A Safety Study Adding Niraparib and Dostarlimab to Radiation Therapy for Rectal Cancers

Study Overview
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Brief Summary
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This clinical trial is designed to determine the maximum tolerated dose of niraparib when combined with dostarlimab and hypofractionated radiation for locally advanced rectal cancer. Once this is determined, this dose will be tested to identify what impact it has on the tumor as well as patient reported outcome measures.

Detailed Description
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Standard of care therapy for resectable locally advanced rectal cancer includes pelvic radiation (short or long course), chemotherapy, and surgery. In this study, participants will: Take niraparib by mouth once daily for up to 12 weeks. Receive radiation therapy once daily for five days (Monday through Friday). Receive intravenous (IV) dostarlimab once every three weeks for up to 12 weeks. Provide feedback about how they feel and their quality of life. This is done through short surveys as well as discussing with the study team. Undergo a sigmoidoscopy (i.e. scope of the tumor) and biopsy about halfway through treatment Provide tumor tissue and blood samples for analysis

Official Title
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A Phase 1b/2 Trial of Preoperative Niraparib, Dostarlimab, and Hypofractionated Radiotherapy for the Treatment of Locally-advanced Rectal Cancers.

Conditions
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Rectal Neoplasms, Rectal Neoplasm Malignant

Intervention / Treatment
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* Drug: Niraparib
* Drug: Dostarlimab
* Radiation: Short course radiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand and willingness to provide independent informed consent; legally authorized representative consent and/or power-of-attorney is not allowed. Age at least 18 years at the time of study drug administration Resectable locally advanced rectal cancer (i.e., T3 to T4 or T1-T4 with N1-2 M0). Recommended to receive preoperative radiation therapy Adequate performance status (ECOG of 0 or 1; or KPS of >70). Agree to adhere to lifestyle considerations throughout study duration Agree to not donate blood during the study or for 90 days after the last dose of study treatment. Exclusion Criteria: Absolute neutrophil count < 1,500 cells /µL Platelets < 100,000 cells/µL Hemoglobin <9 g/dL Serum creatinine > 1.5 x upper limit of normal (ULN) or calculated creatinine clearance 60mL/min using the Cockcroft-Gault equation Total bilirubin > 1.5 x ULN (>2.0 x ULN in patients with known Gilberts syndrome) or direct bilirubin > 1 x ULN Aspartate aminotransferase and alanine aminotransferase > 2.5 x ULN International normalized ratio (INR) or prothrombin time (PT) >1.5× ULN unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin (PTT) is within therapeutic range of intended use of anticoagulants. Activated partial thromboplastin time (aPTT) >1.5× ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Uncontrolled arterial hypertension, i.e. systolic BP > 140 mmHg, diastolic BP > 90 mmHg. Platelet transfusion ≤ 4 weeks prior to initiating protocol therapy. Presence of any M1 metastatic lesions. Prior pelvic radiotherapy Indication for total neoadjuvant therapy or alternative radiation regimen Active Crohn's disease or another inflammatory bowel disease Any T or N stage disease deemed unresectable by colorectal surgery without neoadjuvant therapy Prior anti-PD-L1 therapy, PARPi therapy, or known germline BRCA-1/2 mutation as patients with germline BRCA-1/2 mutations have an increased risk of severe normal tissue injury to combination radiation and PARP inhibition. Received a live vaccine within 14 days of initiating protocol therapy. Received colony stimulating factors ≤ 4 weeks prior to Day 1 of protocol therapy. Major surgery ≤ 3 weeks prior to Day 1 of protocol therapy (participant must recover from any surgical effects). Investigational therapy ≤ 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, prior to Day 1 of protocol therapy. Known hypersensitivity to niraparib and dostarlimab components or excipients. Known grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted > 4 weeks and was related to the most recent treatment. Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) Diagnosis, detection, or treatment of another type of cancer ≤ 2 years prior to initiating protocol therapy (except basal or squamous cell carcinoma of the skin and cervical cancer that has been definitively treated). Known history of ≥ grade 3 immune-related AE with prior immunotherapy, with the exception of non-clinically significant lab abnormalities. Diagnosis of immunodeficiency or has received systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to initiating protocol therapy. Patients with known HIV who have documented detectable viral load or patients with a documented undetectable viral load and a CD 4 count < 350 cells within 6 months of study treatment day 1. Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [qualitative] is detected). 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. History of interstitial lung disease. Active or uncontrolled infection necessitating hospitalization or treatment delay. Known serious, uncontrolled medical disorder or nonmalignant systemic disease that preclude eligibility to undergo low anterior resection (LAR). Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, or any psychiatric disorder that prohibits obtaining informed consent Pregnancy. Actively breastfeeding. Declines to use a highly effective method of contraception from screening through 180 days after the last dose of niraparib and after the last dose of dostarlimab.

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (starting)<br>niraparib, 100 mg orally once daily for up to 12 weeks dostarlimab, 500 mg infused (IV) once every 3 weeks for up to 12 weeks radiation therapy, 5 Gray (Gy) per day for 5 consecutive days | Drug: Niraparib<br>* Niraparib is a drug FDA-approved for use in maintenance treatment of adults with advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.<br>* Other names: Zejula;Drug: Dostarlimab<br>* Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody medication used for the treatment of endometrial cancer.<br>* Other names: Jemperli;Radiation: Short course radiation<br>* Participants will be treated with intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) to minimize mean dose to femoral, pelvic, and lumbar bone marrow. The entire mesorectum will be treated to a total dose of 25 Gy.<br>* Other names: VMAT;|
| Experimental: Cohort 2<br>niraparib, 200 mg orally once daily for up to 12 weeks dostarlimab, 500 mg infused (IV) once every 3 weeks for up to 12 weeks radiation therapy, 5 Gray (Gy) per day for 5 consecutive days | Drug: Niraparib<br>* Niraparib is a drug FDA-approved for use in maintenance treatment of adults with advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.<br>* Other names: Zejula;Drug: Dostarlimab<br>* Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody medication used for the treatment of endometrial cancer.<br>* Other names: Jemperli;Radiation: Short course radiation<br>* Participants will be treated with intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) to minimize mean dose to femoral, pelvic, and lumbar bone marrow. The entire mesorectum will be treated to a total dose of 25 Gy.<br>* Other names: VMAT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of recommended phase 2 niraparib dose | The recommended dose will be determined by incidence of dose limiting toxicities. | From treatment day 1 for 21 weeks. | 
| Determination of the pathologic complete response | Pathologic evaluation of the excised tumor from surgery will determine the pathologic response | Study week 13 | 
| Determination of the clinical complete response rate | Clinical evaluation of the tumor by both flexible sigmoidoscopy and pelvic MRI | Study week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine overall survival (OS) | Time from treatment day 1 to death from any cause | Time (measured in days) until death from any cause, up to 20 years post-treatment. | 
| Determine progression free survival (PFS) | Time (measured in days) to documented disease progression in imaging as described by the RECIST criteria. | From treatment day 1 to disease progression, up to 15 years post-treatment | 
| Determine metastasis free survival | Time (measured in days) to documented disease progression outside of the pelvis or death from any cause. | From treatment day 1 to disease progression or death, up to 20 years post-treatment. | 
| Determine local recurrence free survival | Time (measured in days) to disease progression within the pelvis or death from any cause. | From treatment day 1 to disease progression or death, up to 20 years post-treatment. | 
| Determine ostomy free survival | Time (measured in days) to receipt of permanent ostomy or death from any cause. | From treatment day 1 up to 20 years post-treatment. | 
| Determine objective response rate | Objective response rate, measured using the standardized RECIST criteria, is a reflection of complete tumor response and partial tumor response. The | 3 months post-radiation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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surgery, niraparib, dostarlimab, radiation therapy