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

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

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.

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumor
• Intervention / Treatment: Drug: LDE225; Drug: Wafarin; Drug: Bupropion

• Study Type: Interventional
• Enrollment (Actual): 114
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (PK) parameter AUClast for S- and R-warfarin	Pharmacokinetics of warfarin : Maximum observed plasma concentration after drug administration	7 days
PK parameter AUClast for bupropion	Pharmacokinetics bupropion : Maximum observed plasma concentration after drug administration	7 days
PK parameter AUCinf for bupropion	Pharmacokinetics of bupropion : Maximum observed plasma concentration after drug administration	7 days
PK parameter AUCinf for S- and R-warfarin	Pharmacokinetics of warfarin and bupropion : Maximum observed plasma concentration after drug administration	7 days
PK parameter Cmax for S- and R-warfarin	Pharmacokinetics of warfarin : Maximum observed plasma concentration after drug administration	7 days
PK parameters Cmax for bupropion	Pharmacokinetics of Bupropion : Maximum observed plasma concentration after drug administration	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
effects of LDE225 on the pharmacodynamic activity of warfarin	INR parameter (International Normalized Ratio) will be assessed to evaluate the pharmacodynamic effect of warfarin.	7 days
safety of LDE225 when administered alone and concomitantly with either bupropion or warfarin	safety laboratory parameters, adverse event reports, changes in vital signs, changes in physical examination parameters	28 days cycles
evaluate the preliminary evidence of anti-tumor activity of LDE225 in patients with advanced solid tumors	CT or MRI imaging parameters to determine the objective response rate according to RECIST 1.1 (Response Evaluation Criteria In Solid Tumors)	every other cycle
assess the effect of LDE225 treatment on cardiac function	ECGs will be performed to determine the effect of LDE on the cardiac function.	screening, cycle 4 and EOT
effects of LDE225 on the pharmacodynamic activity of warfarin	PT (Prothrombin time) parameter will be assessed to evaluate the pharmacodynamic effect of warfarin.	7 days
safety of LDE225 when administered alone and concomitantly with either bupropion or warfarin	safety laboratory parameters	28 days cycles
safety of LDE225 when administered alone and concomitantly with either bupropion or warfarin	adverse event reports	28 days cycles
safety of LDE225 when administered alone and concomitantly with either bupropion or warfarin	changes in vital signs	28 days cycles

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Pooler DB, Ness DB, Sarantopoulos J, Squittieri N, Ravichandran S, Britten CD, Amaravadi RK, Vaishampayan U, LoRusso P, Shapiro GI, Olszanski AJ, Perez R, Gutierrez M, O'Rourke MA, Chung V, Lee JJ, Lewis LD. The effect of sonidegib (LDE225) on the pharmacokinetics of bupropion and warfarin in patients with advanced solid tumours. Br J Clin Pharmacol. 2021 Mar;87(3):1291-1302. doi: 10.1111/bcp.14508. Epub 2020 Aug 20.

Helpful Links

• Results for CLDE225A2112 can be found on the Novartis Clinical Trial Results Website

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): August 1, 2016
• Study Completion (Actual): August 1, 2016

Study Registration Dates

• First Submitted: January 15, 2013
• First Submitted That Met QC Criteria: January 15, 2013
• First Posted (Estimate): January 17, 2013

Study Record Updates

• Last Update Posted (Actual): December 19, 2020
• Last Update Submitted That Met QC Criteria: December 16, 2020
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: Adults, Hh (Hedgehog) pathway inhibitor, LDE225, Warfarin, Bupropion, advanced solid tumor, drug-drug interaction, pharmacokinetic
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Dopamine Uptake Inhibitors; Bupropion
• Other Study ID Numbers: CLDE225A2112