A Phase I/II Study of BEZ235 in Patients With Advanced Solid Malignancies Enriched by Patients With Advanced Breast Cancer

Study Overview
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Brief Summary
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This is a first-in-human, phase I/Ib clinical research study with BEZ235, an inhibitor of phosphatidylinositol 3'-kinase (PI3K). The study consists of a dose escalation part followed by a safety dose expansion part: Dose escalation part (advanced solid tumors, including patients with breast cancer being treated with trastuzumab): Patients receive oral BEZ235 once daily on days 1-28 of the first course. Courses will repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of at least 3 patients receive escalating doses of BEZ235, as single agent or in combination with trastuzumab, until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose expected to produce during the first course of treatment dose-limiting toxicity in 33% of patients. Once the MTD has been defined, the safety expansion parts of the trial will be opened for enrollment. Safety dose expansion part (advanced solid tumors, including patients with breast cancer being treated with trastuzumab): Patients will be treated with BEZ235, as single agent or in combination with trastuzumab, given at the MTD, once daily. Treatment of patients will continue until disease progression or occurrence of unacceptable side effects.

Official Title
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A Phase I/II, Multi-center, Open-label Study of BEZ235, Administered Orally on a Continuous Daily Dosing Schedule in Adult Patients With Advanced Solid Malignancies Including Patients With Advanced Breast Cancer

Conditions
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Breast Cancer, Advanced Solid Tumors, Cowden Syndrome

Intervention / Treatment
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* Drug: BEZ235


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: [Single agent dose escalation arm]: Patients with histologically-confirmed, advanced unresectable solid tumors including CS patients who have progressed on (or not been able to tolerate) standard therapy within three months before screening visit or for whom no standard anticancer therapy exists. [Combination part]: Patients with metastatic HER2+ Breast Cancer, after failure of trastuzumab treatment. Eligible patients will have to have tumors carrying molecular alterations of PIK3CA and/or PTEN. [Single agent safety expansion arm]: Patients with histologically-confirmed, advanced unresectable solid tumors including CS patients who have progressed on (or not been able to tolerate) standard therapy within three months before screening visit or for whom no standard anticancer therapy exists. Patients will be prescreened for molecular alterations affecting PIK3CA and/or PTEN. Patients with NSCLC will also be pre-screened for EGFR mutation. Exclusion Criteria: Patients who have brain metastases, which are progressive and/or requiring medical intervention for symptom control Prior treatment with a PI3K inhibitor Acute or chronic liver disease or renal disease Acute or chronic pancreatitis Patients with unresolved diarrhea ≥ CTCAE grade 2 Impaired cardiac function or clinically significant cardiac diseases Patients with diabetes mellitus requiring insulin treatment Patients with known coagulopathies Patients with a history of photosensitivity reactions to other drugs Any of the following ophthalmological findings: Progressive eye disease that could lead to severe loss of visual acuity or visual field loss during the study period Inability to perform the ophthalmic procedures required in this protocol Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol. Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BEZ235 Alone, Dose Escalation<br> | Drug: BEZ235<br> <br> |
| Experimental: BEZ235 + trastuzumab, Dose Escalation<br> | Drug: BEZ235<br> <br> |
| Experimental: BEZ235 Alone, MTD Expansion<br> | Drug: BEZ235<br> <br> |
| Experimental: BEZ235 + Trastuzumab, MTD Expansion<br> | Drug: BEZ235<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| determine the maximum Tolerated Dose (MTD) of BEZ235 as single agent and in combination with trastuzumab (Dose escalation part) |  | at end of study | 
| assess the safety & tolerability of BEZ235 SDS as single agent and in combination with trastuzumab administered to patients at the MTD level (Safety expansion part) |  | at end of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| assess the safety and tolerability of the various formulations of BEZ235 |  | at end of study | 
| Asses the Pharmacokinetics of BEZ235 which includes AUC, Cmax, Tmax, t1/2 as endpoints |  | at end of study | 
| Preliminary anti-tumor activity (tumor response) of BEZ235 SDS as single agent and in combination with trastuzumab |  | end of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoplasms, breast neoplasms, breast diseases, solid tumors, BEZ235, breast cancer, PI3K Inhibitor, Phosphatidylinositol 3, kinase, advanced