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.

Inclusion criteria

1. 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.

2. 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.

3. Availability of a representative tumor specimen, either archival or fresh tumor tissue for PI3K pathway analysis.

4. 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).

5. 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.

6. Treated with 1 or 2 prior lines of treatment Exclusion criteria

1. Disease exclusions:

1. Lymphangioleiomyomatosis (LAM) exclusively
2. 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.
3. 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).