A Drug Interaction Study to Assess the Effect of LY317615 on the Metabolic Pathway of Warfarin

NCT01388335 | Completed Phase 1 Results

• 2 other identifiers: 9763H6Q-MC-JCAX
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 7

Brief 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.

Conditions

Solid Tumor; Lymphoma, Malignant

Outcome Measures

Primary Outcomes (3)

• Pharmacokinetics: Maximum Plasma Concentration (Cmax) of S-Warfarin and R-Warfarin

  Cmax of S-Warfarin and R-Warfarin determined using Geometric Least Squares (LS) mean model that was estimated from a mixed-effects model with repeated measures (MMRM) that included treatment as a fixed effect (warfarin alone as reference, and warfarin with enzastaurin as test), participant as a random effect and random error term.

  Period 1 Day 1 (8 days) and Period 2 (19 up to 30 days): Predose, up to 96 hours postdose

• Pharmacokinetics: Time of Maximal Plasma Concentration (Tmax) of S-Warfarin and R-Warfarin

  Period 1 Day 1 (8 days) and Period 2 (19 up to 30 days): Predose, up to 96 hours postdose

• Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity [AUC(0-∞)] of S-Warfarin and R-Warfarin

  AUC(0-∞) determined using Geometric Least Squares (LS) mean model that was estimated from a mixed-effects model with repeated measures (MMRM) that included treatment as a fixed effect (warfarin alone as reference, and warfarin with enzastaurin as test), participant as a random effect and random error term.

  Period 1 Day 1 (8 days) and Period 2 (19 up to 30 days): Predose, up to 96 hours postdose

Secondary Outcomes (9)

• Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) at Steady State of Enzastaurin, Its Principle Metabolites and Total Analyte

  Period 2 Days 14 and 15 (19 up to 30 days): Predose, up to 24 hours postdose

• Pharmacokinetics: Time of Maximal Plasma Concentration (Tmax) of Enzastaurin, Its Principle Metabolites and Total Analyte

  Period 2 Days 14 and 15 (19 up to 30 days): Predose, up to 24 hours postdose

• Pharmacokinetics: Area Under Concentration-Time Curve Over a Dosing Interval at Steady State (AUCss) of Enzastaurin, Its Principle Metabolites and Total Analyte

  Period 2 Days 14 and 15 (19 up to 30 days): Predose, up to 24 hours postdose

• Pharmacokinetics: Average Concentration During a Dosing Interval Steady State (Cav,ss) of Enzastaurin, Its Principle Metabolites and Total Analyte

  Period 2 Days 14 and 15 (19 up to 30 days): Predose, up to 24 hours post dose

• Pharmacodynamics: Maximum International Normalised Ratio (INRmax) Following Warfarin Alone

  Period 1 (8 days): Predose on Day 1, up to 96 hours postdose or Period 2 (19 up to 30 days): Predose on Day 15, up to 96 hours post warfarin dose

Study Arms (1)

warfarin + enzastaurin

EXPERIMENTAL

On Day 1 of Period 1, a single 5-milligram (mg) oral dose of warfarin will be given, followed by at least a 7-day washout. Period 2: 500 mg enzastaurin administered orally once daily for at least 19 consecutive days and 5 mg warfarin administered as a single oral dose on Day 15. Safety Extension: Participants are allowed to continue receiving enzastaurin alone until disease progression or other discontinuation criteria are met.

Drug: warfarin; Drug: enzastaurin

Interventions

warfarin DRUG

Administered orally

warfarin + enzastaurin

enzastaurin DRUG

Administered orally

Also known as: LY317615

warfarin + enzastaurin

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Eli Lilly and Company: lead

Study Sites (7)

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Bordeaux, 33076, France

Location

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Dijon, 21079, France

Location

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Lille, 59020, France

Location

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Paris, 75908, France

Location

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Rennes, 35062, France

Location

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Saint-Herblain, 44800, France

Location

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Toulouse, 31052, France

Location

MeSH Terms

Conditions

Lymphoma

Interventions

Warfarin; enzastaurin

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Chief Medical Officer
• Organization: Eli Lilly and Company

800-545-5979

Study Officials

• 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)

  Eli Lilly and Company

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Masking: NONE
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 4, 2011
• First Posted: July 6, 2011
• Study Start: August 1, 2011
• Primary Completion: October 1, 2012
• Study Completion: December 1, 2012
• Last Updated: July 1, 2020
• Results First Posted: July 1, 2020

Record last verified: 2020-06

Locations

FR (7)