Clinical trial NCT01769768: Phase I Study to Evaluate the Effect of LDE225 on the Pharmacokinetics of Bupropion and Warfarin in Patients
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Solid Tumor
Keywords: Adults, Hh (Hedgehog) pathway inhibitor, LDE225, Warfarin, Bupropion, advanced solid tumor, drug-drug interaction, pharmacokinetic
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-01-17
Enrollment: 114
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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

Primary outcomes:
measure: Pharmacokinetics (PK) parameter AUClast for S- and R-warfarin
timeFrame: 7 days
measure: PK parameter AUClast for bupropion
timeFrame: 7 days
measure: PK parameter AUCinf for bupropion
timeFrame: 7 days
measure: PK parameter AUCinf for S- and R-warfarin
timeFrame: 7 days
measure: PK parameter Cmax for S- and R-warfarin
timeFrame: 7 days
measure: PK parameters Cmax for bupropion
timeFrame: 7 days
Secondary outcomes:
measure: effects of LDE225 on the pharmacodynamic activity of warfarin
timeFrame: 7 days
measure: safety of LDE225 when administered alone and concomitantly with either bupropion or warfarin
timeFrame: 28 days cycles
measure: evaluate the preliminary evidence of anti-tumor activity of LDE225 in patients with advanced solid tumors
timeFrame: every other cycle
measure: assess the effect of LDE225 treatment on cardiac function
timeFrame: screening, cycle 4 and EOT
measure: effects of LDE225 on the pharmacodynamic activity of warfarin
timeFrame: 7 days
measure: safety of LDE225 when administered alone and concomitantly with either bupropion or warfarin
timeFrame: 28 days cycles
measure: safety of LDE225 when administered alone and concomitantly with either bupropion or warfarin
timeFrame: 28 days cycles
measure: safety of LDE225 when administered alone and concomitantly with either bupropion or warfarin
timeFrame: 28 days cycles
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center Oncology
state: California
city: Kansas City
country: United States
facility: University of Kansas Medical Center CBYM338B2203
state: Kansas
city: Boston
country: United States
facility: Massachusetts General Hospital Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center Dartmouth-Hitchcock Med Ctr
state: New Hampshire
city: Hackensack
country: United States
facility: Hackensack University Medical Center Dept.of HackensackUniv.MedCtr.
state: New Jersey
city: Philadelphia
country: United States
facility: University of Pennsylvania--Abramson Cancer Center Abramson Cancer Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute UPMC Cancer Pavilion
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina Dept.of Neurosciences/MS Ctr.
state: South Carolina
city: Greenville
country: United States
facility: Cancer Centers of the Carolinas SC
state: South Carolina
city: San Antonio
country: United States
facility: Utah Health Science Center at San Antonio
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah / Huntsman Cancer Institute
state: Utah
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.