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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT01451437
First received: October 11, 2011
Last updated: July 23, 2014
Last verified: July 2014
  Purpose

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 + cytarabine in escalating doses 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.


Condition Intervention Phase
Acute Myelogenous Leukemia (AML)
Drug: MK-8242
Drug: cytarabine
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study to Evaluate the Safety and Tolerability and Pharmacokinetic/Pharmacodynamics of MK-8242 Administered Alone and in Combination With Chemotherapy in Subjects With Refractory or Recurrent Acute Myelogenous Leukemia (Protocol No. P07649 (005))

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Number of participants with dose limiting toxicities (DLTs) [ Time Frame: Up to 28 days (Cycle 1) for non-hematologic toxicities and 42 days (Cycle 1) for hematologic toxicities ] [ Designated as safety issue: Yes ]
  • Number of participants with complete remission (CR) at RP2D [ Time Frame: Cycle 4 (up to 112 days) ] [ Designated as safety issue: No ]
  • Number of participants with complete remission with incomplete marrow recovery (CRi) at RP2D [ Time Frame: Cycle 4 (up to 112 days) ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Number of participants with CR at dose levels other than RP2D [ Time Frame: Cycle 4 (up to 112 days) ] [ Designated as safety issue: No ]
  • Number of participants with CRi at dose levels other than RP2D [ Time Frame: Cycle 4 (up to 112 days) ] [ Designated as safety issue: No ]
  • Area under the concentration-time curve (AUC) for MK-8242 alone and in combination with cytarabine [ Time Frame: Cycle 1 Day 1 and Day 7 (pre-dose and through 24 hours postdose) and pre-dose on Days 6 and 8 ] [ Designated as safety issue: No ]
  • Maximum plasma concentration (Cmax) of MK-8242 alone and in combination with cytarabine [ Time Frame: Cycle 1 Day 1 and Day 7 (pre-dose and through 24 hours postdose) and pre-dose on Days 6 and 8 ] [ Designated as safety issue: No ]
  • Time to maximum concentration (Tmax) of MK-8242 alone and in combination with cytarabine [ Time Frame: Cycle 1 Day 1 and Day 7 (pre-dose and through 24 hours postdose) and pre-dose on Days 6 and 8 ] [ Designated as safety issue: No ]
  • Accumulation ratio (R) of MK-8242 alone and in combination with cytarabine [ Time Frame: Cycle 1 Day 1 and Day 7 (pre-dose and through 24 hours postdose) and pre-dose on Days 6 and 8 ] [ Designated as safety issue: No ]
  • Urine concentration of MK-8242 (Part 2 Arm A only) [ Time Frame: Day 1 postdose, and Day 7 ] [ Designated as safety issue: No ]

Estimated Enrollment: 180
Study Start Date: November 2011
Estimated Study Completion Date: October 2014
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A MK-8242 monotherapy Drug: MK-8242
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.
Other Name: SCH 900242
Experimental: Arm B MK-8242 + cytarabine Drug: MK-8242
MK-8242 capsules, orally, once per day on Days 1-7 and Days 15-21 of each 28-day cycle up to a maximum of 12 cycles; the combination arm will initiate when a well-tolerated dose is reached in Arm A such that this dose and one dose level lower are known from a normal healthy volunteer study to be associated with pharmacodynamic effect. The starting dose level is estimated to be 60 mg (BID) or greater. MK-8242 will be administered orally BID in Cycle 1 and once in the morning (QD) on Day 7 in each 28-day cycle. 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.
Other Name: SCH 900242
Drug: cytarabine
Cytarabine, 2 g/m^2, intravenous over 3 hours, every 12 hours on Days 1-4 of each 21-day or 28-day cycle

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • 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 TP53 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 TP53 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

Exclusion criteria:

  • 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
  • For Arm B only: Known hypersensitivity to cytarabine
  Contacts and Locations
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, see Learn About Clinical Studies.

No Contacts or Locations Provided
  More Information

No publications provided

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01451437     History of Changes
Other Study ID Numbers: P07649, 2011-000709-31, MK-8242-005
Study First Received: October 11, 2011
Last Updated: July 23, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 31, 2014