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

NCT01589861 | Terminated Phase 1 DMC

• 1 other identifier: PIKHER2/IPC 2011-001
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

This study is based upon the following points:

• IHC evaluation of PTEN protein expression
• genotyping of PIK3CA exon 9 and 20
• IHC evaluation of phospho-AKT expression
• BKM120 is an effective PI3K inhibitor. BKM120 and anti-HER2 therapy may have a synergistic antitumor activity in preclinical model of HER2+ breast cancer.
• Lapatinib is an effective anti-HER2 therapy in trastuzumab-resistant disease.
• 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.
• 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.

Conditions

Breast Cancer

Outcome Measures

Primary Outcomes (2)

• Phase Ib: maximum-tolerated dose (MTD)

  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.

  Day 28

• Phase II: objective response rate (ORR)

  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.

  until progression assessed up to 1 year

Secondary Outcomes (4)

• safety

  until progression or end of treatment assessed up to 1 year

• clinical benefit (CB)

  until progression assessed up to 1 year

• progression-free survival (PFS)

  until progression assessed up to 1 year

• pharmacokinetics

  D1, D8, D15, D22, D28 post dose

Study Arms (1)

BKM120+Lapatinib

EXPERIMENTAL

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

Interventions

BKM120 + lapatinib DRUG

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

Also known as: BKM120 and lapatinib

BKM120+Lapatinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female or male ≥ 18 years
• WHO performance status ≤ 1
• 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
• For the phase II part, progression on trastuzumab must have occurred within 16 weeks before entering this trial.
• should not have received more than 3 lines of anti-HER2 therapy.
• For the phase II part, activation of PI3K/AKT pathway
• capable of understanding the protocol and has signed the informed consent
• laboratory values within normal range
• Measurable disease
• Patients may have received treatment for brain metastases, but must be neurologically stable
• Baseline LVEF\>50% (MUGA or ECHO)
• Affiliation to social security

You may not qualify if:

• Previous treatment with lapatinib, neratinib or a PI3K inhibitor
• untreated brain metastases.
• acute or chronic liver, renal disease or pancreatitis
• any peripheral neuropathy ≥ CTCAE grade 2
• 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
• diarrhea ≥ CTCAE grade 2
• active cardiac disease
• history of cardiac dysfunction
• poorly controlled diabetes mellitus (HbA1c \> 8 %)
• Other severe and/or uncontrolled concomitant medical conditions
• Impairment of gastrointestinal function that may significantly alter the absorption of BKM120
• been treated with any hematopoietic colony-stimulating growth factors ≤ 2 weeks prior to starting study drug.
• currently receiving treatment with medication with a known risk prolong the QT interval or inducing Torsades de Pointes

Sponsors & Collaborators

• Institut Paoli-Calmettes: lead

Study Sites (1)

Institut Paoli-Calmettes

Marseille, 13008, France

Location

Related Publications (1)

• Guerin M, Rezai K, Isambert N, Campone M, Autret A, Pakradouni J, Provansal M, Camerlo J, Sabatier R, Bertucci F, Charafe-Jauffret E, Hervieu A, Extra JM, Viens P, Lokiec F, Boher JM, Goncalves A. PIKHER2: A phase IB study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer. Eur J Cancer. 2017 Nov;86:28-36. doi: 10.1016/j.ejca.2017.08.025. Epub 2017 Sep 23.

  PMID: 28950146 RESULT

Related Links

• official web site of the sponsor

MeSH Terms

Conditions

Breast Neoplasms

Interventions

NVP-BKM120; Lapatinib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Anthony GONCALVES, MD PhD

  Institut Paoli-Calmettes

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 28, 2012
• First Posted: May 2, 2012
• Study Start: December 1, 2011
• Primary Completion: October 10, 2017
• Study Completion: October 10, 2017
• Last Updated: April 21, 2026

Record last verified: 2017-03

Locations

FR (1)