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

• ClinicalTrials.gov Identifier: NCT01132664
• Recruitment Status: Terminated
• First Posted: May 28, 2010
• Results First Posted: October 30, 2015
• Last Update Posted: August 17, 2016
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Metastatic Breast Cancer; HER2+ Breast Cancer	Drug: BKM120; Drug: Trastuzumab; Drug: Capecitabine	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 72 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: May 2010
• Actual Primary Completion Date: August 2014
• Actual Study Completion Date: August 2014

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Dose Limiting Toxicity (DLT) - Phase l Only [ Time Frame: 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.
2. Overall Response Rate (ORR) - Phase ll [ Time Frame: 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 :

1. Disease Control Rate (DCR) Based on Investigator Assessment- Phase l & ll [ Time Frame: 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.

2. Clinical Benefit Rate (CBR) - Phase l & ll [ Time Frame: 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.

3. Progression Free Survival (PFS) - Based on Investigator Review Using Kaplan Meier - Phase l & ll [ Time Frame: 18 months ]

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham/ Kirklin Clinic Univ AL - PI

Birmingham, Alabama, United States, 35294-0006

United States, Arkansas

Highlands Oncology Group Dept of Highlands Oncology Grp

Fayetteville, Arkansas, United States, 72703

United States, Florida

H. Lee Moffitt Cancer Center & Research Institute

Tampa, Florida, United States, 33612

United States, Michigan

Karmanos Cancer Institute Dept.of KarmanosCancerInst (6)

Detroit, Michigan, United States, 48201

United States, Missouri

Washington University School Of Medicine-Siteman Cancer Ctr WA Siteman

St. Louis, Missouri, United States, 63110

United States, New York

Beth Israel Medical Center BIMC

New York, New York, United States, 10003

United States, Tennessee

Sarah Cannon Research Institute Sarah Cannon Cancer Center SC

Nashville, Tennessee, United States, 37203

Belgium

Novartis Investigative Site

Liege, Belgium, 4000

Novartis Investigative Site

Wilrijk, Belgium, 2610

France

Novartis Investigative Site

Lyon Cedex, France, 69373

Novartis Investigative Site

Saint-Herblain Cédex, France, 44805

Italy

Novartis Investigative Site

Cagliari, CA, Italy, 09134

Novartis Investigative Site

Macerata, MC, Italy, 62100

Novartis Investigative Site

Modena, MO, Italy, 41100

Novartis Investigative Site

Terni, TR, Italy, 05100

Spain

Novartis Investigative Site

Barcelona, Catalunya, Spain, 08035

Novartis Investigative Site

Hospitalet de LLobregat, Catalunya, Spain, 08907

Novartis Investigative Site

Valencia, Comunidad Valenciana, Spain, 46010

United Kingdom

Novartis Investigative Site

Brighton, East Sussex, United Kingdom, BN2 5BE

Novartis Investigative Site

Nottingham, United Kingdom, NG5 1PB

Novartis Investigative Site

Oxford, United Kingdom, OX3 7LJ

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01132664
• Other Study ID Numbers: CBKM120X2107; 2009-015417-46 ( EudraCT Number )
• First Posted: May 28, 2010
• Results First Posted: October 30, 2015
• Last Update Posted: August 17, 2016
• Last Verified: August 2016

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

HER2; metastatic breast cancer; brain metastases; BKM120; PIK3; Herceptin; trastuzumab; capecitabine; open-label; maximum tolerated dose; Phase I/Phase ll

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Capecitabine; Trastuzumab; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological