Safety and Efficacy of BKM120 and Lapatinib in HER2+/PI3K-activated, Trastuzumab-resistant Advanced Breast Cancer (PIKHER2)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01589861
Recruitment Status : Suspended (Data analysis)
First Posted : May 2, 2012
Last Update Posted : March 28, 2017
Information provided by (Responsible Party):
Institut Paoli-Calmettes

Brief Summary:

This study is based upon the following points:

  1. Resistance to trastuzumab, either primary or secondary, is a clinically relevant issue.
  2. PI3K/AKT activation, due to loss of expression/function of PTEN and/or activating mutations of PIK3CA, is a mechanism of resistance with clinical relevance in breast cancer. Such activation can be detected by:

    • IHC evaluation of PTEN protein expression
    • genotyping of PIK3CA exon 9 and 20
    • IHC evaluation of phospho-AKT expression
  3. BKM120 is an effective PI3K inhibitor. BKM120 and anti-HER2 therapy may have a synergistic antitumor activity in preclinical model of HER2+ breast cancer.
  4. Lapatinib is an effective anti-HER2 therapy in trastuzumab-resistant disease.
  5. For the evaluation of novel targeted therapies, selecting a patient population enriched for activation of the target to be modulated should allow to maximize the differences in clinical outcome that are expected in the experimental arm, and thus to minimize the patient number to include.
  6. We propose to test in a phase I/II study the combination of lapatinib and BKM120 in trastuzumab-resistant HER2+ MBC patients, enriched for activation of PI3K/AKT as detected by loss of expression of PTEN (IHC), and/or mutation of PIK3CA and/or overexpression of phospho-AKT (IHC). Only for phase II patients, mutational status will be an inclusion criteria. For phase I patients molecular status will be a retrospective exploratory analysis.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: BKM120 + lapatinib Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 106 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib/II Open-label Study Evaluating Safety and Efficacy of Oral BKM120 in Combination With Lapatinib in HER2+/PI3K-activated, Trastuzumab-resistant Locally Advanced, Recurrent and Metastatic Breast Cancer. PIKHER2/IPC 2011-001
Study Start Date : December 2011
Estimated Primary Completion Date : January 2018
Estimated Study Completion Date : January 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: BKM120+Lapatinib

BKM120 40, 60 or 80 mg/day per os for 28 days cycle

+ Lapatinib 750, 1000 or 1250 mg/day per os for 28 days cycle

Drug: BKM120 + lapatinib
BKM120 40, 60 or 80 mg/day per os for 28 days cycle associated to lapatinib 750, 1000 or 1250 mg/day per os for 28 days cycle until progression or toxicity
Other Name: BKM120 and lapatinib

Primary Outcome Measures :
  1. Phase Ib: maximum-tolerated dose (MTD) [ Time Frame: Day 28 ]
    To determine the maximum-tolerated dose (MTD) of BKM120 when administered orally in combination with daily lapatinib to adult patients trastuzumab-resistant HER2+ locally advanced, recurrent and metastatic breast cancer.

  2. Phase II: objective response rate (ORR) [ Time Frame: until progression assessed up to 1 year ]
    To determine the efficacy of daily BKM120 in combination with daily lapatinib as measured by objective response rate (ORR), defined by complete response (CR) or partial response (PR) of target and non target lesions according to RECIST V1.1., in patients with activation of PI3K/AKT pathway detected according to one at least of the following criteria, measured on primary or metastatic tissue: PTEN negative by IHC and/or somatic mutations (exons 9 and 20) of PIK3CA and/or Overexpression of phospho-AKT by IHC.

Secondary Outcome Measures :
  1. safety [ Time Frame: until progression or end of treatment assessed up to 1 year ]
    Number of patients with adverse events (according to CTCAE V4)

  2. clinical benefit (CB) [ Time Frame: until progression assessed up to 1 year ]
    - To evaluate clinical benefit (CB defined as complete response (CR) + partial response (PR) + Stable disease (SD) > 6 months)

  3. progression-free survival (PFS) [ Time Frame: until progression assessed up to 1 year ]
    - To assess progression-free survival (PFS)

  4. pharmacokinetics [ Time Frame: D1, D8, D15, D22, D28 post dose ]
    - To determine pharmacokinetics profile (CMax, AUC) of oral BKM120 in combination with orally lapatinib and to monitor exposure to lapatinib

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

Inclusion Criteria:

  1. Female or male ≥ 18 years
  2. WHO performance status ≤ 1
  3. Locally advanced, recurrent or metastatic, histologically confirmed HER2 positive (IHC 3+ or FISH positive) breast cancer after failure of trastuzumab treatment.

    while on trastuzumab or within 4 weeks since the last infusion of trastuzumab for metastatic disease within 12 months of the last infusion for patients who received trastuzumab as adjuvant or neoadjuvant treatment

  4. For the phase II part, progression on trastuzumab must have occurred within 16 weeks before entering this trial.
  5. should not have received more than 3 lines of anti-HER2 therapy.
  6. For the phase II part, activation of PI3K/AKT pathway
  7. capable of understanding the protocol and has signed the informed consent
  8. laboratory values within normal range
  9. Measurable disease
  10. Patients may have received treatment for brain metastases, but must be neurologically stable
  11. Baseline LVEF>50% (MUGA or ECHO)
  12. Affiliation to social security

Exclusion Criteria:

  1. Previous treatment with lapatinib, neratinib or a PI3K inhibitor
  2. untreated brain metastases.
  3. acute or chronic liver, renal disease or pancreatitis
  4. any peripheral neuropathy ≥ CTCAE grade 2
  5. any of the following mood disorders, or meets the cut-off score of ≥ 10 in the PHQ-9 or a cut-off of ≥ 15 in the GAD-7 mood scale, respectively, or selects a positive response of '1, 2, or 3' to question number 9 regarding potential for suicidal thoughts ideation in the PHQ-9 (independent of the total score of the PHQ-9)

    • Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others)
    • ≥ CTCAE grade 3 anxiety
  6. diarrhea ≥ CTCAE grade 2
  7. active cardiac disease
  8. history of cardiac dysfunction
  9. poorly controlled diabetes mellitus (HbA1c > 8 %)
  10. Other severe and/or uncontrolled concomitant medical conditions
  11. Impairment of gastrointestinal function that may significantly alter the absorption of BKM120
  12. been treated with any hematopoietic colony-stimulating growth factors ≤ 2 weeks prior to starting study drug.
  13. currently receiving treatment with medication with a known risk prolong the QT interval or inducing Torsades de Pointes
  14. currently being treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A
  15. receiving chronic treatment with steroids or another immunosuppressive agent.
  16. have received chemotherapy or targeted anticancer therapy ≤ 4 weeks (6 weeks for nitrosourea, antibodies [other than trastuzumab] or mitomycin-C) prior to starting study drug or who have not recovered from side effects of such therapy
  17. have received small molecule therapeutics (excluding monoclonal antibodies) ≤ 5 effective half lives prior to starting study drug or who have not recovered from side effects of such therapy
  18. have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
  19. have undergone major surgery ≤ 28 days prior to starting study drug or who have not recovered from side effects of such therapy
  20. Known diagnosis of HIV infection
  21. History of another malignancy within 3 years
  22. Patient is unable or unwilling to abide by the study protocol
  23. pregnant or breast feeding women

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01589861

Institut Paoli-Calmettes
Marseille, France, 13008
Sponsors and Collaborators
Institut Paoli-Calmettes
Principal Investigator: Anthony GONCALVES, MD PhD Institut Paoli-Calmettes

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Institut Paoli-Calmettes Identifier: NCT01589861     History of Changes
Other Study ID Numbers: PIKHER2/IPC 2011-001
First Posted: May 2, 2012    Key Record Dates
Last Update Posted: March 28, 2017
Last Verified: March 2017

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action