Dose-escalation, and Safety Study of LDE225 and Gemcitabine in Locally Advanced or Metastatic Pancreatic Cancer Patients

Novartis Pharmaceuticals18 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Pancreatic Cancer

Interventions

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Patients with locally advanced or metastatic pancreatic adenocarcinoma that have not been previously treated or have progressed despite chemotherapy * Performance status of 0 or 1 per WHO classification * Adequate hematologic , renal and liver function * Adequate blood creatine kinase value (CK \< 1.5ULN) Exclusion Criteria: * Treatment with prior radiotherapy * Pancreatic cancer that is potentially curable by surgery * Women of childbearing potential unless they are using highly effective method of contraception Other protocol-defined inclusion/exclusion criteria may apply Other protocol-defined inclusion/exclusion criteria may apply.

Locations (5)

Massachusetts General Hospital Dept. of Mass General Hospital

Boston, Massachusetts, United States

Memorial Sloan Kettering Cancer Center MSKCC - SC

New York, New York, United States

University of Utah / Huntsman Cancer Institute Huntsman UT

Salt Lake City, Utah, United States

Novartis Investigative Site

Barcelona, Catalonia, Spain

Novartis Investigative Site

Liverpool, United Kingdom

Outcomes

Primary Outcomes

Incidence rate and category of dose limiting toxicities (DLTs)

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.

Time frame: first 8 weeks of study treatment

Secondary Outcomes

Incidence rate of Adverse Events and Serious Adverse Events

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

Time frame: at Informed Consent Form (ICF) sign off until 120 days after the last dose of study drug

Plasma pharmacokinetics(PK) parameters of LDE225

Area Under the Curve (AUC), Maximum observed plasma concentration after drug administration (Cmax), Time to reach Cmax (Tmax), etc.

Time frame: baseline, week 9 of the study

Plasma pharmacokinetics (PK) of gemcitabine

If possible: AUC, Cmax, Tmax, Half life (T1/2), Total body clearance (CL), Apparent volume of distribution at steady state (Vss)

Time frame: Baseline, week 9 of the study

Antitumor efficacy of LDE225+gemcitabine

Efficacy endpoints (Objective response rate and progression free survival) as a function of Hh target gene expression in tumor samples

Time frame: baseline, week 9 of the study

Progression free survival

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.

Time frame: baseline, 8 weeks

Objective Response Rate

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

Time frame: Baseline, 8 weeks

Duration of Response

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.

Time frame: Baseline, 8 weeks

Serum tumor marker Ca 19-9

the effect of LDE225+gemcitabine on changes overtime in the serum tumor marker Ca 19-9 levels from baseline as assessed by central lab

Time frame: On Day 1 of every cycle (cycle = 28 days)