Study to compare the activation of the immune system depending on the chemotherapy scheme used together with PEMBROLIZUM (immunotherapy) in the pre-surgical treatment of triple-negative breast cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Champalimaud Clinical Centre

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Apr 2024 → ongoing

Decision date (initial)

2024-03-13

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Sharp & Dohme Corporation

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy

1) To detect an immunologic activation signal and the immunologically defined most suitable patient population for the synergistic interaction between pembrolizumab and chemotherapy backbone, as assessed by precursor exhausted- and terminally differentiated exhausted T cell subpopulations and transcriptional changes of T cell populations infiltrating tumors at baseline and C2D1 in subjects with TNBC with TILs ≥ 10%.
2) To evaluate the rate of pCR in subjects with locally advanced TNBC with TILs
≥ 10%

Secondary objectives 2

1. Objective: Determine changes in the immunogenic phenotype by longitudinally evaluating RNA-based gene expression signatures (e.g., tumor inflammation signature [TIS ; Ayers 2017 JCI]; expression of granzyme A [GZMA] and perforin 1 [PRF1] [Rooney Cell 2015]; and others) at baseline and at C2D;
2. Objective: To determine the safety and tolerability of the combinations of pembrolizumab plus chemotherapy (either EC/AC or paclitaxel + carboplatin) in the Neoadjuvant and Adjuvant settings.

Conditions and MedDRA coding

High risk (TILs-positive) HR-/HER2- (triple negative) breast cancer

Regulatory references

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Be willing and able to provide written informed consent for the trial.
2. Be a female or male participant who is at least 18 years of age on the day of signing informed consent.
3. Have locally histologically confirmed diagnosis of invasive carcinoma of the breast that is classified as TNBC, as defined by the most recent ASCO/CAP guidelines.
4. Has locally confirmed tumor infiltrating lymphocytes (stromal) (sTILs) equal to or above 10%, as defined by the most recent International Guidelines on TIL Assessment in Breast Cancer.
5. Have previously untreated non-metastatic (M0) TNBC defined as the following combined primary tumor (T) and regional lymph node (N) staging per current AJCC staging criteria for breast cancer staging criteria as assessed by the investigator based on radiological and/or clinical assessment: a. T1c, N1-N2; b. T2, N0-N2; c. T3, N0-N2; d. T4a-d, N0-N2.
6. Provide a core needle biopsy consisting of at least 3 separate tumor cores from the primary tumor at screening to the designated central biobank (or responsible laboratories) and is willing to provide a second biopsy at the end of the first cycle of treatment.
7. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days of treatment initiation.
8. Have left ventricular ejection fraction (LVEF) of ≥50% or ≥ institution lower limit of normal (LLN) as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed at screening.
9. Have adequate organ function as defined in Table 2 of this protocol. Specimens must be collected within 28 days prior to the start of study intervention.
10. Male participants: A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 12 months after the last dose of cyclophosphamide or 6 months after last chemotherapy (whichever occurs last) and refrain from donating sperm during this period. Female participants: A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 12 months after the last dose of cyclophosphamide or 6 months after last chemotherapy (whichever occurs last).

Exclusion criteria 19

1. Has a history of invasive malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
2. Has a known history of Human Immunodeficiency Virus (HIV) infection.
3. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
4. Has a known history of active TB (Bacillus Tuberculosis).
5. Has an active infection requiring systemic therapy.
6. If surgery was performed prior to screening, has persistent adverse events or incomplete wound healing considered clinically relevant by the treating investigator.
7. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant‘s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
8. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
9. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through at least 12 months after the last dose of cyclophosphamide or 6 months after last chemotherapy (whichever occurs last).
10. Has had an allogenic tissue/solid organ transplant.
11. Has received prior chemotherapy, targeted therapy, and radiation therapy within the past 12 months.
12. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
13. Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 4 weeks of the first dose of treatment in this current trial.
14. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
15. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
16. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
17. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
18. Has significant cardiovascular disease, such as: a. History of myocardial infarction, acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the last 6 months; b. Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA class III or IV.
19. Subjects without legal capacity who are unable to understand the nature, scope, significance and consequences of this clinical trial and to consent

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Primary efficacy endpoint: Pathological complete response;
2. Primary translational endpoint: Fate bifurcation is defined as the proportion of TILs with the phenotype T-bet(hi) PD1(mid) CD8+. Quantification of number of T cells per mm2 with different phenotypes will be performed, and averages will be calculated per disease sampling (i.e., pre-treatment and C2D1), per arm and by pCR status.

Investigational products

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

Test 1

Auxiliary 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Champalimaud Clinical Centre

Sponsor organisation

Champalimaud Clinical Centre

Address

Avenida Brasilia S/n

City

Lisbon

Postcode

1400-038

Country

Portugal

Scientific contact point

Organisation

Champalimaud Clinical Centre

Contact name

Márcio Debiasi

Public contact point

Organisation

Champalimaud Clinical Centre

Contact name

Inês Sousa

Third parties 1

Locations

1 EU/EEA country · 3 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 3 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