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Completed

NCT Number: NCT01816594

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

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).

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Key information

Conditions

HER2-positive Newly Diagnosed, Primary Breast Cancer Breast Diseases Breast Neoplasms Neoplasms Neoplasms by Site Skin Diseases Skin and Connective Tissue Diseases

Age range

18 year and older

Sex eligibility

Female

Study type

Interventional

Phase

Phase 2

Primary location

Novartis Investigative Site, Parkville, Victoria, Australia

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

BKM120

Drug

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

Other names: Buparsilib

Trastuzumab

Drug

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

Drug

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.

BKM120 Placebo

Drug

Neoadjuvant BKM120 placebo Administered orally 100 mg/day.

Primary outcomes

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

    Time frame: 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.

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

    Time frame: 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.

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

    Time frame: 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 outcomes

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

    Time frame: 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.

  2. 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

    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.

  3. 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

    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.

  4. Rate of Breast Conserving Surgery (Most Radical Surgery)

    Time frame: 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)

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

    Time frame: 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.

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

    Time frame: 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.

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

    Time frame: 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.

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

    Time frame: 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.

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

    Time frame: 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.

  10. Percentage of Participants With Objective Response Rates by Hormone Receptor Status - Positive Estrogen Receptor (ER+)

    Time frame: 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.

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

    Time frame: 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.

  12. Percentage of Participants With Remaining Ductal Carcinoma in Situ (DCIS) (ypTis)

    Time frame: 18 weeks

    This included participants at definitive surgery irrespective of lymph node status

  13. Percentage of Participants With Node-negative Disease at Definitive Surgery (ypN0)

    Time frame: 18 weeks

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

Sponsors and collaborators

Lead sponsor

Novartis Pharmaceuticals

Industry

Collaborators

  • Breast International Group
  • GBG Forschungs GmbH
  • SOLTI Breast Cancer Research Group

Registry information

Official study 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

Acronym: NeoPHOEBE

Important dates

Study start
2013
Primary completion
2015
Study completion
2015
First posted
Mar 22, 2013
Registry last updated
Nov 14, 2019

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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