4 months

Secondary Outcomes (2)

• Overall Survival

  Up to 3 years, 4 months

• Event Free Survival (EFS)

  Up to 3 years, 4 months

Study Arms (2)

Phase I (low dose cytarabine, MDM2 inhibitor DS-3032b)

EXPERIMENTAL

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; Drug: Milademetan Tosylate

Phase II (low dose cytarabine, MDM2 inhibitor DS-3032b)

EXPERIMENTAL

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; Drug: Milademetan Tosylate; Drug: Venetoclax

Interventions

Cytarabine DRUG

Given SC

Also known as: .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

Phase I (low dose cytarabine, MDM2 inhibitor DS-3032b); Phase II (low dose cytarabine, MDM2 inhibitor DS-3032b)

Milademetan Tosylate DRUG

Given PO

Also known as: DS-3032 Tosylate, DS-3032b, DS-3032b Tosylate

Phase I (low dose cytarabine, MDM2 inhibitor DS-3032b); Phase II (low dose cytarabine, MDM2 inhibitor DS-3032b)

Venetoclax DRUG

Given PO

Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto

Phase II (low dose cytarabine, MDM2 inhibitor DS-3032b)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Senapati J, Muftuoglu M, Ishizawa J, Abbas HA, Loghavi S, Borthakur G, Yilmaz M, Issa GC, Dara SI, Basyal M, Li L, Naqvi K, Pourebrahim R, Jabbour EJ, Kornblau SM, Short NJ, Pemmaraju N, Garcia-Manero G, Ravandi F, Khoury J, Daver N, Kantarjian HM, Andreeff M, DiNardo CD. A Phase I study of Milademetan (DS3032b) in combination with low dose cytarabine with or without venetoclax in acute myeloid leukemia: Clinical safety, efficacy, and correlative analysis. Blood Cancer J. 2023 Jun 29;13(1):101. doi: 10.1038/s41408-023-00871-1.

  PMID: 37386016 DERIVED

Related Links

• MD Anderson Cancer Center Website

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Cytarabine; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Courtney DiNardo, MD/ Associate Professor
• Organization: The University of Texas MD Anderson Cancer Center

CDiNardo@mdanderson.org

713-794-1141

Study Officials

• Courtney DiNardo, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 9, 2018
• First Posted: August 16, 2018
• Study Start: December 17, 2018
• Primary Completion: April 3, 2022
• Study Completion: April 3, 2022
• Last Updated: June 15, 2023
• Results First Posted: June 15, 2023

Record last verified: 2023-05

Locations

US (1)