A Phase II Study of Orally Administered BEZ235 Monotherapy in Patients With Metastatic or Unresectable Malignant PEComa

NCT01690871 | Withdrawn Phase 2 DMC

• 1 other identifier: CBEZ235ZIC01
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Study objectives: 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). Study population: 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.

Conditions

Malignant PEComa (Perivascular Epithelioid Cell Tumors)

Keywords

Malignant PEComa; Angiomyolipoma; Tuberous Sclerosis Complex; Pi3kinase /m-tor inhibitors

Outcome Measures

Primary Outcomes (1)

• Proportion of Patients with best Objective Response Rate (ORR)

  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.

  From treatment start to end of follow-up, assessed up to 30 months

Secondary Outcomes (6)

• Progression Free Survival rate

  32 weeks

• Duration of response

  From Initial response (CR or PR) until objective tumor progression, assessed up to 30 months

• Time to response

  From start of treatment to the initial response, assessed up to 30 months

• Time to disease progression

  From start of treatment to first documented disease progression assessed up to 30 months

• Overall survival

  From start of treatment to date of death (due to any cause) assessed up to 30 months

Study Arms (1)

BEZ235

EXPERIMENTAL

BEZ235 will be supplied in 200mg, 300mg and 400mg sachets packaged in boxes. Each box will contain only sachets of one strength.

Drug: BEZ235

Interventions

BEZ235 DRUG

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.

BEZ235

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed diagnosis of malignant PEComa (included epithelioid AML) of primary disease or of metastatic lesion from archival tissue if it has been obtained within 12 months prior to enrollment in this study. This histological diagnosis includes immunochemistry as follows:
• Immunohistochemically positive expression of a melanocytic marker (HMB45, MelanA or microphtalmia transcription factor) AND of a smooth muscle marker (smooth muscle actin, pan-muscle actin, h-caldesmon or calponin) is mandatory on primary or metastatic tumor biopsy.
• Note: According to Folpe (2002), criteria for malignancy in non-AML PEComas are:
• tumor size of more than 5 cm,
• infiltrative growth pattern,
• high nuclear grade,
• mitotic activity of more than 1/50 high power field (HPF),
• necrosis,
• vascular invasion
• Thus, to be included in the trial, the patient should have tumor presenting with 2 or more criteria for malignancy associated with aggressive clinical behavior.
• If the primary diagnosis was performed more than 12 months before enrollment, the histology of a primary/metastatic lesion should be reconfirmed with a fresh biopsy.
• Availability of a representative tumor specimen, either archival or fresh tumor tissue for PI3K pathway analysis.
• Unresectable/advanced and/or metastatic and documented progressive measurable disease as defined by RECIST 1.1 criteria. Prior to study entry, the progression of the disease should be confirmed by at least 2 sequential CT scans available for documentation (will be collected and hold).
• Presence of measurable disease according to RECIST 1.1. Note: Lesions in previously irradiated areas can only be considered measurable if they have clearly progressed since the radiotherapy.

You may not qualify if:

• Lymphangioleiomyomatosis (LAM) exclusively
• Active uncontrolled or symptomatic CNS metastases Note: A patient with controlled and asymptomatic CNS metastases may participate in this trial. As such, the patient must have completed any prior treatment for CNS metastases \> 28 days (including radiotherapy and/or surgery) prior to start of treatment in this study and should not be receiving chronic corticosteroid therapy for the CNS metastases.
• Concurrent malignancy or malignancy in the last 3 years prior to start the study treatment (with the exception of adequately treated cervical carcinoma in situ or nonmelanoma skin cancer).

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (1)

Novartis Investigative Site

Barcelona, Catalonia, 08025, Spain

Location

MeSH Terms

Conditions

Perivascular Epithelioid Cell Neoplasms; Angiomyolipoma; Tuberous Sclerosis

Interventions

dactolisib

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Adipose Tissue; Hamartoma; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Nervous System Diseases; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 6, 2012
• First Posted: September 24, 2012
• Study Start: September 1, 2012
• Primary Completion: January 1, 2015
• Study Completion: January 1, 2015
• Last Updated: August 2, 2013

Record last verified: 2013-08

Locations

ES (1)