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

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

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Pertuzumab; Drug: Trastuzumab; Drug: FEC; Drug: Docetaxel; Drug: TCH

• Study Type: Interventional
• Enrollment (Actual): 225
• Phase: Phase 2

Contacts and Locations

Study Locations

• Bahamas
  • Nassau, Bahamas, N9311
• Bosnia and Herzegovina
  • Banja Luka, Bosnia and Herzegovina, 78000
  • Sarajevo, Bosnia and Herzegovina, 71000
• Brazil
  • RS
    • Porto Alegre, RS, Brazil, 90610-000
  • SP
    • Sao Paulo, SP, Brazil, 01317-000
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
  • Quebec
    • Montreal, Quebec, Canada, H3G 1A4
• Croatia
  • Pula, Croatia, 52100
• Germany
  • Heidelberg, Germany, 69120
  • Kiel, Germany, 24105
  • Regensburg, Germany, 93053
  • Trier, Germany, 54290
  • Troisdorf, Germany, 53840
  • Ulm, Germany, 89075
• Greece
  • Heraklion, Greece, 71110
  • Thessaloniki, Greece, 56429
• Italy
  • Lazio
    • Roma, Lazio, Italy, 00168
  • Lombardia
    • Monza, Lombardia, Italy, 20900
    • S. Fermo della Battaglia (CO), Lombardia, Italy, 22020
• Korea, Republic of
  • Daegu, Korea, Republic of, 702-210
  • Seoul, Korea, Republic of, 152-703
• Mexico
  • Mexico City, Mexico, 06760
  • Xalapa, Mexico, 91130
• New Zealand
  • Auckland, New Zealand, 1023
• Portugal
  • Aveiro, Portugal, 3814-501
  • Lisboa, Portugal, 1099-023
• Romania
  • Bucharest, Romania, 050098
  • Cluj Napoca, Romania, 400015
  • Iasi, Romania, 700106
• Serbia
  • Belgrade, Serbia, 11000
  • Belgrade, Serbia, 11080
• South Africa
  • Durban, South Africa, 4091
  • Durban, South Africa, 4058
  • Pretoria, South Africa, 0002
• Spain
  • Barcelona, Spain, 08035
  • Cordoba, Spain, 14004
  • Madrid, Spain, 28222
  • Guipuzcoa
    • San Sebastian, Guipuzcoa, Spain, 20014
• Sweden
  • Eskilstuna, Sweden, 63188
  • Stockholm, Sweden, 17176
  • Sundsvall, Sweden, 85186
  • Umea, Sweden, 90185
• Switzerland
  • Baden, Switzerland, 5405
  • Zürich, Switzerland, 8091
  • Zürich, Switzerland, 8008
• Taiwan
  • Taichung, Taiwan, 404
  • Taipei, Taiwan, 00112
• United Kingdom
  • Bournemouth, United Kingdom, BH7 7DW
  • Derby, United Kingdom, DE1 2QY
  • Guildford, United Kingdom, GU2 5XX
  • Newcastle Upon Tyne, United Kingdom, NE7 7DN
  • Southampton, United Kingdom, SO16 6YD
  • Truro, United Kingdom, TR1 3LJ
  • Westcliffe-on-sea, United Kingdom, SS0 0RY

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Pertuzumab; 840 mg loading dose intravenously (IV), then 420 mg IV 3-weekly.; Other Names: Perjeta; Drug: Trastuzumab; 8 mg/kg loading dose IV, then 6 mg/kg every 3 weeks.; Other Names: 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.
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.	Drug: Pertuzumab; 840 mg loading dose intravenously (IV), then 420 mg IV 3-weekly.; Other Names: Perjeta; Drug: Trastuzumab; 8 mg/kg loading dose IV, then 6 mg/kg every 3 weeks.; Other Names: 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.
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.	Drug: Pertuzumab; 840 mg loading dose intravenously (IV), then 420 mg IV 3-weekly.; Other Names: Perjeta; 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.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy: Percentage of Participants With Complete Pathological Response (pCR)	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.	At surgery, after 18 weeks (6 cycles) of treatment
Efficacy: Clinical Response Rate	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.	During each 3-week cycle of 6 total cycles: up to 18 weeks
Efficacy: Time to Clinical Response	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.	Up to 18 weeks
Efficacy: Percentage of Participants Achieving Breast Conserving Surgery	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.	At approximately 18 weeks
Efficacy: Percentage of Participants Without an Overall Survival (OS) Event	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.	From baseline to end of study up to 5 years
Efficacy: Percentage of Participants Without a Disease-Free Survival (DFS) Event	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.	From baseline to end of study up to 5 years
Efficacy: Percentage of Participants Without a Progression-Free Survival (PFS) Event	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.	From baseline to end of study up to 5 years
Safety: Percentage of Participants With Cardiac Symptoms Associated With Symptomatic Left Ventricular Systolic Dysfunction (LVSD)	Percentage of participants with signs or symptoms of cardiac events.	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)
Safety: Percentage of Participants With Asymptomatic Left Ventricular Ejection Fraction (LVEF) Events	Percentage of participants with LVEF events without signs or symptoms of cardiac events.	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)
Safety: Maximum Decrease in Left Ventricular Ejection Fraction (LVEF) Measures	Maximum decrease in LVEF measures is the change from baseline at worst treatment value. LVEF is measured as percentage.	From baseline up to approximately 3.5 years

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• 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, 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.
• 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.

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): January 1, 2016

Study Registration Dates

• First Submitted: September 14, 2009
• First Submitted That Met QC Criteria: September 14, 2009
• First Posted (Estimate): September 15, 2009

Study Record Updates

• Last Update Posted (Estimate): February 6, 2017
• Last Update Submitted That Met QC Criteria: December 12, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Immunological; Docetaxel; Trastuzumab; Pertuzumab
• Other Study ID Numbers: BO22280; 2009-012019-17 (EudraCT Number)