Window of Opportunity Trial, PARP Inhibitor Rucaparib Affect on PD-L1 Expression in Triple Negative Breast Tumors

Study Overview
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Brief Summary
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This is a single arm window of opportunity trial conducted in patients with early stage triple negative breast tumors to evaluate if treatment with a Poly(ADP-ribose) polymerase (PARP) inhibitor will increase expression of programmed cell death-1 with ligand (PD-L1) in triple negative breast tumors.

Detailed Description
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This is a single arm window of opportunity trial conducted in patients with early stage triple negative breast tumors. Patients who are planning to undergo surgery as part of their initial treatment will be eligible for this study. They will be treated with single agent rucaparib for 3 weeks and then proceed to surgery. Core-biopsies obtained at the time of diagnosis and tumor from the surgical resection will be assessed for change in expression of PD-L1 by Immunohistochemical assay (IHC).

Official Title
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Window of Opportunity Trial to Evaluate Change in PD-L1 Expression in Triple Negative Breast Tumors in Response to the PARP Inhibitor Rucaparib

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Rucaparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have histologically documented triple negative breast cancer (TNBC) (defined as ER expression ≤10% by IHC, progesterone receptor (PR) expression≤10% by IHC and HER2 0 or 1+ by IHC or Fluorescence in situ hybridization (FISH) ratio <2 or human epidermal growth factor receptor 2 (HER2) gene copy number of <6) Early stage breast cancer (stage I-III) and not be candidate for neoadjuvant chemotherapy Be informed of the investigational nature of the study and all pertinent aspects of the trial Have Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Have the ability to understand and the willingness to sign a written informed consent document in accordance with institutional and federal guidelines Be ≥ 21 years of age Have serum creatinine < 1.5 x institutional upper limit of normal (IULN) or a calculated creatinine clearance ≥ 30ml/min (calculated by Cockcroft Gault equation), bilirubin ≤ 2.0, and an serum glutamic oxaloacetic transaminase (SGOT)/s erum glutamic pyruvic transaminase (SGPT)/alkaline phosphatase ≤ 2.0 x IULN Have adequate bone marrow function (ANC >1000, Platelets >100,000/ml, Hemoglobin >10gm/dL) Women of childbearing potential or male patients of reproductive potential with female partners of childbearing potential must not consider getting pregnant and must avoid pregnancy during the study and for at least 6 months after the last dose of rucaparib. Female and male patients of reproductive potential must practice highly effective methods of contraception with their partners, if of reproductive potential, during treatment and for 6 months following last dose of rucaparib Exclusion Criteria: Ongoing or prior treatment with a PARPi for breast cancer or other malignancies Receiving concurrent anti-neoplastic therapy for their breast cancer or another malignancy Known documented or suspected hypersensitivity to the components of the study drug or analogs. Pre-existing gastrointestinal disorders or defects (like duodenal stent etc) that would, in the opinion of the investigator, interfere with absorption of rucaparib

Ages Eligible for Study
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Minimum Age: 21 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (rucaparib)<br>Patients will be treated with single agent rucaparib for 3wks and then proceed to surgery. Core-biopsies (at the time of diagnosis) and tumor from the surgical resection will be assessed for change in expression of programmed cell death-1 with ligand (PD-L1) by immunohistochemistry (IHC) . Starting Dose 600 mg twice daily Dose Level -1 500 mg twice daily Dose Level -2 400 mg twice daily Dose Level -3 300 mg twice daily | Drug: Rucaparib<br>* Patients will be treated with single agent rucaparib for 3wks and then proceed to surgery. Core-biopsies (at the time of diagnosis) and tumor from the surgical resection will be assessed for change in expression of PD-L1 by Immunohistochemical assay (IHC).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of expression of PD-L1 by IHC via core biopsy. | To evaluate change in expression of programmed cell death-1 with ligand (PD-L1) by Immunohistochemistry (IHC) of tissue sample via core biopsy after treatment with single agent PARPi (rucaparib). | Six months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure change in expression of Ki67 by IHC after treatment with PARPi. | Measure change in expression of Ki67 by immunohistochemistry of tissue sample via core biopsy after treatment with single agent Poly(ADP-ribose) polymerase inhibitor (PARPi) (rucaparib). | Six months | 
| Measure and quantify change in number of tumor-infiltrating lymphocytes. | Measure and quantify change in number of tumor-infiltrating lymphocytes via blood testing. | Six months | 
| Measure levels of tumor PARylation in pre- and post-PARPi therapy by IHC. | Measure levels of tumor PARylation (the addition of poly-ADP-ribose polymers) in pre- and post-PARPi therapy by immunohistochemistry of tissue sample via core biopsy. | Six months | 
| Measure change in expression of programmed cell death-1 with ligand (PD-L1) pre- and post-PARPi therapy in circulating tumor cells (CTCs). | Measure change in expression of programmed cell death-1 with ligand (PD-L1) pre- and post-PARPi therapy in circulating tumor cells (CTCs) via blood/plasma collection. | Six months | 
| Measure cfDNA mutational expression for homologous recombination deficiency (HRD) and correlate with PD-L1 expression at baseline and change overtime. | Measure circulating free DNA (cfDNA) mutational expression for homologous recombination deficiency (HRD) and correlate with PD-L1 expression at baseline and change overtime via blood/plasma collection. | Six months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, Triple Negative, Breast Tumors, PD-L1, PARP, PARPi, Rucaparib