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The Effect of Enzastaurin on CYP2C9: Enzastaurin - S-Warfarin Drug Interaction Study in Patients With Cancer

Phase 1
18 Years
60 Years
Not Enrolling
Solid Tumor, Lymphoma, Malignant

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Trial Information

The Effect of Enzastaurin on CYP2C9: Enzastaurin - S-Warfarin Drug Interaction Study in Patients With Cancer

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: patients 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 patients with hormone refractory prostate cancer, the following exception is

- Patients 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, patients 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 109/L prior to
treatment, platelets ≥100 x 109/L, and hemoglobin ≥10 g/dL. Patients may receive
erythrocyte transfusions to achieve this hemoglobin level at the discretion of
the investigator. Patients 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 mg/dL.

- Electrolytes: Patients may be entered into the study, if the investigator's opinion
is that any electrolyte disorders, including potassium <3.4 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 patient will be discontinued from the

- Coagulation: normal PT/INR and aPTT

- Have an estimated life expectancy, in the judgment of the investigator, which will
permit the patient to complete the drug interaction phase and at least 1 cycle of the
safety extension phase (if the patient were to participate 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

- Patients 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. Patients with a QTcB prolongation >450/470 msec (males/females) and
patients who have a congenital long-QT-syndrome in their own or family medical
history should be excluded at the investigator's discretion. Patients with
intraventricular conduction delays (for instance, right or left bundle branch blocks)
should also be excluded.

- It is recommended that patients 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

- Patients with complete gastrectomy or other significant GI diseases that, in the
investigator's opinion, may significantly impact drug absorption

- Patients on total parenteral nutrition (TPN)

- Inability to swallow tablets

- Women who are lactating

- Patients with known allergies to enzastaurin or warfarin

- Patients with warfarin-related skin necrosis

- Patients who are known CYP2C9 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

- Patients who have an average weekly alcohol intake that exceeds 21 units per week
(males) and 14 units per week (females) or patients unwilling to stop alcohol
consumption for the duration of the drug interaction phase (Periods 1 and 2) of the
study (1 unit = 12 oz or 360 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

- 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

- Heme-positive stool

- Warfarin is contraindicated in the case of congenital galactosemia, malabsorption
syndromes of glucose and galactose, or lactase deficiency

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label

Outcome Measure:

Pharmacokinetics: maximum plasma concentration (Cmax) of S-warfarin and R-warfarin

Outcome Time Frame:

Period 1 and 2: Predose, up to 96 hours post dose

Safety Issue:


Principal Investigator

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

Investigator Role:

Study Director

Investigator Affiliation:

Eli Lilly and Company


France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Study ID:




Start Date:

August 2011

Completion Date:

December 2012

Related Keywords:

  • Solid Tumor
  • Lymphoma, Malignant
  • Lymphoma