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

Phase 1

Terminated

• Conditions: Acute Myelogenous Leukemia; Myelodysplastic Syndrome
• Interventions: Drug: Milademetan; Drug: AZA

• Registration Number: NCT02319369
• Lead Sponsor: Daiichi Sankyo

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:

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.

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 Timeline

• Study Start: 2014-11-25
• Study First Submitted: 2014-12-15
• Study First Submitted QC: 2014-12-17
• Study First Posted: 2014-12-18
• Primary Completion: 2020-08-21
• Study Completion: 2020-08-21
• Results First Submitted: 2021-08-04
• Status Verified: 2021-09
• Results First Submitted QC: 2021-09-14
• Last Update Submitted: 2021-09-14
• Results First Posted: 2021-10-11
• Last Update Posted: 2021-10-11

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 74

Inclusion Criteria

Not provided

Read More

Exclusion Criteria

Not provided

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part 1A, Milademetan with 5-azacytidine (AZA)	AZA	Participants receive milademetan in combination with 5-azacytidine (AZA), with different dose schedules
Part 2, Cohort 3	AZA	Participants with high-risk myelodysplastic syndrome (MDS) receive the recommended dose for Part 2 of milademetan or milademetan with 5-azacytidine (AZA)
Part 2, Cohort 2	AZA	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)
Part 2, Cohort 1	AZA	Participants with refractory or relapsed acute myelogenous leukemia (AML) receive the recommended dose for Part 2 of milademetan or milademetan with5-azacytidine (AZA)
Part 1, Milademetan Alone	Milademetan	Participants receive milademetan alone with different dose schedules
Part 2, Cohort 1	Milademetan	Participants with refractory or relapsed acute myelogenous leukemia (AML) receive the recommended dose for Part 2 of milademetan or milademetan with5-azacytidine (AZA)
Part 1A, Milademetan with 5-azacytidine (AZA)	Milademetan	Participants receive milademetan in combination with 5-azacytidine (AZA), with different dose schedules
Part 2, Cohort 2	Milademetan	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)
Part 2, Cohort 3	Milademetan	Participants with high-risk myelodysplastic syndrome (MDS) receive the recommended dose for Part 2 of milademetan or milademetan with 5-azacytidine (AZA)

Primary Outcome Measures

Name	Time	Method
Number of Participants With Dose-Limiting Toxicities (DLTs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA)	From the date the participant signed the informed consent form up to 5 years of first participant enrolled	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.
Number of Participants (≥10%) With Treatment-emergent Adverse Events (TEAEs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA)	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	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.

Secondary Outcome Measures

Name	Time	Method
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)	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.
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)	Pharmacokinetic parameter maximum plasma concentration (Cmax) of milademetan was assessed at select time points and the geometric means (coefficient of variation %) are presented.
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)	Pharmacokinetic parameter time to maximum concentration (Tmax) of milademetan was assessed at select time points.
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)	Pharmacokinetic parameter time to maximum concentration (Tmax) was assessed at select time points.
Area Under the Plasma Concentration Curve up to 24 Hours (AUC0-24) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)	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)	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.
Serum Macrophage Inhibitory Cytokine-1 (MIC-1) Fold Change From Baseline Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)	Day 5 (predose) up to Day 22 (predose), up to approximately 6 years of first participant enrolled	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.
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)	Pharmacokinetic parameter maximum plasma concentration (Cmax) was assessed at select time points and the geometric means (coefficient of variation %) are presented.
Area Under the Plasma Concentration Curve up to 24 Hours (AUC0-24) 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)	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.
Serum Macrophage Inhibitory Cytokine-1 (MIC-1) Fold Change From Baseline Following Administration of Milademetan Alone	Day 1 (6 hours postdose) up to Day 21-22 (predose), up to approximately 6 years of first participant enrolled	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.

Trial Locations

Locations (5)

M D Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

University of California San Francisco Medical Center; 🇺🇸 San Francisco, California, United States

University of Kansas Cancer Center; 🇺🇸 Fairway, Kansas, United States

Roswell Park Comprehensive Cancer Center; 🇺🇸 Buffalo, New York, United States

City of Hope National Medical Center; 🇺🇸 Duarte, California, United States