Study of MK-8242 Alone and in Combination With Cytarabine in Participants With Acute Myelogenous Leukemia (P07649)

NCT01451437 | Terminated Phase 1 Results

• 3 other identifiers: P076492011-000709-31MK-8242-005
• Study Type: interventional
• Target: 26
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a study of MK-8242 alone and in combination with cytarabine in adult participants with refractory or recurrent acute myelogenous leukemia (AML). The study will have 2 Arms. Arm A is for participants with refractory or recurrent AML who are considered ineligible for standard chemotherapy. In Part 1 of Arm A, participants will receive MK-8242 monotherapy in escalating doses to determine the recommended phase 2 dose \[RP2D\]. In Part 2, participants will receive monotherapy with MK-8242 to confirm the RP2D and assess preliminary efficacy. Arm B is for participants with recurrent AML following an initial complete remission (CR) or CR with incomplete marrow recovery (CRi) of 6 to 12 months duration. In Part 1 of Arm B, participants will receive MK-8242 in escalating doses + cytarabine to determine the RP2D in combination with cytarabine. In Part 2, participants will receive MK-8242 + cytarabine to confirm the RP2D and assess preliminary efficacy. The pharmacokinetics of MK-8242 will be studied in both arms. With Amendment 4 (22 August 2013) a 21-day dosing cycle is added, with MK-8242 being given on Days 1-7 of each 21-day cycle in both the monotherapy and combination therapy arms; data from Arm A will be used to determine whether a participant receives 21-day or 28-day therapy in Arm B.

Conditions

Acute Myelogenous Leukemia (AML)

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Dose Limiting Toxicities (DLTs)

  DLTs were identified using Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0 for toxicities attributable to the study drug. Hematologic DLTs were defined in the absence of morphological evidence of acute leukemia in the marrow if 1) bone marrow: aplastic marrow with \<5% cellularity without erythroid, myeloid, or megakaryocytic precursors and 2) peripheral blood: absolute neutrophil count (ANC) \<100/µL, platelet count \<10,000/µL, and transfusion-dependent anemia. Non-hematologic DLTs were defined as any ≥Grade 3 toxicity with the following exceptions/clarifications: 1) infection, fatigue, anorexia, or alopecia are not included in determination of the DLT 2) Grade 3 nausea, vomiting, diarrhea, or dehydration occurring in a setting of inadequate treatment 3) any abnormal non-hematological laboratory value ≥Grade 3 will be considered a DLT after 72 hours of appropriate medical intervention if not related to an underlying disease or not attributable to another event.

  Up to 28 days (Cycle 1) for non-hematologic toxicities and 42 days (Cycle 1) for hematologic toxicities

• Number of Participants With Complete Remission (CR) at RP2D

  Clinical activity of MK-8242 given as monotherapy in participants with refractory or recurrent AML measured as participants who achieved CR according to Cheson (2003) criteria at the RP2D. The outcome analysis was not performed since the RP2D for MK-8242 monotherapy could not be established due to early termination of the study.

  End of Treatment (up to 198 days)

• Number of Participants With Complete Remission With Incomplete Marrow Recovery (CRi) at RP2D

  Clinical activity of MK-8242 given as monotherapy in participants with refractory or recurrent AML measured as participants who achieved CRi according to Cheson (2003) criteria at the RP2D. The outcome analysis was not performed since the RP2D for MK-8242 monotherapy could not be established due to early termination of the study.

  End of Treatment (up to 198 days)

Secondary Outcomes (10)

• Number of Participants With CR at Dose Levels Other Than RP2D

  End of Treatment (up to 198 days)

• Number of Participants With CRi at Dose Levels Other Than RP2D

  End of Treatment (up to 198 days)

• Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine

  Cycle 1, Day 1 and Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, and 24 hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], and 24 [Day 7 only] hrs postdose)

• Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine

  Cycle 1, Day 1 and Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 [Day 7 only] hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24 [Day 7 only], 48 [Day 7 only] hrs postdose)

• Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞) for MK-8242 Alone and in Combination With Cytarabine

  Cycle 1 Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24, 48 hrs postdose)

Study Arms (9)

Pt 1 Arm A: MK-8242 30 mg QD

EXPERIMENTAL

Participants received MK-8242 30 mg once daily (QD) monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles in Part 1 Arm A.

Drug: MK-8242

Pt 1 Arm A: MK-8242 60 mg QD

EXPERIMENTAL

Participants received MK-8242 60 mg QD monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles in Part 1 Arm A.

Drug: MK-8242

Pt 1 Arm A: MK-8242 120 mg QD

EXPERIMENTAL

Participants received MK-8242 120 mg QD monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles in Part 1 Arm A.

Drug: MK-8242

Pt 1 Arm A: MK-8242 250 mg QD

EXPERIMENTAL

Participants received MK-8242 250 mg QD monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles in Part 1 Arm A.

Drug: MK-8242

Pt 1 Arm A: MK-8242 120 mg BID

EXPERIMENTAL

Participants received MK-8242 120 mg twice daily (BID) monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles (except Cycle 1 Day 7 on which MK-8242 120 mg was administered QD in the morning) in Part 1 Arm A.

Drug: MK-8242

Pt 1 Arm A: MK-8242 170 mg BID

EXPERIMENTAL

Participants received MK-8242 170 mg BID monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles (except Cycle 1 Day 7 on which MK-8242 170 mg was administered QD in the morning) in Part 1 Arm A.

Drug: MK-8242

Pt 1 Arm A: MK-8242 210 mg BID

EXPERIMENTAL

Participants received MK-8242 210 mg BID monotherapy on Days 1-7 of a 21-day cycle up to a maximum of 12 cycles (except Cycle 1 Day 7 on which MK-8242 210 mg was administered QD in the morning) in Part 1 Arm A.

Drug: MK-8242

Pt 1 Arm A: MK-8242 250 mg BID

EXPERIMENTAL

Participants received MK-8242 250 mg BID monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles (except Cycle 1 Day 7 on which MK-8242 250 mg was administered QD in the morning) in Part 1 Arm A.

Drug: MK-8242

Pt 1 Arm A: MK-8242 300 mg BID

EXPERIMENTAL

Participants received MK-8242 300 mg BID monotherapy on Days 1-7 of a 21-day cycle up to a maximum of 12 cycles (except Cycle 1 Day 7 on which MK-8242 300 mg was administered QD in the morning) in Part 1 Arm A.

Drug: MK-8242

Interventions

MK-8242 DRUG

MK-8242 capsules, orally, once per day on Days 1-7 and Days 15-21 of each 28-day cycle (except Cycle 1 Day 7) up to a maximum of 12 cycles. Starting dose will be 30 mg and will be escalated in successive cohorts until maximum tolerated dose (MTD) is established. Beginning at a dose level of ≥120 mg total daily dose (TDD), the dosing regimen will switch to twice daily (BID). Amendment 4 added a 21-day dosing cycle in which MK-8242 would be given BID on Days 1-7 of each cycle, at the assigned dose level.

Also known as: SCH 900242

Pt 1 Arm A: MK-8242 120 mg BID; Pt 1 Arm A: MK-8242 120 mg QD; Pt 1 Arm A: MK-8242 170 mg BID; Pt 1 Arm A: MK-8242 210 mg BID; Pt 1 Arm A: MK-8242 250 mg BID; Pt 1 Arm A: MK-8242 250 mg QD; Pt 1 Arm A: MK-8242 30 mg QD; Pt 1 Arm A: MK-8242 300 mg BID; Pt 1 Arm A: MK-8242 60 mg QD

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• For Arm A Part 1 (monotherapy/dose escalation): refractory or recurrent AML, not an appropriate candidate for standard therapy
• For Arm A Part 2 (monotherapy/dose confirmation/cohort expansion): refractory or recurrent AML, not an appropriate candidate for standard therapy, and have wild type p53 gene mutation analysis
• For Arm B Part 1 (combination therapy/dose escalation): recurrent AML having achieved an initial CR or CRi of 6-12 months duration and age ≥18 years old and \<70 years old
• For Arm B Part 2 (combination therapy/dose confirmation/cohort expansion): recurrent AML having achieved an initial CR or CRi of 6-12 months duration, age ≥18 years old and \<70 years old, and have wild type P53 gene mutation analysis
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 for all Arm A, or 0 or 1 for all Arm B
• Negative pregnancy test within 72 hours of the first dose of study medication
• Female participants and male participants and their partners who are of childbearing potential must agree to abstain from sexual intercourse or to use an acceptable method of contraception during the study and for 90 days following the last dose of study therapy
• Adequate organ function
• Recovered from the effects of any prior surgery, radiotherapy or anti-neoplastic treatment, with the exception of alopecia
• Must be able to swallow, retain, and absorb oral medications and oral nutrition
• Must follow the appropriate washout period for prohibited treatments

You may not qualify if:

• Active malignancy other than AML
• Leptomeningeal leukemia requiring intrathecal therapy
• For Arm A and B, Part 1 only: history of myelodysplastic syndrome (MDS)
• For Arm A and B, Part 2: AML in the background of MDS may be included
• Isolated extramedullary leukemia without also meeting bone marrow criteria for acute leukemia
• AML blast crisis of chronic myelogenous leukemia (CML)
• Bone marrow transplant with active graft-versus host disease (GVHD) or who receives immunosuppressive therapy
• Uncontrolled active infection that requires systemic treatment
• Clinically significant hepatitis at Screening, or hepatitis C antibody positive, hepatitis B surface antigen positive, or human immunodeficiency virus (HIV) seropositive
• Persistent, unresolved, drug-related toxicity
• Breast-feeding, pregnant, intends to become pregnant or intends to breast feed during the study or has a positive pregnancy test at Screening
• A person participating in any other clinical study with a potentially therapeutic agent or who has received another investigational product within 5 half-lives (if the half-life is known) or 28 days (if the half-life is unknown) prior to Day 1 of cycle 1
• A participant who, within the past 6 months, has had any of the following: myocardial infarction, coronary/peripheral artery bypass graft, cerebrovascular accident, transient ischemic attack, or uncontrolled seizure disorder (i.e., seizures within the past 6 months)
• A participant who, at the time of Screening, presents with: unstable or uncontrolled angina, New York Heart Association (NYHA) class III or IV congestive heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or clinically significant electrocardiogram (ECG) abnormality
• Known bleeding disorder, e.g. hemophilia or disseminated intravascular coagulopathy or on anti-coagulation therapy

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (1)

• Ravandi F, Gojo I, Patnaik MM, Minden MD, Kantarjian H, Johnson-Levonas AO, Fancourt C, Lam R, Jones MB, Knox CD, Rose S, Patel PS, Tibes R. A phase I trial of the human double minute 2 inhibitor (MK-8242) in patients with refractory/recurrent acute myelogenous leukemia (AML). Leuk Res. 2016 Sep;48:92-100. doi: 10.1016/j.leukres.2016.07.004. Epub 2016 Jul 25.

  PMID: 27544076 RESULT

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 11, 2011
• First Posted: October 13, 2011
• Study Start: November 18, 2011
• Primary Completion: September 5, 2014
• Study Completion: September 5, 2014
• Last Updated: August 27, 2018
• Results First Posted: March 4, 2016

Record last verified: 2018-07

Data Sharing

• IPD Sharing: Will share