This is a Phase 1b/2 trial employing a Simon Two Stage design to evaluate the safety,
feasibility, and efficacy (defined as 10% increase in Ki67+ peripheral CD8 T cells
post-treatment) of a single pembrolizumab infusion with or without radiation boost prior to
definitive surgery in patients with operable breast cancer. The study has four arms. Arms 1
and 2 differ by the order of radiation boost and pembrolizumab administration. In arm 3,
patients will receive pembrolizumab alone. A minimum of 6 patients will be enrolled in the
safety run-in portion of the study. An additional 30 patients will be enrolled once
pembrolizumab with the combination radiation is considered feasible and additional funding is
available. Arm 4 represents our control arm in which patients will follow usual care but will
be consented for blood/tissue collection using a separate protocol (Penn IRB 801539).
Inclusion Criteria:
All (male and female) subjects must meet the following criteria during screening to be
enrolled in the study:
1. Is willing and able to provide written informed consent/assent for the trial.
2. A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies:
1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 1 of
protocol OR
2. A WOCBP who agrees to follow the contraceptive guidance during the treatment
period and for at least 30 days (corresponding to time needed to eliminate the
study drug pembrolizumab plus 30 days [a menstruation cycle] for study treatments
with risk of genotoxicity) after the last dose of study treatment.
3. Is 18 years of age on day of signing informed consent.
4. Have an ECOG Performance Status 0 - 1. Evaluation of ECOG is to be performed within 7
days prior to the date of allocation/randomization.
5. Patients with newly diagnosed clinical T1-2 N0-1 M0 breast cancer not eligible for
I-SPY2 or not undergoing neoadjuvant chemotherapy with at least one of the following
features:
- Triple negative breast cancer defined using the ASCO CAP guidelines1 with the
following modification supported by a recent publication2 as ER ≤ 10%, PR ≤ 10%,
and HER2- determined by immunohistochemistry and/or fluorescence in situ
hybridization analyses and with tumor size ≤ 2.0 cm, any nodal status and not
undergoing neoadjuvant chemotherapy
- HR+ HER2- with nodal involvement (node+ disease) confirmed on fine needle
aspiration (FNA) or core needle biopsy and clinical T1 or T2 tumor. FNA or core
needle biopsy of axilla node are standard diagnostic procedure to confirm nodal
involvement.
- HR+ or HR- HER2+ breast cancer with clinical T1 tumor (tumor size ≤ 2 cm), any
nodal status not undergoing neoadjuvant chemotherapy
6. Locally recurrent breast cancer with no prior radiation expecting surgical excision as
part of treatment.
7. Ability to tolerate radiation therapy (e.g., lie flat and hold position).
8. Demonstrate adequate hematologic, renal, hepatic, thyroid and bone marrow function.
All screening labs should be performed within 21 days of treatment initiation.
9. Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication. Medically
accepted methods of birth control include a diaphragm, cervical cap, latex condoms,
surgical sterility, intrauterine devices (IUDs), hormonal implants, injectable
contraceptives, or birth control pills. Subjects of childbearing potential are those
who have not been surgically sterilized or have not been free from menses for > 1
year.
Exclusion Criteria:
1. A history of prior radiotherapy that precludes delivery of hypofractionated
radiotherapy.
2. Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks [could consider shorter interval for kinase inhibitors or other short
half-life drugs] prior to [randomization /allocation].
- Note: Participants must have recovered from all AEs due to previous therapies to
≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
- Note: If participant received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
study treatment.
3. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or in situ cervical cancer that has undergone potentially curative therapy.
4. Has an active autoimmune disease requiring systemic treatment within the past 3 months
or a documented history of clinically severe autoimmune disease, or a syndrome that
requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or
resolved childhood asthma/atopy would be an exception to this rule. Subjects that
require intermittent use of bronchodilators or local steroid injections would not be
excluded from the study. Subjects with hypothyroidism stable on hormone replacement or
Sjogren's syndrome will not be excluded from the study. Steroid prep due to dye
allergies prior to staging scans or use in anti-emetic prophylaxis is allowed.
5. Has evidence of interstitial lung disease or active, non-infectious pneumonitis or has
as a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.
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
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 trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.
10. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
11. 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.
- Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by
local health authority.
12. Has received a live vaccine within 30 days prior to the first dose of trial treatment.
13. History of allergy to pembrolizumab.
