Breast Cancer
Conditions
Keywords
triple-negative breast cancer, HER2+ breast cancer, non-metastatic breast cancer, immunotherapy, atezolizumab, ipatasertib, bevacizumab, trastuzumab, pertuzumab, GzmB+, CD8+
Brief summary
The aim of this study is to determine, using immunohistochemistry (IHC) on biopsies and surgically removed tumor if short-treatment immunotherapy with atezolizumab monotherapy or in combination with other biologic agents (ipatasertib / Bevacizumab / Trastuzumab / Pertuzumab) is associated with increased levels of activated GzmB+ CD8+ T cells from baseline to post treatment sample. Moreover, from baseline to post treatment sample, evolution of others biomarkers will be studied : GzmB/CD8, CD8/FoxP3, CD8/CD68 in IHC, cell proliferation, PD-L1, MHC-I, change in gene expression (RNA-Seq). Tjis study aim also to assess the safety and tolerability of study treatments in this population and to determine the effect of short-term immunotherapy treatment in pCR at surgery. Patients will undergo tumor biopsies at screening and 15 days after the beginning of treatment (if they start neoadjuvant chemotherapy) / at surgery, in order to evaluate in IHC evolution of activated GzmB+ CD8+ T cells and evaluate other markers It targets 2 different cohorts: newly diagnosed, non-metastatic early-stage triple-negative (TNBC) or HER2+ breast cancer. TNBC cohort is composed of 2 open-label, randomized arms, HER2+ of 2 arms. A maximum of 185 patients will be included in the trial Tumor evaluation will be performed by clinical examination and Breast echography at baseline and end of treatment visit. The safety of the product will be assessed at each cycle, through complete clinical exams, biological tests and through the collection of ongoing toxicities or adverse events.
Detailed description
Cohort 1 In TNBC patients t will be composed of 4 open-label, randomized arms: Arm 1A: atezolizumab alone, administered as one single IV infusion on day -15 +/- 48 h Arm 1B: atezolizumab and bevacizumab as one single IV infusion on day -15 +/- 48 h (D1) prior to the date of surgery or the start of the standard of care neoadjuvant systemic treatment. Cohort 2 in HER2-positive patients will be composed of 2 arms: Arm 2A: pertuzumab for one IV infusion on day -15 +/- 48 h (D1) prior to the date of surgery or the start of the standard of care neoadjuvant systemic treatment. Arm 2B: atezolizumab as one single IV infusion in combination with trastuzumab + pertuzumab for one IV infusion on day -15 +/- 48 h (D1) prior to the date of surgery or the start of the standard of care neoadjuvant systemic treatment.
Interventions
Patients randomized to an atezolizumab arm will receive atezolizumab 840 mg IV on D1 (15 days +/- 48 h before the surgery date or the biopsy prior to the start of standard of care neoadjuvant systemic treatment.).
DRUGBevacizumab
Patients in the atezolizumab plus bevacizumab arm will receive a unique dose of bevacizumab as 10 mg/kg administered by IV infusion over 60 mins on day 1 cycle 1 (15 days before surgery +/- 48 h), the same day as atezolizumab.
DRUGPertuzumab
Patients in the atezolizumab plus trastuzumab plus pertuzumab arm will receive single doses of pertuzumab on day 1 administered IV. Pertuzumab will be administered IV at a loading dose of 840 mg.
DRUGTrastuzumab
Patients in the atezolizumab plus trastuzumab plus pertuzumab arm will receive single doses of Trastuzumab on day 1 administered IV. Trastuzumab will be given at a loading dose of 8 mg/kg.
Sponsors
Hoffmann-La Roche
Gustave Roussy, Cancer Campus, Grand Paris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The design of this study follows an adaptive, open, prospective randomized model : Cohort 1 TNBC patients: they will be randomized 1:1 to either atezolizumab alone administered as one single IV infusion on day -15 +/- 48h prior to the date of surgery or the start of the standard of care neoadjuvant systemic treatment, or atezolizumab and bevacizumab as one single IV infusion on day -15 +/- 48h prior to the date of surgery or the start of neoadjuvant treatment Cohort 2 in HER2-positive patients: they will be randomized 1:1 to either trastuzumab and pertuzumab for one IV infusion on day -15 +/- 48h prior to the surgery or the start of neoadjuvant treatment, or atezolizumab as one single IV infusion in combination with trastuzumab and pertuzumab for one IV infusion on day -15 +/- 48h prior to the surgery or the start of neoadjuvant treatment
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol. * Female or male patients aged 18 years or older * Eastern Cooperative Group (ECOG) Performance Status 0-1 * Histologically confirmed female breast cancer with no evidence of metastatic spread * Candidate to surgery upfront or patients with an indication to standard of care neoadjuvant systemic treatment, assuming that systemic treatment starts after the completion of the pre-operative immunotherapy treatment, biopsies are undertaken before the start of the systemic treatment and the decision to administer neoadjuvant systemic treatment is made before randomization * At least 11 mm in tumor size as determined by breast ultrasound * ER, PR and HER2 will be locally assessed and defined as per the french national guidelines: * For the TNBC cohort, ER≤10%, PR≤10% and HER2 not overexpressed/amplified * For the HER2-positive cohort, presence of a HER2 overexpression and/or amplification as per ASCO/CAP guidelines * Adequate haematologic and organ function defined by the following: * ANC ≥ 1,500 cells/µl * Platelet count ≥ 100,000/µl * Haemoglobin ≥ 9.0 g/dL (90g/L) * Serum albumin ≥ 2.5 g/dL * Creatinine ≤ 1.5 x ULN * Bilirubin ≤ 1.5 x ULN, AST or ALT \< 3 x ULN, ALP \< 2.5 x ULN (patients with known Gilbert disease who have serum bilirubin level ≤ 3 × the institutional ULN may be enrolled) * For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen * Patients of child-bearing potential are eligible, provided they have a negative serum β-HCG pregnancy test within 2 weeks or urine pregnancy test within 48 hours prior to the first dose of study treatment, and agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of \< 1% per year during the treatment period and for 5 months after the last dose of atezolizumab, 6 months after the last dose of bevacizumab, 28 days after the last dose of ipatasertib and 7 months after the last dose of pertuzumab and/or trastuzumab. * A woman is considered of childbearing potential following menarche and until becoming post-menopausal (≥ 12 months of non-therapy-induced amenorrhea) unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral oophorectomy and bilateral salpingectomy. * Sexually active women of childbearing potential must agree to use a highly effective method of contraception supplemented by a barrier method, or to abstain from sexual activity during the study and for at least 5 months after discontinuation of atezolizumab treatment, 6 months after the last dose of bevacizumab, 28 days after the last dose of ipatasertib and 7 months after the last dose of pertuzumab and/or trastuzumab. Female subjects should also refrain from breastfeeding throughout this period. * A highly effective birth control method is a one, which can achieve a failure rate of less than 1% per year when used consistently and correctly. Such methods include: combined (estrogen and progestogen containing) hormonal contraception; progestogen-only hormonal contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner (on the understanding that this is the only one partner during the whole study duration), and sexual abstinence during the entire period of risk associated with study treatment. To prevent the risk of interaction between the study drug and hormonal contraceptives, hormonal contraceptives should be supplemented with a barrier method (preferably male condom). Following methods are considered as unacceptable methods (non-exhaustive list): periodic abstinence (calendar, symptothermal, post-ovulation methods) and withdrawal (coitus interruptus). * Sexually actives males patients must agree to use condom during the study and for at least 5 months after discontinuation of atezolizumab treatment, 6 months after the last dose of bevacizumab, 28 days after the last dose of ipatasertib and 7 months after the last dose of pertuzumab and/or trastuzumab. Also, it is recommended their women of childbearing potential partner use a highly effective method of contraception for the same duration. * Patients must be affiliated to a social security system or beneficiary of the same.
Exclusion criteria
Patients who meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Two-fold increase in GzmB+ CD8+ T cell levels from baseline to post-treatment window. | From baseline to post-treatment (14 days) window. | To determine, using immunohistochemistry (IHC) on biopsies and surgically removed tumor whether short-treatment immunotherapy with atezolizumab monotherapy or in combination with other biologic agents is associated with increased levels of activated GzmB+ CD8+ T cells from baseline to post treatment sample. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| pCR | From baseline to post-treatment (14 days) window. | pCR defined as the absence of any residual invasive cancer based on histological evaluation of the resected specimen during definitive breast cancer surgery. |
| Changes in CD8+ expression (Translational Study) | From baseline to post-treatment (14 days) window. | Changes in CD8+ expression from baseline (pre-study) to end of study-treatment biopsies |
| Changes in PD-L1 expression (Translational Study) | From baseline to post-treatment (14 days) window. | Changes in PD-L1 expression from baseline (pre-study) to end of study-treatment biopsies |
| Clinical response after experimental therapy | From baseline to post-treatment (14 days) window. | Clinical response after experimental therapy, defined as a \> 30% decrease in tumour diameter from baseline breast ultrasound based on investigator assessment |
| Changes in immune infiltrates (Translational Study) | From baseline to post-treatment (14 days) window. | Changes from baseline tumour tissue to end of treatment in immune infiltrates. |
| Changes in immune-related gene expression (Translational Study) | From baseline to post-treatment (14 days) window. | Changes from baseline tumour tissue to end of treatment in immune-related gene expression |
| Changes in % of Ki67 (Translational Study) | From baseline to post-treatment (14 days) window. | Changes in % of Ki67 from baseline (pre-study) to end of study-treatment biopsies |
Countries
France
Outcome results
None listed