IRB Study Number 23-1312
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objective
To compare invasive disease-free survival (iDFS) between SG and pembrolizumab versus treatment of physician’s choice (TPC)
Secondary Objectives
To compare overall survival (OS) between the 2 arms
To compare distant disease-free survival (dDFS) as assessed by investigator between the 2 arms
To compare recurrence-free survival (RFS) as assessed by investigator between the 2 arms
To compare safety and tolerability between the 2 arms
To compare time to worsening (TTW) quality of life (QoL) outcomes as measured by Functional Assessment of Cancer Therapy for Breast Cancer (FACT-B) between the 2 arms
Inclusion Criteria
1) Patients must be 18 years of age or older, able to understand and give written informed consent
2) Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
3) Patients must have a history of clinical stage T1, N1-2 or T2-4, N0-2 and histologically confirmed TNBC as determined by the investigator with residual disease in the breast or lymph node(s) after completion of neoadjuvant therapy and surgery. Additionally, the presence of distant metastatic disease must be ruled out.
TNBC criteria for the study is defined as ER and PgR < 10%, HER2-negative per ASCO/CAP guidelines (IHC and/or in situ hybridization [ISH])
TNBC confirmation from posttreatment surgical tissue is preferred if possible
Staging should be done according to the primary tumor-regional lymph node anatomic staging criteria of the American Joint Committee on Cancer, eighth edition
4) Representative formalin-fixed paraffin-embedded (FFPE) tumor specimen in tumor tissue blocks (preferred) or freshly sectioned unstained slides from both pretreatment diagnostic biopsy and from resected surgical specimen:
Pretreatment diagnostic core biopsy: 1 FFPE block (preferred) or 10-15 freshly sectioned unstained slides
Resected residual invasive disease surgical tissue: 1 FFPE block (preferred) or 20-25 freshly sectioned unstained slides Note: While tissue submission from the pretreatment diagnostic core biopsy and surgical resection is required, if the full number of requested slides cannot be obtained, the patient may still be eligible upon discussion with the sponsor medical monitor if < 20 slides are available from the resected surgical tissue.
5) Patients must have received neoadjuvant chemotherapy (taxane and/or anthracycline-based) with or without an aPD-(L)1 agent for a minimum of 6 cycles prior to surgery. Note: For patients who have received pembrolizumab in the neoadjuvant setting, up to 2 cycles of adjuvant pembrolizumab administered with or without radiotherapy is allowed prior to study entry.
6) Adequate excision and surgical removal of all clinically evident disease in the breast and/or lymph nodes as follows:
Breast surgery: total mastectomy with no gross residual disease at the margin of resection, or breast-conserving surgery with histologically negative margins of excision
For patients who underwent breast-conserving surgery, the margins of the resected specimen must be histologically free of invasive tumor and ductal carcinoma in situ (DCIS) as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional operative procedures may be performed to obtain clear margins. If tumor is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible. Patients with margins positive for classic lobular carcinoma in situ (LCIS) are eligible without additional resection.
Lymph node surgery:
In case of positive results from a fine-needle aspiration, core biopsy, or sentinel node biopsy performed prior to preoperative therapy, additional surgical evaluation of the axilla following preoperative therapy should have been performed.
If sentinel node biopsy performed before preoperative therapy was negative, no additional surgery evaluation of the axilla is required after preoperative therapy. If sentinel node biopsy performed before preoperative therapy was positive, an axillary lymph node dissection (ALND) is required after preoperative therapy.
If the only sentinel node identified by isotope scan is in the internal mammary chain, surgical evaluation of the axilla is recommended.
If sentinel node biopsy performed after preoperative therapy is positive (micrometastases and/or macrometastases), ALND is required.
If sentinel node evaluation after preoperative therapy is negative, no further additional surgical evaluation of the axilla is required.
Axillary dissection without sentinel node evaluation is permitted as the initial or sole axillary evaluation after preoperative therapy.
If invasive disease is present in both breasts, participation in the study is permitted as long as the other eligibility criteria are met.
The presence of micrometastases in lymph nodes after preoperative therapy counts as residual disease, whereas the presence of isolated tumor cells (ITCs) does not.
If patients have ITCs in the setting of residual breast disease, at least one of the following are required: further surgical evaluation (ALND) or nodal irradiation.
7) Patients must have received appropriate radiotherapy and have recovered prior to starting study treatment. At a minimum radiotherapy is required for the following:
Breast-conserving surgery: whole breast radiation is required. Regional node radiation is required if the patient presented with cT3-4 or cN2 disease at initial diagnosis.
Total mastectomy: chest wall and regional node radiation is required if the patient presented with cT3-4 or cN2 disease at initial diagnosis.
8) (For patients who received neoadjuvant anthracycline-based regimens) Screening assessment of left ventricular ejection fraction (LVEF) ≥ 50% on echocardiogram (ECHO) or multiple-gated acquisition (MUGA)
9) An interval of no more than 16 weeks between the completion date of surgery and the date of randomization Note: The administration of postsurgical radiotherapy (if indicated) must occur within this time window
10) Patients must have recovered from surgery and AEs due to previously administered neoadjuvant treatment or radiotherapy to less than or equal to Grade 1 or baseline at the time of study entry. Note: The following are an exception to this criterion:
Any grade alopecia
Grade 2 or lower neuropathy
Grade 2 or lower immune-mediated endocrinopathies due to neoadjuvant CPI therapy but patients are stable on endocrine therapy and were able to continue CPI in the preoperative setting Other prior immune-related adverse events (irAEs) are allowed if they resolved, and patient tolerated subsequent CPI therapy without requiring chronic steroid therapy for irAE
11) Adequate hematologic counts without transfusional or growth factor support within 2 weeks of study drug initiation (hemoglobin ≥ 9 g/dL, absolute neutrophil count [ANC] ≥ 1500/mm3, and platelets ≥ 100,000/μL)
12) Adequate hepatic function (bilirubin ≤ 1.5 × upper limit of normal [ULN], aspartate aminotransferase [AST] and alanine aminotransferase [ALT] ≤ 2.5 × ULN, and serum albumin > 3 g/dL)
13) Creatinine clearance ≥ 30 mL/min as assessed by the Cockcroft-Gault equation {Cockcroft 1976}
14) International normalized ratio (INR)/prothrombin time (PT) or activated partial thromboplastin time (aPTT) ≤ 1.5 ULN unless patient is currently receiving therapeutic anticoagulant therapy
15) Male patients and female patients of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception.
16) Patients with HIV must be on antiretroviral therapy (ART) and have a well-controlled HIV infection/disease defined as:
Patients on ART must have a CD4+ T-cell count ≥ 350 cells/mm3 at time of screening.
Patients on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening.
Patients on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to study entry (Day 1).
The combination ART regimen must not contain any medications that may interfere with SN-38 or pembrolizumab metabolism.
17) Patients must be willing and able to comply with the requirements and restrictions in this protocol.
Exclusion Criteria
1) Stage IV (metastatic) breast cancer
2) Prior neoadjuvant HER2-directed therapy
3) History of any prior (ipsi- or contralateral) invasive breast cancer. Note: Prior DCIS is allowed.
4) Patients with known germline BRCA mutations
5) Evidence of recurrent disease following preoperative therapy and surgery
6) Patients may not be participating in a study with an investigational agent or investigational device within 4 weeks prior to randomization. Patients participating in observational studies are eligible.
7) History of other malignancy within the last 5 years except for appropriately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, Stage I uterine cancer, or other nonbreast malignancies with an outcome similar to those mentioned above
8) Patients who need radiotherapy treatment but are contraindicated due to medical reasons (eg, connective tissue disorder or prior ipsilateral breast radiation)
9) (For patients who received neoadjuvant anthracycline-based regimens) Inadequate cardiac function postoperatively, ie, screening LVEF < 50% on ECHO or MUGA
10) Have previously received topoisomerase 1 inhibitors or ADCs containing a topoisomerase inhibitor
11) Major surgical procedure unrelated to breast cancer or significant traumatic injury within approximately 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment
12) Positive serum pregnancy test (Appendix 11.4) or women who are breastfeeding
13) Known or severe (Grade 3 or higher) hypersensitivity or allergy to SG, or pembrolizumab, their metabolites, or formulation excipient
14) Have received prior therapy with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
15) Met any of the following criteria for cardiac disease:
a) Myocardial infarction or unstable angina pectoris within 6 months of enrollment.
b) History of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring antiarrhythmic medications (except for atrial fibrillation that is well controlled with antiarrhythmic medication); history of QT interval prolongation
c) New York Heart Association (NYHA) Class III or greater congestive heart failure or known LVEF of < 50%
16) Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) or gastrointestinal perforation within 6 months of enrollment
17) Patients positive for HIV-1 or 2 with a history of Kaposi sarcoma and/or Multicentric Castleman Disease
18) Have active hepatitis B virus (HBV) or hepatitis C virus (HCV). In patients with a history of HBV or HCV, patients with detectable viral loads will be excluded.
Patients who test positive for hepatitis B surface antigen (HBsAg) are excluded. Patients with a history of HBV infection who test positive for hepatitis B core antibody (anti-HBc) will require HBV DNA by quantitative polymerase chain reaction (PCR) for confirmation of active disease.
Patients who test positive for HCV antibody will require HCV RNA by quantitative PCR for confirmation of active disease. Patients with a known history of HCV or a positive HCV antibody test will not require an HCV antibody at screening and will only require HCV RNA by quantitative PCR for confirmation of active disease.
19) Have undergone an allogenic tissue or solid organ transplant
20) Concurrent serious uncontrolled infections requiring treatment
21) Has a diagnosis of immunodeficiency or receiving systemic corticosteroid therapy (higher than physiologic doses) ≥ 10 mg of prednisone per day or equivalent or any other form of immunosuppressive therapy within 14 days prior to randomization.
22) Has received a live or live-attenuated vaccine within 30 days prior to randomization. Administration of killed vaccines are allowed.
23) Has an active autoimmune disease that has required systemic treatment in the past 2 years (eg, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
24) Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
25) Have other concurrent medical or psychiatric conditions that, in the investigator’s opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations
26) If required per local guidelines, any patient with a blood uracil level ≥ 150 ng/mL is excluded from receiving capecitabine in combination with pembrolizumab as TPC. If required per local guidelines, patients with known dihydropyrimidine dehydrogenase deficiency (by genotyping) are also excluded from receiving capecitabine and do not need to have blood uracil levels assessed at screening.
