A prospective, multicentre, open-label, randomized, Phase II study of Pembrolizumab in combination with neo-adjuvant EC-Paclitaxel regimen in HER2-negative inflammatory Breast Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Paoli Calmettes

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

31 Oct 2024 → ongoing

Decision date (initial)

2024-10-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-514899-41-00

EudraCT number

2016-001868-11

WHO UTN

U1111-1310-3401

ClinicalTrials.gov

NCT03515798

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy, Pharmacodynamic

To assess the pathological complete response rate (ypT0/Tis, ypN0 following American Joint Committee on Cancer (AJCC)-8th version classification) following neoadjuvant EC-paclitaxel chemotherapy plus pembrolizumab.
To assess separately in a run-in phase if neoadjuvant chemotherapy with anthracycline-based induction Q3w pembrolizumab exposes IBC patients to significant toxicity rates.

Secondary objectives 3

1. To describe the safety profile and tolerability of pembrolizumab in combination with neoadju-vant EC-paclitaxel chemotherapy
2. To estimate in each arm the pathological complete response rates, invasive disease-free, event-free and overall survivals
3. To obtain pre- and post-treatment tissue and blood samples for pharmacodynamics meas-urements and biological/immunological correlates

Conditions and MedDRA coding

Breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. Male/female participants who are at least 18 years of age on the day of signing informed consent
2. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
3. Able to comply with the protocol
4. Patient affiliated to the national “Social Security” regimen or beneficiary of this regimen, or any other regimen of social security
5. Patient (or legally acceptable representative if applicable) has provided written informed consent for the trial
6. Previously untreated, histologically confirmed diagnosis of breast cancer and confirmed inflammatory breast cancer defined as follows: - T4d any N following American Joint Committee on Cancer (AJCC)-8th ver-sion classification: breast erythema, edema and/or peau d'orange, occupying at least 1/3 of the breast, with or without underlying palpable mass, duration of history of no more than 6 months
7. HER2 negative tumors by immunohistochemistry (IHC 0 or 1+) or fluores-cent/chromogenic in situ hybridization (FISH- or CISH-)
8. Hormone receptors status known
9. No metastases
10. Have adequate organ function. Specimens must be collected within 10 days prior to the start of study treatment
11. Adequate hematologic function: absolute neutrophil count ≥ 1.5 x 109/L AND platelets ≥ 100 x 109 AND Hb ≥ 9.0 g/dL or ≥5.6 mmol/L, Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
12. Adequate liver function: total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN AND - ASAT ≤ 2.5 ULN AND ALAT ≤ 2.5 ULN
13. Adequate kidney function: serum creatinine ≤ 1.5 ULN or creatinine clearance ≥ 30 mL/min for participant with creatinine levels >1.5 × institutional ULN, Creatinine clear-ance (CrCl) should be calculated per institutional standard
14. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 ULN unless subject is receiving anticoagulant therapy, as long as PT or TCA is within therapeutic range of in-tended use of the anticoagulants
15. Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% (isotopic or ul-trasound methods)
16. 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 and 4 months after the last dose of pembrolizumab, whichever come last. Note: Abstinence is acceptable if this is the established and preferred contraception for the subject
17. 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 6 months after the last dose of study treatment and refrain from donating sperm during this period (corresponding to time needed to eliminate any study treatments plus an additional 120 days (a spermatogenesis cycle) for study treatments with risk of genotoxicity at any dose)

Exclusion criteria 21

1. Has metastatic breast cancer
2. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
3. If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
4. 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 (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
5. Has a history of (non-infectious) pneumonitis that required steroids or has current pneu-monitis
6. Has an active infection requiring systemic therapy
7. Has a 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
8. Has known psychiatric or substance abuse disorders that would interfere with coopera-tion with the requirements of the trial
9. Is pregnant or breastfeeding, or expecting to conceive or father children within the pro-jected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment
10. 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 (e.g., CTLA-4, OX 40, CD137)
11. Has HER2-positive breast cancer
12. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
13. Has known history of Hepatitis B (e.g., HBsAg reactive) or known active Hepatitis C virus infection (e.g., HCV RNA [qualitative] is detected)
14. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vac-cines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live at-tenuated vaccines and are not allowed
15. Has bilateral breast cancer
16. Prior allogeneic stem cell or solid organ transplantation
17. A WOCBP who has a positive serum pregnancy test within 72 hours prior to randomiza-tion
18. 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 the first dose of study treatment
19. Has known active CNS disease or carcinomatous meningitis
20. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppres-sive therapy within 7 days prior to the first dose of study drug
21. Has a known history of active TB (Bacillus Tuberculosis)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Central evaluation of pathological complete response rate as defined as absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of NAST (i.e., ypT0/is, ypN0 in the current AJCC staging system)
2. Dose Limiting Toxicity (DLT) rates as defined as incidence of DLT during the 21 days following the first administration of pembrolizumab in combination with EC, will be assessed in the first 6 patients

Secondary endpoints 5

1. Occurrence of serious adverse events and adverse events starting grade 2 or grade 1 (run-in period) according to the National Cancer Institute (NCI) Common Terminology Criteria for Ad-verse Events (CTCAE) V5.0
2. Local evaluation of pathological complete response rate as defined as absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of NAST (i.e., ypT0/is, ypN0 in the current AJCC staging system)
3. Invasive disease-free survival (IDFS), as defined as time from surgery to the first documented occurrence of an event, defined as: Ipsilateral invasive breast tumor recurrence or Ipsilateral local-regional invasive breast cancer recurrence or Distant recurrence or contralateral invasive breast cancer or death from any cause
4. Event free survival (EFS), defined as time from randomization to disease progression, disease recurrence (local, regional, distant, or contralateral [invasive or non-invasive]), or death from any cause)
5. Overall survival (OS), defined as time from randomization to death from any cause

Investigational products

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

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Paoli Calmettes

Sponsor organisation

Institut Paoli Calmettes

Address

232 Boulevard De Sainte Marguerite, Bp 156 Bp 156

City

Marseille

Postcode

13009

Country

France

Scientific contact point

Organisation

Institut Paoli Calmettes

Contact name

Pr Anthony GONCALVES

Public contact point

Organisation

Institut Paoli Calmettes

Contact name

Marina LAROSE

Locations

1 EU/EEA country · 13 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 6 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