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

Novartis Pharmaceuticals50 enrolled

Overview

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).

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

HER2-positive Newly Diagnosed, Primary Breast Cancer

Interventions

BKM120DRUG

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

TrastuzumabDRUG

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.

PaclitaxelDRUG

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.

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (7)

Novartis Investigative Site

Parkville, Victoria, Australia

Novartis Investigative Site

Parkville, Victoria, Australia

Novartis Investigative Site

Salzburg, Austria

Novartis Investigative Site

Lübeck, Germany

Outcomes

Primary Outcomes

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.

Time frame: After 6 weeks

Pathological Complete Response (pCR) Rate at the Time of Surgery - PIK3CA Wild Type (WT)

Time frame: After 6 weeks

Pathological Complete Response (pCR) Rate at the Time of Surgery - PIK3CA Mutant (MT)

Time frame: After 6 weeks

Secondary Outcomes

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.

Data from ClinicalTrials.gov

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Neoadjuvant BKM120 placebo Administered orally 100 mg/day.

Novartis Investigative Site

Offenbach, Germany

Novartis Investigative Site

Seville, Andalusia, Spain

Novartis Investigative Site

Madrid, Spain

Time frame: 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

Time frame: 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

Time frame: 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)

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: After Week 6

Percentage of Participants With pCR Rates by Hormone Receptor Status Negative Estrogen Receptor (ER-)

Time frame: 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.

Time frame: After Week 6

Percentage of Participants With Objective Response Rates by Hormone Receptor Status - Negative Estrogen Receptor (ER-)

Time frame: 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

Time frame: 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'.

Time frame: 18 weeks