Clinical trial NCT01451437: Study of MK-8242 Alone and in Combination With Cytarabine in Participants With Acute Myelogenous Leukemia (P07649)
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))
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Acute Myelogenous Leukemia (AML)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2011-10-13
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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 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

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

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Up to 28 days (Cycle 1) for non-hematologic toxicities and 42 days (Cycle 1) for hematologic toxicities
measure: Number of Participants With Complete Remission (CR) at RP2D
timeFrame: End of Treatment (up to 198 days)
measure: Number of Participants With Complete Remission With Incomplete Marrow Recovery (CRi) at RP2D
timeFrame: End of Treatment (up to 198 days)
Secondary outcomes:
measure: Number of Participants With CR at Dose Levels Other Than RP2D
timeFrame: End of Treatment (up to 198 days)
measure: Number of Participants With CRi at Dose Levels Other Than RP2D
timeFrame: End of Treatment (up to 198 days)
measure: Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine
timeFrame: 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)
measure: Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine
timeFrame: 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)
measure: Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞) for MK-8242 Alone and in Combination With Cytarabine
timeFrame: 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)
measure: Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine
timeFrame: 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)
measure: Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine
timeFrame: 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)
measure: Apparent Terminal Half-life (t1/2) for MK-8242 Alone and in Combination With Cytarabine
timeFrame: 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)
measure: Accumulation Ratio (R) of MK-8242 Alone and in Combination With Cytarabine
timeFrame: 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 [Day 7 only], 48 [Day 7 only] hrs postdose)
measure: Urine Concentration of MK-8242 (Part 2 Arm A Only)
timeFrame: Day 1 (predose and postdose) and Day 7 (postdose)
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.