A Study of Pertuzumab in Combination With Herceptin and Chemotherapy in Participants With HER2-Positive Breast Cancer

• ClinicalTrials.gov Identifier: NCT00976989
• Recruitment Status: Completed
• First Posted: September 15, 2009
• Results First Posted: June 20, 2016
• Last Update Posted: February 6, 2017
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: September 14, 2009
• First Posted Date: September 15, 2009
• Results First Submitted Date: March 28, 2016
• Results First Posted Date: June 20, 2016
• Last Update Posted Date: February 6, 2017
• Study Start Date: November 2009
• Actual Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 11, 2016)

• Safety: Percentage of Participants With Symptomatic Cardiac Events as Assessed by the Investigator [ Time Frame: From baseline up to approximately 3.5 years ]
  Left ventricular systolic dysfunction (LVSD) as assessed by the Investigator, including Grade 3, 4 or 5 symptomatic LVSD with symptomatic cardiac events.
• Safety: Percentage of Participants With Left Ventricular Ejection Fraction (LVEF) Decline During Pre-operative (Neoadjuvant) Period [ Time Frame: From baseline up to approximately 18 weeks ]
  Percentage of participants with LVEF measures decline of ≥ 10% from baseline and to a value of <50% during the pre-operative (neoadjuvant) period.

• Original Primary Outcome Measures (submitted: September 14, 2009): Tolerability during neoadjuvant treatment: symptomatic cardiac events, LVEF [ Time Frame: throughout cycles 1-6, complete cardiac questionnaire every 3 weeks, LVEF cycles 2, 4 and 6 ]

Current Secondary Outcome Measures (submitted: December 12, 2016)

• Efficacy: Percentage of Participants With Complete Pathological Response (pCR) [ Time Frame: At surgery, after 18 weeks (6 cycles) of treatment ]
  pCR is defined as the absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. pCR is evaluated after 6 cycles of treatment and surgery or following withdrawal from the study whichever occurs sooner.
• Efficacy: Clinical Response Rate [ Time Frame: During each 3-week cycle of 6 total cycles: up to 18 weeks ]
  Tumor response is defined as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) and is identified as per local practice. Clinical response rate is defined as the percentage of participants who achieve a response of CR or PR at any time pre-surgery. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by mammogram or magnetic resonance imaging (MRI) and clinical breast examination (CBE), CR is disappearance of all target lesions; PR is >=30% decrease in the sum of the longest diameter of target lesions.
• Efficacy: Time to Clinical Response [ Time Frame: Up to 18 weeks ]
  Time to clinical response is defined as the time from the date of first dose received to the first date of assessment of clinical response. Clinical response is defined as a response of CR or PR at any time pre-surgery. Per RECIST v1.0 for target lesions and assessed by mammogram or MRI and CBE, CR is disappearance of all target lesions; PR is >=30% decrease in the sum of the longest diameter of target lesions.
• Efficacy: Percentage of Participants Achieving Breast Conserving Surgery [ Time Frame: At approximately 18 weeks ]
  This is the percentage of participants who achieved breast conserving surgery out of the intent-to-treat population without inflammatory breast cancer, as these participants received mastectomy irrespective of their response to neoadjuvant (pre-operative) treatment.
• Efficacy: Percentage of Participants Without an Overall Survival (OS) Event [ Time Frame: From baseline to end of study up to 5 years ]
  Overall survival (OS) was defined as the time from randomization to the date of death from any cause. Participants who were alive or lost to follow-up were censored at the last known alive date. Participants with no post-baseline information were censored at the date of randomization plus one day.
• Efficacy: Percentage of Participants Without a Disease-Free Survival (DFS) Event [ Time Frame: From baseline to end of study up to 5 years ]
  The DFS was defined as the time from the first date of no disease (i.e., date of surgery) to the first documentation of progressive disease (PD) or death. PD was assessed using RECIST v1.0 and MRI and CBE. It was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions. Any evidence of contralateral disease in situ was not considered as PD. Participants who were withdrawn from the study without documented PD were censored at the date of the last assessment when the participant was known to be disease-free.
• Efficacy: Percentage of Participants Without a Progression-Free Survival (PFS) Event [ Time Frame: From baseline to end of study up to 5 years ]
  Progression-free survival was defined as the time from the date of randomization to the first documentation of PD or death from any cause, whichever occurred first. PD was assessed using RECIST v1.0 and MRI and CBE. It was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions. Participants who were withdrawn from the study without documented PD were censored at the date of the last assessment when the participant was known to be free from PD. Participants without post-baseline assessments but known to be alive were censored at the time of randomization plus one day.
• Safety: Percentage of Participants With Cardiac Symptoms Associated With Symptomatic Left Ventricular Systolic Dysfunction (LVSD) [ Time Frame: From Baseline to end of Neoadjuvant Period (up to 18 weeks), Adjuvant Period (up to 1.5 years), Follow-up Period (up to 3.5 years) ]
  Percentage of participants with signs or symptoms of cardiac events.
• Safety: Percentage of Participants With Asymptomatic Left Ventricular Ejection Fraction (LVEF) Events [ Time Frame: From baseline to end of Neoadjuvant Period (up to 18 weeks), Adjuvant Period (up to 1.5 years), Follow-up Period (up to 3.5 years) ]
  Percentage of participants with LVEF events without signs or symptoms of cardiac events.
• Safety: Maximum Decrease in Left Ventricular Ejection Fraction (LVEF) Measures [ Time Frame: From baseline up to approximately 3.5 years ]
  Maximum decrease in LVEF measures is the change from baseline at worst treatment value. LVEF is measured as percentage.

Original Secondary Outcome Measures (submitted: September 14, 2009)

• Pathological complete response rate [ Time Frame: at surgery, after 6 cycles of treatment ]
• Safety: AEs, laboratory parameters, LVEF, ECG [ Time Frame: throughout study, laboratory parameters assessed every 3 weeks, LVEF and ECG every 2-3 cycles ]
• Clinical response rate, time to response, disease-free survival, progression-free survival, overall survival [ Time Frame: throughout study, tumour assessment/breast examination every 3 weeks ]

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

Descriptive Information

• Brief Title: A Study of Pertuzumab in Combination With Herceptin and Chemotherapy in Participants With HER2-Positive Breast Cancer
• Official Title: A Randomised, Multicentre, Multinational Phase II Study to Evaluate Pertuzumab in Combination With Trastuzumab, Given Either Concomitantly or Sequentially With Standard Anthracycline-based Chemotherapy or Concomitantly With a Non-anthracycline-based Chemotherapy Regimen, as Neoadjuvant Therapy for Patients With Locally Advanced, Inflammatory or Early Stage HER2-positive Breast Cancer
• Brief Summary: This 3 arm study will assess the tolerability, safety and efficacy of 3 neoadjuvant treatment regimens in participants with locally advanced, inflammatory or early stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Before surgery, participants will be randomized to receive either A) 6 cycles of pertuzumab plus trastuzumab (Herceptin), with 5-fluorouracil/epirubicin/cyclophosphamide (FEC) for cycles 1-3 and docetaxel for cycles 4-6, or B) FEC for cycles 1-3 followed by pertuzumab plus trastuzumab with docetaxel for cycles 4-6, or C) 6 cycles of pertuzumab plus trastuzumab with docetaxel and carboplatin. Pertuzumab will be administered at a loading dose of 840 mg intravenously (iv), then 420 mg iv 3-weekly, trastuzumab at a loading dose of 8 mg/kg iv, then 6 mg/kg iv 3-weekly, docetaxel at 75 mg/m^2 iv, increased to 100 mg/m^2 iv 3-weekly, and FEC and carboplatin iv 3-weekly at standard doses. Following surgery participants will receive trastuzumab 6 mg/kg iv 3-weekly for a total of 1 year, as well as adequate chemo-, radio- and hormone therapy. Anticipated time on study treatment is 4-12 months, and target sample size is 200-300.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: Pertuzumab
  840 mg loading dose intravenously (IV), then 420 mg IV 3-weekly.
  Other Name: Perjeta
• Drug: Trastuzumab
  8 mg/kg loading dose IV, then 6 mg/kg every 3 weeks.
  Other Name: Herceptin
• Drug: FEC
  5-fluorouracil 500 mg/m^2, epirubicin 100 mg/m^2 and cyclophosphamide 600 mg/m^2.
• Drug: Docetaxel
  75 mg/m^2 for the first dose; 100 mg/m^2 if no dose limiting toxicity occurs.
• Drug: TCH
  Trastuzumab followed by carboplatin at target area under the plasma concentration-time curve (AUC) 6 and docetaxel at a starting dose of 75 mg/m^2. All treatments were given every three weeks by the IV route.

Study Arms

• Experimental: T+P Concomitant Anthracycline-based chemotherapy
  5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab (T) and pertuzumab (P) every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
  Interventions:

  • Drug: Pertuzumab
  • Drug: Trastuzumab
  • Drug: FEC
  • Drug: Docetaxel
• Experimental: T+P Sequential Anthracycline-based chemotherapy
  FEC every three weeks for three cycles, followed by docetaxel, trastuzumab (T) and pertuzumab (P) every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.
  Interventions:

  • Drug: Pertuzumab
  • Drug: Trastuzumab
  • Drug: FEC
  • Drug: Docetaxel
• Experimental: T+P Concomitant Non-Anthracycline chemotherapy
  Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab (P) every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
  Interventions:

  • Drug: Pertuzumab
  • Drug: TCH

Publications *

• Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Waldron-Lynch M, Eng-Wong J, Kirk S, Cortes J. Long-term efficacy analysis of the randomised, phase II TRYPHAENA cardiac safety study: Evaluating pertuzumab and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer. Eur J Cancer. 2018 Jan;89:27-35. doi: 10.1016/j.ejca.2017.10.021. Epub 2017 Dec 8.
• Swain SM, Schneeweiss A, Gianni L, Gao JJ, Stein A, Waldron-Lynch M, Heeson S, Beattie MS, Yoo B, Cortes J, Baselga J. Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with pertuzumab. Ann Oncol. 2017 Apr 1;28(4):761-768. doi: 10.1093/annonc/mdw695. Erratum In: Ann Oncol. 2018 Apr 1;29(4):1075. Ann Oncol. 2018 Jul 1;29(7):1607. Ann Oncol. 2019 Aug 1;30(8):1404.
• Schneeweiss A, Chia S, Hegg R, Tausch C, Deb R, Ratnayake J, McNally V, Ross G, Kiermaier A, Cortes J. Evaluating the predictive value of biomarkers for efficacy outcomes in response to pertuzumab- and trastuzumab-based therapy: an exploratory analysis of the TRYPHAENA study. Breast Cancer Res. 2014 Jul 8;16(4):R73. doi: 10.1186/bcr3690.
• Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortes J. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013 Sep;24(9):2278-84. doi: 10.1093/annonc/mdt182. Epub 2013 May 22.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 14, 2009): 225
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: January 2016
• Actual Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• female participants, age >/=18 years
• advanced, inflammatory or early stage unilateral invasive breast cancer
• HER2-positive breast cancer
• baseline left ventricular ejection fraction (LVEF) >/=55%

Exclusion Criteria:

• metastatic disease (Stage IV) or bilateral breast cancer
• previous anticancer therapy or radiotherapy for any malignancy
• other malignancy, except for carcinoma in situ of the cervix, or basal cell carcinoma
• clinically relevant cardiovascular disease
• current chronic treatment with corticosteroids of >10mg methylprednisolone or equivalent

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: Bahamas, Bosnia and Herzegovina, Brazil, Canada, Croatia, Germany, Greece, Italy, Korea, Republic of, Mexico, New Zealand, Portugal, Romania, Serbia, South Africa, Spain, Sweden, Switzerland, Taiwan, United Kingdom

Administrative Information

• NCT Number: NCT00976989
• Other Study ID Numbers: BO22280; 2009-012019-17 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Clinical Trials, Study Director, Hoffmann-La Roche
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: May 2016