| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly diagnosed, non-metastatic early triple negative or HER2+ breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Early brest cancer newly diagnosed |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075566 |
| E.1.2 | Term | Triple negative breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10065430 |
| E.1.2 | Term | HER2 positive breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine, using immunohistochemistry (IHC) on biopsies and surgically removed tumor if short-treatment immunotherapy is associated with increase of activated GzmB+ CD8+ T cells levels from baseline to post treatment sample |
|
| E.2.2 | Secondary objectives of the trial |
• To determine, using immunohistochemistry (IHC) on biopsies pre and post-treatment if short-treatment immunotherapy is associated with an increase in immunogenicity as determined by increase ratio of GzmB/CD8, CD8/FoxP3, CD8/CD68 ratio, as compared to control arm
• To assess the safety and tolerability of study treatments in this population
• To determine the effect of short-term immunotherapy treatment in pCR at surgery
• To assess the effect of immunotherapy alone or in combination with other therapies in tumor cell proliferation
• To determine modifications of different immune biomarkers under treatment vs baseline including but not limited to CD8, PDL-1 and MHC-I
• To assess changes in immune-related gene expression, in tumor tissue prior to and after study treatment as performed by RNA-seq
• To assess the effect of immunotherapy on pCR in patients treated with neoadjuvant chemotherapy
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Patient should understand, sign, and date the written informed consent form (including the consent to collect tissue, blood and stool samples, as specified by the protocol) prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol.
- Female patients aged 18 years or older
- ECOG performance status 0-1
- Female patients with histologically confirmed breast cancer with no evidence of metastatic spread
- Candidate to surgery upfront or patients with an indication of neoadjuvant chemotherapy, assuming chemotherapy starts after the completion of the pre-operative immunotherapy treatment, biopsies are undertaken before the start of the systemic chemotherapy and the decision to administer neoadjuvant chemotherapy 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 ASCO/CAP guidelines
o For the TNBC cohort, ER < 1%, PR < 1% and HER2 not overexpressed/amplififed
o 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:
o ANC ≥> 1,500 cells/µl
o Platelet count ≥> 100,000/µl
o Haemoglobin ≥ 9.0 g/dL (90 g/L)
o Serum albumin ≥> 2.5 g/dL
o Creatinine ≤ 1.5 x ULN
o 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)
o 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 bevacuzimab and 7 months for 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, 6 months after the last dose of ipatasertib and 7 months after the last dose of pertuzumab and 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).
- Patients must be affiliated to a social security system or beneficiary of the same
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|
| E.4 | Principal exclusion criteria |
- Evidence of metastatic breast cancer
- HR+ and/or HER2+ (for the TNBC cohort) and HER2- (for the HER2+ cohort)
- Any systemic therapy (...) or radiotherapy for current breast cancer disease before study entry
- Previous systemic treatment for other neoplasms within 1 year prior to randomization
- Active malignancy (except for non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in-situ) within the past 36 months prior to study entry
- Known intolerance to any of the study drugs or any of their excipients
- Patients with prior allogeneic stem cell or solid organ transplantation
- Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study or within 5 months after the last dose of atezolizumab
- Treatment with systemic immunostimulatory agents (...) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment
- Treatment with systemic immunosuppressive medication (...) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: (...)
- Active or history of autoimmune disease or immune deficiency, with the exception of history of treated autoimmune-related hypothyroidism and Type 1 diabetes mellitus on insulin regimen
- History of idiopathic pulmonary fibrosis (including pneumonitis or interstitial lung disease), drug-induced pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis (history of radiation pneumonitis in the radiation field (fibrosis) is permitted).
- History of HIV infection
- Patients with active hepatitis infection (...) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (...) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
-Active tuberculosis
-Current treatment with anti-viral therapy for HBV
-Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies
-Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol
-Participation in another clinical study with an investigational product during the last 28 days and while on study treatment
-Currently known to have a history or ongoing serious retinopathy and/or history of retinal vein occlusion
-History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
-Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation or to any component of the other drugs on the study
-Severe infection within 4 weeks prior to initiation of study treatment (...)
-Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
-Significant cardiovascular disease, such as (...)
-Uncontrolled hypertension defined by systolic pressure > 150 and/or diastolic pressure > 110 mmHg, with or without anti-hypertensive medication. Patients with initial blood pressure elevations are eligible if initiation or adjustment of anti-hypertensive medication lowers blood pressure to meet entry criteria
-History of stroke or transient ischemic attack within 6 months prior to randomisation
-History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomisation
-History of haemoptysis (> 1/2 teaspoon of bright red blood per episode) or other serious haemorrhage or at risk of bleeding (gastrointestinal history of bleeds, gastrointestinal ulcers etc.) within 1 month prior to randomisation
-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 an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent
-Pregnant or breastfeeding women
-Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent.
-For TNBC Cohort (...) : uncontrolled hypertension, serous retinopathy, strock or transient ischemic attack (<6months), abdominal dysfunction (<6months), haemoptysis, alteration of medications absorption, Clinically significant abnormalities of glucose metabolism, bowel inflammation disease, treatment with strong CYP3A inhibitors/inducers, Grade >= 2 hypercholesterolemia or hypertriglyceridemia, lung and/or liver disease. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Two-fold increase in GzmB+ CD8+ T cell levels from baseline to post-treatment window |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Changes in CD8+, PDL-1 and % of Ki67 expression from baseline (pre-study) to end of study-treatment biopsies
• Changes from baseline in PD-L1 and MHC-I levels to end-of study-treatment
• Changes from baseline tumor tissue to end of treatment in immune infiltrates, immune-related gene expression
• Incidence, nature and severity of Adverse Events graded according to NCI-CTCAE v5.0 collected during treatment and up to 4 weeks post-surgery
• Clinical response after experimental therapy, defined as a > 30% decrease in tumor diameter from baseline breast ultrasound based on investigator assessment
• pCR defined as the absence of any residual invasive cancer based on histological evaluation of the resected specimen during definitive breast cancer surgery.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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