A Drug Interaction Study to Assess the Effect of LY317615 on the Metabolic Pathway of Warfarin
Condition: Solid Tumor; Lymphoma, Malignant
MeSH terms: Lymphoma
Intervention: warfarin; enzastaurin
Intervention description: Administered orally; Administered orally
Intervention MeSH terms: Warfarin
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to assess the effect of enzastaurin (LY317615), on a protein
      (enzyme CYP2C9) which is involved in the metabolic pathway of warfarin in participants with
      solid tumors or lymphomas. Information about any side effects that may occur will also be
      collected. This is a drug interaction study so the treatment of the disease will not be the
      main purpose of the study.

      This is a Phase 1, open label, fixed sequence, 2 period study conducted in participants with
      solid tumors or lymphomas. The duration of participation in this study will be up to
      approximately 38 days not including screening, after which participants will be allowed to
      continue receiving enzastaurin. There is no planned duration for the extension phase of this
      study; participants will be allowed to continue to receive enzastaurin until fulfilling one
      of the criteria for discontinuation, such as unacceptable toxicity or disease progression.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Have given written informed consent approved by Eli Lilly and Company (Lilly) and the
             ethical review board (ERB) governing the site

          -  Have a histologic or cytologic diagnosis of cancer (lymphoma or solid tumor), with
             clinical or radiologic evidence of locally advanced and/or metastatic disease for
             which no life-prolonging therapy exists (Note: participants with glioblastoma, known
             central nervous system (CNS) metastases and other hematologic malignancies [except
             lymphoma] are excluded from this study)

          -  Men or women with reproductive potential must use an approved contraceptive method, if
             appropriate, during and for 3 months after discontinuation of study treatment. All
             methods of contraception should meet the criteria of highly effective
             contraceptives(failure rate of <1% per year) such as implants, injectables, combined
             oral contraceptives, some intrauterine devices, sexual abstinence, or vasectomized
             partner. Women with childbearing potential must have a negative serum pregnancy test
             ≤3 days prior to the first dosing day in the study (Period 1, Day 1).

          -  Have a performance status of 0 to 2 on the Eastern Cooperative Oncology Group (ECOG)
             scale and, in the investigator's opinion, are suitable for participation in the study

          -  Have discontinued all previous therapies for cancer, including chemotherapy,
             radiotherapy, anticancer hormone therapy, or other investigational therapy for at
             least 30 days prior to study entry (6 weeks for mitomycin-C or nitrosoureas), and have
             recovered from the acute effects of therapy

          -  For participants with hormone refractory prostate cancer, the following exception is
             permitted:

               -  Participants receiving luteinizing hormone-releasing hormone (LHRH) analogue
                  therapy (leuprolide, goserelin, or triptorelin) prior to starting this study
                  should have that therapy continued while on this study.

               -  In addition, participants who have received nonsteroidal antiandrogen therapy in
                  the form of bicalutamide should have discontinued therapy at least 6 weeks prior
                  to study entry (4 weeks if on flutamide or nilutamide).

          -  Have adequate organ function including:

               -  Bone Marrow Reserve: absolute neutrophil count (ANC) ≥1.5 x 10˄9/liter (L) prior
                  to treatment, platelets ≥100 x 10˄9/L, and hemoglobin ≥10 grams/deciliter (g/dL).
                  Participants may receive erythrocyte transfusions to achieve this hemoglobin
                  level at the discretion of the investigator. Participants may be allowed
                  erythropoietin of choice as per standard of care.

               -  Hepatic: bilirubin within 1.5 times the upper limit of normal (ULN), and
                  transaminases ≤2.5 times ULN or ≤5 times ULN when liver metastases are known.

               -  Renal: serum creatinine ≤1.5 milligrams/deciliter (mg/dL).

          -  Electrolytes: Participants may be entered into the study, if the investigator's
             opinion is that any electrolyte disorders, including potassium <3.4 milliequivalent
             per liter (mEq/L), calcium <8.4 mg/dL, or magnesium <1.2 mEq/L, may be appropriately
             managed and stabilized by the time of the laboratory evaluation on the baseline day in
             Period 1. If electrolytes have not been stabilized during this time, the participant
             will be discontinued from the study.

          -  Coagulation: normal prothrombin time/INR (PT/INR) and activated partial thromboplastin
             time (aPTT)

          -  Have an estimated life expectancy, in the judgment of the investigator, which will
             permit the participant to complete the drug interaction phase and at least 1 cycle of
             the safety extension phase (if the participant were to take part in the safety
             extension)

        Exclusion Criteria:

          -  Have received treatment within 28 days of the initial dose of study drug with an
             experimental agent for non-cancer indications that has not received regulatory
             approval for any indication

          -  Participants with glioblastoma, Central Nervous System (CNS) metastases, or
             hematologic malignancies other than lymphoma are excluded from this study.

          -  Serious concomitant systemic disorder, including active infection, incompatible with
             the study (at the discretion of the investigator)

          -  History of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infections

          -  Cardiac: Have a serious cardiac condition, such as myocardial infarction within 6
             months, angina, or heart disease, as defined by the New York Heart Association Class
             III or IV. Participants with a QTcB prolongation >450/470 millisecond (msec)
             (males/females) and participants who have a congenital long-QT-syndrome in their own
             or family medical history should be excluded at the investigator's discretion.
             Participants with intraventricular conduction delays (for instance, right or left
             bundle branch blocks) should also be excluded.

          -  It is recommended that participants with baseline arrhythmias (persistent or
             paroxysmal ventricular or supraventricular arrhythmias, including atrial fibrillation
             [occasional premature atrial contractions [APCs] or premature ventricular contractions
             [PVCs] are acceptable] or bradycardia (heart rate <50) be excluded, at the
             investigator's discretion.

          -  Known family history of unexplained sudden death

          -  Personal history of unexplained syncope within the last year

          -  The use of concomitant medications that prolong the QT/QTc interval

          -  Participants with complete gastrectomy or other significant GI diseases that, in the
             investigator's opinion, may significantly impact drug absorption

          -  Participants on total parenteral nutrition (TPN)

          -  Inability to swallow tablets

          -  Women who are lactating

          -  Participants with known allergies to enzastaurin or warfarin

          -  Participants with warfarin-related skin necrosis

          -  Participants who are known cytochrome P450 (CYP) 2C9 poor or intermediate metabolizers

          -  Drugs that are known inhibitors or inducers of CYP3A are specifically excluded. Foods
             that are known inhibitors of CYP3A (for example, grapefruit or grapefruit juice or
             Seville oranges or Seville orange juice) are also specifically excluded during Period
             1 and Period 2 of the study.

          -  Drugs with narrow therapeutic windows and that are also known substrates of CYP2C9,
             CYP2C8, CYP2C19, and CYP3A are excluded.

          -  Use of any known inducers or inhibitors of CYP2C9 within 30 days (or at least 5
             half-lives, whichever is shorter) prior to enrollment. Drugs that are inhibitors or
             inducers of CYP2C9 are also excluded throughout Periods 1 and 2. Drugs that are known
             to increase the hypoprothrombinemic effect of warfarin are excluded prior to
             enrollment and throughout Periods 1 and 2.

          -  Use of other anticoagulants or antithrombolytics within 14 days prior to screening or
             during Periods 1 and 2

          -  Use of low-dose aspirin (or higher doses) within 14 days prior to screening and during
             Period 1 and 2 of the study (allowed during continued safety extension phase)

          -  Use of high-dose acetaminophen (paracetamol) within 14 days of Period 1 and during
             Period 1 and 2 of the study

          -  Participants who have an average weekly alcohol intake that exceeds 21 units per week
             (males) and 14 units per week (females) or participants unwilling to stop alcohol
             consumption for the duration of the drug interaction phase (Periods 1 and 2) of the
             study (1 unit = 12 ounces (oz) or 360 milliliters (mL) of beer; 5 oz or 150 mL of
             wine; 1.5 oz or 45 mL of distilled spirits).

          -  Use of drugs of abuse, as evidenced by history, and/or positive findings on urinary
             drug screening, unless prescribed by a physician (for example, narcotic pain
             medication)

          -  Failure for any reason to satisfy the investigator for adequate fitness to participate
             in the study

          -  Major surgery or lumbar puncture in the past 6 weeks

          -  Protein C (functional) activity or Protein S antigen concentration below the normal
             range

          -  Heme-positive stool

          -  Warfarin is contraindicated in the case of congenital galactosemia, malabsorption
             syndromes of glucose and galactose, or lactase deficiency