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

Metastatic Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01132664
• Other study ID #: CBKM120X2107
• Secondary ID: 2009-015417-46
• Status: Terminated
• Phase: Phase 1/Phase 2
• First received: May 7, 2010
• Last updated: September 29, 2015
• Start date: May 2010
• Est. completion date: August 2014

Study information

• Verified date: September 2015
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationBelgium: Federal Agency for Medicinal Products and Health ProductsFrance: Agence nationale de sécurité du médicament et des produits de santé (ANSM)Italy: The Italian Medicines AgencySpain: Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 72
• Est. completion date: August 2014
• Est. primary completion date: August 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Neoplasms
• HER2+ Breast Cancer
• Metastatic Breast Cancer

Intervention

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.
• 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).
• Capecitabine
1000 mg/m2 twice a day from day 1 to Day 14 of a 21-day cycle.

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Liege
Belgium	Novartis Investigative Site	Wilrijk
France	Novartis Investigative Site	Lyon Cedex
France	Novartis Investigative Site	Saint-Herblain Cédex
Italy	Novartis Investigative Site	Cagliari	CA
Italy	Novartis Investigative Site	Macerata	MC
Italy	Novartis Investigative Site	Modena	MO
Italy	Novartis Investigative Site	Terni	TR
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
United Kingdom	Novartis Investigative Site	Brighton	East Sussex
United Kingdom	Novartis Investigative Site	Nottingham
United Kingdom	Novartis Investigative Site	Oxford
United States	University of Alabama at Birmingham/ Kirklin Clinic Univ AL - PI	Birmingham	Alabama
United States	Karmanos Cancer Institute Dept.of KarmanosCancerInst (6)	Detroit	Michigan
United States	Highlands Oncology Group Dept of Highlands Oncology Grp	Fayetteville	Arkansas
United States	Sarah Cannon Research Institute Sarah Cannon Cancer Center SC	Nashville	Tennessee
United States	Beth Israel Medical Center BIMC	New York	New York
United States	Washington University School Of Medicine-Siteman Cancer Ctr WA Siteman	St. Louis	Missouri
United States	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Belgium,  France,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Primary	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	No
Secondary	Disease Control Rate (DCR) Based on Investigator Assessment- Phase l & ll	Disease control rate (DCR) is the rate of patients with BOR equal to CR, PR, or stable disease (SD) as per RECIST criteria.; 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	No
Secondary	Clinical Benefit Rate (CBR) - Phase l & ll	CBR is patients with CR, PR or stable disease (SD) = 24 weeks according to RECIST by the investigator.; 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	No
Secondary	Progression Free Survival (PFS) - Based on Investigator Review Using Kaplan Meier - Phase l & ll. PFS Was Analyzed Only in Patients With Known PIK3 Status, Thus Only 26/50 Patients Were Analyzed.		18 months	No