A Phase II Study of Orally Administered BEZ235 Monotherapy in Patients With Metastatic or Unresectable Malignant PEComa
The primary objective is to determine the efficacy of BEZ235 on Objective Response Rate (best response on study) according to RECIST 1.1 criteria
The secondary objectives are:
- To determine the progression free survival rate at 32 weeks in the included population
- To assess the duration of response among responders
- To evaluate time to response
- To evaluate the time to progression
- To assess the overall survival
- To evaluate safety and tolerability of BEZ235
The exploratory objectives are:
- To identify molecular and genomic profiles of PEComas and their potential relationship to clinical outcome by analyzing PIK3CA, Ras, Raf, TSC, AKT and PTEN alteration in tumor samples (archival or fresh pre-treatment tumor biopsy) and PIK3CA in circulating DNA.
- To determine biomarkers relevant to BEZ235 activity by analyzing the expression of phosphoproteins p-AKT, p-S6, p-4EBP1 at screening and during treatment as well as biomarkers for the proliferation (Ki-67) and apoptosis (PARP) (only if fresh tissue (optional) is available).
The patient population consists of patients 18 years old or older with progressive unresectable/advanced or metastatic malignant PEComas previously treated for unresectable/advanced/metastatic disease with 1 to 2 prior lines of chemotherapy. Patients must have adequate hematologic, renal, cardiac and hepatic functions and not be previously treated with a mTOR inhibitor.
Number of patients:
16 to 33 patients
Overview of study design:
This is a prospective, multicenter, open-label, single arm, two-stage phase II study to investigate the efficacy and tolerability of BEZ235 in patients with progressive metastatic or unresectable/advanced malignant PEComas. The patient should have received 1 or 2 prior lines of chemotherapy.
BEZ235 will be administered until disease progression. Sixteen patients will be enrolled into Stage 1 and observed for at least 32 weeks at which time an interim analysis will be performed (plus eventually 4-5 weeks for confirmation of responses occurring on or closely before this cut-off date). If the number of patients with a response (CR or PR) is 2 or less, the trial will be stopped for futility. If 3 or more patients experience a response enrollment will continue up to 33 patients (Stage 2).
An Independent Data Monitoring Committee (IDMC) will be constituted for reviewing the interim analysis.
Malignant PEComa (Perivascular Epithelioid Cell Tumors)
|Study Design:||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase II Study of Orally Administered BEZ235 Monotherapy in Patients With Metastatic or Unresectable Malignant PEComa|
- Proportion of Patients with best Objective Response Rate (ORR) [ Time Frame: From treatment start to end of follow-up, assessed up to 30 months ] [ Designated as safety issue: No ]Objective Response Rate is defined as the proportion of patients with a best overall response of Complete Response (CR) or Partial Response (PR) according to RECIST. 1.1.
- Progression Free Survival rate [ Time Frame: 32 weeks ] [ Designated as safety issue: No ]Time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.
- Duration of response [ Time Frame: From Initial response (CR or PR) until objective tumor progression, assessed up to 30 months ] [ Designated as safety issue: No ]Duration of response (DR) is measured from the time of initial response (CR or PR) until objective tumor progression.
- Time to response [ Time Frame: From start of treatment to the initial response, assessed up to 30 months ] [ Designated as safety issue: No ]Time to response (TTR) is defined as time from treatment start until initial response (CR, PR)
- Time to disease progression [ Time Frame: From start of treatment to first documented disease progression assessed up to 30 months ] [ Designated as safety issue: No ]Time from date of start of treatment to the date of event defined as the first documented progression or death due to underlying cancer. If a patient has not had an event, time to progression is censored at the date of last adequate tumor assessment.
- Overall survival [ Time Frame: From start of treatment to date of death (due to any cause) assessed up to 30 months ] [ Designated as safety issue: No ]Time from date of start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last known date patient alive.
- Number of Adverse Events as a Measure of Safety and Tolerability [ Time Frame: up to 30 months ] [ Designated as safety issue: Yes ]The incidence of treatment-emergent adverse events (new or worsening from baseline) will be summarized by system organ class and or preferred term, severity (based on CTCAE grades), type of adverse event, relation to the study drug. Laboratory data will be graded according to CTCAE version 4.03 if relevant. For laboratory tests where grades are not defined according to CTCAE, abnormalities will be assessed according to laboratory normal ranges.
|Study Start Date:||September 2012|
|Estimated Study Completion Date:||January 2015|
|Estimated Primary Completion Date:||January 2015 (Final data collection date for primary outcome measure)|
BEZ235 will be supplied in 200mg, 300mg and 400mg sachets packaged in boxes. Each box will contain only sachets of one strength.
Patients will be provided with an adequate supply of study treatment for self-administration at home. Unless otherwise warranted, new study drug packages will be provided to the patient at Cycle 1 Day 1 (start of treatment) and at Day 1 of each following treatment cycle. The first dose of BEZ235 (Cycle1 Day1) must be taken at the hospital.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01690871
|Novartis Investigative Site|
|Barcelona, Cataluña, Spain, 08025|
|Study Director:||Novartis Pharmaceuticals||Novartis Pharmaceuticals|