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

• Status: Completed
• Trial end date: 2012-06-01
• Target enrollment: 0
• Participant gender: Female

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Novartis Pharmaceuticals
• Treatments: Capecitabine; Dactolisib; Lapatinib; Trastuzumab

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