A Study Evaluating the Efficacy and Safety of Adjuvant Atezolizumab or Placebo and Trastuzumab Emtansine for Participants With HER2-Positive Breast Cancer at High Risk of Recurrence Following Preoperative Therapy (Astefania)

• ClinicalTrials.gov Identifier: NCT04873362
• Recruitment Status: Recruiting
• First Posted: May 5, 2021
• Last Update Posted: April 18, 2024
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: April 21, 2021
• First Posted Date: May 5, 2021
• Last Update Posted Date: April 18, 2024
• Actual Study Start Date: May 4, 2021
• Estimated Primary Completion Date: June 25, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 4, 2021)

Invasive Disease-free Survival (IDFS) [ Time Frame: From randomization up to approximately 6 years ]

IDFS event is defined as the time from randomization to the first occurrence of the following events: ipsilateral invasive breast tumor recurrence, ipsilateral local-regional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, death from any cause.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: May 4, 2021)

• IDFS Including Second Primary Non-breast Invasive Cancer [ Time Frame: From baseline up to 10 years ]
• Disease-free Survival (DFS) [ Time Frame: From baseline up to 10 years ]
• Overall Survival (OS) [ Time Frame: From baseline up to 10 years ]
• Distant Recurrence-free Interval (DRFI) [ Time Frame: From baseline up to 10 years ]
• Number of Participants with Clinically Meaningful Deterioration in Global Health Status/Quality of Life (GHS/QoL) Physical, Role, and Cognitive Function [ Time Frame: From baseline until 2 years after study treatment completion/discontinuation visit (approximately 3 years) ]
  Clinically Meaningful Deterioration will be Measured by Scales of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer (EORTC QLQ C30)
• Mean Absolute Scores in GHS/QoL, Physical, Role, and Cognitive Function, as Assessed Using the EORTC QLQ-C30 [ Time Frame: From baseline until 2 years after study treatment completion/discontinuation visit (approximately 3 years) ]
  The European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30) is a self-reported measure. Functioning and symptoms items are scored on a 4-point scale: 1=Not at all, 2=A little, 3=Quite a bit, 4=Very much. GHS and QoL items are scored on a 7-point scale: 1=Very poor, 2, 3, 4, 5, 6, 7=Excellent. Scores will be transformed to a range of 0 to 100, with higher scores (i.e. closer to 100) reflecting better functioning, better GHS/QoL, and worse symptoms.
• Mean Change From Baseline Scores in GHS/QoL, Physical, Role, and Cognitive Function, as Assessed Using the EORTC QLQ-C30 [ Time Frame: From baseline until 2 years after study treatment completion/discontinuation visit (approximately 3 years) ]
  The European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30) is a self-reported measure. Functioning and symptoms items are scored on a 4-point scale: 1=Not at all, 2=A little, 3=Quite a bit, 4=Very much. GHS and QoL items are scored on a 7-point scale: 1=Very poor, 2, 3, 4, 5, 6, 7=Excellent. Scores will be transformed to a range of 0 to 100, with higher scores (i.e. closer to 100) reflecting better functioning, better GHS/QoL, and worse symptoms.
• Percentage of Participants with Adverse Events (AEs) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0) [ Time Frame: From baseline up to 10 years ]
• Maximum Serum Concentrations (Cmax) for Atezolizumab [ Time Frame: Day 1 of Cycles 1 and 4 pre-infusion, Day 1 of Cycles 1 and 4 after 30 minutes post-infusion, Day 1 of Cycles 2, 3 and 8 pre-infusion (cycle=21 days) and at study treatment completion/discontinuation visit (approximately 11 months after Cycle 1 Day 1) ]
• Cmax for Trastuzumab Emtansine [ Time Frame: Day 1 of Cycles 1 and 4 pre-infusion, Day 1 of Cycles 1 and 4 after 30 minutes post-infusion, (cycle=21 days) and at study treatment completion/discontinuation visit (approximately 11 months after Cycle 1 Day 1) ]
• Cmax for Total Trastuzumab [ Time Frame: Day 1 of Cycles 1 and 4 pre-infusion, Day 1 of Cycles 1 and 4 after 30 minutes post-infusion, (cycle=21 days) and at study treatment completion/discontinuation visit (approximately 11 months after Cycle 1 Day 1) ]
• Cmax for DM1 [ Time Frame: Day 1 of Cycles 1 and 4 pre-infusion, Day 1 of Cycles 1 and 4 after 30 minutes post-infusion, (cycle=21 days) and at study treatment completion/discontinuation visit (approximately 11 months after Cycle 1 Day 1) ]
  DM1 = a thiol-containing maytansinoid anti-microtubule agent; N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine
• Minimum Serum Concentrations (Cmin) for Atezolizumab [ Time Frame: Day 1 of Cycles 1 and 4 pre-infusion, Day 1 of Cycles 1 and 4 after 30 minutes post-infusion, Day 1 of Cycles 2, 3 and 8 (cycle=21 days) and at study treatment completion/discontinuation visit (approximately 11 months after Cycle 1 Day 1) ]
• Percentage of Participants with Anti-drug Antibodies (ADAs) to Atezolizumab [ Time Frame: Day 1 of Cycles 1 and 4 pre-infusion, Day 1 of Cycles 1 and 4 after 30 minutes post-infusion, Day 1 of Cycles 2, 3 and 8 (cycle=21 days) and at study treatment completion/discontinuation visit (approximately 11 months after Cycle 1 Day 1) ]
• Percentage of Participants with ADAs to Trastuzumab Emtansine [ Time Frame: Day 1 of Cycles 1 and 4 pre-infusion, Day 1 of Cycles 1 and 4 after 30 minutes post-infusion, (cycle=21 days) and at study treatment completion/discontinuation visit (approximately 11 months after Cycle 1 Day 1) ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study Evaluating the Efficacy and Safety of Adjuvant Atezolizumab or Placebo and Trastuzumab Emtansine for Participants With HER2-Positive Breast Cancer at High Risk of Recurrence Following Preoperative Therapy
• Official Title: A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of Adjuvant Atezolizumab or Placebo and Trastuzumab Emtansine for HER2-Positive Breast Cancer at High Risk of Recurrence Following Preoperative Therapy
• Brief Summary: This is a Phase III, two-arm, randomized, double-blind placebo-controlled study in participants with HER2-positive primary breast cancer who have received preoperative chemotherapy and HER2-directed therapy, including trastuzumab followed by surgery, with a finding of residual invasive disease in the breast and/or axillary lymph nodes.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: Atezolizumab
  Atezolizumab will be administered at a dose of 1200 mg every three weeks (Q3W) for 14 cycles.
  Other Name: Tecentriq, RO5541267, MPDL3280A
• Drug: Trastuzumab Emtansine
  Trastuzumab emtansine will be administered at a dose of 3.6 mg/kg Q3W for 14 weeks.
  Other Name: Kadcyla, T-DM1, RO5304020
• Drug: Placebo
  Placebo matched to atezolizumab will be administered at a dose of 1200 mg Q3W for 14 cycles.
• Drug: Trastuzumab
  Trastuzumab will be used to complete 14 cycles of study treatment if trastuzumab emtansine is discontinued for toxicity not considered to be related to the trastuzumab component of the drug.
  Other Name: Herceptin

Study Arms

• Active Comparator: Arm A: Placebo + Trastuzumab Emtansine
  Participants will receive an intravenous (IV) infusion of placebo prior to the IV infusion of trastuzumab emtansine on Day 1 of each 21-day cycle for a total of 14 cycles.
  Interventions:

  • Drug: Trastuzumab Emtansine
  • Drug: Placebo
  • Drug: Trastuzumab
• Experimental: Arm B: Atezolizumab + Trastuzumab Emtansine
  Participants will receive an IV infusion of atezolizumab prior to the IV infusion of trastuzumab emtansine on Day 1 of each 21-day cycle for a total of 14 cycles.
  Interventions:

  • Drug: Atezolizumab
  • Drug: Trastuzumab Emtansine
  • Drug: Trastuzumab

• Publications *: Hurvitz SA, Bachelot T, Bianchini G, Harbeck N, Loi S, Park YH, Prat A, Gilham L, Boulet T, Gochitashvili N, Monturus E, Lambertini C, Nyawira B, Knott A, Restuccia E, Schmid P. ASTEFANIA: adjuvant ado-trastuzumab emtansine and atezolizumab for high-risk, HER2-positive breast cancer. Future Oncol. 2022 Oct;18(32):3563-3572. doi: 10.2217/fon-2022-0485. Epub 2022 Nov 16.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 13, 2021): 1700
• Original Estimated Enrollment (submitted: May 4, 2021): 1590
• Estimated Study Completion Date: June 29, 2035
• Estimated Primary Completion Date: June 25, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically confirmed invasive breast carcinoma
• Centrally-confirmed human epidermal growth factor receptor 2 (HER2)-positive invasive breast cancer
• Centrally confirmed PD-L1 and hormone receptor status
• Clinical stage at disease presentation (prior to neoadjuvant therapy): cT4/anyN/M0, any cT/N2-3/M0, or cT1-3/N0-1/M0 (participants with cT1mi/T1a/T1b/N0 are not eligible)
• Completion of pre-operative systemic chemotherapy including at least 9 weeks of taxane and 9 weeks of trastuzumab (anthracycline and/or additional HER2-targeted agents are permitted)
• <=12 weeks between primary surgery and randomization
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
• Screening left ventricular ejection fraction (LVEF) >= 50% and no decrease in LVEF by >15% from the pre-chemotherapy LVEF. If no pre-chemotherapy LVEF, screening LVEF >= 55%
• Life expectancy >= 6 months
• Adequate hematologic and end organ function

Exclusion Criteria:

• Stage IV breast cancer
• An overall response of disease progression according to the investigator at the conclusion of preoperative systemic therapy
• Prior treatment with T-DM1, or atezolizumab, or other immune checkpoint inhibitors
• History of exposure to various cumulative doses of anthracyclines
• History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or ductal carcinoma in situ (DCIS)
• Current grade >=2 peripheral neuropathy
• History of idiopathic pulmonary fibrosis, organizing pneumonia, or pneumonitis
• History of or active autoimmune disease or immune deficiency
• Treatment with immunostimulatory or immunosuppressive agents
• Cardiopulmonary dysfunction
• Any known active liver disease

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Reference Study ID Number: WO42633 https://forpatients.roche.com/; 888-662-6728 (U.S. and Canada); global-roche-genentech-trials@gene.com

• Listed Location Countries: Australia, Austria, Belgium, Brazil, Bulgaria, China, Czechia, Denmark, France, Germany, Greece, Hong Kong, Hungary, India, Italy, Kenya, Korea, Republic of, Mexico, New Zealand, Poland, Portugal, Romania, Russian Federation, Singapore, Spain, Taiwan, Thailand, Turkey, Uganda, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT04873362
• Other Study ID Numbers: WO42633; 2020-003681-40 ( EudraCT Number ); 2023-503568-18-00 ( Other Identifier: EU CT )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• 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: April 2024