Clinical trial NCT02319369: 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 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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Acute Myelogenous Leukemia
Myelodysplastic Syndrome
Keywords: High Risk Myelodysplastic Syndrome
Relapsed/Refractory
Newly Diagnosed
Unfit for Chemotherapy
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
First posted: 2014-12-18
Enrollment: 74
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Parts 1 and 1A are sequential, then Part 2 is parallel
Primary purpose: TREATMENT

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

Eligibility 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.

Primary outcomes:
measure: Number of Participants With Dose-Limiting Toxicities (DLTs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA)
timeFrame: From the date the participant signed the informed consent form up to 5 years of first participant enrolled
measure: Number of Participants (≥10%) With Treatment-emergent Adverse Events (TEAEs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA)
timeFrame: 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
Secondary outcomes:
measure: Maximum Plasma Concentration (Cmax) Following Administration of Milademetan Alone
timeFrame: 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)
measure: Maximum Plasma Concentration (Cmax) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)
timeFrame: 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)
measure: Time to Maximum Concentration (Tmax) Following Administration of Milademetan Alone
timeFrame: 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)
measure: Time to Maximum Concentration (Tmax) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)
timeFrame: 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)
measure: Trough Plasma Concentration (Ctrough) Following Administration of Milademetan Alone
timeFrame: 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)
measure: Area Under the Plasma Concentration Curve up to 24 Hours (AUC0-24) Following Administration of Milademetan Alone
timeFrame: 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)
measure: Area Under the Plasma Concentration Curve up to 24 Hours (AUC0-24) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)
timeFrame: 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)
measure: Serum Macrophage Inhibitory Cytokine-1 (MIC-1) Fold Change From Baseline Following Administration of Milademetan Alone
timeFrame: Day 1 (6 hours postdose) up to Day 21-22 (predose), up to approximately 6 years of first participant enrolled
measure: Serum Macrophage Inhibitory Cytokine-1 (MIC-1) Fold Change From Baseline Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)
timeFrame: Day 5 (predose) up to Day 22 (predose), up to approximately 6 years of first participant enrolled
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Medical Center
state: California
city: Fairway
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
Study officials:
affiliation: Daiichi Sankyo
name: Global Clinical Leader
role: STUDY_DIRECTOR
References: