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

NCT ID: NCT01471847

Last Updated: 2020-12-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-02-29
• Study Completion Date: 2012-06-30

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.

Conditions

Locally Advance Breast Cancer (LABC); Metastatic Breast Cancer (MBC)

Keywords

Locally advanced; metastatic; breast cancer; HER2 positive; PI3K; mTOR; trastuzumab; targeted therapy; LABC; MBC

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

BEZ235 + Trastuzumab (Phase l /Phase ll)

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.

Group Type: EXPERIMENTAL

BEZ235 + Trastuzumab Phase l/Phase ll)

Intervention Type: DRUG

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).

Lapatinib + Capecitabine (Phase II)

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 .

Group Type: ACTIVE_COMPARATOR

Lapatinib + Capecitabine (Phase II)

Intervention Type: DRUG

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

Interventions

BEZ235 + Trastuzumab Phase l/Phase ll)

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).

Intervention Type: DRUG

Lapatinib + Capecitabine (Phase II)

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

Intervention Type: DRUG

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)

• 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

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Leicester, , United Kingdom

Novartis Investigative Site

Manchester, , United Kingdom

Countries

Brazil; France; Netherlands; United States; Spain; United Kingdom

Related Links

https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=8603

Results for CBEZ235B2203 can be found on the Novartis Clinical Trials Website

Other Identifiers

CBEZ235B2203

Identifier Type: -

Identifier Source: org_study_id