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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: LDE225
* Drug: Wafarin
* Drug: Bupropion


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LDE225+Warfarin<br>At least 15 evaluable patients with advanced solid tumors will be enrolled into the study into the warfarin group. | Drug: LDE225<br>* 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.<br>Drug: Wafarin<br>* 15 mg single dose of warfarin (oral tablet) will be given to patients.<br>|
| Experimental: LDE225+Bupropion<br>At least 15 evaluable patients with advanced solid tumors will be enrolled into the study into the Bupropion group | Drug: LDE225<br>* 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.<br>Drug: Bupropion<br>* 75 mg single dose of bupropion(oral tablet, from an immediate release formulation) will be given to patients<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adults, Hh (Hedgehog) pathway inhibitor, LDE225, Warfarin, Bupropion, advanced solid tumor, drug-drug interaction, pharmacokinetic