Pembrolizumab with or without mRNA 2752 in Treating Patients with High Grade Ductal Breast Carcinoma In Situ
- Plan on having surgical treatment for her DCIS
- Have at least 2 of the following high risk features associated with her DCIS-high grade (grade II-III), palpable mass, hormone receptor negative (less than 1%), Her2 positive, young age (less than 45 years old), and large size (greater than 5 cm)
- Patients with a history of tamoxifen and/or aromatase inhibitor use for treatment or prevention are eligible but should discontinue these medications at least 2 weeks prior to starting this trial
- Be willing and able to provide written informed consent/assent for the trial
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
- Absolute neutrophil count (ANC) >= 1,500/mcL (within 10 days of treatment initiation)
- Platelets >= 100,000/mcL (within 10 days of treatment initiation)
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (within 10 days of treatment initiation)
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN; creatinine clearance should be calculated per institutional standard (within 10 days of treatment initiation)
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 10 days of treatment initiation)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X ULN (within 10 days of treatment initiation)
- Albumin >= 2.5 mg/dL (within 10 days of treatment initiation)
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
- A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential (WOCBP) OR * A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 90 days corresponding to time needed to eliminate any study treatment plus 30 days (a menstruation cycle) after the last dose of study treatment
- A male participant must agree to use a contraception during the treatment period and for at least 90 days corresponding to time needed to eliminate any study treatment plus an additional 120 days (a spermatogenesis cycle) after the last dose of study treatment and refrain from donating sperm during this period
- 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 treatment
- 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 trial treatment
- Is not interested in surgical treatment for her DCIS
- Has invasive breast cancer; this does not include microinvasion
- Has a known history of active TB (Bacillus tuberculosis)
- Hypersensitivity to pembrolizumab or any of its excipients
- Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
- 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
- Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
- 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
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) infection; note: no testing for hepatitis B and hepatitis C is required unless mandated by local health authority
- 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–Guerin (BCG), and typhoid vaccine; seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist) are live attenuated vaccines and are not allowed
I. To determine the maximum tolerated dose (MTD), and recommended dose for subsequent expansion cohort, of intralesionally administered pembrolizumab in patients with ductal carcinoma in situ (DCIS) of the breast. (Dose escalation phase)
II. To define the dose-limiting toxicities (DLTs), tolerability, and feasibility of intralesional administration of pembrolizumab in patients with DCIS. (Dose escalation phase)
III. To determine the response rate to intralesional pembrolizumab with or without lipid nanoparticle encapsulating messenger ribonucleic acids (mRNAs) encoding human OX40L/IL-23/IL-36gamma mRNA-2752 (mRNA 2752) in patients with DCIS, as measured by an increase (baseline versus [vs.] post treatment) in intralesional CD8+ T cells, compared to untreated controls. (Dose expansion phase)
I. To determine whether intralesional pembrolizumab with or without mRNA 2752 decreases tumor volume on magnetic resonance (MRI) imaging.
II. To determine the extent of cell death within the DCIS lesions (pre- vs. post-therapy) using a cleaved caspase 3 immunohistochemistry (IHC) assay.
III. To characterize changes in the immune landscape of DCIS following intralesional administration of pembrolizumab with or without mRNA 2752.
IV. To characterize changes in peripheral blood-based immune biomarkers.
V. To evaluate outcomes stratified by immune subtype based multiplex IHC clustering analysis.
VI. To use the Morisita-Horn index to describe spatial relationships among immune cell populations.
OUTLINE: This is a dose-escalation study of pembrolizumab followed by a dose-expansion study.
DOSE-ESCALATION COHORT: Patients receive pembrolizumab intralesionally on day 1. Treatment repeats every 3 weeks for 2 cycles. Beginning 3 weeks after the last dose, patients undergo standard of care surgery (partial mastectomy or mastectomy).
DOSE-EXPANSION COHORT: Patients are assigned to 1 of 2 arms.
ARM A: Patients receive pembrolizumab intralesionally on day 1. Treatment repeats every 3 weeks for 2-4 cycles. Beginning 3 weeks after the last dose, patients undergo standard of care surgery (partial mastectomy or mastectomy).
ARM B: Patients receive pembrolizumab intralesionally and mRNA 2752 intralesionally on day 1. Treatment repeats every 3 weeks for 2-4 cycles. Beginning 3 weeks after the last dose, patients undergo standard of care surgery (partial mastectomy or mastectomy).
After completion of study treatment, patients are followed up at 1-3 weeks and 8 weeks after surgery.
Trial Phase Phase I
Trial Type Treatment
University of California San Francisco
Laura Jean Esserman
- Primary ID 16704
- Secondary IDs NCI-2017-01320, 16-19401
- Clinicaltrials.gov ID NCT02872025