Clinical Trials /

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

NCT02319369

Description:

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 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 AML 2. newly diagnosed AML unfit for intensive chemotherapy 3. high-risk 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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Safety, Tolerability and Pharmacokinetics of Milademetan Alone and With 5-Azacitidine (AZA) in Acute Myelogenous Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)
  • Official Title: A Phase 1 Dose Escalation Study of DS-3032b, an Oral MDM2 Inhibitor, as Single Agent and in Combination With 5-Azacitidine in Subjects With Acute Myelogenous Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Clinical Trial IDs

  • ORG STUDY ID: DS3032-A-U102
  • NCT ID: NCT02319369

Conditions

  • Acute Myelogenous Leukemia
  • Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
MilademetanOral MDM2 InhibitorPart 1, Milademetan Alone
AZA5-AzacitidinePart 1A, Milademetan with AZA

Purpose

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 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 AML 2. newly diagnosed AML unfit for intensive chemotherapy 3. high-risk 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 subjects have either discontinued the study or
      completed at least 6 months of treatment. After the primary analysis, the main study will be
      closed. Subjects who are still on study at least 6 months after enrollment of the last
      subject in the study may be eligible to continue receiving study drug in a separate extension
      phase of the protocol
    

Trial Arms

NameTypeDescriptionInterventions
Part 1, Milademetan AloneExperimentalParticipants receive milademetan alone with different dose schedules
  • Milademetan
Part 1A, Milademetan with AZAExperimentalParticipants receive milademetan in combination with AZA, with different dose schedules
  • Milademetan
  • AZA
Part 2, Cohort 1ExperimentalParticipants with refractory or relapsed AML receive the recommended dose for Part 2 of milademetan or milademetan with AZA
  • Milademetan
  • AZA
Part 2, Cohort 2ExperimentalParticipants with newly diagnosed AML unfit for intensive chemotherapy receive the recommended dose for Part 2 of milademetan or milademetan with AZA
  • Milademetan
  • AZA
Part 2, Cohort 3ExperimentalParticipants with high-risk MDS receive the recommended dose for Part 2 of milademetan or milademetan with AZA
  • Milademetan
  • AZA

Eligibility Criteria

        Inclusion Criteria

          1. Has a diagnosis of refractory or relapsed AML or high risk MDS for inclusion in Part
             1, Part 1A, and Part 2 (Cohorts 1 and 3).

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

          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.

          6. 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.

          7. Is fully informed about their illness and the investigational nature of the study
             protocol (including foreseeable risks and possible side effects).

          8. 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.

          9. Is able and willing to provide bone marrow biopsies/aspirates as requested by the
             protocol.

         10. Is willing to undergo malignancy genotyping for TP53 mutation, insertion, or deletion
             at screening.

         11. Has a life expectancy of at least 3 months.

             Other criteria for Part 2, Cohort 2 (newly diagnosed AML unfit for intensive
             chemotherapy) The following criteria should be met by participants in Dose Expansion
             Cohort 2 who never received prior treatment for AML. These participants need not meet
             inclusion criteria 1 and 2 (above).

         12. Participant is ineligible for intensive induction chemotherapy by meeting at least 1
             (a or b) of the following criteria:

               1. Is ≥ 75 years of age with ECOG performance status 0 to 2.

               2. Is 18 to 74 years old and has any of the following comorbidities:

                    -  Known congestive heart failure (New York Heart Association class 3) or
                       ejection fraction ≤ 50%

                    -  ECOG performance status 3 not related to leukemia

                    -  Any other comorbidity that the physician judges to be incompatible with
                       conventional intensive chemotherapy, but meets all the inclusion criteria
                       except 1 and 2.

        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 DS-3032b, is on immunosuppressive therapy post-HSCT at the time of
             screening, or has clinically significant GVHD (use of topical steroids for ongoing
             skin GVHD will be permitted). Has a washout period of ≥ 2 weeks or at least 4
             half-lives (whichever is longer) from their last systemic immunosuppressive treatment
             for GVHD.

         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 14 days of first
             receipt of DS-3032b [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 > 450 ms for males or > 470 ms for females 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with dose-limiting toxicities (DLTs) by the end of the dose escalation part
Time Frame:within 5 years
Safety Issue:
Description:Categories: for milademetan alone, for milademetan in the combination treatment with AZA

Secondary Outcome Measures

Measure:Pharmacokinetics: Maximum plasma concentration (Cmax)
Time Frame:within 6 years
Safety Issue:
Description:Categories: for milademetan alone, for milademetan in the combination treatment with AZA
Measure:Pharmacokinetics: Time to Cmax (Tmax)
Time Frame:within 6 years
Safety Issue:
Description:Categories: for milademetan alone, for milademetan in the combination treatment with AZA
Measure:Pharmacokinetics: Plasma concentration before next dose (Ctrough)
Time Frame:within 6 years
Safety Issue:
Description:Categories: for milademetan alone, for milademetan in the combination treatment with AZA
Measure:Pharmacokinetics: Area under the plasma concentration curve for 24 hours (AUC0-24)
Time Frame:within 6 years
Safety Issue:
Description:Categories: for milademetan alone, for milademetan in the combination treatment with AZA
Measure:Pharmacodynamics: Macrophage inhibitory cytokine-1 (MIC-1) serum levels
Time Frame:within 6 years
Safety Issue:
Description:Categories: for milademetan alone, for milademetan in the combination treatment with AZA

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Daiichi Sankyo, Inc.

Trial Keywords

  • High Risk Myelodysplastic Syndrome

Last Updated