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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02319369
Recruitment Status : Active, not recruiting
First Posted : December 18, 2014
Last Update Posted : May 11, 2020
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 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.


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 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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 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 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)
Study Start Date : November 2014
Estimated Primary Completion Date : July 2021
Estimated Study Completion Date : April 2022


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
Other Name: 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 as a single oral capsule or as a combination of multiple oral capsules containing 5 mg, 20 mg, 80 mg, and/or 200 mg
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 acute myelogenous leukemia (AML) receive the recommended dose for Part 2 of milademetan or milademetan with5-azacytidine (AZA)
Drug: AZA
AZA will be administered at 75 mg/m^2 subcutaneously or intravenously
Other Name: 5-Azacitidine

Drug: Milademetan
Milademetan will be administered as a single oral capsule 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 Name: Oral MDM2 Inhibitor

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

Drug: Milademetan
Milademetan will be administered as a single oral capsule 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 Name: Oral MDM2 Inhibitor

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

Drug: Milademetan
Milademetan will be administered as a single oral capsule 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 Name: Oral MDM2 Inhibitor




Primary Outcome Measures :
  1. Number of participants with dose-limiting toxicities (DLTs) following administration of milademetan alone and in combination with 5-azacitidine (AZA) (Part 1 and 1A) [ Time Frame: Within 5 years of first participant enrolled ]
  2. Number of participants with treatment emergent adverse events (TEAEs) following administration of milademetan alone and in combination with 5-azacitidine (AZA) by the End-of-Study Follow-up period (End of the dose expansion part) [ Time Frame: Within 6 months of first participant enrolled up to 30 days after the last dose in the last participant ]
  3. Participants who achieved complete remission (CR), CR with incomplete blood count recovery, or morphologic leukemia-free state for AML and who attained CR, marrow CR (mCR) or partial remission for high-risk MDS as best response (Part 2 only) [ Time Frame: Within 6 years of first participant enrolled ]

Secondary Outcome Measures :
  1. Pharmacokinetics: Maximum plasma concentration (Cmax) following administration of milademetan alone and in combination with 5-azacitidine (AZA) [ Time Frame: Within 6 years of first participant enrolled ]
  2. Pharmacokinetics: Time to Cmax (Tmax) following administration of milademetan alone and in combination with 5-azacitidine (AZA) [ Time Frame: Within 6 years of first participant enrolled ]
  3. Pharmacokinetics: Plasma concentration before next dose (Ctrough) following administration of milademetan alone and in combination with 5-azacitidine (AZA) [ Time Frame: Within 6 years of first participant enrolled ]
  4. Pharmacokinetics: Area under the plasma concentration curve for 24 hours (AUC0-24) following administration of milademetan alone and in combination with 5-azacitidine (AZA) [ Time Frame: Within 6 years of first participant enrolled ]
  5. Pharmacodynamics: Macrophage inhibitory cytokine-1 (MIC-1) serum levels following administration of milademetan alone and in combination with 5-azacitidine (AZA) [ Time Frame: Within 6 years of first participant enrolled ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 (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.

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


Locations
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United States, California
City of Hope National Medical Center
Duarte, California, United States, 91010
University of California San Francisco Medical Center
San Francisco, California, United States, 94143
United States, Kansas
University of Kansas Cancer Center
Fairway, Kansas, United States, 66205
United States, New York
Roswell Park Comprehensive Cancer Center
Buffalo, New York, United States, 14263
United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77031
Sponsors and Collaborators
Daiichi Sankyo, Inc.
Investigators
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Study Director: Global Clinical Leader Daiichi Sankyo, Inc.
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Responsible Party: Daiichi Sankyo, Inc.
ClinicalTrials.gov Identifier: NCT02319369    
Other Study ID Numbers: DS3032-A-U102
First Posted: December 18, 2014    Key Record Dates
Last Update Posted: May 11, 2020
Last Verified: May 2020
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 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/
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (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.
URL: https://vivli.org/ourmember/daiichi-sankyo/

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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
Relapsed/Refractory
Newly Diagnosed
Unfit for Chemotherapy
Additional relevant MeSH terms:
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Leukemia
Preleukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Syndrome
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