Phase 1b/2 Study of BKM120 Plus Trastuzumab in Patients With HER2-positive Breast Cancer

A Phase Ib/II, Open Label, Multi-center Study Evaluating the Safety and Efficacy of BKM120 in Combination With Trastuzumab in Patients With Relapsing HER2 Overexpressing Breast Cancer Who Have Previously Failed Trastuzumab

This study will assess the safety and efficacy of BKM120 in combination with trastuzumab in patients with relapsing HER2 overexpressing breast cancer who have previously failed trastuzumab.

The study will further assess the safety and preliminary efficacy of BKM120 in combination with trastuzumab and capecitabine in patients with relapsing HER2 overexpressing breast cancer and brain metastases (BM) who have previously failed trastuzumab.

Study Overview

• Status: Terminated
• Conditions: Metastatic Breast Cancer; HER2+ Breast Cancer
• Intervention / Treatment: Drug: BKM120; Drug: Trastuzumab; Drug: Capecitabine

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Liege, Belgium, 4000
    • Novartis Investigative Site
  • Wilrijk, Belgium, 2610
    • Novartis Investigative Site
• France
  • Lyon Cedex, France, 69373
    • Novartis Investigative Site
  • Saint-Herblain Cédex, France, 44805
    • Novartis Investigative Site
• Italy
  • CA
    • Cagliari, CA, Italy, 09134
      • Novartis Investigative Site
  • MC
    • Macerata, MC, Italy, 62100
      • Novartis Investigative Site
  • MO
    • Modena, MO, Italy, 41100
      • Novartis Investigative Site
  • TR
    • Terni, TR, Italy, 05100
      • Novartis Investigative Site
• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
    • Hospitalet de LLobregat, Catalunya, Spain, 08907
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46010
      • Novartis Investigative Site
• United Kingdom
  • Nottingham, United Kingdom, NG5 1PB
    • Novartis Investigative Site
  • Oxford, United Kingdom, OX3 7LJ
    • Novartis Investigative Site
  • East Sussex
    • Brighton, East Sussex, United Kingdom, BN2 5BE
      • Novartis Investigative Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-0006
      • University of Alabama at Birmingham/ Kirklin Clinic Univ AL - PI
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Highlands Oncology Group Dept of Highlands Oncology Grp
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute Dept.of KarmanosCancerInst (6)
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University School Of Medicine-Siteman Cancer Ctr WA Siteman
  • New York
    • New York, New York, United States, 10003
      • Beth Israel Medical Center BIMC
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute Sarah Cannon Cancer Center SC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• World Health Organization (WHO) Performance Status of ≤ 2
• Patients with HER2+ breast cancer by local laboratory testing (immunohistochemistry [IHC] 3+ staining or fluorescence in situ hybridization [FISH] confirmation for IHC 2+ and 1+)

• Documented tumor resistance to trastuzumab:

  • Recurrence while on trastuzumab or within 12 months since the last infusion for patients who received trastuzumab as adjuvant treatment
  • Progression while on or within 4 weeks since the last infusion of trastuzumab for patients who received trastuzumab for metastatic disease.

• Documented evidence of progressive disease per Response Evaluation Criteria in Solid Tumors (RECIST) on trastuzumab-based therapy defined as:

  • Phase Ib: at any time before study entry
  • Phase II: within 16 weeks before date of first dosing

• Received at least 1 but no more than 4 prior anit-HER2 based regimens including at least 1 regimen containing trastuzumab (adjuvant or neo-adjuvant trastuzumab will be considered as one prior regimen). HER2 directed therapies are defined as comprising trastuzumab, lapatinib, and trastuzumab-DM1 (T-DM1) only.

  • Phase II only: trastuzumab, T-DM1 or lapatinib must be part of the most recent line of therapy

• Previous lines of cytotoxic chemotherapy:

  • Phase Ib: no more than 4 lines of cytotoxic chemotherapy
  • Phase II: no more than 3 lines of cytotoxic chemotherapy

Measurable disease:

• Phase Ib: patient has at least one measurable lesion or non-measurable disease as defined per RECIST
• Phase II: patient has at least one measureable lesion as defined per RECIST

|| Specific Inclusion Criteria for patients in BM cohorts:

• Patient has evidence of progressing brain metastases and/or new metastatic brain lesion(s) without leptomeningeal disease.
• Patient has received prior WBRT and/or SRS at at >28 and >/= 14 days, respectively, prior to starting study drug and the patient must have recovered from the side effects of the therapy
• WHO performance status of </=1
• PT INR </= 1.5
• Any number of prior HER2-directed and cytotoxic regimens, and the most recent line may be any type of anti-neoplastic therapy

|| Exclusion Criteria:

• Patients with untreated brain metastases
• Patients with acute or chronic liver, renal disease or pancreatitis
• Patients with any peripheral neuropathy ≥ Common Terminology Criteria for Adverse Events (CTCAE) grade 2
• Patients with a history of mood disorders or ≥ CTCAE grade 3 anxiety
• Patient with clinical manifest diabetes mellitus or steroid-induced diabetes mellitus

|| Specific Exclusion Criteria for patients in BM cohorts

• Prior treatment with capecitabine
• Patient has known dihydropyrimidine dehydrogenase (DPD) deficiency
• Patient is currently receiving treatment with EIAED
• Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HER2+ metastatic breast cancer; Patients with HER2-overexpressing metastatic breast cancer, with or without PIK3 signaling pathway alteration, who have previously failed trastuzumab	Drug: BKM120; Buparlisib (BKM120) is the investigational drug. Burparlisib was supplied as 10 mg and 50 mg hard gelatin capsules. Buparlisib was dosed on a flat scale of mg/day and not adjusted to body weight or body surface area. Buparlisib capsules were packaged in high density polyethylene bottles with a plastic child resistant closure.; Drug: Trastuzumab; Trastuzumab was used in this study according to the local regulations in each participating country. A loading dose (4 mg/kg) of trastuzumab was administered (if required as assessed by the principal Investigator based on the timing of the last trastuzumab dose prior to enrollment) on Day -7 over 90 minutes, followed by weekly intravenous infusion of 2 mg/kg maintenance doses from Day 1 of Cycle 1 (over 30 minutes if the previous infusion was well tolerated).
Experimental: HER2+ metastatic breast cancer with BM; Patients with HER2-overexpressing metastatic breast cancer and brain metastases, with or without PIK3 signaling pathway alteration, who have previously failed trastuzumab	Drug: BKM120; Buparlisib (BKM120) is the investigational drug. Burparlisib was supplied as 10 mg and 50 mg hard gelatin capsules. Buparlisib was dosed on a flat scale of mg/day and not adjusted to body weight or body surface area. Buparlisib capsules were packaged in high density polyethylene bottles with a plastic child resistant closure.; Drug: Trastuzumab; Trastuzumab was used in this study according to the local regulations in each participating country. A loading dose (4 mg/kg) of trastuzumab was administered (if required as assessed by the principal Investigator based on the timing of the last trastuzumab dose prior to enrollment) on Day -7 over 90 minutes, followed by weekly intravenous infusion of 2 mg/kg maintenance doses from Day 1 of Cycle 1 (over 30 minutes if the previous infusion was well tolerated).; Drug: Capecitabine; 1000 mg/m2 twice a day from day 1 to Day 14 of a 21-day cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Limiting Toxicity (DLT) - Phase l Only	Determination of the maximum tolerated dose (MTD) in the dose escalation part of the study was based upon the estimation of the probability of DLT in Cycle 1 in patients of the dose-determining set.	cycle 1 - 28 days
Overall Response Rate (ORR) - Phase ll	Objective response rate (ORR) was defined as the rate of patients with best overall response (BOR) equal to complete response (CR) or partial response (PR) according to RECIST 1.0 from the Investigators review. Per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 assessed of the disease status by imaging (i.e. CT/MRI): Complete Response (CR) = Disappearance of all tumor lesions; Partial Response (PR)= >=30% shrinkage of lesions; Overall Response (OR) = patients with CR and PR.	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Control Rate (DCR) Based on Investigator Assessment- Phase l & ll	Disease control rate (DCR) = patients with complete response (CR), partial response (PR) or stable disease (SD) as per RECIST criteria. Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 assessed the disease status by imaging (i.e. CT/MRI): CR = disappearance of all tumor lesions; PR = >=30% shrinkage of lesions; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD); PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline.	18 months
Clinical Benefit Rate (CBR) - Phase l & ll	CBR = patients with CR, PR or SD ≥ 24 weeks according to RECIST by the investigator. Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 assessed the disease status by imaging (i.e. CT/MRI): CR = Disappearance of all tumor lesions; PR= >=30% shrinkage of lesions; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD; PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline.	18 months
Progression Free Survival (PFS) - Based on Investigator Review Using Kaplan Meier - Phase l & ll		18 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: May 7, 2010
• First Submitted That Met QC Criteria: May 27, 2010
• First Posted (Estimate): May 28, 2010

Study Record Updates

• Last Update Posted (Estimate): August 17, 2016
• Last Update Submitted That Met QC Criteria: August 9, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: capecitabine; HER2; open-label; trastuzumab; brain metastases; Herceptin; metastatic breast cancer; maximum tolerated dose; BKM120; PIK3; Phase I/Phase ll
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Trastuzumab; Capecitabine
• Other Study ID Numbers: CBKM120X2107; 2009-015417-46 (EudraCT Number)