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

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ClinicalTrials.gov Identifier: NCT01132664
Recruitment Status : Terminated (Due to the rare patient population and challenges to enroll patients.)
First Posted : May 28, 2010
Results First Posted : October 30, 2015
Last Update Posted : August 17, 2016
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE May 7, 2010
First Posted Date  ICMJE May 28, 2010
Results First Submitted Date August 4, 2015
Results First Posted Date October 30, 2015
Last Update Posted Date August 17, 2016
Study Start Date  ICMJE May 2010
Actual Primary Completion Date August 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 29, 2015)
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 27, 2010)
Adverse event frequencies by patient and DLT frequencies by cohort [ Time Frame: 18 months ]
Change History Complete list of historical versions of study NCT01132664 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 7, 2016)
  • 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.
  • 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.
  • Progression Free Survival (PFS) - Based on Investigator Review Using Kaplan Meier - Phase l & ll [ Time Frame: 18 months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: May 27, 2010)
Number of patients with an objective response after at least two cycles of therapy [ Time Frame: 18 months ]
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 1b/2 Study of BKM120 Plus Trastuzumab in Patients With HER2-positive Breast Cancer
Official Title  ICMJE 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
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 Provided
Study Type  ICMJE Interventional
Study Phase Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Metastatic Breast Cancer
  • HER2+ Breast Cancer
Intervention  ICMJE
  • 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.
Study Arms
  • Experimental: HER2+ metastatic breast cancer
    Patients with HER2-overexpressing metastatic breast cancer, with or without PIK3 signaling pathway alteration, who have previously failed trastuzumab
    Interventions:
    • Drug: BKM120
    • Drug: Trastuzumab
  • 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
    Interventions:
    • Drug: BKM120
    • Drug: Trastuzumab
    • Drug: Capecitabine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: January 19, 2015)
72
Original Estimated Enrollment  ICMJE
 (submitted: May 27, 2010)
70
Actual Study Completion Date August 2014
Actual Primary Completion Date August 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   France,   Italy,   Spain,   United Kingdom,   United States
Removed Location Countries Canada
 
Administrative Information
NCT Number  ICMJE NCT01132664
Other Study ID Numbers  ICMJE CBKM120X2107
2009-015417-46 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date August 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP