Clinical trial NCT01816594: NeoPHOEBE: Neoadjuvant Trastuzumab + BKM120 in Combination With Weekly Paclitaxel in HER2-positive Primary Breast Cancer
Official title: NeoPHOEBE: Pi3k Inhibition in Her2 OverExpressing Breast cancEr: A Phase II, Randomized, Parallel Cohort, Two Stage, Double-blind, Placebo-controlled Study of Neoadjuvant Trastuzumab Versus Trastuzumab + BKM120 in Combination With Weekly Paclitaxel in HER2-positive, PIK3CA Wild-type and PIK3CA Mutant Primary Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HER2-positive Newly Diagnosed, Primary Breast Cancer
Keywords: HER2
breast cancer
neoadjuvant
PI3K inhibitor
first line chemotherapy
trastuzumab
GBG
SOLTI
BIG
Lead sponsor: Novartis
Sponsor class: INDUSTRY
Collaborators: name: Breast International Group
name: GBG Forschungs GmbH
name: SOLTI Breast Cancer Research Group
First posted: 2013-03-22
Enrollment: 50
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Pathological Complete Response (pCR) Rate at the Time of Surgery - All Participants
timeFrame: After 6 weeks
measure: Pathological Complete Response (pCR) Rate at the Time of Surgery - PIK3CA Wild Type (WT)
timeFrame: After 6 weeks
measure: Pathological Complete Response (pCR) Rate at the Time of Surgery - PIK3CA Mutant (MT)
timeFrame: After 6 weeks
Secondary outcomes:
measure: Overall Objective Clinical Response Rate at the End of the Biologic Window (After Week 6) Compared to Baseline (Key Secondary) - All Participants
timeFrame: After week 6
measure: Overall Objective Clinical Response Rate at the End of the Biologic Window (After Week 6) Compared to Baseline (Key Secondary) - PIK3A Wild Type Participants
timeFrame: After week 6
measure: Overall Objective Clinical Response Rate at the End of the Biologic Window (After Week 6) Compared to Baseline (Key Secondary) - PIK3A Mutant Participants
timeFrame: After week 6
measure: Rate of Breast Conserving Surgery (Most Radical Surgery)
timeFrame: 18 weeks
measure: Percentage of Participants With No Invasive and Non-invasive (DCIS) Residuals in Breast and Lymph Nodes Per GBG Definition
timeFrame: After Week 6
measure: Percentage of Participants With No Invasive and Non-invasive (DCIS) Residuals in Breast and Lymph Nodes Per MD Anderson Definition
timeFrame: After Week 6
measure: Overall Objective Response Rate (ORR) Prior to Surgery for All Participants
timeFrame: prior to surgery
measure: Percentage of Participants With pCR Rates by Hormone Receptor Status - Positive Estrogen Receptor (ER+)
timeFrame: After Week 6
measure: Percentage of Participants With pCR Rates by Hormone Receptor Status Negative Estrogen Receptor (ER-)
timeFrame: After Week 6
measure: Percentage of Participants With Objective Response Rates by Hormone Receptor Status - Positive Estrogen Receptor (ER+)
timeFrame: After Week 6
measure: Percentage of Participants With Objective Response Rates by Hormone Receptor Status - Negative Estrogen Receptor (ER-)
timeFrame: After Week 6
measure: Percentage of Participants With Remaining Ductal Carcinoma in Situ (DCIS) (ypTis)
timeFrame: 18 weeks
measure: Percentage of Participants With Node-negative Disease at Definitive Surgery (ypN0)
timeFrame: 18 weeks
Other outcomes:
Locations:
city: Parkville
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Parkville
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Salzburg
country: Austria
facility: Novartis Investigative Site
city: Lubeck
country: Germany
facility: Novartis Investigative Site
city: Offenbach
country: Germany
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Madrid
country: Spain
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.