BreastVAX: Radiation Boost to Enhance Immune Checkpoint Blockade Therapy

Study Overview
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Brief Summary
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The primary objective is to determine the feasibility of combining pembrolizumab with a single fraction radiation boost in patients with early/ operable breast cancer. The secondary objectives are to assess clinical response on pre- and post-treatment clinical, imaging, and histology exams, and to assess immune response on pre and post treatment blood and tissue samples by tracking change in Ki67 + CD8 T cells in peripheral blood and in extent of tumor infiltrating lymphocytes

Detailed Description
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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).

Official Title
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Preoperative Use of Radiation Boost to Enhance Effectiveness of Immune Checkpoint Blockade Therapy in Operable Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Radiation: Hypofractionated radiotherapy
* Drug: Pembrolizumab infusion
* Procedure: Blood and tissue sampling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All (male and female) participants must meet the following criteria during screening to be enrolled in the study: Is willing and able to provide written informed consent/assent for the trial. Is ≥ 18 years of age on day of signing informed consent. Have an ECOG Performance Status 0 - 1 at screening. Patients with: Newly diagnosed clinical T1-2 N0-1 M0 breast cancer not eligible for I-SPY2 (to prevent recruitment competition) 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 publication as ER ≤ 10%, PR ≤ 10%, and HER2(-) determined by immunohistochemistry and/or fluorescence in situ hybridization analyses and with tumor size ≤ 2.0 cm via breast ultrasound if deemed appropriate by the PI, any nodal status, and not undergoing neoadjuvant chemotherapy. Hormone receptor(+) HER2(-) (HR+ HER2[-]) breast caner with nodal involvement (node+ disease) confirmed on fine needle aspiration (FNA) or core needle biopsy and clinical T1 or T2 tumor determined by breast ultrasound if deemed appropriate by the PI. FNA or core needle biopsy of axilla node are standard diagnostic procedure to confirm nodal involvement. HR+ or HR- and HER2(+) breast cancer with clinical T1 tumor (tumor size ≤ 2 cm via breast ultrasound if deemed appropriate by the PI), any nodal status, and not undergoing neoadjuvant chemotherapy OR Locally recurrent breast cancer with no prior radiation expecting surgical excision as part of treatment • 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) as defined in Appendix 2 of the study protocol OR Locally recurrent breast cancer with no prior radiation expecting surgical excision as part of treatment. A female participant is eligible to participate if she is not pregnant (see Appendix 2), not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) as defined in Appendix 2 OR A WOCBP who agrees to follow the contraceptive guidance in Appendix 2 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. Female participants 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. Participants of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. Ability to tolerate radiation therapy (e.g., lie flat and hold position). Demonstrate adequate hematologic, renal, hepatic, thyroid and bone marrow function. All screening labs should be performed within 21 days of treatment initiation. Adequate organ function defined as follows: ANC ≥1500/mcL Platelets ≥100,000 / mcL Hemoglobin ≥9g/dL Serum Creatinine ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/ min for participant with creatinine levels > 1.5 X institutional ULN Total Bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 ULN AST & ALT ≤ 2.5 X ULN 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1<br>Arm 1 will receive radiotherapy on day -14 and pembrolizumab on day -7. Subjects in all arms will undergo surgery on day 0 and follow the same postoperative blood sampling and safety schedule. | Radiation: Hypofractionated radiotherapy<br>* Radiation boost (RT) 7 Gy x 1 fraction on Day -14/Day -7 (arm 1) or Day -7/Day -14<br>* Other names: Radiation therapy;Drug: Pembrolizumab infusion<br>* Pembrolizumab infusion flat dosing 200 mg delivered over 30 minutes.<br>* Other names: Checkpoint blockade administration;Procedure: Blood and tissue sampling<br>* Blood will be collected for laboratory studies and complete correlative studies to examine how the subject's immune system is responding to treatment. On day 0, samples of tumor and any lymph nodes removed from armpit will be analyzed by the UPenn Department of Pathology according to standard practice.<br>* Other names: Correlative studies;|
| Active Comparator: Arm 2<br>Arm 2 will receive pembrolizumab on day -14 and radiotherapy on day -7. Subjects in all arms will undergo surgery on day 0 and follow the same postoperative blood sampling and safety schedule. | Radiation: Hypofractionated radiotherapy<br>* Radiation boost (RT) 7 Gy x 1 fraction on Day -14/Day -7 (arm 1) or Day -7/Day -14<br>* Other names: Radiation therapy;Drug: Pembrolizumab infusion<br>* Pembrolizumab infusion flat dosing 200 mg delivered over 30 minutes.<br>* Other names: Checkpoint blockade administration;Procedure: Blood and tissue sampling<br>* Blood will be collected for laboratory studies and complete correlative studies to examine how the subject's immune system is responding to treatment. On day 0, samples of tumor and any lymph nodes removed from armpit will be analyzed by the UPenn Department of Pathology according to standard practice.<br>* Other names: Correlative studies;|
| Active Comparator: Arm 3<br>Arm 3 will receive pembrolizumab on day -14. Subjects in all arms will undergo surgery on day 0 and follow the same postoperative blood sampling and safety schedule. | Drug: Pembrolizumab infusion<br>* Pembrolizumab infusion flat dosing 200 mg delivered over 30 minutes.<br>* Other names: Checkpoint blockade administration;Procedure: Blood and tissue sampling<br>* Blood will be collected for laboratory studies and complete correlative studies to examine how the subject's immune system is responding to treatment. On day 0, samples of tumor and any lymph nodes removed from armpit will be analyzed by the UPenn Department of Pathology according to standard practice.<br>* Other names: Correlative studies;|
| Other: Arm 4<br>Arm 4 will not receive any study treatment. Subjects will undergo surgery on day 0 and follow a preoperative (Day 0) and postoperative blood (Day 30) and tissue (Day 0) sampling schedule. | Procedure: Blood and tissue sampling<br>* Blood will be collected for laboratory studies and complete correlative studies to examine how the subject's immune system is responding to treatment. On day 0, samples of tumor and any lymph nodes removed from armpit will be analyzed by the UPenn Department of Pathology according to standard practice.<br>* Other names: Correlative studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of preoperative pembrolizumab administration combined with radiation boost in patients with operable breast cancer | Feasibility is defined as patient tolerability of the investigational treatment and no excessive delay in surgery in our participants. The interval to breast-conserving surgery and mastectomy was based on review of our records in patients undergoing breast cancer surgery in 2016. The average time to breast conservation surgery is 24.3 days (80% between 9 and 51 days) and for mastectomy with reconstruction 41.6 days (80% between 10 and 67 days). | 2 years | 
| Assess clinical response of treatment | Evaluate clinical response using the following assessments: clinical breast exam breast ultrasonography (US) imaging (optional) for tumor dimension changes. and histology (pathology) exams, Pathologic response is assess histologically on post-treatment tumor tissues. A major pathologic response will be defined as <10% viable invasive tumor in treated | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess immune response on pre- and post-treatment blood and tissue samples | Assess immune response on pre- and post-treatment blood and tissue samples This study will track change in Ki67 + CD8 T cells in peripheral blood and in extent of tumor infiltrating lymphocytes (TIL). | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immune checkpoint blockade