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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01471847
First received: October 10, 2011
Last updated: November 30, 2012
Last verified: November 2012
  Purpose

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.


Condition Intervention Phase
Locally Advance Breast Cancer (LABC)
Metastatic Breast Cancer (MBC)
Drug: BEZ235 + Trastuzumab Phase l/Phase ll)
Drug: Lapatinib + Capecitabine (Phase II)
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Incidence of Dose Limiting Toxicities (DLT) in the first cycle - phase lb [ Time Frame: First treatment cycle (28 days) ] [ Designated as safety issue: Yes ]

    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)


  • Progression Free Survival (PFS) based on local radiological assessment - phase ll [ Time Frame: Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months) ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Progression Free Survival (PFS) - Phase lb [ Time Frame: Randomization, Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months) ] [ Designated as safety issue: No ]
    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.

  • Overall Response Rate (ORR)- Phase lb [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Proportion of patients with a best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1

  • Clinical Benefit Rate (CBR) (Phase lb) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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

  • Frequency and severity of Adverse Events - Phase lb [ Time Frame: until 30 days after treatment discontinuation ] [ Designated as safety issue: Yes ]
    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.

  • BEZ235 plasma and trastuzumab serum concentrations - phase lb [ Time Frame: Pre-dose (cycle 1 through 9) and 4-6 hours post-dose (cycle 1 and 2) ] [ Designated as safety issue: No ]
    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.

  • Overall Response Rate (ORR) - phase ll [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Proportion of patients with a best overall response of CR or PR according to RECIST 1.1

  • Clinical Benefit Rate (CBR) - phase ll [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    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

  • Time to overall response (TTR) - phase ll [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Time from randomization until first documented response.

  • Duration of overall response (DR) - phase ll [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Time between the first documented response and first documented progression or death due to underlying cancer.

  • Median overall survival (OS) (phase ll) [ Time Frame: Randomization, death (expected average:24 months) ] [ Designated as safety issue: No ]
    Time from randomization to the date of death due to any cause.

  • PFS based on central radiological assessment (phase ll) [ Time Frame: Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months) ] [ Designated as safety issue: No ]
    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.

  • Frequency and severity of adverse events (phase ll) [ Time Frame: Until 30 days after treatment discontinuation ] [ Designated as safety issue: Yes ]
    Incidence of adverse events (based on CTCAE Version 4) summarized by system organ class and/or preferred term, severity and relation to study treatment.

  • Efficacy in subgroups of patients with activated/non-activated PI3K pathway (phase ll) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Efficacy (e.g. PFS, ORR, CBR) according to PI3K activation and treatment group.


Enrollment: 5
Study Start Date: February 2012
Study Completion Date: June 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.

Drug: 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).

Active Comparator: 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 .
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


  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01471847

Locations
Spain
Novartis Investigative Site
Madrid, Spain, 28050
United Kingdom
Novartis Investigative Site
Leicester, United Kingdom, LE1 5WW
Novartis Investigative Site
Manchester, United Kingdom, M20 2BX
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01471847     History of Changes
Other Study ID Numbers: CBEZ235B2203
Study First Received: October 10, 2011
Last Updated: November 30, 2012
Health Authority: United States: Food and Drug Administration
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica (Phase II part only)
Australia: Department of Health and Ageing Therapeutic Goods Administration (Phase II part only)
Belgium: Federal Agency for Medicinal Products and Health Products (Phase II part only)
Brazil: National Health Surveillance Agency (Phase II part only)
Canada: Health Canada (Phase II part only)
China: State Food and Drug Administration (TBD) [Phase II part only]
Czech Republic: State Institute for Drug Control (Phase II part only)
France: Afssaps - French Health Products Safety Agency (Phase II part only)
Germany: Federal Institute for Drugs and Medical Devices (Phase II part only)
Hong Kong: Department of Health
Hungary: National Institute of Pharmacy (Phase II part only)
Italy: National Institute of Health (Phase II part only)
Japan: Pharmaceuticals and Medical Devices Agency (Phase II part only)
Korea: Korea Food and Drug Administration (KFDA) [Phase II part only]
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO) Russia: Ministry of Health and Social Development of the Russian Federation
Singapore: Health Sciences Authority (Phase II part only)
Spain: Spanish Agency of Medicines
Taiwan: Department of Health (Phase II part only)
Thailand: Food and Drug Administration (Phase II part only)
Turkey: Ministry of Health (Phase II part only)
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Novartis:
Locally advanced
metastatic
breast cancer
HER2 positive
PI3K
mTOR
trastuzumab
targeted therapy
LABC
MBC

Additional relevant MeSH terms:
Trastuzumab
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Capecitabine
Lapatinib
Fluorouracil
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 21, 2014