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

Phase 2

Completed

Conditions: HER2-positive Newly Diagnosed, Primary Breast Cancer

Interventions: Drug: BKM120
Drug: Paclitaxel
Drug: Trastuzumab
Drug: BKM120 Placebo

Registration Number: NCT01816594

Lead Sponsor: Novartis Pharmaceuticals

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 50

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
BKM120 + Trastuzumab + paclitaxel	BKM120	BKM120 (oral, pan-class I PI3K inhibitor) in combination with trastuzumab and paclitaxel.
BKM120 PBO + Trastuzumab + paclitaxel	Paclitaxel	BKM120 placebo in combination with trastuzumab and paclitaxel
BKM120 PBO + Trastuzumab + paclitaxel	BKM120 Placebo	BKM120 placebo in combination with trastuzumab and paclitaxel
BKM120 + Trastuzumab + paclitaxel	Trastuzumab	BKM120 (oral, pan-class I PI3K inhibitor) in combination with trastuzumab and paclitaxel.
BKM120 + Trastuzumab + paclitaxel	Paclitaxel	BKM120 (oral, pan-class I PI3K inhibitor) in combination with trastuzumab and paclitaxel.
BKM120 PBO + Trastuzumab + paclitaxel	Trastuzumab	BKM120 placebo in combination with trastuzumab and paclitaxel

Primary Outcome Measures

Name	Time	Method
Pathological Complete Response (pCR) Rate at the Time of Surgery - PIK3CA Wild Type (WT)	After 6 weeks	Rate of pCR (as defined by NSABP criteria - absence of invasive disease in the breast \[ypT0\]) is the number of of participants with pathological complete response (pCR) at the time of surgery. Participants were to be considered in pCR if there was no invasive cancer in the breast or only non-invasive in situ cancer in the breast specimen. NSABP guidelines do not take into account the histological nodal status to define the pCR.
Pathological Complete Response (pCR) Rate at the Time of Surgery - All Participants	After 6 weeks	Rate of pCR (as defined by NSABP criteria - absence of invasive disease in the breast \[ypT0\]) is the number of of participants with pathological complete response (pCR) at the time of surgery. Participants were to be considered in pCR if there was no invasive cancer in the breast or only non-invasive in situ cancer in the breast specimen. NSABP guidelines do not take into account the histological nodal status to define the pCR.
Pathological Complete Response (pCR) Rate at the Time of Surgery - PIK3CA Mutant (MT)	After 6 weeks	Rate of pCR (as defined by NSABP criteria - absence of invasive disease in the breast \[ypT0\]) is the number of of participants with pathological complete response (pCR) at the time of surgery. Participants were to be considered in pCR if there was no invasive cancer in the breast or only non-invasive in situ cancer in the breast specimen. NSABP guidelines do not take into account the histological nodal status to define the pCR.

Secondary Outcome Measures

Name	Time	Method
Overall Objective Clinical Response Rate at the End of the Biologic Window (After Week 6) Compared to Baseline (Key Secondary) - All Participants	After week 6	Percentage of Overall objective clinical response rate = Complete Response + Partial Response rate, measured by US bidimentional ulltrasound (or MRI) and assessed by world health organization (WHO) criteria.
Overall Objective Clinical Response Rate at the End of the Biologic Window (After Week 6) Compared to Baseline (Key Secondary) - PIK3A Wild Type Participants	After week 6	Percentage of Overall objective clinical response rate = Complete Response + Partial Response rate, measured by US bidimentional ulltrasound (or MRI) and assessed by world health organization (WHO) criteria.
Overall Objective Clinical Response Rate at the End of the Biologic Window (After Week 6) Compared to Baseline (Key Secondary) - PIK3A Mutant Participants	After week 6	Percentage of Overall objective clinical response rate = Complete Response + Partial Response rate, measured by US bidimentional ulltrasound (or MRI) and assessed by world health organization (WHO) criteria.
Rate of Breast Conserving Surgery (Most Radical Surgery)	18 weeks	Rate of patients with breast conserving surgery. Participants who did not have breast surgery were also considered as having breast conservation surgery (BCS)
Percentage of Participants With No Invasive and Non-invasive (DCIS) Residuals in Breast and Lymph Nodes Per GBG Definition	After Week 6	Rate of pCR defined as no invasive and non-invasive (DCIS) residuals in breast and lymph nodes (ypT0, ypN0 \[GBG definition\]). If patient had a sentinel node biopsy before treatment which was negative and no axilla dissection was performed after treatment completion, such patient was considered to be pN0 for both secondary pCR definitions. Surgical breast and axillary node resection specimens were evaluated for pathologic tumor response according to NSABP guidelines.
Percentage of Participants With No Invasive and Non-invasive (DCIS) Residuals in Breast and Lymph Nodes Per MD Anderson Definition	After Week 6	Rate of pCR defined as no invasive residuals in breast and lymph nodes (ypT0/Tis, ypN0 \[MD Anderson definition\]). If a patient had a sentinel node biopsy before treatment which was negative and no axilla dissection was performed after treatment completion, such patient was considered to be pN0 for both secondary pCR definitions.
Overall Objective Response Rate (ORR) Prior to Surgery for All Participants	prior to surgery	Number of Overall objective response rate = Complete Response + Partial Response rate, measured by US bidimentional ulltrasound (or MRI) and assessed by world health organization (WHO) criteria. CR: Complete disappearance of all tumor signs in the breast as assessed by ultrasound or MRI. The response of the axillary nodes was not to be considered. PR: Reduction in the product of the two largest perpendicular diameters of the primary tumor size by 50% or more assessed by ultrasound or MRI. In patients with multifocal or multicentric disease, the lesion with the largest diameters should be chosen for follow-up. The response of the axillary nodes was not to be considered.
Percentage of Participants With pCR Rates by Hormone Receptor Status - Positive Estrogen Receptor (ER+)	After Week 6	pCR defined as no invasive and non-invasive (DCIS) residuals in breast and lymph nodes (ypT0, ypN0 \[GBG definition\]); pCR defined as no invasive residuals in breast and lymph nodes (ypT0/Tis, ypN0 \[MD Anderson definition\]). If participant had a sentinel node biopsy before treatment which was negative and no axilla dissection was performed after treatment completion, such participant was considered to be pN0 for both secondary pCR definitions.
Percentage of Participants With pCR Rates by Hormone Receptor Status Negative Estrogen Receptor (ER-)	After Week 6	pCR defined as no invasive and non-invasive (DCIS) residuals in breast and lymph nodes (ypT0, ypN0 \[GBG definition\]); pCR defined as no invasive residuals in breast and lymph nodes (ypT0/Tis, ypN0 \[MD Anderson definition\]). If participant had a sentinel node biopsy before treatment which was negative and no axilla dissection was performed after treatment completion, such participant was considered to be pN0 for both secondary pCR definitions.
Percentage of Participants With Objective Response Rates by Hormone Receptor Status - Positive Estrogen Receptor (ER+)	After Week 6	Objective response rate = Complete Response + Partial Response rate, measured by US bidimentional ulltrasound (or MRI) and assessed by world health organization (WHO) criteria. CR: Complete disappearance of all tumor signs in the breast as assessed by ultrasound or MRI. The response of the axillary nodes was not to be considered. PR: Reduction in the product of the two largest perpendicular diameters of the primary tumor size by 50% or more assessed by ultrasound or MRI. In patients with multifocal or multicentric disease, the lesion with the largest diameters should be chosen for follow-up. The response of the axillary nodes was not to be considered.
Percentage of Participants With Objective Response Rates by Hormone Receptor Status - Negative Estrogen Receptor (ER-)	After Week 6	Objective response rate = Complete Response + Partial Response rate, measured by US bidimentional ulltrasound (or MRI) and assessed by world health organization (WHO) criteria. CR: Complete disappearance of all tumor signs in the breast as assessed by ultrasound or MRI. The response of the axillary nodes was not to be considered. PR: Reduction in the product of the two largest perpendicular diameters of the primary tumor size by 50% or more assessed by ultrasound or MRI. In patients with multifocal or multicentric disease, the lesion with the largest diameters should be chosen for follow-up. The response of the axillary nodes was not to be considered.
Percentage of Participants With Remaining Ductal Carcinoma in Situ (DCIS) (ypTis)	18 weeks	This included participants at definitive surgery irrespective of lymph node status
Percentage of Participants With Node-negative Disease at Definitive Surgery (ypN0)	18 weeks	Node-negative disease at definitive surgery (ypN0) were considered as binary variables of 'response' versus 'non response'.