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

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ClinicalTrials.gov Identifier: NCT02319369
Recruitment Status : Recruiting
First Posted : December 18, 2014
Last Update Posted : August 10, 2018
Sponsor:
Information provided by (Responsible Party):
Daiichi Sankyo, Inc.

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 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.


Condition or disease Intervention/treatment Phase
Acute Myelogenous Leukemia Myelodysplastic Syndrome Drug: Milademetan Drug: AZA Phase 1

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

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 156 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Parts 1 and 1A are sequential, then Part 2 is parallel
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Study Start Date : November 2014
Estimated Primary Completion Date : July 2021
Estimated Study Completion Date : July 2021


Arm Intervention/treatment
Experimental: Part 1, Milademetan Alone
Participants receive milademetan alone with different dose schedules
Drug: Milademetan
Milademetan will be administered as a single oral capsule or as a combination of multiple oral capsules containing 5 mg, 20 mg, 80 mg, and/or 200 mg milademetan
Other Name: Oral MDM2 Inhibitor

Experimental: Part 1A, Milademetan with AZA
Participants receive milademetan in combination with AZA, with different dose schedules
Drug: Milademetan
Milademetan will be administered as a single oral capsule or as a combination of multiple oral capsules containing 5 mg, 20 mg, 80 mg, and/or 200 mg milademetan
Other Name: Oral MDM2 Inhibitor

Drug: AZA
AZA will be administered at 75 mg/m^2 subcutaneously or intravenously
Other Name: 5-Azacitidine

Experimental: Part 2, Cohort 1
Participants with refractory or relapsed AML receive the recommended dose for Part 2 of milademetan or milademetan with AZA
Drug: Milademetan
Milademetan will be administered as a single oral capsule or as a combination of multiple oral capsules containing 5 mg, 20 mg, 80 mg, and/or 200 mg milademetan
Other Name: Oral MDM2 Inhibitor

Drug: AZA
AZA will be administered at 75 mg/m^2 subcutaneously or intravenously
Other Name: 5-Azacitidine

Experimental: Part 2, Cohort 2
Participants with newly diagnosed AML unfit for intensive chemotherapy receive the recommended dose for Part 2 of milademetan or milademetan with AZA
Drug: Milademetan
Milademetan will be administered as a single oral capsule or as a combination of multiple oral capsules containing 5 mg, 20 mg, 80 mg, and/or 200 mg milademetan
Other Name: Oral MDM2 Inhibitor

Drug: AZA
AZA will be administered at 75 mg/m^2 subcutaneously or intravenously
Other Name: 5-Azacitidine

Experimental: Part 2, Cohort 3
Participants with high-risk MDS receive the recommended dose for Part 2 of milademetan or milademetan with AZA
Drug: Milademetan
Milademetan will be administered as a single oral capsule or as a combination of multiple oral capsules containing 5 mg, 20 mg, 80 mg, and/or 200 mg milademetan
Other Name: Oral MDM2 Inhibitor

Drug: AZA
AZA will be administered at 75 mg/m^2 subcutaneously or intravenously
Other Name: 5-Azacitidine




Primary Outcome Measures :
  1. Number of participants with dose-limiting toxicities (DLTs) by the end of the dose escalation part [ Time Frame: within 5 years ]
    Categories: for milademetan alone, for milademetan in the combination treatment with AZA

  2. Number of participants with treatment emergent adverse events (TEAEs) by the end of the End-of-Study Follow-up period up to 30 days after the last dose in the last participant (at the end of the dose expansion part) [ Time Frame: after all subjects have either discontinued the study or completed at least 6 months of treatment, within 6 years ]

Secondary Outcome Measures :
  1. Pharmacokinetics: Maximum plasma concentration (Cmax) [ Time Frame: within 6 years ]
    Categories: for milademetan alone, for milademetan in the combination treatment with AZA

  2. Pharmacokinetics: Time to Cmax (Tmax) [ Time Frame: within 6 years ]
    Categories: for milademetan alone, for milademetan in the combination treatment with AZA

  3. Pharmacokinetics: Plasma concentration before next dose (Ctrough) [ Time Frame: within 6 years ]
    Categories: for milademetan alone, for milademetan in the combination treatment with AZA

  4. Pharmacokinetics: Area under the plasma concentration curve for 24 hours (AUC0-24) [ Time Frame: within 6 years ]
    Categories: for milademetan alone, for milademetan in the combination treatment with AZA

  5. Pharmacodynamics: Macrophage inhibitory cytokine-1 (MIC-1) serum levels [ Time Frame: within 6 years ]
    Categories: for milademetan alone, for milademetan in the combination treatment with AZA



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02319369


Contacts
Contact: Andrew Ruwe, PhD 513-579-9911 ext 2353 a.ruwe@medpace.com

Locations
United States, California
City of Hope National Medical Center Completed
Duarte, California, United States, 91010
University of California San Francisco Medical Center Active, not recruiting
San Francisco, California, United States, 94143
United States, Texas
M D Anderson Recruiting
Houston, Texas, United States, 77031
Sponsors and Collaborators
Daiichi Sankyo, Inc.
Investigators
Study Director: Global Clinical Leader Daiichi Sankyo, Inc.

Responsible Party: Daiichi Sankyo, Inc.
ClinicalTrials.gov Identifier: NCT02319369     History of Changes
Other Study ID Numbers: DS3032-A-U102
First Posted: December 18, 2014    Key Record Dates
Last Update Posted: August 10, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at http://www.clinicalstudydatarequest.com. 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://www.clinicalstudydatarequest.com/Study-Sponsors-DS-Details.aspx
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Analytic Code
Time Frame: Studies for which the medicine and indication have received EU and US marketing approval on or after 01 January 2014 or by the US or EU Health Authorities when regulatory submissions in both 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 and the European Union 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.
URL: https://www.clinicalstudydatarequest.com/Study-Sponsors-DS-Details.aspx

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Daiichi Sankyo, Inc.:
High Risk Myelodysplastic Syndrome

Additional relevant MeSH terms:
Syndrome
Leukemia
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors