Atezolizumab plus RP1 oncolytic immunotherapy in the NeoAdjuvant setting of Triple-Negative Breast Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Curie

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

5 Apr 2024 → 7 May 2025

Decision date (initial)

2023-08-18

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

F. Hoffmann-La Roche Ltd · REPLIMUNE, Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

Safety run-in: To evaluate safety and toxicity of the combination Atezolizumab plus RP1 oncolytic immunotherapy.
Phase II: To evaluate the rate of Residual Cancer Burden (RCB) 0-1, as assessed by local pathologist, at the time of definitive surgery in subjects with early TNBC who have completed at least one cycle of treatment.

Secondary objectives 11

1. To evaluate the safety and toxicity of the combination therapy for all evaluable patients with less than 3 cycles of treatment
2. To evaluate the rate of RCB 0-1; for the patients with no increase in ctDNA after cycle 3
3. To evaluate the safety and toxicity of the combination therapy, for the patients with no increase in ctDNA after cycle 3
4. To assess the invasive disease-free survival (iDFS), for the patients with no increase in ctDNA after cycle 3
5. To correlate the percentage of baseline TILs with RCB 0-1 rates, for the patients with no increase in ctDNA after cycle 3
6. To correlate baseline PD-L1 expression with RCB 0-1 rates, for the patients with no increase in ctDNA after cycle 3
7. To correlate the response by PET-CT with RCB 0-1 rates, for the patients with no increase in ctDNA after cycle 3
8. To correlate the response by breast MRI with RCB 0-1 rates, for the patients with no increase in ctDNA after cycle 3
9. To evaluate the rate of Breast Conservation Surgery (BCS) at the time of definitive surgery, for the patients with no increase in ctDNA after cycle 3
10. Association between RCB rates and response by radiomics analyses, for the patients with no increase in ctDNA after cycle 3
11. For the patients with increase in ctDNA after cycle 3 and treated by standard therapeutic approach (very few patients are expected): to describe the patient population.

Conditions and MedDRA coding

Patients with early-stage Triple Negative Breast Cancer

Study design 4 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

1. Female subject
2. Age ≥ 18 years old
3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1
4. Newly diagnosed Triple-Negative Breast Cancer (TNBC), defined as the absence of ER expression and PR expression, and of HER2 overexpression, must be determined by local testing of a screening tumor sample as defined by ASCO/CAP guidelines
5. TNBC defined as the following combined primary tumor (T), regional lymph node (N), and metastatic (M) AJCC staging criteria: cT ≥15 - ≤30 mm, N0, M0 according to Mammogram, breast Ultrasound and MRI, and PET-CT. In case of a difference in the measurement of the primary tumor among different imaging methods, the breast MRI measurement is the reference
6. Unicentric, unifocal and unilateral disease
7. Tumor-infiltrating lymphocytes (TILs) ≥ 30%, as defined by the International TILs Working Group 2014
8. ctDNA dosing at baseline
9. Agreement to provide tissue samples (biopsy at screening and on-treatment), and at surgery for immune monitoring and translational research activities
10. Agreement to perform blood samples at screening, on-treatment, and at surgery for immune monitoring and translational research activities
11. Adequate bone marrow function as defined below (Laboratory Parameters realized within 14 days before inclusion): Absolute neutrophil count ≥1500/µL, i.e. 1.5x109/L; Hemoglobin ≥ 9.0 g/dL; Platelets ≥100000/µL, i.e. 100x109/L
12. Adequate liver function as defined below (Laboratory Parameters realized within 14 days before inclusion): Serum total bilirubin ≤ 1.5 x ULN. In case of known Gilbert’s syndrome ≤ 3 x UNL is allowed; AST (SGOT) ≤ 3.0 x ULN; ALT (SGPT) ≤ 3.0 x ULN
13. Adequate renal function as defined below (Laboratory Parameters realized within 14 days before inclusion): Creatinine ≤ 1.5 x UNL or eGFR≥40ml/min/1.73m^2
14. Adequate coagulant function as defined below (Laboratory Parameters realized within 14 days before inclusion): International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 x ULN; Partial Thromboplastin Time (PTT) or activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN
15. Left ventricular ejection fraction (LVEF) ≥ 50% by cardiac ultrasound. LVEF performed in routine is accepted if done within 28 days prior to the beginning of screening
16. Serum pregnancy test (for subjects of childbearing potential) negative within 72 hours prior to first dose of study administration
17. Women of childbearing potential (WOCBP)* must agree to use 1 highly effective method of contraception during the screening period, during the treatment of the study and at least 6 months after the last administration of study treatment. It is strongly recommended for the male partner of a female subject to also use male condom plus spermicide throughout this period
18. Signed Informed Consent form (ICF) obtained prior to any study procedure
19. Affiliated to Social Security System.

Exclusion criteria 25

1. Inflammatory breast cancer.
2. Prior treatment with an oncolytic virus-based therapy.
3. Patients with active significant herpetic infections or prior complications of HSV-1 infection (e.g., herpetic keratitis, encephalitis, or disseminated herpes infection). Note: patients who suffer from sporadic cold sore lesions may be enrolled as long as no active lesions are present at the time of inclusion. See Management of Herpes Infections of the protocole for further guidance.
4. Patients who require intermittent or chronic use of systemic (oral or IV) antivirals with known antiherpetic activity (e.g., acyclovir).
5. Diagnosis of immunodeficiency.
6. Has active autoimmune disease (e.g. inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, and multiple sclerosis, celiac disease, Wegener’s granulomatosis) that has required systemic treatment in the past 3 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Note: Subjects with childhood atopy or asthma, vitiligo, alopecia, Graves’s disease, Hashimoto’s thyroiditis, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc...) is not considered a form of systemic treatment.
7. Prior systemic immunosuppressive medication (except physiologic corticosteroid replacement therapy) within 30 days of planned start of study therapy.
8. Any live (attenuated) vaccine within 14 days of planned start of study therapy.
9. Prior immunotherapy, including tumor vaccine, cytokine, anti-CTLA4, PD-1/PD-L1 blockade or similar agents, TCR-based or CAR-T cell based adoptive cell therapy.
10. Known history of, or any evidence of active, non-infectious pneumonitis.
11. Active infection including: Tuberculosis (TB) (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice) - 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. - HIV infection.
12. Has a history of a second malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for 5 years.
13. Any excipient in RP1 or Atezolizumab known to induce allergic reaction.
14. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction transient ischemic attack, congestive heart failure or cerebral vascular accident within the previous 12 months, unstable arrhythmias, and/or unstable angina.
15. Medical condition requiring current systemic anticoagulation, or a history of congenital hypercoagulable condition. Subjects taking aspirin at doses < 325 mg per day are eligible provided that prothrombin time is within the institutional range of normal. Use of local anticoagulation for port maintenance is permitted.
16. Diabetes mellitus Type 1 or poorly controlled Type 2 diabetes mellitus defined as a screening hemoglobin A1C ≥ 8 % or a fasting plasma glucose ≥ 160 mg/dL (or 8.8 mmol/L).
17. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 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.
18. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
19. Prior organ transplantation.
20. Subjects with urinary outflow obstruction.
21. Contraindication to breast MRI (magnetic resonance imaging) and PET scan (positron emission tomography).
22. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to inclusion or 4 weeks after the end of treatment.
23. Pregnant and/or lactating women.
24. 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.
25. Vulnerable persons according to the article L.1121-6 of the CSP (Public Health Code), adults who are the subject of a measure of legal protection or unable to express their consent according to article L.1121-8 of the CSP.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Safety run-in: The incidence, nature and severity of adverse events, with severity graded according to NCI CTCAE v5.0
2. Phase II: Residual cancer burden RCB 0-1 rate at time of surgery in patients with no increase in ctDNA after cycle 3.

Secondary endpoints 11

1. The safety and toxicity of the combination therapy will be estimated from the treatment start to the surgery, in terms of duration and severity based on CTCAE v5.0, among all evaluable patients with less than 3 cycles
2. The rate of RCB 0-1 will be estimated with its 95% exact confidence interval; among patients with no increase in ctDNA after cycle 3
3. The safety and toxicity of the combination therapy will be estimated from the treatment start to the surgery, in terms of duration and severity based on CTCAE v5.0, among patients with no increase in ctDNA after cycle 3
4. Invasive disease-free survival (iDFS) in all evaluable subjects will be estimated using the Kaplan-Meier method. iDFS is defined as the time from the date of inclusion to the date of loco-regional relapse, distant relapse, or death, whatever happens first; for patients without such events, the date of last contact will be used, among patients with no increase in ctDNA after cycle 3
5. The percentage of TILs will be estimated and compared between RCB rates 0-1 versus 2-3; TILs will be assessed according to the International TILs Working Group 2014 2 and the RCB 0-1 rate according to Symmans et al.1; Among patients with no increase in ctDNA after cycle 3
6. The pre-treatment expression of PD-L1 (continuous variable and dichotomous variable) will be estimated and compared between RCB rates 0-1 versus 2-3; PD-L1 expression will be assessed using the PD-L1 IHC SP142 assay with the IC scoring system, among patients with no increase in ctDNA after cycle 3
7. Association between RCB rates and response by PET-CT or breast MRI will be studied, among patients with no increase in ctDNA after cycle 3
8. To correlate the response by breast MRI with RCB 0-1 rates, among patients with no increase in ctDNA after cycle 3
9. The rate of Breast Conservation Surgery (BCS) will be presented, among patients with no increase in ctDNA after cycle 3
10. Association between RCB rates and response by radiomics analyses, among patients with no increase in ctDNA after cycle 3
11. For the patients with increase in ctDNA after cycle 3 and treated by standard therapeutic approach (3 patients expected), the rate of patients with increased ctDNA and a descriptive analysis of this population will be performed.

Investigational products

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

Test 2

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

Emanuela ROMANO

Public contact point

Organisation

Institut Curie

Contact name

Emanuela ROMANO

Locations

1 EU/EEA country · 1 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

Summary of results Art. 37(4) CTR

Documents 4 files

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

Application history

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