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

• ClinicalTrials.gov Identifier: NCT01816594
• Recruitment Status: Completed
• First Posted: March 22, 2013
• Results First Posted: November 14, 2019
• Last Update Posted: November 14, 2019
• Sponsor: Novartis Pharmaceuticals
• Collaborators: Breast International Group; German Breast Group; SOLTI Breast Cancer Research Group
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: March 14, 2013
• First Posted Date: March 22, 2013
• Results First Submitted Date: July 11, 2016
• Results First Posted Date: November 14, 2019
• Last Update Posted Date: November 14, 2019
• Actual Study Start Date: September 3, 2013
• Actual Primary Completion Date: February 18, 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 24, 2019)

• 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.
• 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.
• 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.

Original Primary Outcome Measures (submitted: March 21, 2013)

Pathological complete response (pCR) rate [ Time Frame: week 18 ]

Rate of pCR (as defined by NSABP criteria - absence of invasive disease in the breast [ypT0]) at the time of surgery.

Current Secondary Outcome Measures (submitted: October 24, 2019)

• 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.
• 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.
• 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.
• 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)
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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
• 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'.

Original Secondary Outcome Measures (submitted: March 21, 2013)

• Overall objective clinical response rate at the end of the biologic window and prior to surgery [ Time Frame: baseline, week 6, week 18 ]
  Overall objective clinical response rate = CR + PR rate, measured by US (or MRI) and assessed by world health organization (WHO) criteria.
• Efficacy by other pCR definitions [ Time Frame: baseline, week 18 ]
  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]); Percent of patients with remaining DCIS in breast at definitive surgery irrespective of lymph node status
• pCR and clinical response by hormone receptor status (Estrogene Receptor (ER)+ versus ER-) [ Time Frame: baseline, week 18 ]
  pCR and clinical response by hormone receptor status
• Number of patients with node-negative disease at definitive surgery (ypN0) [ Time Frame: 18 weeks ]
  Percent of patients with node-negative disease at surgery
• Rate of breast conserving surgery [ Time Frame: 18 weeks ]
  Rate of patients with breast conserving surgery
• Safety and tolerability [ Time Frame: 18 weeks ]
  Frequency and severity of hematological and non-hematological adverse events and laboratory abnormalities

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: NeoPHOEBE: Neoadjuvant Trastuzumab + BKM120 in Combination With Weekly Paclitaxel in HER2-positive Primary Breast Cancer
• Official 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
• Brief Summary: 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

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
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: HER2-positive Newly Diagnosed, Primary Breast Cancer

Intervention

• Drug: BKM120
  Neo-adjuvant BKM120 (oral pan-class I PI3K inhibitor, continuous daily dosing). BKM120 was administered orally 100 mg/day.
  Other Name: Buparsilib
• Drug: Trastuzumab
  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.
• Drug: Paclitaxel
  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.
• Drug: BKM120 Placebo
  Neoadjuvant BKM120 placebo Administered orally 100 mg/day.

Study Arms

• Experimental: BKM120 + Trastuzumab + paclitaxel
  BKM120 (oral, pan-class I PI3K inhibitor) in combination with trastuzumab and paclitaxel.
  Interventions:

  • Drug: BKM120
  • Drug: Trastuzumab
  • Drug: Paclitaxel
• Placebo Comparator: BKM120 PBO + Trastuzumab + paclitaxel
  BKM120 placebo in combination with trastuzumab and paclitaxel
  Interventions:

  • Drug: Trastuzumab
  • Drug: Paclitaxel
  • Drug: BKM120 Placebo

• Publications *: Loibl S, de la Pena L, Nekljudova V, Zardavas D, Michiels S, Denkert C, Rezai M, Bermejo B, Untch M, Lee SC, Turri S, Urban P, Kummel S, Steger G, Gombos A, Lux M, Piccart MJ, Von Minckwitz G, Baselga J, Loi S. Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+ primary breast cancer: A randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE). Eur J Cancer. 2017 Nov;85:133-145. doi: 10.1016/j.ejca.2017.08.020. Epub 2017 Sep 17.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 21, 2015): 50
• Original Estimated Enrollment (submitted: March 21, 2013): 220
• Actual Study Completion Date: February 18, 2015
• Actual Primary Completion Date: February 18, 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Germany, Spain
• Removed Location Countries: Belgium, Brazil, France, Italy, New Zealand, Peru, Singapore, Switzerland

Administrative Information

• NCT Number: NCT01816594
• Other Study ID Numbers: CBKM120F2203
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

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

• URL: http://www.clinicalstudydatarequest.com

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current

Collaborators

• Breast International Group
• German Breast Group
• SOLTI Breast Cancer Research Group

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: October 2019