Clinical trial NCT00907517: Study of SCH 900776 (MK-8776) With and Without Cytarabine in Participants With Acute Leukemias (P05247)
Official title: A Phase 1 Dose-Escalation Study of SCH 900776 in Combination With Cytarabine in Subjects With Acute Leukemias (Protocol No. P05247)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Myelogenous Leukemia, Acute
Leukemia, Lymphocytic, Acute
Leukemia, Lymphoblastic, Acute, Philadelphia-Positive
Myelogenous Leukemia, Chronic, Aggressive Phase
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2009-05-22
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study of SCH 900776 (MK-8776) will evaluate its safety and tolerability when given in combination with cytarabine to participants with acute leukemias. Participants in the Dose-Escalation Part will be enrolled in cohorts that will receive sequentially higher doses of MK-8776 in combination with standard doses of cytarabine. Only one combination treatment cycle of approximately 4 to 6 weeks is anticipated, but participants may receive additional cycles if clinically indicated after discussion between the Investigator and the Sponsor. The recommended combination doses for a Phase 2 trial (RP2D) will be determined based on safety and biological activity. Up to 10 to 15 additional participants will be studied at the combination RP2D.


Eligibility criteria: Inclusion Criteria:

* Must have a histologically or cytologically confirmed diagnosis of relapsed and/or refractory acute leukemia, including:

  * acute myelogenous leukemia (AML), including AML arising from myelodysplasia (MDS) or myeloproliferative disorder (MPD);
  * acute lymphocytic leukemia, including Philadelphia chromosome-positive (Ph+) ALL (Dose-Escalation Part only);
  * chronic myelogenous leukemia (CML) in accelerated phase (AP) or blast crisis (BC) of either myeloid or lymphoid origin (Dose-Escalation Part only);
  * treatment-related high-grade MDS (i.e. refractory anemia with excess blasts in transformation \[RAEBT\]);
  * MPD in transformation \[eg, CMMoL-T (5%-19% blasts)\].
* Must have recurred or progressed following standard therapy or failed standard therapy, or have disease for which no standard therapy currently exists.
* Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
* Females of childbearing potential must have a negative pregnancy test within 5 days prior to first dose of cytarabine.
* Females of childbearing potential and males whose sexual partner is 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 treatment.
* Must have adequate renal function as evidenced by a serum creatinine level \<=1.5 x upper limit of normal (ULN) or a calculated creatinine clearance \>=60 mL/min.
* Participants, except ones with known Gilbert's Syndrome, must have adequate hepatic function as evidenced by a serum bilirubin level \<=1.5 mg/dL AND serum levels of aspartate and alanine aminotransferase (AST/ALT) \<=5 x the ULN for the reference laboratory.
* Must have adequate cardiac function with a left ventricular ejection fraction (LVEF) of \>=45% (echocardiogram or multiple-gated acquisition \[MUGA\] scan).
* Must be recovered from the effects of any prior surgery, radiotherapy, or systemic antineoplastic therapy.
* Participants who are refractory to or relapsed after prior allogeneic or autologous stem cell transplant are eligible.

Exclusion Criteria:

* Must not have known hypersensitivity to MK-8776 or cytarabine or to any of their excipients or have received therapy with another Checkpoint kinase 1 (CHK1) inhibitor.
* Must not have persistent, unresolved Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v 3.0) ≥ Grade 2 drug-related toxicity (except alopecia, erectile impotence, hot flashes, decreased libido, hematologic toxicity) associated with previous treatment.
* Must not have known human immunodeficiency virus (HIV), hepatitis B or hepatitis C, or have a known history of liver cirrhosis or active alcohol abuse.
* Must not be New York Heart Association (NYHA) Class III (has marked limitation in activity due to symptoms, even during less than ordinary activity \[e.g. walking short distances \>20-100 m\]; is comfortable only at rest) or Class IV (has severe limitations; experiences symptoms even while at rest; mostly bed bound).
* Must not have undergone major surgery within 3 weeks prior to first study drug administration after enrollment.
* Must not have known active central nervous system (CNS) or leptomeningeal leukemia.
* Must not have received radiation therapy within 2 weeks prior to first study treatment administration after enrollment or radiation therapy to \>25% of bone marrow.
* Must not have received more than 4 prior induction regimens.
* Must not have a peripheral blast count ≥50,000/mm\^3.
* Must not have active, uncontrolled graft versus host disease (GVHD) post-allogeneic stem cell transplant.
* Must not have had any of the following within 6 months prior to first study treatment administration after enrollment: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or seizure disorder.
* Must not have a known bleeding diathesis, e.g. hemophilia, or disseminated intravascular coagulation.
* Must not have an active, uncontrolled infection.
* Must not have a history of cytarabine-related neurotoxicity.
* Must not have a baseline corrected QT (QTc) interval \>470 msec (i.e. CTCAE v 3.0 Grade ≥2).
* Must not currently be a smoker and/or must not be likely to smoke during the study.
* Females must not be breast-feeding, pregnant, or intend to become pregnant.

Primary outcomes:
measure: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT)
timeFrame: Throughout Cycle 1 (Up to 6 weeks)
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to 45 days after last dose of study treatment (Up to 180 days)
measure: Number of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: Up to 135 days
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Karp JE, Thomas BM, Greer JM, Sorge C, Gore SD, Pratz KW, Smith BD, Flatten KS, Peterson K, Schneider P, Mackey K, Freshwater T, Levis MJ, McDevitt MA, Carraway HE, Gladstone DE, Showel MM, Loechner S, Parry DA, Horowitz JA, Isaacs R, Kaufmann SH. Phase I and pharmacologic trial of cytosine arabinoside with the selective checkpoint 1 inhibitor Sch 900776 in refractory acute leukemias. Clin Cancer Res. 2012 Dec 15;18(24):6723-31. doi: 10.1158/1078-0432.CCR-12-2442. Epub 2012 Oct 23.