A Drug Interaction Study to Assess the Effect of LY2603618 on the Metabolic Pathway of Desipramine

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company
ClinicalTrials.gov Identifier:
NCT01358968
First received: May 20, 2011
Last updated: January 16, 2013
Last verified: January 2013
  Purpose

The purpose of this study is to assess the effect LY2603618 on a protein (enzyme CYP2D6) which is involved in the metabolic pathway of Desipramine in patients with cancer. This is a drug interaction study so the treatment of the disease will not be the main purpose of the study.

The study involves two single doses of 50mg, 1 tablet by mouth, on Day 1 of Period 1 and 2. In Period 1 Desipramine will be administered alone, In Period 2 Desipramine will be administered in combination with LY2603618. LY2603618 will be administered as a 275mg IV infusion over 1hr.

Desipramine will be administered at the end of the LY2603618 infusion. Information about any side effects that may occur will also be collected.


Condition Intervention Phase
Cancer
Drug: LY2603618
Drug: Desipramine
Drug: Pemetrexed
Drug: Gemcitabine
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Study in Cancer Patients to Evaluate the Ability of LY2603618 to Act as an Inhibitor of CYP2D6 Using Desipramine as a Probe Substrate

Resource links provided by NLM:


Further study details as provided by Eli Lilly and Company:

Primary Outcome Measures:
  • Plasma pharmacokinetics,of LY2603618 the maximum concentration of the drug in the plasma after dosing (Cmax) [ Time Frame: Period 2 only: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144 hours post dose ] [ Designated as safety issue: No ]
  • Plasma pharmacokinetics of Desipramine the maximum concentration of the drug in the plasma after dosing (Cmax) [ Time Frame: Periods 1 and 2: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 (period 2 only) hours post dose ] [ Designated as safety issue: No ]
  • Plasma pharmacokinetics of LY2603618 the area under the plasma concentration vs time curve from time zero to infinity (AUC0-∞) [ Time Frame: Period 2 only: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144 hours post dose ] [ Designated as safety issue: No ]
  • Plasma pharmacokinetics of Desipramine, the area under the plasma concentration vs time curve from time zero to infinity (AUC0-∞) [ Time Frame: Period 1 and 2:Predose, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144 and 168 (period 2 only) hours post dose ] [ Designated as safety issue: No ]
  • Plasma pharmacokinetics of LY2603618 the area under the plasma concentration vs time curve from time zero to the last observed plasma concentration of drug (AUC0-tlast) [ Time Frame: Period 2 only: Predose 1,2,4,6,8,12,24,48,72,96,120,144 hours post dose. ] [ Designated as safety issue: No ]
  • Plasma pharmacokinetics of Desipramine the area under the plasma concentration vs time curve from time zero to the last observed plasma concentration of drug (AUC0-tlast). [ Time Frame: Period 1 and 2: predose,0.5,1,2,4,8,12,24,48,72,96,120,144 and 168 (period 2 only) hours post dose. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Number of participants with a tumor response [ Time Frame: Baseline to study completion (estimate of 20 months) ] [ Designated as safety issue: No ]

Estimated Enrollment: 60
Study Start Date: June 2011
Study Completion Date: December 2012
Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LY2603618

Single 50 mg oral dose of desipramine on day 1 of study period 1. Single 275 mg intravenous infusion of LY2603618 followed by single 50 mg oral dose of desipramine on day 1 of study period 2. Patients may then receive additional doses of LY2603618 in combination as follows: 1000 mg/m^2 intravenous dose of gemcitabine on days 1, 8 and 15 and 230 mg intravenous dose of LY2603618 on days 2, 9 and 16 of 28 day cycles OR 500 mg/m^2 intravenous dose of pemetrexed on day 1 and 275 mg intravenous dose of LY2603618 on day 2 of 21 day cycles.

Patients will be allowed to continue to receive the combination therapy until fulfilling of the criteria for discontinuation, such as unacceptable toxicity or disease progression.

Drug: LY2603618
Administered intravenously.
Drug: Desipramine
Administered orally
Drug: Pemetrexed
Administered intravenously
Other Names:
  • ALIMTA®
  • LY231514
Drug: Gemcitabine
Administered intravenously
Other Names:
  • Gemzar®
  • LY188011

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Have a histological or cytological diagnosis of cancer (solid tumor), with clinical or radiologic evidence of locally advanced and/or metastatic disease, for which no life-prolonging therapy exists (that is, refractory to standard therapy and/or therapies known to provide clinical benefit, or for which no standard therapy exists). Note: Patients who have had progressive disease after receiving pemetrexed for metastatic disease are excluded from receiving the combination with pemetrexed during the safety extension study. Patients who have had progressive disease after receiving gemcitabine for metastatic disease are excluded from receiving the combination with gemcitabine during the safety extension study.
  • Have a body surface area (BSA) greater than or equal to 1.37 m^2
  • Have given written informed consent prior to any study-specific procedures
  • Have adequate hematologic, hepatic and renal function
  • Have a performance status of less than or equal to 2 on the Eastern Cooperative Oncology Group (ECOG) scale
  • Have discontinued all previous treatments for cancer, including chemotherapy, radiotherapy, anticancer hormone therapy or other investigational therapy for at least 30 days prior to study entry and recovered from the acute effects of therapy (at least 42 days for mitomycin-C or nitrosoureas, or 60 days for biologics)
  • Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures
  • Males and females with reproductive potential: Must agree to use medically approved contraceptive precautions during the study and for at least 3 months following the last dose of study drug
  • Females with childbearing potential: Have had a negative serum pregnancy test less than or equal to 7 days before the first dose of study drug and must also not be breastfeeding
  • Have an estimated life expectancy, in the judgment of the investigator, that will permit the patient to complete 1 full cycle of treatment beyond the drug interaction portion of the study (approximately 8 weeks)
  • Are able to swallow tablets
  • Prior radiation therapy for treatment of cancer is allowed to <25% of the bone marrow and patients must have recovered from the acute toxic effects of their treatment prior to study enrollment. Prior radiation to the whole pelvis is not allowed. Prior radiotherapy must be completed at least 4 weeks before study entry.

Exclusion Criteria:

  • Have received treatment within 28 days of the initial dose of study drug with an experimental agent for noncancer indications that has not received regulatory approval for any indication
  • Poor metabolizer (PM) status for CYP2D6 (genotyped)
  • Have previously completed or withdrawn from this study or any other study investigating LY2603618 or any other checkpoint kinase one (Chk1) inhibitor
  • Have known allergy to gemcitabine, pemetrexed, desipramine or LY2603618 or any ingredient of gemcitabine, pemetrexed, desipramine or LY2603618 (like Captisol®)
  • Have serious preexisting medical conditions (left to the discretion of the investigator) other than advanced cancer
  • Have symptomatic central nervous system (CNS) malignancy or metastasis (screening not required). Patients with treated CNS metastases are eligible for this study if they are not currently receiving corticosteroids and/or anticonvulsants, and their disease is asymptomatic and radiographically stable for at least 90 days.
  • Have current hematologic malignancies or either acute or chronic leukemia
  • Have an active fungal, bacterial, and/or known viral infection including human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis (screening is not required)
  • Have QTc interval of >500 msec on screening electrocardiogram (ECG)
  • Have ECG abnormalities on the screening ECG such as significant conduction abnormalities, ischemic changes (such as prior Q-wave myocardial infarction and/or marked ischemic ST- and T-wave), arrhythmias (such as persistent or paroxysmal ventricular or supraventricular arrhythmias,including atrial fibrillation), or other ECG abnormalities that would put the patient at unnecessary risk in the opinion of the investigator
  • Drugs with narrow therapeutic windows and that are also known substrates of CYP2D6 or drugs that are classified as sensitive substrates of CYP2D6 are excluded
  • Drugs or herbal supplements that are known inhibitors of CYP2D6 are excluded during the study, and during the 30-day period (or a minimum of 5 half-lives, whichever is less) prior to study start
  • 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 24 hours before the study through the end of the study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01358968

Locations
United States, Tennessee
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.
Memphis, Tennessee, United States, 38120
Sponsors and Collaborators
Eli Lilly and Company
Investigators
Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-371-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST) Eli Lilly and Company
  More Information

No publications provided

Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT01358968     History of Changes
Other Study ID Numbers: 13526, I2I-MC-JMMI
Study First Received: May 20, 2011
Last Updated: January 16, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Gemcitabine
Pemetrexed
Desipramine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Radiation-Sensitizing Agents
Folic Acid Antagonists
Antidepressive Agents, Tricyclic
Antidepressive Agents
Psychotropic Drugs
Central Nervous System Agents
Adrenergic Uptake Inhibitors
Adrenergic Agents
Neurotransmitter Agents
Neurotransmitter Uptake Inhibitors

ClinicalTrials.gov processed this record on October 16, 2014