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

NCT01471847 | Completed Phase 1

• 1 other identifier: CBEZ235B2203
• Study Type: interventional
• Target: 5
• Locations: 2 countries
• Sites: 3

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

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (13)

• Progression Free Survival (PFS) - Phase lb

  Randomization, Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months)

• Overall Response Rate (ORR)- Phase lb

  12 months

• Clinical Benefit Rate (CBR) (Phase lb)

  12 months

• Frequency and severity of Adverse Events - Phase lb

  until 30 days after treatment discontinuation

• BEZ235 plasma and trastuzumab serum concentrations - phase lb

  Pre-dose (cycle 1 through 9) and 4-6 hours post-dose (cycle 1 and 2)

Study Arms (2)

BEZ235 + Trastuzumab (Phase l /Phase ll)

EXPERIMENTAL

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)

Lapatinib + Capecitabine (Phase II)

ACTIVE COMPARATOR

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)

Interventions

BEZ235 + Trastuzumab Phase l/Phase ll) 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).

BEZ235 + Trastuzumab (Phase l /Phase ll)

Lapatinib + Capecitabine (Phase II) 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

Lapatinib + Capecitabine (Phase II)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (3)

Novartis Investigative Site

Madrid, 28050, Spain

Location

Novartis Investigative Site

Leicester, LE1 5WW, United Kingdom

Location

Novartis Investigative Site

Manchester, M20 2BX, United Kingdom

Location

Related Links

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

MeSH Terms

Conditions

Breast Neoplasms; Neoplasm Metastasis

Interventions

dactolisib; Lapatinib; Capecitabine; Clinical Trials, Phase II as Topic

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Clinical Trials as Topic; Clinical Studies as Topic; Epidemiologic Study Characteristics; Epidemiologic Methods; Investigative Techniques; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 10, 2011
• First Posted: November 16, 2011
• Study Start: February 1, 2012
• Primary Completion: June 1, 2012
• Study Completion: June 1, 2012
• Last Updated: December 9, 2020

Record last verified: 2018-02

Locations

ES (1); GB (2)