Back to resultsA Phase II Study of Orally Administered BEZ235 Monotherapy in Patients With Metastatic or Unresectable Malignant PEComa
Primary Purpose
Malignant PEComa (Perivascular Epithelioid Cell Tumors)
Status
Withdrawn
Phase
Phase 2
Locations
Spain
Study Type
Interventional
Intervention
BEZ235
Sponsored by
About this trial
This is an interventional treatment trial for Malignant PEComa (Perivascular Epithelioid Cell Tumors) focused on measuring Malignant PEComa, Angiomyolipoma, Tuberous Sclerosis Complex, Pi3kinase /m-tor inhibitors
Eligibility Criteria
Inclusion criteria
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.
- Treated with 1 or 2 prior lines of treatment Exclusion criteria
1. Disease exclusions:
- 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).
Sites / Locations
- Novartis Investigative Site
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
BEZ235
Arm Description
BEZ235 will be supplied in 200mg, 300mg and 400mg sachets packaged in boxes. Each box will contain only sachets of one strength.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Progression Free Survival rate
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
Duration of response (DR) is measured from the time of initial response (CR or PR) until objective tumor progression.
Time to response
Time to response (TTR) is defined as time from treatment start until initial response (CR, PR)
Time to disease progression
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 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
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.
Full Information
NCT ID
NCT01690871
First Posted
September 6, 2012
Last Updated
August 1, 2013
Sponsor
Novartis Pharmaceuticals
1. Study Identification
Unique Protocol Identification Number
NCT01690871
Brief Title
A Phase II Study of Orally Administered BEZ235 Monotherapy in Patients With Metastatic or Unresectable Malignant PEComa
Official Title
A Phase II Study of Orally Administered BEZ235 Monotherapy in Patients With Metastatic or Unresectable Malignant PEComa
Study Type
Interventional
2. Study Status
Record Verification Date
August 2013
Overall Recruitment Status
Withdrawn
Study Start Date
September 2012 (undefined)
Primary Completion Date
January 2015 (Anticipated)
Study Completion Date
January 2015 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant PEComa (Perivascular Epithelioid Cell Tumors)
Keywords
Malignant PEComa, Angiomyolipoma, Tuberous Sclerosis Complex, Pi3kinase /m-tor inhibitors
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
BEZ235
Arm Type
Experimental
Arm Description
BEZ235 will be supplied in 200mg, 300mg and 400mg sachets packaged in boxes. Each box will contain only sachets of one strength.
Intervention Type
Drug
Intervention Name(s)
BEZ235
Intervention Description
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.
Primary Outcome Measure Information:
Title
Proportion of Patients with best Objective Response Rate (ORR)
Description
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.
Time Frame
From treatment start to end of follow-up, assessed up to 30 months
Secondary Outcome Measure Information:
Title
Progression Free Survival rate
Description
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.
Time Frame
32 weeks
Title
Duration of response
Description
Duration of response (DR) is measured from the time of initial response (CR or PR) until objective tumor progression.
Time Frame
From Initial response (CR or PR) until objective tumor progression, assessed up to 30 months
Title
Time to response
Description
Time to response (TTR) is defined as time from treatment start until initial response (CR, PR)
Time Frame
From start of treatment to the initial response, assessed up to 30 months
Title
Time to disease progression
Description
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.
Time Frame
From start of treatment to first documented disease progression assessed up to 30 months
Title
Overall survival
Description
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.
Time Frame
From start of treatment to date of death (due to any cause) assessed up to 30 months
Title
Number of Adverse Events as a Measure of Safety and Tolerability
Description
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.
Time Frame
up to 30 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria
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.
Treated with 1 or 2 prior lines of treatment Exclusion criteria
1. Disease exclusions:
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Barcelona
State/Province
Cataluña
ZIP/Postal Code
08025
Country
Spain
12. IPD Sharing Statement
Learn more about this trial
A Phase II Study of Orally Administered BEZ235 Monotherapy in Patients With Metastatic or Unresectable Malignant PEComa
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