Clinical trial NCT02622074: Safety and Efficacy Study of Pembrolizumab (MK-3475) in Combination With Chemotherapy as Neoadjuvant Treatment for Participants With Triple Negative Breast Cancer (TNBC) (MK-3475-173/KEYNOTE-173)
Official title: A Phase 1b Study to Evaluate Safety and Clinical Activity of Pembrolizumab (MK-3475) in Combination With Chemotherapy as Neoadjuvant Treatment for Triple Negative Breast Cancer (TNBC) - (KEYNOTE 173)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Triple Negative Breast Neoplasms
Keywords: Programmed Cell Death-1 (PD1, PD-1)
Programmed Death-Ligand 1 (PDL1, PD-L1)
Triple Negative Breast Cancer
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2015-12-04
Enrollment: 60
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety, tolerability and clinical activity of pembrolizumab (MK-3475) in combination with six chemotherapy regimens as neoadjuvant treatment for participants with triple negative breast cancer (TNBC).


Eligibility criteria: Inclusion Criteria:

* Has previously untreated, locally advanced TNBC.
* Is able to provide 2 core needle biopsies from the primary tumor at screening to the central laboratory and agrees to have a core needle biopsy after single dose pembrolizumab treatment if tumor biopsy is feasible as judged by the investigator.
* Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Has adequate organ function.
* Females of childbearing potential must be willing to use adequate contraception for the course of the study through 12 months after the last dose of study drug for participants receiving cyclophosphamide and through 6 months after the last dose of study drug for participants who do not receive cyclophosphamide.

Exclusion Criteria:

* Has evidence of metastatic breast cancer, concurrent bilateral invasive breast cancer, or inflammatory breast cancer.
* Has another malignancy within the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative surgery, or in situ cervical cancer.
* Has received prior chemotherapy, targeted therapy, radiation therapy, immunotherapy that targets immune checkpoints, co-stimulatory or co-inhibitory pathways for T cell receptors within the past 12 months.
* Is currently participating and receiving study therapy, or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study drug.
* Has received a live vaccine within 30 days of the first dose of study drug.
* Has an active autoimmune disease that has required systemic treatment in past 2 years.
* Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
* Has a known history of Human Immunodeficiency Virus (HIV).
* Has known active Hepatitis B or Hepatitis C.
* Has evidence of current pneumonitis.
* Has a history of non-infectious pneumonitis requiring treatment with steroids or a history of interstitial lung disease.
* Has an active infection requiring systemic therapy.
* Has significant cardiovascular disease, such as: History of myocardial infarction, acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the last 6 months; Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA class III or IV
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
* Is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the study, starting with the screening visit through 12 months after the last dose of trial treatment for participants who have received cyclophosphamide, and for six months after the last dose of study medication for participants who have not.
* Has a known hypersensitivity to the components of the study drug or its analogs.

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs) Graded Using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0)
timeFrame: Cycle 1 Day 1 through end of Cycle 3 and Cycle 6 Day 1 through end of Cycle 7 (Up to ~150 days from first dose of first combination regimen); Each cycle was 21 days.
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to approximately 28 months (through Interim database cut-off date of 31-May-2018)
measure: Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
timeFrame: Up to approximately 28 months (through Interim database cut-off date of 31-May-2018)
Secondary outcomes:
measure: Pathological Complete Response (pCR) Rate Using the Definition of ypT0 ypN0 (No Invasive or Noninvasive Residual in Breast or Nodes)
timeFrame: Up to approximately 9 months (at the time of definitive surgery)
measure: Pathological Complete Response (pCR) Rate Using the Definition of ypT0/Tis ypN0 (No Invasive Residual in Breast or Nodes; Noninvasive Breast Residuals Allowed)
timeFrame: Up to approximately 9 months (at the time of definitive surgery)
measure: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator Review: First Combination Regimen
timeFrame: At the end of Cycle 5 following treatment with the first combination regimen (KNp, KNpCb, or KTCb) (Up to ~4 months); Each cycle was 21 days.
measure: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator Review: Second Combination Regimen
timeFrame: After completion of the second combination regimen (KAC; Cycle 9) but prior to surgery (Up to ~9 months); Each cycle was 21 days.
measure: Event-Free Survival (EFS) Rate at Month 6
timeFrame: Month 6
measure: Event-Free Survival (EFS) Rate at Month 12
timeFrame: Month 12
measure: Event-Free Survival (EFS) Rate at Month 24
timeFrame: Month 24
measure: Overall Survival (OS) Rate at Month 6
timeFrame: Month 6
measure: Overall Survival (OS) Rate at Month 12
timeFrame: Month 12
measure: Overall Survival (OS) Rate at Month 24
timeFrame: Month 24
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Schmid P, Salgado R, Park YH, Munoz-Couselo E, Kim SB, Sohn J, Im SA, Foukakis T, Kuemmel S, Dent R, Yin L, Wang A, Tryfonidis K, Karantza V, Cortes J, Loi S. Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: results from the phase 1b open-label, multicohort KEYNOTE-173 study. Ann Oncol. 2020 May;31(5):569-581. doi: 10.1016/j.annonc.2020.01.072. Epub 2020 Feb 14.
citation: Perez-Garcia J, Soberino J, Racca F, Gion M, Stradella A, Cortes J. Atezolizumab in the treatment of metastatic triple-negative breast cancer. Expert Opin Biol Ther. 2020 Sep;20(9):981-989. doi: 10.1080/14712598.2020.1769063. Epub 2020 May 25.