Dose-escalation, and Safety Study of LDE225 and Gemcitabine in Locally Advanced or Metastatic Pancreatic Cancer Patients
This phase Ib study includes two phases: dose escalation phase and safety expansion phase.
During the dose escalation phase, successive cohorts of eligible patients (minimum 3 and maximum 6 evaluable patients per cohort) will receive increasing oral doses of LDE225 administered on a continuous once daily (QD) dose in combination of gemcitabine. This phase of the study will determine the maximum tolerated dose (MTD) and/ or recommended dose for expansion (RDE) of LDE225 administered in combination with gemcitabine in locally advanced or metastatic pancreatic adenocarcinoma patients.
During the safety expansion phase, once the MTD of LDE225 is established, additional patients will be enrolled and treated at the MTD of LDE225 in combination with gemcitabine in order to further evaluate its safety, tolerability and explore the potential efficacy of the combined treatments on the patients in locally advanced or metastatic pancreatic adenocarcinoma.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase Ib, Open-label, Multicenter, Dose-escalation, Safety and Tolerability Study of LDE225 in Combination With Gemcitabine in Patients With Locally Advanced or Metastatic Pancreatic Adenocarcinoma|
- Incidence rate and category of dose limiting toxicities (DLTs) [ Time Frame: first 8 weeks of study treatment ] [ Designated as safety issue: No ]Dose limiting toxicities that occur during the first 8 weeks (56 days) of treatment with LDE225+gemcitabine. Dose limiting toxicity is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness, or concomitant medications that meets study specific criteria.
- Incidence rate of Adverse Events and Serious Adverse Events [ Time Frame: at Informed Consent Form (ICF) sign off until 120 days after the last dose of study drug ] [ Designated as safety issue: Yes ]Adverse events and serious adverse events, changes in hematology and chemistry values and assessment of physical and neurological examinations, vital signs and electrocardiograms that occur during the reported period
- Plasma pharmacokinetics(PK) parameters of LDE225 [ Time Frame: baseline, week 9 of the study ] [ Designated as safety issue: No ]Area Under the Curve (AUC), Maximum observed plasma concentration after drug administration (Cmax), Time to reach Cmax (Tmax), etc.
- Plasma pharmacokinetics (PK) of gemcitabine [ Time Frame: Baseline, week 9 of the study ] [ Designated as safety issue: No ]If possible: AUC, Cmax, Tmax, Half life (T1/2), Total body clearance (CL), Apparent volume of distribution at steady state (Vss)
- Antitumor efficacy of LDE225+gemcitabine [ Time Frame: baseline, week 9 of the study ] [ Designated as safety issue: No ]Efficacy endpoints (Objective response rate and progression free survival) as a function of Hh target gene expression in tumor samples
- Progression free survival [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]the effect of LDE225+gemcitabine on progression free survival. Progression Free Survival is defined as the time from date of enrollment to the date of the first documented progression, or death due to any cause, or start of new anti-cancer therapy.
- Objective Response Rate [ Time Frame: Baseline, 8 weeks ] [ Designated as safety issue: No ]The effect of LDE225+gemcitabine on objective response rate. Objective response rate is defined as the proportion of patients with a confirmed complete response (CR) or partial response (PR) as their best overall response per RECIST 1.0
- Duration of Response [ Time Frame: Baseline, 8 weeks ] [ Designated as safety issue: No ]The effect of LDE225+gemcitabine on duration of response. Duration of response is defined as the time from the first occurrence of complete response or partial response until the date of the first documented disease progression or death due to underlying cancer.
- Serum tumor marker Ca 19-9 [ Time Frame: On Day 1 of every cycle (cycle = 28 days) ] [ Designated as safety issue: No ]the effect of LDE225+gemcitabine on changes overtime in the serum tumor marker Ca 19-9 levels from baseline as assessed by central lab
|Study Start Date:||March 2012|
|Estimated Study Completion Date:||May 2014|
|Estimated Primary Completion Date:||March 2014 (Final data collection date for primary outcome measure)|
Increasing doses of LDE225 (from 400 mg) once a day + 1000 mg/m2 of gemcitabine on days 1, 8 and 15 of every 28 day cycle.
Patients will receive increasing doses of LDE225 (from 400 mg), depending on the cohort they are assigned to, orally once daily and standard doses of gemcitabine (1000 mg/m2) on days 1, 8 and 15 of every 28-day cycle. Patients will receive the study treatment until they progressed, experience unacceptable toxicity, withdraw from the study, or the investigator decides it is in their best interest to discontinue the study treatment.
|Contact: Novartis Pharmaceuticals||1-888-669-6682|
|Contact: Novartis Pharmaceuticals|
|United States, Massachusetts|
|Massachusetts General Hospital Dept. of Mass General Hospital||Recruiting|
|Boston, Massachusetts, United States, 02114|
|Contact: Susan Sheehan, RN 617-724-9347 SSHEEHAN1@PARTNERS.ORG|
|Principal Investigator: Eunice Kwak|
|United States, New York|
|Memorial Sloan Kettering Cancer Center MSKCC - SC||Recruiting|
|New York, New York, United States, 10021|
|Contact: Kristen Gary 646-227-2142 email@example.com|
|Principal Investigator: Kenneth Yu|
|United States, Utah|
|University of Utah / Huntsman Cancer Institute Huntsman UT||Recruiting|
|Salt Lake City, Utah, United States, 84103|
|Contact: Scott J Ellis 801-587-5597 firstname.lastname@example.org|
|Principal Investigator: Sunil Sharma|
|Novartis Investigative Site||Active, not recruiting|
|Barcelona, Cataluña, Spain, 08035|
|Novartis Investigative Site||Recruiting|
|Liverpool, United Kingdom, L7 8XP|
|Study Director:||Novartis Pharmaceuticals||Novartis Pharmaceuticals|