A Study of Rucaparib Administered With Radiation in Patients With Triple Negative Breast Cancer With an Incomplete Response Following Chemotherapy

Study Overview
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Brief Summary
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The purpose of this study is to test the safety of a study drug called Rucaparib, administered in combination with the type of radiation therapy that is usually given to women with your form of breast cancer.

Official Title
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A Phase I Study of Rucaparib Administered Concurrently With Postoperative Radiotherapy in Patients With Triple Negative Breast Cancer With an Incomplete Pathologic Response Following Neoadjuvant Chemotherapy

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Rucaparib
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female, ≥ 18 years of age. Non-metastatic, histologically or cytologically-confirmed TNBC (defined as ER <1%, PR <1%, her-2-neu 0-1+ by IHC or FISH-negative or as per MD discretion), with evidence of residual disease in the breast or lymph nodes after neoadjuvant chemotherapy, at the time of definitive surgical treatment. Non-metastatic, histologically or cytologically-confirmed hormone-receptor positive, Her2/neu negative breast cancer (defined as ER >1% or PR >1% AND Her-2/neu 0-1+ by IHC or FISH-negative, or as per MD discretion), with evidence of residual grade 3 invasive breast cancer AND either 1) >5 cm of residual disease in the breast OR 2) ≥ 4 axillary LNs in the axilla after neoadjuvant chemotherapy, at the time of definitive surgical treatment. Definitive surgical treatment with breast-conserving surgery or mastectomy and axillary lymph node evaluation. At least 6-month life expectancy, ECOG Performance status < 2. Willingness to discontinue any cytotoxic chemotherapeutic agents, and biologic therapy at least 2 weeks prior to the start of RT. Adequate organ function (assessed within 30 days prior to initiation of protocol treatment, unless otherwise indicated) as follows: Hematology Absolute Neutrophil Count (ANC) ≥1500/mm^3 Platelet Count ≥100,000/mm^3 Hemoglobin ≥9.0 g/dL (after transfusion if required) Renal Function Creatinine Serum ≤ 1.5 mg/dL or Creatinine Clearance ≥ 45 mL/min^a Hepatic Function Bilirubin ≤ 1.5 mg/dL Aspartate Aminotransferase (AST) ≤ 2.5 x ULN^b Alanine Aminotransferase (ALT) ≤ 2.5 x ULN ULN = upper normal limit of institution's normal range If calculated creatinine clearance is < 45mL/min, a 24-hour urine collection for creatinine clearance may be performed Subjects with documented Gilbert's disease may have bilirubin up to 2.5 mg/dL Negative serum pregnancy test within 14 days prior to study treatment if a woman has child-bearing potential. Subjects of child bearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. Ability to swallow and retain oral medications. Written informed consent obtained from subject and ability for subject to comply with the requirements of the study. 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 duration of study participation. Should a woman become pregnant while participating on study, she should inform the treating physician immediately. Exclusion Criteria: Gross residual tumor on imaging or positive margins after breast conserving surgery that are un-excised, as radiation dose in the study will be limited to 60 Gy. Complete pathologic response to NAC. Receipt of PARP inhibitor prior to RT. Pregnant or expecting to conceive within the projected duration of the trial, starting with screening visit through 180 days after the last dose of trial treatment. Prior history of radiation therapy to the ipsilateral breast and/or regional nodes is not allowed (prior RT to other sites is permitted). Patients with breast augmentation implants are excluded. History of allergic reactions attributed to compounds of similar chemical or biologic composition to rucaparib. Concomitant anti-neoplastic treatment is not allowed during protocol treatment and should be completed at least 2 weeks prior to commencement of protocol treatment, with resolution of associated acute toxicities. Bisphosphonates are permitted without restriction even during protocol treatment. Maintenance pembrolizumab is permitted during the protocol treatment. Significant comorbidity: Patients with clinically significant and uncontrolled major disease or disorder that could exacerbate potential toxicities, confound safety assessments, require excluded therapy for management, or limit study compliance. Ongoing therapy with other investigational agents. Patients may not be receiving any other investigational agents. Unresolved toxicity from other agents. Patients with unresolved CTCAE v4.03 Grade 3 or greater toxicity from prior administration of another investigational drug and/or anti-cancer treatment are not eligible.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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
Interventional Model Description: This is a single-arm Phase I study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rucaparib Administered With Radiation<br>Treatment will consist of rucaparib at one dose level (300 mg BID, 400 mg BID, 500 mg BID or 600 mg BID) concurrently with a 6-week course of radiotherapy and 4 additional weeks of maintenance rucaparib at the same dose level. Radiotherapy will consist of 50 Gy in 2 Gy per fraction to the breast or chest wall with or without regional nodes plus a 10 Gy boost to the lumpectomy cavity, to a total dose of 60 Gy. A 10 Gy boost to the post-mastectomy scar is allowed at the discretion of the treating physician. | Drug: Rucaparib<br>* one dose level (300 mg BID, 400 mg BID, 500 mg BID or 600 mg BID) concurrently with a 6-week course of radiotherapy and 4 additional weeks of maintenance rucaparib at the same dose level.<br>Radiation: Radiotherapy<br>* 50 Gy in 2 Gy per fraction to the breast or chest wall with or without regional nodes plus a 10 Gy boost to the lumpectomy cavity, to a total dose of 60 Gy. A 10 Gy boost to the post-mastectomy scar is allowed at the discretion of the treating physician.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| defining the maximum tolerated dose (MTD) | proportion of subjects encountering toxicity at each dose level. The trial will be monitored using TITE-CRM. Assuming a model for the time to occurrence of toxic response as a function of dose, the method allows information from all enrolled patients to be used when allocating a new patient to a dose level. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rucaparib, Radiotherapy, Triple Negative Breast Cancer, 18-002