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

Phase 1

Terminated

Conditions: Metastatic Breast Cancer
HER2+ Breast Cancer

Interventions: Drug: BKM120
Drug: Trastuzumab
Drug: Capecitabine

Registration Number: NCT01132664

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 72

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
HER2+ metastatic breast cancer	BKM120	Patients with HER2-overexpressing metastatic breast cancer, with or without PIK3 signaling pathway alteration, who have previously failed trastuzumab
HER2+ metastatic breast cancer with BM	BKM120	Patients with HER2-overexpressing metastatic breast cancer and brain metastases, with or without PIK3 signaling pathway alteration, who have previously failed trastuzumab
HER2+ metastatic breast cancer	Trastuzumab	Patients with HER2-overexpressing metastatic breast cancer, with or without PIK3 signaling pathway alteration, who have previously failed trastuzumab
HER2+ metastatic breast cancer with BM	Trastuzumab	Patients with HER2-overexpressing metastatic breast cancer and brain metastases, with or without PIK3 signaling pathway alteration, who have previously failed trastuzumab
HER2+ metastatic breast cancer with BM	Capecitabine	Patients with HER2-overexpressing metastatic breast cancer and brain metastases, with or without PIK3 signaling pathway alteration, who have previously failed trastuzumab

Primary Outcome Measures

Name	Time	Method
Dose Limiting Toxicity (DLT) - Phase l Only	cycle 1 - 28 days	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.
Overall Response Rate (ORR) - Phase ll	18 months	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.

Secondary Outcome Measures

Name	Time	Method
Disease Control Rate (DCR) Based on Investigator Assessment- Phase l & ll	18 months	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.
Clinical Benefit Rate (CBR) - Phase l & ll	18 months	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.
Progression Free Survival (PFS) - Based on Investigator Review Using Kaplan Meier - Phase l & ll	18 months

Trial Locations

Locations (8): H. Lee Moffitt Cancer Center & Research Institute
🇺🇸
Tampa, Florida, United States
Sarah Cannon Research Institute Sarah Cannon Cancer Center SC
🇺🇸
Nashville, Tennessee, United States
Novartis Investigative Site
🇬🇧
Oxford, United Kingdom
Beth Israel Medical Center BIMC
🇺🇸
New York, New York, United States
Karmanos Cancer Institute Dept.of KarmanosCancerInst (6)
🇺🇸
Detroit, Michigan, United States
Washington University School Of Medicine-Siteman Cancer Ctr WA Siteman
🇺🇸
St. Louis, Missouri, United States
University of Alabama at Birmingham/ Kirklin Clinic Univ AL - PI
🇺🇸
Birmingham, Alabama, United States
Highlands Oncology Group Dept of Highlands Oncology Grp
🇺🇸
Fayetteville, Arkansas, United States