Safety, Tolerability and Pharmacokinetics of Milademetan Alone and With 5-Azacitidine (AZA) in Acute Myelogenous Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

NCT02319369 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: DS3032-A-U102
• Study Type: interventional
• Target: 74
• Locations: 1 country
• Sites: 5

Brief Summary

This study will take place in parts:

• Dose Escalation (Part 1): Participants receive milademetan alone with different dose schedules
• Dose Escalation (Part 1A): Participants receive milademetan in combination with 5-azacytidine (AZA), with different dose schedules The recommended dose for Part 2 will be selected.
• Dose Expansion (Part 2): After Part 1A, participants will receive the recommended Part 2 dose schedule. There will be three groups - those with:
• refractory or relapsed acute myelogenous leukemia (AML)
• newly diagnosed AML unfit for intensive chemotherapy
• high-risk myelodysplastic syndrome (MDS)
• End-of-Study Follow-Up: Safety information will be collected until 30 days after the last treatment. This is the end of the study. The recommended dose for the next study will be selected.

Conditions

Acute Myelogenous Leukemia; Myelodysplastic Syndrome

Keywords

High Risk Myelodysplastic Syndrome; Relapsed/Refractory; Newly Diagnosed; Unfit for Chemotherapy

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Dose-Limiting Toxicities (DLTs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA)

  A DLT was defined as any treatment-emergent adverse event not attributable to disease or disease-related processes occurring during the observation period (Cycle 1) in each dose-level cohort and is Grade (Gr) 3 or higher according to NCI CTCAE Version 5.0 (Version 4.03 before 01 Apr 2018), with these exceptions: for elevations in hepatic function enzymes, a DLT is defined as: Gr ≥3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels lasting \>3 days; AST/ALT \>5 × ULN if accompanied by ≥Gr 2 elevation in bilirubin. Potential DLTs include: Participants who are unable to complete at least 75% of milademetan or AZA in Cycle 1 as a result of non-disease-related Gr ≥2 events; Persistent bone marrow aplasia in the absence of malignant cell infiltration, and failure to recover a peripheral absolute neutrophil count ≥0.5 × 10\^9/L and platelets ≥20 × 10\^9/L while withholding study drug, resulting in \>2-week delay in initiating Cycle 2.

  From the date the participant signed the informed consent form up to 5 years of first participant enrolled

• Number of Participants (≥10%) With Treatment-emergent Adverse Events (TEAEs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA)

  A treatment-emergent adverse event (TEAE) is defined as an adverse event that emerges during the treatment period (up to 30 days after last dose), having been absent at pre-treatment; or reemerges during treatment, having been present at baseline but stopped prior to treatment; or worsens in severity after starting treatment relative to the pre-treatment state, when the adverse event is continuous.

  From the date the participant signed the informed consent form up to 30 days after the last dose in the last participant, up to approximately 6 years of first participant enrolled

Secondary Outcomes (9)

• Maximum Plasma Concentration (Cmax) Following Administration of Milademetan Alone

  Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 1 (Cohorts 1-9d) and Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days)

• Maximum Plasma Concentration (Cmax) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)

  Predose, 0.5 hour (hr), 1 hr, 2 hr, 3 hr, 6 hr of Cycle 1, Day 1 (AZA); Predose, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6-10 hr of Day 5, Day 7 (predose) (Cohorts 10e and 12e), Day 8 (Cohorts 11f and 13f), and Day 14 (Cohorts 10e-13f) (each cycle is 28 days)

• Time to Maximum Concentration (Tmax) Following Administration of Milademetan Alone

  Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 1 (Cohorts 1-9d) and Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days)

• Time to Maximum Concentration (Tmax) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)

  Predose, 0.5 hour (hr), 1 hr, 2 hr, 3 hr, 6 hr of Cycle 1, Day 1 (AZA); Predose, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6-10 hr of Day 5, Day 7 (predose) (Cohorts 10e and 12e), Day 8 (Cohorts 11f and 13f), and Day 14 (Cohorts 10e-13f) (each cycle is 28 days)

• Trough Plasma Concentration (Ctrough) Following Administration of Milademetan Alone

  Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days)

Study Arms (5)

Part 1, Milademetan Alone

EXPERIMENTAL

Participants receive milademetan alone with different dose schedules

Drug: Milademetan

Part 1A, Milademetan with 5-azacytidine (AZA)

EXPERIMENTAL

Participants receive milademetan in combination with 5-azacytidine (AZA), with different dose schedules

Drug: Milademetan; Drug: AZA

Part 2, Cohort 1

EXPERIMENTAL

Participants with refractory or relapsed acute myelogenous leukemia (AML) receive the recommended dose for Part 2 of milademetan or milademetan with5-azacytidine (AZA)

Drug: AZA; Drug: Milademetan

Part 2, Cohort 2

EXPERIMENTAL

Participants with newly diagnosed acute myelogenous leukemia (AML) unfit for intensive chemotherapy receive the recommended dose for Part 2 of milademetan or milademetan with 5-azacytidine (AZA)

Drug: AZA; Drug: Milademetan

Part 2, Cohort 3

EXPERIMENTAL

Participants with high-risk myelodysplastic syndrome (MDS) receive the recommended dose for Part 2 of milademetan or milademetan with 5-azacytidine (AZA)

Drug: AZA; Drug: Milademetan

Interventions

Milademetan DRUG

Milademetan will be administered daily as oral capsules or as a combination of multiple oral capsules containing 5 mg, 20 mg, 80 mg, and/or 200 mg

Also known as: Oral MDM2 Inhibitor

Part 1, Milademetan Alone; Part 1A, Milademetan with 5-azacytidine (AZA)

AZA DRUG

AZA will be administered at 75 mg/m\^2 subcutaneously or intravenously

Also known as: 5-Azacitidine

Part 1A, Milademetan with 5-azacytidine (AZA); Part 2, Cohort 1; Part 2, Cohort 2; Part 2, Cohort 3

Eligibility Criteria

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

You may qualify if:

• Has a diagnosis of refractory or relapsed (R/R) AML or high-risk MDS:
• Part 1 and 1A (Dose Escalation)
• Participants with R/R AML, OR
• Participants with untreated, high-risk MDS or participants who have received prior MDS treatment regimens.
• Participants ≥18 years old.
• Part 2 (Dose Expansion)
• Cohort 1: R/R AML
• Participants who have treatment failure to prior AML therapy or have relapsed after prior AML therapy.
• Participants ≥18 years old.
• Cohort 2: Newly diagnosed AML
• Participants with newly diagnosed AML who are ineligible for intensive induction chemotherapy. Participants must have had no prior AML treatment, with the exceptions of therapy for antecedent hematologic malignancies or hydroxyurea.
• Participants ≥75 years old, OR Participants between 18 and 74 years old (inclusive) with at least one of the specific protocol-defined comorbidities.
• Cohort 3: High-risk MDS
• Participants with untreated, high-risk MDS or who received up to 2 prior MDS treatment regimens.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.

You may not qualify if:

• Has a diagnosis of acute promyelocytic leukemia.
• Has a malignancy that is known to contain a non-synonymous mutation, insertion, or deletion in the TP53 gene determined previously or at screening.
• Has presence of central nervous system (CNS) involvement of leukemia or a history of primary CNS leukemia.
• Has a second concurrent primary malignancy that required active treatment within the previous 2 years, except for localized cancers that have apparently been cured, such as non-melanoma skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast.
• Has any condition that would preclude adequate absorption of DS-3032b, including refractory nausea and vomiting, malabsorption, biliary shunt, significant bowel resection, and/or graft-versus-host disease (GVHD) affecting the gut.
• Has an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, known human immunodeficiency virus infection, or active hepatitis B or C infection.
• Has a concomitant medical condition that would increase the risk of toxicity.
• Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE Grade ≤ 1, or baseline. Subjects with chronic Grade 2 toxicities may be eligible at the discretion of the Investigator and Sponsor (eg, Grade 2 chemotherapy-induced neuropathy).
• Has received Hematopoietic Stem Cell Transplantation (HSCT) within 60 days of the first dose of study drugs or has clinically significant GVHD or GVHD requiring initiation of systemic treatment or systemic treatment escalation within 21 days prior to Screening and/or \>Grade 1 persistent or clinically significant GVHD or other non-hematologic toxicity related to HCT.
• Is receiving concomitant treatment with a strong inhibitor or inducer of cytochrome P450 3A4/5.
• Has received any therapies intended to treat malignancy within 7 days (small molecules) or 21 days (anti-body/immune based biologics) of first receipt of study drugs \[except for hydroxyurea, which must be discontinued at least 48 hours (Day -2) prior to study treatment\].
• Had major surgery within 4 weeks prior to study drug treatment.
• Participated in a therapeutic clinical study within a washout time of 2 weeks or 5 half-lives of the drug/biologic (whichever is longer) before starting study drug treatment under this protocol, or current participation in other therapeutic investigational procedures.
• Has prolongation of corrected QT interval using Fridericia's method (QTcF) at rest, where the mean QTcF interval is \> 480 ms based on triplicate electrocardiograms (ECGs).
• Is pregnant or breastfeeding.

Sponsors & Collaborators

• Daiichi Sankyo: lead

Study Sites (5)

City of Hope National Medical Center

Duarte, California, 91010, United States

Location

University of California San Francisco Medical Center

San Francisco, California, 94143, United States

Location

University of Kansas Cancer Center

Fairway, Kansas, 66205, United States

Location

Roswell Park Comprehensive Cancer Center

Buffalo, New York, 14263, United States

Location

M D Anderson Cancer Center

Houston, Texas, 77031, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Recurrence

Interventions

milademetan; Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Contact for Clinical Trial Information
• Organization: Daiichi Sankyo

CTRinfo@dsi.com

908-992-6400

Study Officials

• Global Clinical Leader

  Daiichi Sankyo

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

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

Model Details: Parts 1 and 1A are sequential, then Part 2 is parallel

Study Record Dates

• First Submitted: December 15, 2014
• First Posted: December 18, 2014
• Study Start: November 25, 2014
• Primary Completion: August 21, 2020
• Study Completion: August 21, 2020
• Last Updated: October 11, 2021
• Results First Posted: October 11, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.

Locations

US (5)