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Phase I Study to Evaluate the Effect of LDE225 on the Pharmacokinetics of Bupropion and Warfarin in Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01769768
First received: January 15, 2013
Last updated: August 15, 2016
Last verified: August 2016
  Purpose
This is a multi center, open-label study to evaluate the drug-drug interaction of LDE225 on the PK of bupropion and warfarin patients with advanced solid tumors. Subjects will receive 800mg daily of LDE225 and two separate doses of either bupropion or warfarin.

Condition Intervention Phase
Advanced Solid Tumor
Drug: LDE225
Drug: Wafarin
Drug: Bupropion
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase Ib, Multi-center, Two Parallel Group, Open-label, Drug-drug Interaction Study to Assess the Effect of LDE225 on the Pharmacokinetics of Bupropion and Warfarin in Patients With Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Pharmacokinetics (PK) parameter AUClast for S- and R-warfarin [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
    Pharmacokinetics of warfarin : Maximum observed plasma concentration after drug administration

  • PK parameter AUClast for bupropion [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
    Pharmacokinetics bupropion : Maximum observed plasma concentration after drug administration

  • PK parameter AUCinf for bupropion [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
    Pharmacokinetics of bupropion : Maximum observed plasma concentration after drug administration

  • PK parameter AUCinf for S- and R-warfarin [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
    Pharmacokinetics of warfarin and bupropion : Maximum observed plasma concentration after drug administration

  • PK parameter Cmax for S- and R-warfarin [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
    Pharmacokinetics of warfarin : Maximum observed plasma concentration after drug administration

  • PK parameters Cmax for bupropion [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
    Pharmacokinetics of Bupropion : Maximum observed plasma concentration after drug administration


Secondary Outcome Measures:
  • effects of LDE225 on the pharmacodynamic activity of warfarin [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
    INR parameter (International Normalized Ratio) will be assessed to evaluate the pharmacodynamic effect of warfarin.

  • safety of LDE225 when administered alone and concomitantly with either bupropion or warfarin [ Time Frame: 28 days cycles ] [ Designated as safety issue: Yes ]
    safety laboratory parameters, adverse event reports, changes in vital signs, changes in physical examination parameters

  • evaluate the preliminary evidence of anti-tumor activity of LDE225 in patients with advanced solid tumors [ Time Frame: every other cycle ] [ Designated as safety issue: No ]
    CT or MRI imaging parameters to determine the objective response rate according to RECIST 1.1 (Response Evaluation Criteria In Solid Tumors)

  • assess the effect of LDE225 treatment on cardiac function [ Time Frame: screening, cycle 4 and EOT ] [ Designated as safety issue: Yes ]
    ECGs will be performed to determine the effect of LDE on the cardiac function.

  • effects of LDE225 on the pharmacodynamic activity of warfarin [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
    PT (Prothrombin time) parameter will be assessed to evaluate the pharmacodynamic effect of warfarin.

  • safety of LDE225 when administered alone and concomitantly with either bupropion or warfarin [ Time Frame: 28 days cycles ] [ Designated as safety issue: Yes ]
    safety laboratory parameters

  • safety of LDE225 when administered alone and concomitantly with either bupropion or warfarin [ Time Frame: 28 days cycles ] [ Designated as safety issue: Yes ]
    adverse event reports

  • safety of LDE225 when administered alone and concomitantly with either bupropion or warfarin [ Time Frame: 28 days cycles ] [ Designated as safety issue: Yes ]
    changes in vital signs


Enrollment: 114
Study Start Date: April 2013
Study Completion Date: August 2016
Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LDE225+Warfarin
At least 15 evaluable patients with advanced solid tumors will be enrolled into the study into the warfarin group.
Drug: LDE225
LDE225 800 mg once daily dosing will begin on Cycle 1 Day 1 of a 28-day cycle.Treatment with LDE225 for both groups will continue until the patient experiences unacceptable toxicity that precludes further treatment, disease progression, withdrawal of consent and/or at the discretion of the investigator.
Drug: Wafarin
15 mg single dose of warfarin (oral tablet) will be given to patients.
Experimental: LDE225+Bupropion
At least 15 evaluable patients with advanced solid tumors will be enrolled into the study into the Bupropion group
Drug: LDE225
LDE225 800 mg once daily dosing will begin on Cycle 1 Day 1 of a 28-day cycle.Treatment with LDE225 for both groups will continue until the patient experiences unacceptable toxicity that precludes further treatment, disease progression, withdrawal of consent and/or at the discretion of the investigator.
Drug: Bupropion
75 mg single dose of bupropion(oral tablet, from an immediate release formulation) will be given to patients

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Adults
  • Patients with cytopathologically or histopathologically confirmed diagnosis of an advanced solid tumor which has progressed despite standard therapy, or for which no standard therapy exists or patients with locally advanced or metastatic basal cell carcinoma who are not amendable or eligible for standard therapy.
  • Protocol-defined renal , liver and bone marrow function

Exclusion Criteria:

  • CNS (Central Nervous System) tumors as well as history of brain metastases
  • Systemic anticancer treatment (including biologic therapy/antibodies) within 2 weeks before first dose of study treatment (6 weeks for nitrosourea, mitomycin, and monoclonal antibodies).
  • Radiation therapy within 4 weeks before first dose
  • Investigational agents within 4 weeks before start of study therapy
  • Patients with known allergy/hypersensitivity to warfarin or bupropion and/or related compounds
  • Patients with a history of/or active bleeding disorders
  • Patients receiving treatment with vitamin K, Coumadin or other agents containing warfarin and heparin. Heparin flush to maintain patency of a central venous access device is allowed.
  • Patients receiving treatment with bupropion.
  • Patients who have neuromuscular disorders that are associated with elevated CK (Creatine phosphokinase) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
  • Known diagnosis of human immunodeficiency virus (HIV), Hepatitis B or C (testing is not mandatory for study entry)
  • Patients currently receiving systemic corticosteroids

Other protocol-defined inclusion/exclusion criteria may apply

  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: NCT01769768

Locations
United States, California
City of Hope National Medical Center Oncology
Duarte, California, United States, 91010
United States, Kansas
University of Kansas Medical Center CBYM338B2203
Kansas City, Kansas, United States, 66160
United States, Massachusetts
Massachusetts General Hospital Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02114
United States, Michigan
Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, New Hampshire
Dartmouth Hitchcock Medical Center Dartmouth-Hitchcock Med Ctr
Lebanon, New Hampshire, United States, 03756
United States, New Jersey
Hackensack University Medical Center Dept.of HackensackUniv.MedCtr.
Hackensack, New Jersey, United States, 07601
United States, Pennsylvania
University of Pennsylvania--Abramson Cancer Center Abramson Cancer Center
Philadelphia, Pennsylvania, United States, 19104
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States, 19111-2497
University of Pittsburgh Cancer Institute UPMC Cancer Pavilion
Pittsburgh, Pennsylvania, United States, 15232
United States, South Carolina
Medical University of South Carolina Dept.of Neurosciences/MS Ctr.
Charleston, South Carolina, United States, 29425
Cancer Centers of the Carolinas SC
Greenville, South Carolina, United States, 29605
United States, Texas
Utah Health Science Center at San Antonio
San Antonio, Texas, United States, 78229
United States, Utah
University of Utah / Huntsman Cancer Institute
Salt Lake City, Utah, United States, 84112
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01769768     History of Changes
Other Study ID Numbers: CLDE225A2112 
Study First Received: January 15, 2013
Last Updated: August 15, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Novartis:
Adults, Hh (Hedgehog) pathway inhibitor, LDE225, Warfarin, Bupropion, advanced solid tumor, drug-drug interaction, pharmacokinetic

Additional relevant MeSH terms:
Warfarin
Bupropion
Anticoagulants
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs
Dopamine Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Dopamine Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Cytochrome P-450 CYP2D6 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on December 06, 2016