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

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

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 Overview

• Status: Completed
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Drug: LDE225+gemcitabine

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• United Kingdom
  • Liverpool, United Kingdom, L7 8XP
    • Novartis Investigative Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Dept. of Mass General Hospital
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan Kettering Cancer Center MSKCC - SC
  • Utah
    • Salt Lake City, Utah, United States, 84103
      • University of Utah / Huntsman Cancer Institute Huntsman UT

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: LDE225+gemcitabine; 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.

Drug: LDE225+gemcitabine; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	first 8 weeks of study treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	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)	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	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.	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	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.	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	On Day 1 of every cycle (cycle = 28 days)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Results for CLDE225X2103 can be found on the Novartis Clinical Trial Results Website

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): July 1, 2014

Study Registration Dates

• First Submitted: December 5, 2011
• First Submitted That Met QC Criteria: December 6, 2011
• First Posted (Estimate): December 7, 2011

Study Record Updates

• Last Update Posted (Actual): December 19, 2020
• Last Update Submitted That Met QC Criteria: December 16, 2020
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: metastatic pancreatic cancer; gemcitabine; adenocarcinoma; locally advanced; LDE225
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gemcitabine
• Other Study ID Numbers: CLDE225X2103; 2010-024218-70 (EudraCT Number)