Impact of neoadjuvant immunotherapy in early stage breast cancer before standard therapy (BIS-Program)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Gustave Roussy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

7 Mar 2022 → 17 Dec 2024

Decision date (initial)

2024-09-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-512826-26-00

EudraCT number

2020-004696-41

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

To determine, using immunohistochemistry (IHC) on biopsies and surgically removed tumor whetherif short-treatment immunotherapy with atezolizumab in combination with other biologic agents is associated with increased levels of activated GzmB+ CD8+ T cells from baseline to post treatment sample compared to the control arm (TNBC Cohort: Atezolizumab; HER2+ Cohort: Trastuzumab + Pertuzumab).

Secondary objectives 8

1. To determine, using immunohistochemistry (IHC) on biopsies and surgically removed tumor whether short-treatment immunotherapy with atezolizumab in combination with other biologic agents is associated with increased immunogenicity as determined by increase ratio of GzmB/CD8, CD8/FoxP3, CD8/CD68 ratio baseline to post treatment sample
2. To assess the safety and tolerability of study treatments in this population
3. To determine the effect of short-term immunotherapy treatment in pCR at surgery
4. To assess the effect of immunotherapy alone or in combination with other therapies in tumor cell proliferation
5. To determine modifications of different immune biomarkers under treatment vs baseline including but not limited to CD8, PD-L1 and MHC-I
6. To assess changes in immune-related gene expression, in tumor tissue prior to and after study treatment as performed by RNA-seq
7. To assess the effect of immunotherapy on pCR in patients treated with neoadjuvant chemotherapy
8. To assess development of post-treatment anti-drug-antibody (ADA) against Pembrolizumab induced by prior administration of atezolizumab in TNBC patients who will have Pembrolizumab as neoadjuvant systemic treatment.

Conditions and MedDRA coding

Newly diagnosed, non-metastatic early-stage triple-negative or HER2+ breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 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
2. Female or male patients aged 18 years or older
3. ECOG performance status 0-1
4. Patients with histologically confirmed breast cancer with no evidence of metastatic spread
5. 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
6. At least 11 mm in tumor size as determined by breast ultrasound
7. ER, PR and HER2 will be locally assessed and defined as per the french national guidelines: o For the TNBC cohort, ER≤10%, PR≤10% and HER2 not overexpressed/amplified o For the HER2-positive cohort, presence of a HER2 overexpression and/or amplification as per ASCO/CAP guidelines
8. 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.
9. 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 after the last dose of pertuzumab and/or trastuzumab.
10. 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
11. 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 and 7 months after the last dose of pertuzumab and/or trastuzumab. Female subjects should also refrain from breastfeeding throughout this period
12. 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).
13. 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 bevacizumaband 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.
14. Patients must be affiliated to a social security system or beneficiary of the same

Exclusion criteria 36

1. Evidence of metastatic breast cancer
2. ER≥10% or PR≥10% and/or HER2+ (for the TNBC cohort) and HER2- (for the HER2+ cohort)
3. Any systemic therapy (e.g, chemotherapy, targeted therapy, immune-therapy) or radiotherapy for current breast cancer disease before study entry
4. Previous systemic treatment for other neoplasms within 1 year prior to randomization
5. 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
6. Known intolerance to any of the study drugs or any of their excipients
7. Patients with prior allogeneic stem cell or solid organ transplantation
8. 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
9. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin−2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment
10. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate and thalidomide) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: o Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids as premedication for hypersensitivity reaction (e.g., CT scan premedication)) are eligible for the study after Medical Monitor approval has been obtained o Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study o Patients who received intranasal, inhaled, topical or local steroid injections (e.g., intra articular injection)
11. 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
12. Symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea
13. 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).
14. Patients who underwent major surgery within 28 days prior to inclusion or until the surgical wound is fully healed
15. History of HIV infection
16. Patients with active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
17. Patients with a history of cirrhosis
18. Active tuberculosis
19. Current treatment with anti-viral therapy for HBV
20. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies
21. Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol
22. Participation in another clinical study with an investigational product during the last 28 days and while on study treatment
23. Currently known to have a history or ongoing serious retinopathy and/or history of retinal vein occlusion
24. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
25. 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
26. Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
27. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
28. Significant cardiovascular disease, such as: o History of myocardial infarction, acute coronary syndromes or coronary angioplasty/stenting/bypass grafting within the past 6 months, o Congestive Heart Failure (CHF) NYHA class III or IV or history of CHF NYHA class III or IV, unless an echocardiogram or multi-gated acquisition scan performed within 3 months day 1 reveals a left ventricular ejection fraction ≥ 55%
29. 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
30. History of stroke or transient ischemic attack within 6 months prior to randomisation
31. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomisation
32. 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
33. 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
34. Pregnant or breastfeeding women
35. Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent.
36. For the TNBC cohort (exclusion criteria in relation to bevacizumab): • 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 • Currently known to have a history or ongoing serous retinopathy and/or history of retinal vein occlusion • History of stroke or transient ischemic attack within 6 months prior to randomization • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomization • 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 randomization • History of active inflammatory bowel disease (e.g. Crohn’s disease and ulcerative colitis) or active bowel inflammation (e.g. diverticulitis) • Grade  2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia • Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections (pneumocystis pneumonia or cytomegalovirus pneumonia) • Known clinically significant history of liver disease consistent with Child Pugh Class B or C, including active viral or other hepatitis (e.g., positive for hepatitis B surface antigen [HBsAg] or hepatitis C virus [HCV] antibody at screening), current drug or alcohol abuse, or cirrhosis

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Presence/ of two-fold increase in GzmB+ CD8+ T cell levels from baseline to post-treatment window in biopsies.

Secondary endpoints 6

1. Changes in CD8+, PD-L1, MHC-I and % of Ki67 expression from baseline (pre-study) to end of study-treatment biopsies
2. Changes from baseline tumor tissue to end of treatment in immune infiltrates, immune-related gene expression
3. Incidence, nature and severity of Adverse Events graded according to NCI-CTCAE v5.0 collected during treatment and up to 4 weeks post-surgery
4. Clinical response after experimental therapy, defined as a > 30% decrease in tumor diameter from baseline breast ultrasound based on investigator assessment
5. pCR defined as the absence of any residual invasive cancer based on histological evaluation of the resected specimen during definitive breast cancer surgery
6. Rate of anti-Pembrolizumab antibodies at day 1 of cycle 2 Pembrolizumab (only patients in TNBC cohort, who will have Pembrolizumab as neoadjuvant systemic treatment).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Gustave Roussy

Sponsor organisation

Institut Gustave Roussy

Address

114 Rue Edouard Vaillant

City

Villejuif

Postcode

94800

Country

France

Scientific contact point

Organisation

Institut Gustave Roussy

Contact name

Bureau projet Promotion- DRC

Public contact point

Organisation

Institut Gustave Roussy

Contact name

Bureau projet Promotion- DRC

Locations

1 EU/EEA country · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 4 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications