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
- breastcancer10027656
- Registration Number
- NL-OMON35443
- Lead Sponsor
- ovartis
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Withdrawn
- Sex
- Not specified
- Target Recruitment
- 5
Inclusion criteria applicable to Phase Ib and II:
* 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 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 applicable for Phase Ib and II:
* 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 treatment
* 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 criterion 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
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Incidence of DLTs in the first cycle</p><br>
- Secondary Outcome Measures
Name Time Method <p>Secundary<br /><br>Progression Free Survival (PFS)<br /><br>Overall Response Rate (ORR)<br /><br>Clinical Benefit Rate (CBR; CR or PR or SD> 24 weeks)<br /><br>Frequency and severity of adverse events; other safety data as considered<br /><br>appropriate<br /><br>BEZ235 plasma and trastuzumab serum concentrations<br /><br><br /><br>Exploratory<br /><br>Levels of markers of glucose metabolism<br /><br>Levels of pAKT, p4EBP1 and pS6 in peripheral blood mononuclear cell (PBMC)<br /><br>Mutation, loss and/or amplification of K-ras, PIK3CA, PTEN etc. in tissue</p><br>