- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01816594
NeoPHOEBE: Neoadjuvant Trastuzumab + BKM120 in Combination With Weekly Paclitaxel in HER2-positive Primary Breast Cancer (NeoPHOEBE)
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
Study Overview
Status
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Victoria
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Parkville, Victoria, Australia, 3050
- Novartis Investigative Site
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Parkville, Victoria, Australia, 3002
- Novartis Investigative Site
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Salzburg, Austria, 5020
- Novartis Investigative Site
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Lubeck, Germany, 23538
- Novartis Investigative Site
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Offenbach, Germany, 63069
- Novartis Investigative Site
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Madrid, Spain, 28222
- Novartis Investigative Site
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Andalucia
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Sevilla, Andalucia, Spain, 41013
- Novartis Investigative Site
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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 Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: TRIPLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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EXPERIMENTAL: BKM120 + Trastuzumab + paclitaxel
BKM120 (oral, pan-class I PI3K inhibitor) in combination with trastuzumab and paclitaxel.
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Neo-adjuvant BKM120 (oral pan-class I PI3K inhibitor, continuous daily dosing).
BKM120 was administered orally 100 mg/day.
Other Names:
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.
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PLACEBO_COMPARATOR: BKM120 PBO + Trastuzumab + paclitaxel
BKM120 placebo in combination with trastuzumab and paclitaxel
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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.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Pathological Complete Response (pCR) Rate at the Time of Surgery - All Participants
Time Frame: After 6 weeks
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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.
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After 6 weeks
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Pathological Complete Response (pCR) Rate at the Time of Surgery - PIK3CA Wild Type (WT)
Time Frame: After 6 weeks
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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.
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After 6 weeks
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Pathological Complete Response (pCR) Rate at the Time of Surgery - PIK3CA Mutant (MT)
Time Frame: After 6 weeks
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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.
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After 6 weeks
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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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
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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.
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After week 6
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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
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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.
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After week 6
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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
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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.
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After week 6
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Rate of Breast Conserving Surgery (Most Radical Surgery)
Time Frame: 18 weeks
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Rate of patients with breast conserving surgery.
Participants who did not have breast surgery were also considered as having breast conservation surgery (BCS)
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18 weeks
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Percentage of Participants With No Invasive and Non-invasive (DCIS) Residuals in Breast and Lymph Nodes Per GBG Definition
Time Frame: After Week 6
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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.
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After Week 6
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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
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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.
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After Week 6
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Overall Objective Response Rate (ORR) Prior to Surgery for All Participants
Time Frame: prior to surgery
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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.
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prior to surgery
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Percentage of Participants With pCR Rates by Hormone Receptor Status - Positive Estrogen Receptor (ER+)
Time Frame: After Week 6
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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.
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After Week 6
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Percentage of Participants With pCR Rates by Hormone Receptor Status Negative Estrogen Receptor (ER-)
Time Frame: After Week 6
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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.
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After Week 6
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Percentage of Participants With Objective Response Rates by Hormone Receptor Status - Positive Estrogen Receptor (ER+)
Time Frame: After Week 6
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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.
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After Week 6
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Percentage of Participants With Objective Response Rates by Hormone Receptor Status - Negative Estrogen Receptor (ER-)
Time Frame: After Week 6
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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.
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After Week 6
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Percentage of Participants With Remaining Ductal Carcinoma in Situ (DCIS) (ypTis)
Time Frame: 18 weeks
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This included participants at definitive surgery irrespective of lymph node status
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18 weeks
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Percentage of Participants With Node-negative Disease at Definitive Surgery (ypN0)
Time Frame: 18 weeks
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Node-negative disease at definitive surgery (ypN0) were considered as binary variables of 'response' versus 'non response'.
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18 weeks
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Collaborators and Investigators
Publications and helpful links
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- CBKM120F2203
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
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
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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