Neoplasms

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Breast Neoplasms

Breast Diseases

Skin Diseases

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Paclitaxel

Albumin-Bound Paclitaxel

Trastuzumab

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Antineoplastic Agents, Immunological

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

BKM120 placebo in combination with trastuzumab and paclitaxel

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

BKM120

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 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.

Neoadjuvant BKM120 placebo Administered orally 100 mg/day.

BKM120 Placebo

Novartis Pharmaceuticals

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.

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

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

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

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.

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 patients with breast conserving surgery. Participants who did not have breast surgery were also considered as having breast conservation surgery (BCS)

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.

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.

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.

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.

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.

This included participants at definitive surgery irrespective of lymph node status

Node-negative disease at definitive surgery (ypN0) were considered as binary variables of 'response' versus 'non response'.

Breast International Group

German Breast Group

SOLTI Breast Cancer Research Group

All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 18 months.

Trastuzumab + BKM120 + Paclitaxel

Trastuzumab + BKM120 PBO + Paclitaxel

Total

Age, Continuous

Sex: Female, Male

Caucasian/white

Asian/Oriental

Other

Race/Ethnicity, Customized

All randomized patients (N=50) were included in the intention-to-treat set and in the safety analysis set, since all patients started study treatment. Intent-to-treat set (ITT)/full analysis set (FAS) (pooled): The full analysis set comprised all patients to whom study treatment had been assigned by randomization.

Study Director

Intent-to-treat set (ITT)/full analysis set (FAS) (pooled): The full analysis set comprised all patients to whom study treatment had been assigned by randomization. Patients who were randomized but did not start study treatment were not replaced and were considered as treatment failures similarly to other patients with no pCR assessment.

Pathological Complete Response (pCR) Rate at the Time of Surgery - All Participants

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

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

Overall Objective Clinical Response Rate at the End of the Biologic Window (After Week 6) Compared to Baseline (Key Secondary) - All Participants

Overall Objective Clinical Response Rate at the End of the Biologic Window (After Week 6) Compared to Baseline (Key Secondary) - PIK3A Wild Type Participants

Overall Objective Clinical Response Rate at the End of the Biologic Window (After Week 6) Compared to Baseline (Key Secondary) - PIK3A Mutant Participants

Rate of Breast Conserving Surgery (Most Radical Surgery)

Percentage of Participants With No Invasive and Non-invasive (DCIS) Residuals in Breast and Lymph Nodes Per GBG Definition

Percentage of Participants With No Invasive and Non-invasive (DCIS) Residuals in Breast and Lymph Nodes Per MD Anderson Definition

Overall Objective Response Rate (ORR) Prior to Surgery for All Participants

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

Trastuzumab + BKM120 + Paclitaxel ( ER+)

BKM120 placebo in combination with trastuzumab and paclitaxel in patients with positive estrogen receptor participants

Trastuzumab + BKM120 PBO + Paclitaxel (ER+)

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

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

Trastuzumab + BKM120 + Paclitaxel (ER-)

BKM120 placebo in combination with trastuzumab and paclitaxel in negative estrogen receptor participants

Trastuzumab + BKM120 PBO + Paclitaxel (ER-)

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

Trastuzumab + BKM120 + Paclitaxel (ER+)

BKM120 placebo in combination with trastuzumab and paclitaxel in positive estrogen receptor participants

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
NeoPHOEBE: Neoadjuvant Trastuzumab + BKM120 in Combination With Weekly Paclitaxel in HER2-positive Primary Breast Cancer	NCT01816594	HER2-positive N...	BKM120 Trastuzumab Paclitaxel BKM120 Placebo	18 Years -	Novartis
NeoPHOEBE: Neoadjuvant Trastuzumab + BKM120 in Combination With Weekly Paclitaxel in HER2-positive Primary Breast Cancer	NCT01816594	HER2-positive N...	BKM120 Trastuzumab Paclitaxel BKM120 Placebo	18 Years -	Novartis

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