An Adaptive Randomized Neoadjuvant Two Arm Trial in Triple-negative Breast Cancer Comparing a Mono Atezolizumab Window Followed by a Atezolizumab - CTX Therapy With Atezolizumab - CTX Therapy (neoMono)
Overview
- Phase
- Phase 2
- Intervention
- Atezolizumab 840 MG in 14 ML Injection
- Conditions
- Triple-negative Breast Cancer
- Sponsor
- Palleos Healthcare GmbH
- Enrollment
- 442
- Locations
- 1
- Primary Endpoint
- Pathological Complete Response (ypT0/is, ypN0)
- Status
- Terminated
- Last Updated
- 3 months ago
Overview
Brief Summary
This is a randomized, open-label, adaptive, two arm, multicentre, Phase II trial comparing a neoadjuvant chemotherapy with PDL1-inhibition (Atezolizumab) and Atezolizumab two-week window to chemotherapy with PDL1-inhibition (Atezolizumab) and identify biomarkers predicting (early) response to or resistance against Atezolizumab (alone and with CTX) allowing patients stratification in future clinical trials
Detailed Description
This is a randomized, open-label, adaptive, two arm, multicenter phase II trial that enrolled female and male patients with primary TNBC (defined as ER/PR \< 10% and HER2-negative) with tumor stages cT1c - cT4d (cN0 and cN+). Patients are randomized to Arm A and B. Randomization is stratified by PD-L1 expression on immune cells (IC-status) and anatomic tumor stage (according to the AJCC 8th edition Anatomic Stage Groups I, II andIII). PD-L1 status is determined by central pathology using the VENTANA PD-L1 (SP142) assay and is defined by PD-L1 IC expression. Patients in Arm A receive a 2-week monotherapy of Atezolizumab 840 mg q2w prior to initiation of a 12-week neoadjuvant CTX therapy with Paclitaxel 80 mg/m2 i.v. q1w x 12 doses + Carboplatin AUC of 2 i.v. q1w x 12 doses + Atezolizumab 1200 mg day 1 every 3 weeks for 4 doses followed by Epirubicin 90 mg/m2 + Cyclophosphamide 600 mg/m2, both q3w for 4 cycles + Atezolizumab 1200 mg day 1 every 3 weeks for 4 doses. Patients in Arm B are treated with a neoadjuvant 12-week regimen of Paclitaxel 80 mg/m² i.v. q1w x 12 doses + Carboplatin AUC of 2 i.v. q1w x 12 doses + Atezolizumab 1200 mg day 1 every 3 weeks for 4 doses without a monotherapy window. This is followed by Epirubicin 90 mg/m² + Cyclophosphamide 600 mg/m2, both q3w for 4 cycles + Atezolizumab 1200 mg day 1 every 3 weeks for 4 doses. Patients in both arms undergo surgery after 29 - 30 weeks therapy in total for Arm A and 27 - 28 weeks therapy in total for Arm B (3 - 4 weeks after last dose of neoadjuvant therapy). Safety and toxicities under therapy are supervised via regular DSMB meetings. After surgery, patients are treated according to the local SoC therapy for TNBC and followed-up for 24 months.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Female and male patients, age at diagnosis 18 years and above
- •Written informed consent prior to admission to this study
- •Histologically confirmed unilateral primary invasive carcinoma of the breast
- •Clinical T1c - T4d
- •Stage N0-N3 until 21 patients (5%) with stage N3 are randomized, thereafter N0-N2
- •Triple negative breast cancer defined by and confirmed by central pathology:
- •ER negative (\<10% positive cells in IHC) and PR negative (\<10% positive cells on IHC)
- •HER2 negative breast cancer:
- •Either defined by IHC: ICH scores of 0-1 or an ICH score of 2 in combination with a negative in-situ-hybridization (ISH)
- •Or defined by ISH: negative ISH
Exclusion Criteria
- •Previous history of malign diseases, non-melanoma skin cancer and carcinoma of the cervix are allowed if treated with curative intent
- •Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of Paclitaxel, Carboplatin, Epirubicin, Cyclophosphamide or Atezolizumab
- •Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol
- •Concurrent treatment with other drugs that are contraindicating the use of the study drugs
- •Existing pregnancy
- •Breastfeeding
- •Sequential breast cancer
- •Concurrent treatment with other experimental drugs and participation in another clinical trial or clinical research project (except registry study) within 30 days prior to study entry
- •Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study including but not confined to:
- •Uncompensated chronic heart failure or systolic dysfunction (LVEF \< 55%, congestive heart failure (CHF) New York Heart Association (NYHA) classes II-IV),
Arms & Interventions
Arm A
2 weeks Atezolizumab monotherapy before biopsy, followed by a 12-week therapy with Paclitaxel + Carboplatin+ Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.
Intervention: Atezolizumab 840 MG in 14 ML Injection
Arm A
2 weeks Atezolizumab monotherapy before biopsy, followed by a 12-week therapy with Paclitaxel + Carboplatin+ Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.
Intervention: Atezolizumab 1200 MG in 20 ML Injection
Arm A
2 weeks Atezolizumab monotherapy before biopsy, followed by a 12-week therapy with Paclitaxel + Carboplatin+ Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.
Intervention: Carboplatin
Arm A
2 weeks Atezolizumab monotherapy before biopsy, followed by a 12-week therapy with Paclitaxel + Carboplatin+ Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.
Intervention: Paclitaxel
Arm A
2 weeks Atezolizumab monotherapy before biopsy, followed by a 12-week therapy with Paclitaxel + Carboplatin+ Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.
Intervention: Epirubicin
Arm A
2 weeks Atezolizumab monotherapy before biopsy, followed by a 12-week therapy with Paclitaxel + Carboplatin+ Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.
Intervention: Cyclophosphamide
Arm A
2 weeks Atezolizumab monotherapy before biopsy, followed by a 12-week therapy with Paclitaxel + Carboplatin+ Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.
Intervention: Biopsy Arm A
Arm A
2 weeks Atezolizumab monotherapy before biopsy, followed by a 12-week therapy with Paclitaxel + Carboplatin+ Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.
Intervention: Surgery
Arm B
12-week therapy with Paclitaxel + Carboplatin + Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.
Intervention: Atezolizumab 1200 MG in 20 ML Injection
Arm B
12-week therapy with Paclitaxel + Carboplatin + Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.
Intervention: Carboplatin
Arm B
12-week therapy with Paclitaxel + Carboplatin + Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.
Intervention: Paclitaxel
Arm B
12-week therapy with Paclitaxel + Carboplatin + Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.
Intervention: Epirubicin
Arm B
12-week therapy with Paclitaxel + Carboplatin + Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.
Intervention: Cyclophosphamide
Arm B
12-week therapy with Paclitaxel + Carboplatin + Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.
Intervention: Biopsy Arm B
Arm B
12-week therapy with Paclitaxel + Carboplatin + Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.
Intervention: Surgery
Outcomes
Primary Outcomes
Pathological Complete Response (ypT0/is, ypN0)
Time Frame: after 29-30 weeks in Arm A and after 27-28 weeks in Arm B.
Pathological Complete Response defined as no residual invasive tumor cells in the breast and in the lymph nodes (ypT0/is, ypN0).
Secondary Outcomes
- Number of Adverse Events by Grade(from date of randomization up to 24 months)
- Pathological Complete Response (ypT0/is, ypN0) (ER/PR Expression of <1%).(after 29-30 weeks in Arm A and after 27-28 weeks in Arm B)
- Pathological Complete Response (ypT0/is, ypN0) (ER/PR Between 1 and 10 %).(after 29-30 weeks in Arm A and after 27-28 weeks in Arm B)
- Pathological Complete Response (ypT0, ypN0)(after 29-30 weeks in Arm A and after 27-28 weeks in Arm B.)
- Near Pathological Complete Response (Near pCR)(after 29-30 weeks in Arm A and after 27-28 weeks in Arm B.)
- Pathological Complete Response (no Invasive Tumor)(after 29-30 weeks in Arm A and after 27-28 weeks in Arm B.)
- Decrease of Ki-67 Expression by ≥ 30% Compared to Baseline as Continuous Predictor After 14 (Arm A)/28 Days (armB) (+/- 2 Days) of Treatment(after 14/28 days (+/- 2 days) of treatment)
- Decrease of Ki-67 Expression After 28 Days (+/- 2 Days) of Treatment for Arm A and Arm B.(after 28 days (+/- 2 days) of treatment)
- Stromal Tumor-infiltrating Lymphocytes (TILs) ≥ 60% After 14 (Arm A)/28 Days (ArmB)(after 14/28 days (+/- 2 days) of treatment)
- Tumor-infiltrating Lymphocytes (TILs) ≥ 60% After 28 Days(after 28 days (+/- 2 days) of treatment)
- Complete Cell Cycle Arrest (CCCA) After 14 (Arm A)/28 Days (armB) (+/- 2 Days) of Treatment(after 14/28 days (+/- 2 days) of treatment)
- Complete Cell Cycle Arrest (CCCA) After 28 Days (+/- 2 Days) of Treatment(after 28 days (+/- 2 days) of treatment)
- Low Cellularity (< 500 Tumor Cells) After 14 (Arm A)/28 Days (Arm B) (+/- 2 Days) of Treatment(after 14/28 days (+/- 2 days) of treatment)
- Low Cellularity (< 500 Tumor Cells) After 28 Days (+/- 2 Days) of Treatment(after 28 days (+/- 2 days) of treatment)
- Combined Early Response After 14 (Arm A)/28 (Arm B) Days (+/- 2 Days) of Treatment(after 14/28 days (+/- 2 days) of treatment)
- Combined Early Response After 28 Days (+/- 2 Days) of Treatment(after 28 days (+/- 2 days) of treatment)
- Disease Free Survival (DFS)(from randomization up to 24 months until date of occurrence of no disease to the first occurrence of disease recurrence or death from any cause)
- Overall Survival (OS).(from randomization up to 24 months until date of death from any cause.)
- Event Free Survival (EFS)(from randomization up to 24 months until date of death from any cause, failure to achieve remission after induction therapy, relapse in any site, or second malignancy)