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A Study To Evaluate the Efficacy and Safety Of Atezolizumab or Placebo in Combination With Neoadjuvant Doxorubicin + Cyclophosphamide Followed By Paclitaxel + Trastuzumab + Pertuzumab In Early Her2-Positive Breast Cancer

NCT03726879

Description:

This study (also known as IMpassion050) will evaluate the efficacy and safety of atezolizumab compared with placebo when given in combination with neoadjuvant dose-dense anthracycline (doxorubicin) + cyclophosphamide followed by paclitaxel + trastuzumab + pertuzumab (ddAC-PacHP) in patients with early HER2-positive breast cancer (T2-4, N1-3, M0).

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: A Study To Evaluate the Efficacy and Safety Of Atezolizumab or Placebo in Combination With Neoadjuvant Doxorubicin + Cyclophosphamide Followed By Paclitaxel + Trastuzumab + Pertuzumab In Early Her2-Positive Breast Cancer
  • Official Title: A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial To Evaluate the Efficacy and Safety Of Atezolizumab or Placebo in Combination With Neoadjuvant Doxorubicin + Cyclophosphamide Followed By Paclitaxel + Trastuzumab + Pertuzumab In Early Her2-Positive Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: BO40747
  • NCT ID: NCT03726879

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
AtezolizumabTecentriqAtezolizumab +ddAC-PacHP
PlaceboPlacebo + ddAC-PacHP
DoxorubicinAdriamycinAtezolizumab +ddAC-PacHP
CyclophosphamideCytoxan, NeosarAtezolizumab +ddAC-PacHP
PaclitaxelTaxolAtezolizumab +ddAC-PacHP
TrastuzumabHerceptinAtezolizumab +ddAC-PacHP
PertuzumabPerjetaAtezolizumab +ddAC-PacHP
Trastuzumab EmtansineKadcylaAtezolizumab +ddAC-PacHP

Purpose

This study (also known as IMpassion050) will evaluate the efficacy and safety of atezolizumab compared with placebo when given in combination with neoadjuvant dose-dense anthracycline (doxorubicin) + cyclophosphamide followed by paclitaxel + trastuzumab + pertuzumab (ddAC-PacHP) in patients with early HER2-positive breast cancer (T2-4, N1-3, M0).

Trial Arms

NameTypeDescriptionInterventions
Atezolizumab +ddAC-PacHPExperimentalParticipants will receive atezolizumab 840 mg IV Q2W for 4 cycles during neoadjuvant phase with ddAC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 IV), followed by atezolizumab 1200 mg IV Q3W for 4 cycles with paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks, trastuzumab 6 mg/kg IV (with an initial 8-mg/kg IV loading dose) Q3W for 4 cycles, and pertuzumab 420 mg IV (with an initial 840-mg IV loading dose) Q3W for 4 cycles. During the adjuvant phase, participants will continue to receive the following study treatments Q3W to complete up to 1 year of HER2-target therapy inclusive of therapy given both in the neoadjuvant and adjuvant setting: atezolizumab 1200 mg IV Q3W, trastuzumab 6 mg/kg IV (with an initial 8-mg/kg IV loading dose) Q3W, and pertuzumab 420 mg IV (with an initial 840-mg IV loading dose) Q3W. Participants who do not achieve pCR have the option of receiving blinded atezolizumab + trastuzumab emtansine post surgery for 14 cycles.
  • Atezolizumab
  • Doxorubicin
  • Cyclophosphamide
  • Paclitaxel
  • Trastuzumab
  • Pertuzumab
  • Trastuzumab Emtansine
Placebo + ddAC-PacHPPlacebo ComparatorParticipants will receive placebo 840 mg IV Q2W for 4 cycles during neoadjuvant phase with ddAC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 IV), followed by placebo 1200 mg IV Q3W for 4 cycles with paclitaxel 80 mg/m2 IV weekly for 12 continuous weeks, trastuzumab 6 mg/kg IV (with an initial 8-mg/kg IV loading dose) Q3W for 4 cycles, and pertuzumab 420 mg IV (with an initial 840-mg IV loading dose) Q3W for 4 cycles. During the adjuvant phase, participants will continue to receive the following study treatments Q3W to complete up to 1 year of HER2-target therapy inclusive of therapy given both in the neoadjuvant and adjuvant setting: placebo 1200 mg IV Q3W, trastuzumab 6 mg/kg IV (with an initial 8-mg/kg IV loading dose) Q3W, and pertuzumab 420 mg IV (with an initial 840-mg IV loading dose) Q3W. Participants who do not achieve pCR have the option of receiving blinded atezolizumab + trastuzumab emtansine post surgery for 14 cycles.
  • Placebo
  • Doxorubicin
  • Cyclophosphamide
  • Paclitaxel
  • Trastuzumab
  • Pertuzumab
  • Trastuzumab Emtansine

Eligibility Criteria

        Inclusion Criteria:

          -  Confirmed diagnosis of HER2-positive breast cancer, and hormonal and PD-L1 status, as
             documented through central testing of a representative tumor tissue specimen

          -  Primary breast tumor size of > 2 cm by any radiographic measurement

          -  Stage at presentation: T2-T4, N1-N3, M0 as determined by AJCC staging system, 8th
             edition

          -  Pathologic confirmation of nodal involvement with malignancy must be determined by
             fine needle aspiration or core-needle biopsy. Surgical excision of lymph nodes is not
             permitted.

          -  Patients with multifocal tumors are eligible provided at least one focus is sampled
             and centrally confirmed as HER2-positive.

          -  Patients with multicentric tumors are eligible provided all discrete lesions are
             sampled and centrally confirmed as HER2-positive.

          -  Eastern Cooperative Oncology Group Performance Status of 0 or 1

          -  Baseline LVEF >= 55% measured by echocardiogram (ECHO) or multiple-gated acquisition
             (MUGA) scans

          -  Adequate hematologic and end-organ function obtained within 14 days prior to
             initiation of study treatment

          -  For women of childbearing potential: agreement to remain abstinent or use
             contraceptive methods, and agreement to refrain from donating eggs

          -  For men: agreement to remain abstinent or use contraceptive measures, and agreement to
             refrain from donating sperm

        Exclusion Criteria:

          -  Prior history of invasive breast cancer

          -  Stage IV (metastatic) breast cancer

          -  Patients with synchronous bilateral invasive breast cancer

          -  Prior systemic therapy for treatment of breast cancer

          -  Previous therapy with anthracyclines or taxanes for any malignancy

          -  Ulcerating or inflammatory breast cancer

          -  Undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph
             nodes

          -  Sentinel lymph node procedure or axillary lymph node dissection prior to initiation of
             neoadjuvant therapy

          -  History of other malignancy within 5 years prior to screening, with the exception of
             those patients who have a negligible risk of metastasis or death

          -  Cardiopulmonary dysfunction

          -  Dyspnea at rest

          -  Active or history of autoimmune disease or immune deficiency

          -  Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment
             or within 5 months after the final dose of atezolizumab/placebo, 6 months after the
             final dose of doxorubicin, 12 months after the final dose of cyclophosphamide, 6
             months after the final dose of paclitaxel, or 7 months after the final dose of
             trastuzumab, pertuzumab, or trastuzumab emtansine whichever occurs last

        Exclusion Criteria Related to Trastuzumab Emtansine in the Adjuvant Setting:

          -  Patients who achieved pCR

          -  Evidence of clinically evident gross residual or recurrent disease following
             neoadjuvant therapy and surgery

          -  Unable to complete surgery with curative intent after conclusion of neoadjuvant
             systemic therapy

          -  Patient discontinued treatment with trastuzumab because of toxicity during the
             neoadjuvant phase of the study

          -  Clinically significant history of liver disease, including cirrhosis, current alcohol
             abuse, autoimmune hepatic disorders, or sclerosis cholangitis

          -  Patients with Grade >=2 peripheral neuropathy

          -  Prior treatment with trastuzumab emtansine
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants with Pathological Complete Response (pCR)
Time Frame:From randomization to approximately 24 months
Safety Issue:
Description:pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (NAST) (i.e., ypT0/is ypN0 in the current American Joint Committee on Cancer [AJCC] staging system, 8th edition) in the intent-to-treat (ITT) population.

Secondary Outcome Measures

Measure:Percentage of Participants with pCR Based on Hormone Receptor Status
Time Frame:From randomization to approximately 24 months
Safety Issue:
Description:pCR (ypT0/is ypN0) based upon hormone receptor status (estrogen receptor [ER]/progesterone receptor [PgR] positive or ER/PgR negative).
Measure:Percentage of Participants with pCR Based on PD-L1 Status
Time Frame:From randomization to approximately 24 months
Safety Issue:
Description:pCR (ypT0/is ypN0) based upon PD-L1 status (IC 0; IC 1/2/3)
Measure:Event-Free Survival (EFS)
Time Frame:From randomization to first documented disease recurrence, unequivocal tumor progression determined by the treating investigator, or death from any cause (up to approximately 48 months)
Safety Issue:
Description:EFS defined as the time from randomization to the first documented disease recurrence, unequivocal tumor progression determined by the treating investigator, or death from any cause, whichever occurs first, in all patients and based upon hormone receptor status (ER/PgR positive or ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3).
Measure:Disease-Free Survival (DFS)
Time Frame:Time from surgery to first documented disease recurrence or death from any cause (up to approximately 48 months)
Safety Issue:
Description:DFS defined as the time from surgery to the first documented disease recurrence or death from any cause, whichever occurs first, in all patients who undergo surgery and based upon hormone receptor status (ER/PgR positive or ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3).
Measure:Overall Survival (OS)
Time Frame:From randomization to date of death from any cause (up to approximately 48 months)
Safety Issue:
Description:OS defined as the time from randomization to death from any cause in all patients and based upon hormone receptor status (ER/PgR positive or ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3).
Measure:Mean Changes From Baseline in Function (Role, Physical)
Time Frame:Baseline; Day 1 of Cycle 1-9, on Day 1 of every other cycle thereafter until Cycle 22; at the treatment discontinuation or early termination visit and follow up visit. Cycle 1-4, each cycle is 14 days. Cycle 5-22, each cycle is 21 days.
Safety Issue:
Description:Mean changes from baseline score in function (role, physical) will be assessed by the functional scales of EORTC QLQ-C30.
Measure:Mean Changes From Baseline in Global Health Status
Time Frame:Baseline; Day 1 of Cycle 1-9, on Day 1 of every other cycle thereafter until Cycle 22; at the treatment discontinuation or early termination visit and follow up visit. Cycle 1-4, each cycle is 14 days. Cycle 5-22, each cycle is 21 days.
Safety Issue:
Description:Mean changes from baseline will be assessed by the GHC/HRQoL scales of the EORTC QLQ-C30.
Measure:Percentage of Participants With Adverse Events
Time Frame:Baseline to end of study (approximately 48 months)
Safety Issue:
Description:
Measure:Maximum Serum Concentration (Cmax) of Atezolizumab
Time Frame:Day 1 of Cycle 1, 2, 3, 4, 8, 12, 16, at treatment discontinuation visit. Cycle 1-4, each cycle is 14 days. Cycle 8-16, each cycle is 21 days.
Safety Issue:
Description:Cmax is the maximum (or peak) concentration that a study drug achieves in the body.
Measure:Minimum Serum Concentration (Cmin) of Atezolizumab
Time Frame:Day 1 of Cycle 1, 2, 3, 4, 8, 12, 16, at treatment discontinuation visit. Cycle 1-4, each cycle is 14 days. Cycle 8-16, each cycle is 21 days.
Safety Issue:
Description:Cmin is the minimum (or trough) concentration that a study drug achieves in the body.
Measure:Trough Concentration (Ctrough) for Pertuzumab and Trastuzumab in Serum
Time Frame:Day 1 of Cycle 1, 8, 12, and at treatment discontinuation visit. Cycle 1-4, each cycle is 14 days. Cycle 8-16, each cycle is 21 days.
Safety Issue:
Description:
Measure:Maximum Serum Concentration (Cmax) of Trastuzumab Emtansine in Serum
Time Frame:Day 1 of Cycle 9 and Cycle 12, at treatment disontinuation visit. Cycle 9 and 12 are each 21 days.
Safety Issue:
Description:
Measure:Minimum Serum Concentration (Cmin) of Trastuzumab Emtansine in Serum
Time Frame:Day 1 of Cycle 9 and Cycle 12, at treatment disontinuation visit. Cycle 9 and 12 are each 21 days.
Safety Issue:
Description:
Measure:Percentage of Participants with Treatment-Emergent Anti-Drug Antibodies (ADAs) to Atezolizumab
Time Frame:Day 1 of Cycle 1, 2, 3, 4, 8, 12, 16, at treatment discontinuation visit. Cycle 1-4, each cycle is 14 days. Cycle 8-16, each cycle is 21 days.
Safety Issue:
Description:
Measure:Percentage of Participants with Treatment-Emergent Anti-Drug Antibodies (ADAs) to Trastuzumab
Time Frame:Day 1 of Cycle 1, 8, 12 and at treatment discontinuation visit. Cycle 1-4, each cycle is 14 days. Cycle 8-16, each cycle is 21 days.
Safety Issue:
Description:
Measure:Percentage of Participants with Treatment-Emergent Anti-Drug Antibodies (ADAs) to Pertuzumab
Time Frame:Day 1 of Cycle 1, 8, 12, and at treatment discontinuation visit. Cycle 1-4, each cycle is 14 days. Cycle 8-16, each cycle is 21 days.
Safety Issue:
Description:
Measure:Percentage of Participants with Treatment-Emergent Anti-Drug Antibodies (ADAs) to Trastuzumab Emtansine
Time Frame:Day 1 of Cycle 9 and Cycle 12, at treatment disontinuation visit. Cycle 9 and 12 are each 21 days.
Safety Issue:
Description:
Measure:Percentage of Particpants with pCR Based on PIK3CA Mutation Status
Time Frame:From randomization to approximately 24 months
Safety Issue:
Description:
Measure:EFS Based on PIK3CA Mutation Status
Time Frame:From randomization to first documented disease recurrence, unequivocal tumor progression determined by the treating investigator, or death from any cause (up to approximately 48 months)
Safety Issue:
Description:
Measure:DFS Based on PIK3CA Mutation Status
Time Frame:Time from surgery to first documented disease recurrence or death from any cause (up to approximately 48 months)
Safety Issue:
Description:
Measure:OS Based on PIK3CA Mutation Status
Time Frame:From randomization to date of death from any cause (up to approximately 48 months)
Safety Issue:
Description:

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

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