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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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HER2-positive Newly Diagnosed, Primary Breast Cancer

Intervention / Treatment
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* Drug: BKM120
* Drug: Trastuzumab
* Drug: Paclitaxel
* Drug: BKM120 Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BKM120 + Trastuzumab + paclitaxel<br>BKM120 (oral, pan-class I PI3K inhibitor) in combination with trastuzumab and paclitaxel. | Drug: BKM120<br>* Neo-adjuvant BKM120 (oral pan-class I PI3K inhibitor, continuous daily dosing). BKM120 was administered orally 100 mg/day.<br>* Other names: Buparsilib;Drug: Trastuzumab<br>* 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.<br>Drug: Paclitaxel<br>* 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.<br>|
| Placebo Comparator: BKM120 PBO + Trastuzumab + paclitaxel<br>BKM120 placebo in combination with trastuzumab and paclitaxel | Drug: Trastuzumab<br>* 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.<br>Drug: Paclitaxel<br>* 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.<br>Drug: BKM120 Placebo<br>* Neoadjuvant BKM120 placebo Administered orally 100 mg/day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response (pCR) Rate at the Time of Surgery - All Participants | 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. | After 6 weeks | 
| Pathological Complete Response (pCR) Rate at the Time of Surgery - PIK3CA Wild Type (WT) | 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. | After 6 weeks | 
| Pathological Complete Response (pCR) Rate at the Time of Surgery - PIK3CA Mutant (MT) | 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. | After 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Objective Clinical Response Rate at the End of the Biologic Window (After Week 6) Compared to Baseline (Key Secondary) - All Participants | 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. | After week 6 | 
| Overall Objective Clinical Response Rate at the End of the Biologic Window (After Week 6) Compared to Baseline (Key Secondary) - PIK3A Wild Type Participants | 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. | After week 6 | 
| Overall Objective Clinical Response Rate at the End of the Biologic Window (After Week 6) Compared to Baseline (Key Secondary) - PIK3A Mutant Participants | 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. | After week 6 | 
| Rate of Breast Conserving Surgery (Most Radical Surgery) | Rate of patients with breast conserving surgery. Participants who did not have breast surgery were also considered as having breast conservation surgery (BCS) | 18 weeks | 
| Percentage of Participants With No Invasive and Non-invasive (DCIS) Residuals in Breast and Lymph Nodes Per GBG Definition | 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. | After Week 6 | 
| Percentage of Participants With No Invasive and Non-invasive (DCIS) Residuals in Breast and Lymph Nodes Per MD Anderson Definition | 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. | After Week 6 | 
| Overall Objective Response Rate (ORR) Prior to Surgery for All Participants | 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. | prior to surgery | 
| Percentage of Participants With pCR Rates by Hormone Receptor Status - Positive Estrogen Receptor (ER+) | 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. | After Week 6 | 
| Percentage of Participants With pCR Rates by Hormone Receptor Status Negative Estrogen Receptor (ER-) | 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. | After Week 6 | 
| Percentage of Participants With Objective Response Rates by Hormone Receptor Status - Positive Estrogen Receptor (ER+) | 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. | After Week 6 | 
| Percentage of Participants With Objective Response Rates by Hormone Receptor Status - Negative Estrogen Receptor (ER-) | 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. | After Week 6 | 
| Percentage of Participants With Remaining Ductal Carcinoma in Situ (DCIS) (ypTis) | This included participants at definitive surgery irrespective of lymph node status | 18 weeks | 
| Percentage of Participants With Node-negative Disease at Definitive Surgery (ypN0) | Node-negative disease at definitive surgery (ypN0) were considered as binary variables of 'response' versus 'non response'. | 18 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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trastuzumab, HER2, breast cancer, neoadjuvant, PI3K inhibitor, first line chemotherapy, GBG, SOLTI, BIG