NeoPHOEBE: Neoadjuvant Trastuzumab + BKM120 in Combination With Weekly Paclitaxel in HER2-positive Primary Breast Cancer

NCT ID: NCT01816594

Last Updated: 2019-11-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-09-03
• Study Completion Date: 2015-02-18

Brief Summary

This randomized, parallel cohort, two stage, double-blind, placebo-controlled study evaluated the oral PI3K inhibitor BKM120 in combination with trastuzumab and paclitaxel in HER2-positive, PIK3CA wild-type and PIK3CA mutant primary breast cancer prior to surgery (neo-adjuvant setting).

Detailed Description

NeoPHOEBE evaluated the efficacy (as defined by pCR) of BKM120 (an oral PI3K inhibitor) in combination with trastuzumab and paclitaxel in a randomized, placebo-controlled, neo-adjuvant study in women diagnosed with primary breast cancer >1.5 cm (by US or MRI) with centrally confirmed HER2 overexpression or amplification, who have not previously undergone treatment for invasive breast cancer.

Prior to the initiation of paclitaxel, there was a 6-week "biologic window" with trastuzumab plus BKM120 or placebo only. The study was conducted separately in two cohorts (PIK3CA mutated and PI3K3CA wild-type) using a two-stage approach. Within each cohort patients were randomized into one of the following treatment arms:

Arm 1: BKM120 plus trastuzumab for 6 weeks followed by BKM120 and trastuzumab plus weekly paclitaxel for an additional 12 weeks.

Arm 2: BKM120 placebo plus trastuzumab for 6 weeks followed by BKM120 placebo plus trastuzumab plus weekly paclitaxel for an additional 12 weeks.

After completion of study treatment, patients were to have undergone definitive surgery.

Conditions

HER2-positive Newly Diagnosed, Primary Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

BKM120 + Trastuzumab + paclitaxel

BKM120 (oral, pan-class I PI3K inhibitor) in combination with trastuzumab and paclitaxel.

Group Type: EXPERIMENTAL

BKM120

Intervention Type: DRUG

Neo-adjuvant BKM120 (oral pan-class I PI3K inhibitor, continuous daily dosing). BKM120 was administered orally 100 mg/day.

Trastuzumab

Intervention Type: DRUG

Trastuzumab is a humanized monoclonal antibody directed against the extracellular juxtamembrane domain of the HER2 receptor. Administered 4mg/kg i.v. load followed by 2mg/kg i.v. weekly.

Paclitaxel

Intervention Type: DRUG

Paclitaxel is a cytotoxic agent with proven antitumor activity in a variety of solid tumors. The antitumor activity of paclitaxel is based on tubulin-binding and stabilization of non-functional microtubule bundles, thereby blocking normal mitotic spindle development and subsequent cell division. Administered weekly 80mg/m2 i.v.

BKM120 PBO + Trastuzumab + paclitaxel

BKM120 placebo in combination with trastuzumab and paclitaxel

Group Type: PLACEBO_COMPARATOR

Trastuzumab

Intervention Type: DRUG

Trastuzumab is a humanized monoclonal antibody directed against the extracellular juxtamembrane domain of the HER2 receptor. Administered 4mg/kg i.v. load followed by 2mg/kg i.v. weekly.

Paclitaxel

Intervention Type: DRUG

Paclitaxel is a cytotoxic agent with proven antitumor activity in a variety of solid tumors. The antitumor activity of paclitaxel is based on tubulin-binding and stabilization of non-functional microtubule bundles, thereby blocking normal mitotic spindle development and subsequent cell division. Administered weekly 80mg/m2 i.v.

BKM120 Placebo

Intervention Type: DRUG

Neoadjuvant BKM120 placebo Administered orally 100 mg/day.

Interventions

BKM120

Neo-adjuvant BKM120 (oral pan-class I PI3K inhibitor, continuous daily dosing). BKM120 was administered orally 100 mg/day.

Intervention Type: DRUG

Trastuzumab

Trastuzumab is a humanized monoclonal antibody directed against the extracellular juxtamembrane domain of the HER2 receptor. Administered 4mg/kg i.v. load followed by 2mg/kg i.v. weekly.

Intervention Type: DRUG

Paclitaxel

Paclitaxel is a cytotoxic agent with proven antitumor activity in a variety of solid tumors. The antitumor activity of paclitaxel is based on tubulin-binding and stabilization of non-functional microtubule bundles, thereby blocking normal mitotic spindle development and subsequent cell division. Administered weekly 80mg/m2 i.v.

Intervention Type: DRUG

BKM120 Placebo

Neoadjuvant BKM120 placebo Administered orally 100 mg/day.

Intervention Type: DRUG

Other Intervention Names

Buparsilib

Eligibility Criteria

Inclusion Criteria

• Patient had provided a signed study ICF prior to any screening procedure
• Patient was a female ≥ 18 years of age
• Patient has an ECOG performance status of 0-1
• Patient has a unilateral (multifocal or multicentric disease allowed), histologically confirmed, newly diagnosed early breast cancer >2cm by clinical examination and/or >1.5 cm confirmed by ultrasound or by MRI
• Patient has tumor tissue available for central review of ER, HER2 and PI3K status with centrally confirmed HER2-positive disease and known PI3KCA mutation status
• Patient has adequate bone marrow, renal and liver function
• Patient is able to swallow and retain oral medication

Exclusion Criteria

• Patient has received prior systemic treatment for currently diagnosed disease
• Patient has a known contraindications, hypersensitivity or intolerance to trastuzumab, paclitaxel or products containing cremophor
• Patient has bilateral breast cancer or metastatic disease or inflammatory breast cancer
• LVEF below 50% as determined by MUGA scan or ECHO
• Patient has active cardiac disease or a history of cardiac abnormalities as defined in the protocol
• Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120
• Patient is currently receiving warfarin or other coumarin derived anti-coagulants
• Patient is currently receiving chronic treatment with corticosteroids or another immunosuppressive agents (standard premedication for paclitaxel and local applications allowed)
• Patient is currently receiving treatment with drugs known to be strong inhibitors or inducers of CYP3A
• Patient has certain scores on an anxiety and depression mood questionnaires
• Pregnant or nursing (lactating) women or patients not willing to apply apply highly effective contraception as defined in the protocol

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Breast International Group

OTHER

Sponsor Role: collaborator

GBG Forschungs GmbH

OTHER

Sponsor Role: collaborator

SOLTI Breast Cancer Research Group

OTHER

Sponsor Role: collaborator

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Parkville, Victoria, Australia

Novartis Investigative Site

Parkville, Victoria, Australia

Novartis Investigative Site

Salzburg, , Austria

Novartis Investigative Site

Lübeck, , Germany

Novartis Investigative Site

Offenbach, , Germany

Novartis Investigative Site

Seville, Andalusia, Spain

Novartis Investigative Site

Madrid, , Spain

Countries

Australia; Austria; Germany; Spain

References

Loibl S, de la Pena L, Nekljudova V, Zardavas D, Michiels S, Denkert C, Rezai M, Bermejo B, Untch M, Lee SC, Turri S, Urban P, Kummel S, Steger G, Gombos A, Lux M, Piccart MJ, Von Minckwitz G, Baselga J, Loi S. Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+ primary breast cancer: A randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE). Eur J Cancer. 2017 Nov;85:133-145. doi: 10.1016/j.ejca.2017.08.020. Epub 2017 Sep 17.

Reference Type: DERIVED

PMID: 28923573 (View on PubMed)

Other Identifiers

CBKM120F2203

Identifier Type: -

Identifier Source: org_study_id