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

A Phase 1 Study of Milademetan (DS 3032b), an Oral MDM2 Inhibitor, In Dose Escalation as a Single Agent and In Dose Escalation/Expansion In Combination With 5 Azacitidine In Subjects With Acute Myelogenous Leukemia (AML) or High Risk Myelodysplastic Syndrome (MDS)

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:

  1. refractory or relapsed acute myelogenous leukemia (AML)
  2. newly diagnosed AML unfit for intensive chemotherapy
  3. 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.

Study Overview

• Status: Terminated
• Conditions: Myelodysplastic Syndrome; Acute Myelogenous Leukemia
• Intervention / Treatment: Drug: Milademetan; Drug: Milademetan; Drug: AZA

Detailed Description

The primary analysis will occur after all participants have either discontinued the study or completed at least 6 months of treatment. After the primary analysis, the main study will be closed. Participants who are still on study at least 6 months after enrollment of the last participant in the study may be eligible to continue receiving study drug in a separate extension phase of the protocol

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
    • San Francisco, California, United States, 94143
      • University of California San Francisco Medical Center
  • Kansas
    • Fairway, Kansas, United States, 66205
      • University of Kansas Cancer Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Comprehensive Cancer Center
  • Texas
    • Houston, Texas, United States, 77031
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

1. 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.

2. Has an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.

   • As an exception, participants with newly diagnosed AML between 18 and 74 years old (inclusive) in Part 2 Cohort 2 with ECOG Performance Status of 3 will be eligible.
3. Has protocol-defined adequate renal, hepatic and blood clotting functions.
4. Is able to provide written informed consent (or authorized representative), comply with protocol visits and procedures, and take oral medication, and does not have any active infection or comorbidity that would interfere with therapy.

5. If female, is either postmenopausal (no menstrual period for a minimum of 12 months), surgically sterile, or, if of childbearing potential, has a negative serum pregnancy test upon entry into this study and is willing to use maximally effective birth control during the period of therapy and for 6 months following the last investigational drug dose.

   • If male, is surgically sterile or willing to use a maximally effective double-barrier contraception method upon enrollment, during the course of the study, and for 6 months following the last investigational drug dose.
6. Is fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects).
7. Signs and dates 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.
8. Is able and willing to provide bone marrow biopsies/aspirates as requested by the protocol.
9. Is willing to undergo malignancy genotyping for TP53 mutation, insertion, or deletion at screening.

Exclusion Criteria

1. Has a diagnosis of acute promyelocytic leukemia.
2. Has a malignancy that is known to contain a non-synonymous mutation, insertion, or deletion in the TP53 gene determined previously or at screening.
3. Has presence of central nervous system (CNS) involvement of leukemia or a history of primary CNS leukemia.
4. 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.
5. 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.
6. Has an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, known human immunodeficiency virus infection, or active hepatitis B or C infection.
7. Has a concomitant medical condition that would increase the risk of toxicity.
8. 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).
9. 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.
10. Is receiving concomitant treatment with a strong inhibitor or inducer of cytochrome P450 3A4/5.
11. 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].
12. Had major surgery within 4 weeks prior to study drug treatment.
13. 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.
14. 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).
15. Is pregnant or breastfeeding.
16. Has 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.
17. Prior treatment with an MDM2 inhibitor.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1, Milademetan Alone; Participants receive milademetan alone with different dose schedules	Drug: Milademetan; 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; Other Names: Oral MDM2 Inhibitor; Drug: Milademetan; Milademetan will be administered daily as oral capsules or as a combination of multiple oral capsules containing 5, 20, 80, and/or 200 mg. An alternate combination of 30 mg, 80 mg, and/or 100 mg milademetan may be utilized.; Other Names: Oral MDM2 Inhibitor
Experimental: Part 1A, Milademetan with 5-azacytidine (AZA); Participants receive milademetan in combination with 5-azacytidine (AZA), with different dose schedules	Drug: Milademetan; 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; Other Names: Oral MDM2 Inhibitor; Drug: Milademetan; Milademetan will be administered daily as oral capsules or as a combination of multiple oral capsules containing 5, 20, 80, and/or 200 mg. An alternate combination of 30 mg, 80 mg, and/or 100 mg milademetan may be utilized.; Other Names: Oral MDM2 Inhibitor; Drug: AZA; AZA will be administered at 75 mg/m^2 subcutaneously or intravenously; Other Names: 5-Azacitidine
Experimental: Part 2, Cohort 1; Participants with refractory or relapsed acute myelogenous leukemia (AML) receive the recommended dose for Part 2 of milademetan or milademetan with5-azacytidine (AZA)	Drug: Milademetan; 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; Other Names: Oral MDM2 Inhibitor; Drug: Milademetan; Milademetan will be administered daily as oral capsules or as a combination of multiple oral capsules containing 5, 20, 80, and/or 200 mg. An alternate combination of 30 mg, 80 mg, and/or 100 mg milademetan may be utilized.; Other Names: Oral MDM2 Inhibitor; Drug: AZA; AZA will be administered at 75 mg/m^2 subcutaneously or intravenously; Other Names: 5-Azacitidine
Experimental: Part 2, Cohort 2; 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: Milademetan; 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; Other Names: Oral MDM2 Inhibitor; Drug: Milademetan; Milademetan will be administered daily as oral capsules or as a combination of multiple oral capsules containing 5, 20, 80, and/or 200 mg. An alternate combination of 30 mg, 80 mg, and/or 100 mg milademetan may be utilized.; Other Names: Oral MDM2 Inhibitor; Drug: AZA; AZA will be administered at 75 mg/m^2 subcutaneously or intravenously; Other Names: 5-Azacitidine
Experimental: Part 2, Cohort 3; Participants with high-risk myelodysplastic syndrome (MDS) receive the recommended dose for Part 2 of milademetan or milademetan with 5-azacytidine (AZA)	Drug: Milademetan; 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; Other Names: Oral MDM2 Inhibitor; Drug: Milademetan; Milademetan will be administered daily as oral capsules or as a combination of multiple oral capsules containing 5, 20, 80, and/or 200 mg. An alternate combination of 30 mg, 80 mg, and/or 100 mg milademetan may be utilized.; Other Names: Oral MDM2 Inhibitor; Drug: AZA; AZA will be administered at 75 mg/m^2 subcutaneously or intravenously; Other Names: 5-Azacitidine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Plasma Concentration (Cmax) Following Administration of Milademetan Alone	Pharmacokinetic parameter maximum plasma concentration (Cmax) of milademetan was assessed at select time points and the geometric means (coefficient of variation %) are presented.	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)	Pharmacokinetic parameter maximum plasma concentration (Cmax) was assessed at select time points and the geometric means (coefficient of variation %) are presented.	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	Pharmacokinetic parameter time to maximum concentration (Tmax) of milademetan was assessed at select time points.	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)	Pharmacokinetic parameter time to maximum concentration (Tmax) was assessed at select time points.	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	Pharmacokinetic parameter plasma concentration before next dose (Ctrough) of milademetan was assessed at Cycle 1, Day 15 and the geometric means (coefficient of variation %) are presented.	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)
Area Under the Plasma Concentration Curve up to 24 Hours (AUC0-24) Following Administration of Milademetan Alone	Pharmacokinetic parameter area under the plasma concentration curve up to 24 hours (AUC0-24) of milademetan was assessed at select time points and the geometric means (coefficient of variation %) are presented.	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)
Area Under the Plasma Concentration Curve up to 24 Hours (AUC0-24) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)	Pharmacokinetic parameter area under the plasma concentration curve up to 24 hours (AUC0-24) was assessed at select time points and the geometric means (coefficient of variation %) are presented.	Predose, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6-10 hr of Cycle 1, Day 5 (Cohorts 10e and 12e) and Predose of Cycle 1, Day 14 (Cohorts 10e, 11f, and 12e) (each cycle is 28 days)
Serum Macrophage Inhibitory Cytokine-1 (MIC-1) Fold Change From Baseline Following Administration of Milademetan Alone	Pharmacodynamic biomarker serum macrophage inhibitory cytokine-1 (MIC-1) concentrations of milademetan were assessed for Cohorts 1 though 9d. Fold change is the ratio of post-baseline MIC-1 values with respect to the baseline values and is the measure of change of MIC-1 from baseline.	Day 1 (6 hours postdose) up to Day 21-22 (predose), up to approximately 6 years of first participant enrolled
Serum Macrophage Inhibitory Cytokine-1 (MIC-1) Fold Change From Baseline Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)	Pharmacodynamic biomarker serum macrophage inhibitory cytokine-1 (MIC-1) concentrations were assessed for Cohorts 10e though 13f. Fold change is the ratio of post-baseline MIC-1 values with respect to the baseline values and is the measure of change of MIC-1 from baseline.	Day 5 (predose) up to Day 22 (predose), up to approximately 6 years of first participant enrolled

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): November 25, 2014
• Primary Completion (Actual): August 21, 2020
• Study Completion (Actual): August 21, 2020

Study Registration Dates

• First Submitted: December 15, 2014
• First Submitted That Met QC Criteria: December 17, 2014
• First Posted (Estimate): December 18, 2014

Study Record Updates

• Last Update Posted (Actual): October 11, 2021
• Last Update Submitted That Met QC Criteria: September 14, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Newly Diagnosed; Relapsed/Refractory; High Risk Myelodysplastic Syndrome; Unfit for Chemotherapy
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine
• Other Study ID Numbers: DS3032-A-U102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No