A Dose-escalation Study of MK-8776 (SCH 900776) With and Without Gemcitabine in Participants With Solid Tumors or Lymphoma (MK-8776-002/P05248)
Condition: Hodgkin Disease; Lymphoma, Non-Hodgkin; Neoplasms
MeSH terms: Lymphoma; Hodgkin Disease; Lymphoma, Non-Hodgkin
Intervention: MK-8776; Gemcitabine
Intervention description: IV infusion; IV infusion
Intervention MeSH terms: Gemcitabine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 45.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This study of MK-8776 (SCH 900776) will evaluate its safety and tolerability when given as
      monotherapy or in combination with gemcitabine to participants with advanced solid tumors or
      lymphoma. Participants will be enrolled in cohorts that will receive sequentially higher
      doses of MK-8776 in combination with standard doses of gemcitabine The recommended
      combination doses for a Phase 2 trial (combination-RP2D) will be determined based on safety
      and biological activity. Up to 10 to 15 additional participants may be studied at the
      combination-RP2D.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Must have a diagnosis of an advanced solid tumor malignancy or lymphoma (non-Hodgkin's
             or Hodgkin's lymphoma).

          -  Must have histological or cytological evidence of malignancy.

          -  Must have an advanced malignancy, metastatic or unresectable. For Part A of the study,
             the metastatic or unresectable malignancy should have recurred or progressed following
             standard therapy or failed standard therapy; or for which no standard therapy
             currently exists, or for which they are not candidates for standard therapy. For Parts
             B and C of the study, participants with advanced tumors for which gemcitabine is
             considered standard therapy (eg, pancreatic cancer), may be enrolled without having
             received prior gemcitabine. Standard therapy is defined as therapy that is approved in
             a particular line of therapy or considered as standard of care based on published peer
             reviewed data in a specific line of therapy.

          -  Gemcitabine-naïve participants with tumors known to be responsive to gemcitabine or
             participants previously treated with gemcitabine who did not progress while on
             treatment or who are currently still responding to treatment should only be enrolled
             in cohorts for which gemcitabine doses are >=1000 mg/m². Participants previously
             treated with gemcitabine, whose disease has progressed wile on treatment, can be
             enrolled to any part.

          -  Must be ambulatory with an Eastern Cooperative Oncology Group (ECOG) performance
             status of 0 or 1.

          -  Participants (and/or parent/guardian for participants who otherwise are unable to
             provide independent consent) must be willing to give written informed consent and able
             to adhere to dose and visit schedules.

          -  Female participants of childbearing potential must have a negative pregnancy test
             within 7 days of first dose of protocol therapy.

          -  Female participants of childbearing potential and male participants whose sexual
             partners 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 protocol therapy. Acceptable methods of contraception
             include condoms (male or female) with or without spermicidal agent, diaphragm or
             cervical cap with spermicide, medically prescribed intrauterine device (IUD), oral or
             injectable hormonal contraceptive, and surgical sterilization (eg, hysterectomy or
             tubal ligation).

          -  Must have adequate bone marrow reserve as evidenced by a white blood cell (WBC) count
             >=3,000/ μL, absolute neutrophil count (ANC) >=1,500/μL AND platelet count
             >=100,000/μL.

          -  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 those with known Gilbert's Syndrome, must have adequate hepatic
             function as evidenced by a serum bilirubin level <=1.5 x the ULN AND serum levels of
             aspartate and alanine aminotransferase (AST/ALT) levels <=3 x the ULN for the
             reference lab (participants with known hepatic metastases must have serum AST/ALT
             levels <=5 x the ULN for the reference lab).

          -  Must be recovered from the effects of any prior surgery, radiotherapy or systemic
             antineoplastic therapy.

        Exclusion Criteria:

          -  Has a known hypersensitivity to MK-8776 or gemcitabine or to any of their excipients
             or has received therapy with another Checkpoint kinase 1 (CHK1) inhibitor.

          -  Has received any prohibited medication more recently than the indicated washout period
             prior to first dose of protocol therapy or must continue to receive prohibited
             medications. Prohibited medications: cytochrome P450 1A2 inhibitors, any chemotherapy,
             or investigational drugs.

          -  Has significant underlying cardiac conduction system abnormalities such as
             bifascicular or greater block (eg, right bundle branch block with left anterior
             hemiblock or first degree atrioventricular block), fixed-rate pacemaker, or chronic
             atrial fibrillation with variable ventricular rate.

          -  Has persistent, unresolved Common Terminology Criteria for Adverse Events (CTCAE) v
             3.0 >=Grade 2 drug-related toxicity (except alopecia, erectile impotence, hot flashes,
             and decreased libido) associated with previous treatment.

          -  Has known human immunodeficiency virus (HIV), hepatitis B, hepatitis C, or a known
             history of liver cirrhosis or active alcohol abuse.

          -  Is New York Heart Association (NYHA) Class III.

          -  Has any other medical or psychiatric condition that, in the opinion of the
             investigator, might interfere with the subject's participation in the trial or
             interfere with the interpretation of trial results.

          -  Has undergone major surgery within 3 weeks prior to first study drug administration
             after enrollment.

          -  Has central nervous system (CNS) or leptomeningeal metastases.

          -  Has received radiation therapy within 3 weeks prior to first study drug administration
             after enrollment or radiation therapy to >25% of bone marrow.

          -  Has received >3 prior chemotherapy regimens (may have received prior gemcitabine). A
             participant may not have experienced any CTCAE v 3.0 >Grade 1 myelotoxicity
             (neutropenia and/or thrombocytopenia) with any prior regimen, including gemcitabine.
             Participants with >3 prior chemotherapy regimens, one or more of which were targeted,
             nonmyelosuppressive agents, may be considered on a case-by-case basis after discussion
             with the sponsor.

          -  Has undergone previous allogeneic or autologous stem cell transplant.

          -  Has had any of the following within 6 months prior to first study drug 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.

          -  Has a known bleeding diathesis, eg, hemophilia.

          -  Has a baseline QTc interval >450 msec (ie, CTCAE v 3.0 Grade ≥2) at screening (within
             21 days prior to 1st dose of MK-8776, mean of triplicate readings within approximately
             5 minutes).

          -  History of risk factors for Torsades de Pointes, including clinical history of heart
             failure, hypo- or hyperkalemia or hypomagnesemia (supplementation or other appropriate
             interventions to bring levels within normal institutional limits prior to
             administration of MK-8776 is acceptable), or family history of Long QT Syndrome.

          -  Currently a smoker and/or is likely to smoke during the study.

          -  Female participant who is breast-feeding, pregnant, or intends to become pregnant.

          -  Participating in any other interventional clinical study. (Participants participating
             in another noninterventional study may be considered after discussion with the
             sponsor.)

          -  Part of the staff personnel directly related to this study.

          -  Family member of one of the investigational staff.