Safety, Tolerability and Pharmacokinetics of Milademetan Alone and With 5-Azacitidine (AZA) in 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 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.
- 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).
- Has an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
- Has protocol-defined adequate renal, hepatic and blood clotting functions.
- 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.
- 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.
- Is fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects).
- 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.
- Is able and willing to provide bone marrow biopsies/aspirates as requested by the protocol.
- Is willing to undergo malignancy genotyping for TP53 mutation, insertion, or deletion at screening.
- 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).
- Participant is ineligible for intensive induction chemotherapy by meeting at least 1 (a or b) of the following criteria:
- Is ≥ 75 years of age with ECOG performance status 0 to 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.
- Has a diagnosis of acute promyelocytic leukemia.
- Has a malignancy that is known to contain a non synonymous mutation, insertion, or deletion in the TP53 gene determined previously or at screening.
- Has presence of central nervous system (CNS) involvement of leukemia or a history of primary CNS leukemia.
- 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.
- 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.
- Has an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, known human immunodeficiency virus infection, or active hepatitis B or C infection.
- Has a concomitant medical condition that would increase the risk of toxicity.
- 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).
- 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.
- Is receiving concomitant treatment with a strong inhibitor or inducer of cytochrome P450 3A4/5.
- 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].
- Had major surgery within 4 weeks prior to study drug treatment.
- 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.
- 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).
- Is pregnant or breastfeeding.
- 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.
- Prior treatment with an MDM2 inhibitor.
Locations & Contacts
Status: Temporarily closed to accrual
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Trial Objectives and Outline
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 Phase & Type
Daiichi Sankyo, Inc.
Secondary IDs NCI-2015-00023
Clinicaltrials.gov ID NCT02319369