Tiragolumab and atezolizumab associated with chemotherapy in triple negative breast cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Curie, Institut Curie

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

27 Mar 2024 → ongoing

Decision date (initial)

2023-06-14

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Others

To determine the efficacy of a double immunotherapy based on atezolizumab-tiragolumab combination associated with chemotherapy in cohort A (early setting) and cohort B (metastatic setting) among patients with TNBC.

Secondary objectives 7

1. To determine the safety and tolerability of atezolizumab, tiragolumab and chemotherapy.
2. To further assess the efficacy of a double immunotherapy based on atezolizumab-tiragolumab combination associated with chemotherapy as measured by: - For cohort A: alternative definitions of pCR rate, 3 years-iDFS and OS. - For cohort B: ORR, DoR, 6 months-CBR and OS.
3. To describe the changes in Patient Reported Outcomes (PROs) and Health-Related Quality of Life (HRQOL) in patients treated with atezolizumab, tiragolumab and chemotherapy.
4. To evaluate the performance of potentially predictive or prognostic (bio)markers, including those associated with tumor heterogeneity and plasticity upon treatment.
5. To investigate 68Ga-FAPI PET/CT clinical validity as compared to 18F-FDG-PET/CT in TNBC patients treated with atezolizumab, tiragolumab and chemotherapy.
6. To compare the prognostic impact of the conventional and standardized response assessment using PERCIST 1.0 (metabolic criteria: 18F-FDG PET only) with new criteria for immunotherapy using PERCIMT, “PET Response Evaluation Criteria for Immunotherapy” (combined criteria: 18F-FDG PET and CT scan).
7. To identify improved tools for surveillance and monitoring of TNCB patients.

Conditions and MedDRA coding

Early and metastatic triple negative breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 23

1. Age ≥ 18 years old
2. Female
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
4. Histological diagnosis of carcinoma of the breast, acccording to AJCC 8th edition that is estrogen receptor negative (ER-), progesterone receptor negative (PR-) and HER2- negative according to local testing on the most recent tumor sample examined. a. ER-negative and PR-negative are defined as having an immunohistochemistry (IHC) < 10% b. HER2 negative is defined as per the 2018 American Society of Clinical Oncology (ASCO) - College of American Pathologists (CAP) guidelines Note: Cohort A (early setting): patients will be enrolled regardless of their tumor PD-L1 status. Cohort B (metastatic setting): patients will be enrolled regardless of their tumor PD-L1 status but participants with PD-L1 negative tumor status (i.e.<1% defined by Immunohistochemistry with Ventana SP142) will be capped at 40%. i.e.<1% defined by immunohistochemistry with Ventana SP142) will be capped at 40%.
5. Agreement to perform new study-related biopsies and blood sampling as described in the study schedule of activity.
6. Tumor considered as accessible by biopsy, according to the investigator. Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, and lavage samples are not acceptable. Tumor tissue from bone metastases is not acceptable.
7. For female of childbearing potential (WCBP): negative serum or urinary pregnancy test within 2 weeks prior to first dose of study administration.
8. Women of childbearing potential must agree to use one highly effective method of contraception during the screening period, during the course of the study and at least 12 months after the last administration of study treatment.
9. Adequate bone marrow function as defined below: Absolute neutrophil count ≥1000/μL, i.e., 1.0x109/L, Hemoglobin ≥ 9.0 g/dL, Platelets ≥100000/μL, i.e., 100x109/L
10. Adequate liver function as defined below: Serum total bilirubin ≤ 1.5 x ULN. In case of known Gilbert’s syndrome ≤ 3 x UNL is allowed; AST ≤ 3.0 x ULN, ALT ≤ 3.0 x ULN
11. Adequate renal function as defined below: Creatinine ≤ 1.5 x UNL or eGFR≥40ml/min/1.73m²
12. Adequate coagulant function as defined below: International Normalized Ratio (INR) ≤ 1.5 x ULN
13. Completion of all necessary screening procedures within 28 days prior to inclusion
14. Signed Informed Consent form (ICF) obtained prior to any study related procedure
15. Patients must be covered by a health insurance system
16. Cohort A only: For tumor stage T1c, nodal stage N1-2, by at least one radiographic or clinical measurement. For tumor stage T2-4, nodal stage N0-2, by at least one radiographic or clinical measurement.
17. Cohort A only: Multifocal, multicentric unilateral or bilateral breast adenocarcinoma tumors are allowed provided that all foci are ER-/PR-/HER2- according to local testing.
18. Cohort A only: Left ventricular ejection fraction (LVEF) ≥ 50%.
19. Cohort B only: No prior line of chemotherapy / or systemic therapy for metastatic disease (patients with known germline BRCA1 or BRCA2 mutations may have been treated with one prior line of therapy with PARP inhibitor).
20. Cohort B only: Radiation therapy for metastatic disease is permitted. There is no required washout period for radiation therapy. Patients should be recovered from the effects of radiation.
21. Cohort B only: Prior chemotherapy in the neoadjuvant or adjuvant setting is allowable if treatment was completed  12 months prior to inclusion.
22. Cohort B only: Patients with documented liver metastases: AST and ALT Patients with documented liver metastases: AST and ALT  5  ULN
23. Cohort B only: Have a life expectancy of at least 3 months.

Exclusion criteria 28

1. Pregnant and/or lactating women
2. Contra-indications to 18F-FDG PET/CT and/or 68Ga-FAPI-46 PET/CT
3. Patients in whom tumor deposits are not detected by 18F-FDG PET/CT
4. Subject with a significant medical, neuro-psychiatric, substance abuse or surgical condition, currently uncontrolled by treatment, which, in the principal investigator’s opinion, may interfere with completion of the study.
5. TNM stage T4d breast cancer (inflammatory breast cancer).
6. Known HIV
7. Active infection including: Hepatitis B (known positive HBV surface antigen (HBsAg) result). Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible; Hepatitis C. Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
8. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, active tuberculosis, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the subject to give written informed consent
9. Concomitant use of other investigational drugs
10. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia. Subjects with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician
11. Active or prior documented autoimmune disease (including inflammatory bowel disease, celiac disease, Wegener’s granulomatosis) within the past 3 years. Note: Subjects with childhood atopy or asthma, vitiligo, alopecia, Grave’s disease, Hashimoto’s thyroiditis, on a stable dose of thyroid replacement hormone or psoriasis not requiring systemic treatment (within the past 2 years), and patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are not excluded.
12. Known history of, or any evidence of active, non-infectious pneumonitis. (Note: History of radiation pneumonitis in the radiation field [fibrosis] is permitted).
13. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
14. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary (CHO) cells or any component of the atezolizumab formulation
15. Any live (attenuated) vaccine within 30 days of planned start of study therapy
16. Treatment with systemic immunosuppressive medications (including but not limited to corticosteroids, cyclophosphamide, azathioprine, cyclosporine, methotrexate, thalidomide, and antitumor necrosis factor [TNF] agents) within 2 weeks prior to inclusion, or anticipated requirement for systemic immunosuppressive medications during the trial. a. Patients who have received acute, low-dose (≤ 10 mg oral prednisone or equivalent), systemic immunosuppressant medications may be enrolled in the study. b. The use of corticosteroids (≤10 mg oral prednisone or equivalent) for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low dose supplemental corticosteroids for adrenocortical insufficiency are allowed
17. Prior treatment with anti-PD-1 or anti-PD-L1 therapeutic antibody within 6 months
18. Prior allogeneic stem cell or solid organ transplantation
19. Known active EBV
20. Known lymphoepithelioma-like carcinoma
21. Patients with an obstruction of urine flow (according to the current SmPc of cyclophosphamide)
22. Oligometastatic patients if they require locoregional treatment
23. Cohort A: Presence of any distant metastasis
24. Cohort A: Known germline BRCA1 or BRCA2 mutation
25. Cohort A: Contra-indication for treatment by nab-paclitaxel, doxorubicin, cyclophosphamide, carboplatin or known allergy to any tested substances or any excipients (e.g; chemotherapy or immunotherapy formulations).
26. Cohort B: Contra-indication for treatment by nab-paclitaxel or known allergy to any tested substances or any excipients (e.g; chemotherapy or immunotherapy formulations).
27. Cohort B: Leptomeningeal disease and known CNS disease, except for treated asymptomatic CNS metastases, provided all of the following criteria are met: - Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, pons, medulla, or spinal cord) - Treated and stable CNS metastases since at least 4 weeks before inclusion, - No ongoing requirement for corticosteroids as therapy for CNS disease - No stereotactic radiation within 7 days or whole brain radiation within 14 days prior to inclusion - No evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study Note: asymptomatic brain metastases discovered during the screening, by e.g. 68Ga-FAPI-46 PET/CT and deemed accessible to stereotactic radiation therapy could remain in the study after discussion with the study medical monitors.
28. Cohort B: Prior malignancy other than breast cancer active within the previous 5 years, except for localized cancers that are considered to have been cured and in the opinion of the investigator present a low risk for recurrence. Examples include basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Cohort A: rate of pathological complete response (pCR) defined as ypT0/Tis ypN0 (i.e., no invasive residual in breast or nodes; as centrally assessed at the time of definitive surgery). Cohort B: 6 months progression-free survival rate (6 months-PFS), defined as the proportion of patients without progression (as assessed by central review per Positron Emission Tomography Response Evaluation Criteria in Solid Tumors (PERCIST) v1.0) or death within 6 months after the date of inclusion.

Secondary endpoints 7

1. SAEs (serious adverse events) and AEs (adverse events) according to NCI CTCAE v5.0, by grade and their relationship to atezolizumab and/or tiragolumab and/or chemotherapy.
2. Alternative definition of pCR rate: - ypT0 ypN0 - Residual cancer burden (RCB) - 3 years-iDFS (invasive disease-free survival) - ORR (objective response rate) - DoR (duration of response) - 6-month-CBR (clinical benefit rate) - OS (overall survival)
3. The 5 Dimension 5 Level (EQ-5D-5L) scale measured at different timepoints. The measures of interest are: - The mean difference in the change from baseline to different timepoints in total/subscale scores. - Time to deterioration in pain, physical functioning, and role functioning and global health status/QoL.
4. Relationship between clinical characteristics, efficacy outcomes and candidate (bio)markers of response, which may include, but are not limited to: - proteins (PD-L1 expression…), - RNA and DNA analyses, omics analysis in tumor tissues or blood (ctDNA…), - functional imaging (PET/CT) analysis - combination of the biomarkers mentioned above, such as omics - combination of the biomarkers mentioned above, such as omics data, ctDNA, 68Ga-FAPI and 18F-FDG.
5. Comparison of 68Ga-FAPI PET/CT and 18F-FDG PET/CT prognostic performances, separately and combined.
6. To determine which criteria for response assessment (PERCIST 1.0 versus PERCIMT) are most directly correlated to clinical outcomes.
7. Quantitative and qualitative analyses of circulating tumor DNA (ctDNA) collected at baseline and during therapy. - Analysis of combined detection of ctDNA, 68Ga-FAPI and 18F-FDG-PET/CT.

Investigational products

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

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Curie

Sponsor organisation

Institut Curie

Address

26 Rue D Ulm

City

Paris

Postcode

75005

Country

France

Scientific contact point

Organisation

Institut Curie

Contact name

François-Clément Bidard

Public contact point

Organisation

Institut Curie

Contact name

François-Clément Bidard

Institut Curie

Sponsor organisation

Institut Curie

Address

26 Rue D Ulm

City

Paris

Postcode

75005

Country

France

Scientific contact point

Organisation

Institut Curie

Contact name

François-Clément Bidard

Public contact point

Organisation

Institut Curie

Contact name

François-Clément Bidard

Locations

1 EU/EEA country · 2 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 13 files

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

Application history

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