A Phase Ib/II Study of BEZ235 and Trastuzumab in Patients With HER2-positive Breast Cancer Who Failed Prior to Trastuzumab

Study Overview
=================
Brief Summary
-----------------
This is a prospective, multi-center, open-label, phase Ib/ II study (two parts) with patients that have locally advanced or metastatic HER2+ breast cancer. The first part (phase Ib) will investigate the MTD/ RP2D of the combination therapy of BEZ235 BID and weekly trastuzumab using a Bayesian model. Once MTD/ RP2D is established the second part (phase II) will start. Phase II will evaluate the efficacy and the safety of weekly trastuzumab plus BEZ235 BID compared to capecitabine and lapatinib.

Official Title
-----------------
A Phase Ib/Randomized Phase II Study of BEZ235 and Trastuzumab Versus Lapatinib and Capecitabine in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer Who Failed Prior to Trastuzumab

Conditions
-----------------
Locally Advance Breast Cancer (LABC), Metastatic Breast Cancer (MBC)

Intervention / Treatment
-----------------
* Drug: BEZ235 + Trastuzumab Phase l/Phase ll)
* Drug: Lapatinib + Capecitabine (Phase II)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient is a female ≥ 18 years of age Patient has a histologically and/or cytologically confirmed diagnosis of HER2-positive invasive breast cancer with inoperable locally advanced or metastatic disease Patients with controlled or asymptomatic CNS metastases are eligible Patient has adequate bone marrow and organ functions, and has recovery from all clinically significant toxicities related to prior anti-neoplastic therapies Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelets ≥ 100 x 109/L Hemoglobin (Hgb) ≥ 9.0 g/dL INR ≤ 2 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (or ≤ 5.0 x ULN if liver metastases are present) Total serum bilirubin ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, a total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN) Serum creatinine ≤ 1.5 x ULN Fasting plasma glucose (FPG) ≤ 140mg/dL [7.8 mmol/L] HbA1c ≤ 8% Patient has received prior trastuzumab (alone or in combination) but NO more than 3 prior cytotoxic chemotherapy lines Prior endocrine and radiotherapy allowed Patient has ECOG performance status of 0-2 (Phase Ib) or 0-1 (Phase II) Additional inclusion criteria for phase II: Available tumor tissue (archival or fresh) for biomarker analysis; known PI3K activation status At least one measurable lesion as per RECIST 1.1 Patient has received prior treatment with a taxane Patient has trastuzumab-resistance disease defined as: Recurrence while on trastuzumab (or T-DM1) or within 12 months since the last infusion in the adjuvant setting Progression while on or within 4 weeks since the last infusion of trastuzumab (or T-DM1) in the locally advanced or metastatic setting Exclusion Criteria: Previous treatment with PI3K and/or mTOR inhibitors Symptomatic/uncontrolled Central Nervous System (CNS) metastases Concurrent malignancy or malignancy in the last 3 years prior to enrollment Wide field radiotherapy ≤ 28 days or limited field radiation for palliation ≤ 14 days prior to starting study drug Active cardiac disease (e.g. LVEF less than institutional lower limit of normal, QTcF > 480 msec, unstable angina pectoris, ventricular, supraventricular or nodal arrhythmias) Inadequately controlled hypertension Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BEZ235 Treatment at start of study treatment with drugs with a known risk to induce Torsades de Pointes, moderate and strong inhibitors or inducers of isoenzyme CYP3A4, warfarin and coumadin analogues, LHRH agonists Intolerance or contraindications to trastuzumab treatment Pregnant or nursing (lactating) woman Additional exclusion criteria for phase II: Prior treatment with capecitabine and lapatinib Intolerance or contraindications to capecitabine and lapatinib Previous treatment with HER-2 targeted agents other than trastuzumab or T-DM1 Peripheral neuropathy ≥ Grade 2

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BEZ235 + Trastuzumab (Phase l /Phase ll)<br>Phase l: Eligible patients will receive increasing doses of oral BEZ235 administered on a continuous twice daily (BID) schedule + weekly trastuzumab at a fixed dose of 2 mg/kg. Treatment will be organized into cycles of 28 days. Phase ll: Eligible patients will receive weekly trastuzumab (2 mg/kg) + oral BEZ235 on a continuous twice daily (BID schedule) at the MTD or RP2D. Treatment will be organized into cycles of 21 days. | Drug: BEZ235 + Trastuzumab Phase l/Phase ll)<br>* Phase l: Patients will receive increasing doses of oral BEZ235 (BID) together with standard weekly trastuzumab at a fixed dose. BEZ235 doses will be escalated in cohorts of 3 to 6 patients guided by an adaptive Bayesian logistic regression model with overdose control until MTD/RP2D has been established. Phase ll: If randomized to the trastuzumab + BEZ235 arm, patients will receive standard weekly trastuzumab in combination with oral BEZ235 (BID) at the MTD or RP2D and will continue on study treatment until PD, unacceptable toxicity or until other pre-defined discontinuation criteria are met. They will have regular safety assessments and will be evaluated for response to treatment according to RECIST every 2 cycles for the first 36 weeks then every 12 weeks until disease progression (or start of new anti-neoplastic therapy).<br>|
| Active Comparator: Lapatinib + Capecitabine (Phase II)<br>Eligible patients will receive lapatinib (1250 mg given orally once daily on days 1 through 21) in combination with capecitabine (2000 mg/m2/day administered orally in 2 doses approximately 12 hours apart on days 1 through 14). Treatment will be organized into cycles of 21 days . | Drug: Lapatinib + Capecitabine (Phase II)<br>* If randomized to the lapatinib + capecitabine treatment arm, patients will receive standard lapatinib plus capecitabine until PD, unacceptable toxicity or until other pre-defined discontinuation criteria are met. Patients will have regular safety assessments and will be evaluated for response to treatment according to RECIST every 2 cycles for the first 36 weeks then every 12 weeks until disease progression (or start of new anti-neoplastic therapy). After progression, survival f-up will continue. All patients participating in the Phase II part of the study will be required to have available archival or fresh tumor tissue for biomarker analysis prior to treatment start<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicities (DLT) in the first cycle - phase lb | DLT is defined as treatment-related toxicity (classified according Common Toxicity Criteria for Adverse Events (CTCAE) Version 4) occurring during the first 28 treatment days and meeting specific protocol-predefined criteria. The information will be integrated in a Bayesian logistic regression model with overdose control to estimate the maximum tolerated dose (MTD) | First treatment cycle (28 days) | 
| Progression Free Survival (PFS) based on local radiological assessment - phase ll | PFS is defined as the time from randomization until objective tumor progression or death from any cause. Radiological assessments will be performed every 6 weeks for the first 36 weeks after treatment start, then every 12 weeks. | Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) - Phase lb | Time from treatment start until objective tumor progression or death from any cause. Radiological assessments will be performed every 8 weeks for the first 32 weeks after treatment start, then every 12 weeks. | Randomization, Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months) | 
| Overall Response Rate (ORR)- Phase lb | Proportion of patients with a best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 | 12 months | 
| Clinical Benefit Rate (CBR) (Phase lb) | Proportion of patients with a best overall response of CR, PR or stable disease (SD) with a duration of 24 weeks or longer according to RECIST 1.1 | 12 months | 
| Frequency and severity of Adverse Events - Phase lb | Incidence of adverse events (based on common terminology criteria for adverse events (CTCAE) Version 4) summarized by system organ class and/or preferred term, severity and relation to study treatment. | until 30 days after treatment discontinuation | 
| BEZ235 plasma and trastuzumab serum concentrations - phase lb | BEZ235 plasma and trastuzumab serum concentrations obtained during the two sampling windows (pre-dose and post-dose). No pharmacokinetic parameters will be calculated and no formal statistical analysis will be performed. | Pre-dose (cycle 1 through 9) and 4-6 hours post-dose (cycle 1 and 2) | 
| Overall Response Rate (ORR) - phase ll | Proportion of patients with a best overall response of CR or PR according to RECIST 1.1 | 12 months | 
| Clinical Benefit Rate (CBR) - phase ll | Proportion of patients with a best overall response of CR, PR or SD with a duration of 24 weeks or longer according to RECIST 1.1 | 12 months | 
| Time to overall response (TTR) - phase ll | Time from randomization until first documented response. | 12 months | 
| Duration of overall response (DR) - phase ll | Time between the first documented response and first documented progression or death due to underlying cancer. | 12 months | 
| Median overall survival (OS) (phase ll) | Time from randomization to the date of death due to any cause. | Randomization, death (expected average:24 months) | 
| PFS based on central radiological assessment (phase ll) | Time from randomization until objective tumor progression or death from any cause. Radiological assessments will be performed every 6 weeks for the first 36 weeks after treatment start, then every 12 weeks, centrally collected and read. | Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months) | 
| Frequency and severity of adverse events (phase ll) | Incidence of adverse events (based on CTCAE Version 4) summarized by system organ class and/or preferred term, severity and relation to study treatment. | Until 30 days after treatment discontinuation | 
| Efficacy in subgroups of patients with activated/non-activated PI3K pathway (phase ll) | Efficacy (e.g. PFS, ORR, CBR) according to PI3K activation and treatment group. | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
breast cancer, Locally advanced, metastatic, HER2 positive, PI3K, mTOR, trastuzumab, targeted therapy, LABC, MBC