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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Metastatic Breast Cancer, HER2+ Breast Cancer

Intervention / Treatment
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* Drug: BKM120
* Drug: Trastuzumab
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HER2+ metastatic breast cancer<br>Patients with HER2-overexpressing metastatic breast cancer, with or without PIK3 signaling pathway alteration, who have previously failed trastuzumab | Drug: BKM120<br>* 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.<br>Drug: Trastuzumab<br>* 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).<br>|
| Experimental: HER2+ metastatic breast cancer with BM<br>Patients with HER2-overexpressing metastatic breast cancer and brain metastases, with or without PIK3 signaling pathway alteration, who have previously failed trastuzumab | Drug: BKM120<br>* 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.<br>Drug: Trastuzumab<br>* 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).<br>Drug: Capecitabine<br>* 1000 mg/m2 twice a day from day 1 to Day 14 of a 21-day cycle.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2, BKM120, PIK3, metastatic breast cancer, brain metastases, Herceptin, trastuzumab, capecitabine, open-label, maximum tolerated dose, Phase I/Phase ll