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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Rectal Neoplasms; Rectal Neoplasm Malignant
• Intervention / Treatment: Drug: Niraparib; Drug: Dostarlimab; Radiation: Short course radiation

Detailed Description

Standard of care therapy for resectable locally advanced rectal cancer includes pelvic radiation (short or long course), chemotherapy, and (if indicated) 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

• Study Type: Interventional
• Enrollment (Estimated): 38
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Joseph M. Caster, M.D., Ph.D.; Phone Number: 319-353-8836; Email: joseph-caster@uiowa.edu
• Study Contact Backup: Name: Saima Sharif, M.D.; Email: saima-sharif@uiowa.edu

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Recruiting
      • Holden Comprehensive Cancer Center at the University of Iowa
      • Contact: Sandy Vollstedt, RN, BSN, OCN; Phone Number: 319-353-7143; Email: sandy-vollstedt@uiowa.edu
      • Contact: Heather Brown, RN, BAN, OCN; Phone Number: (319) 384-7912; Email: heather-brown@uiowa.edu
      • Principal Investigator: Joseph M Caster, MD, PhD
      • Sub-Investigator: Saima Sharif, MD
      • Sub-Investigator: Joseph Cullen, MD, FACS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 total neoadjuvant therapy consisting of preoperative radiation therapy followed by systemic FOLFOX chemotherapy
• 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
• Recommended to receive a chemotherapy regimen other than FOLFOX chemotherapy. CapeOX (oral xeloda plus oxaliplatin) is an acceptable alternative as it contains the core fluoropyrimidine + oxaliplatin backbone.
• Indication for alternative radiation dose or fractionation regimen.
• Active Crohn's disease or another inflammatory bowel disease
• Any T or N stage disease that is 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 (e.g., granulocyte colony-stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior to Day 1 of protocol therapy.
• Major surgery within 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
• 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. Participant must have a negative serum pregnancy test within 72 hours prior to taking study treatment if of childbearing potential and agrees 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, or is of nonchildbearing potential. Nonchildbearing potential is defined as follows (by other than medical reasons):

  1. ≥ 60 years of age
  2. Post-hysterectomy. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound.
• Actively breastfeeding. Participant must agree to not breastfeed during the study or for 8 weeks after the last dose of study treatment.
• Declines to use a highly effective method of contraception (see Section 5.2.1 for a list of acceptable birth control methods). Eligible patients must agree to highly effective methods of contraception starting with the first dose of study treatment through 180 days after the last dose of niraparib and dostarlimab.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 (starting); 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; Niraparib is a drug FDA-approved for use in maintenance treatment of adults with advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.; Other Names: Zejula; Drug: Dostarlimab; Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody medication used for the treatment of endometrial cancer.; Other Names: Jemperli; Radiation: Short course radiation; 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.; Other Names: IMRT; VMAT
Experimental: Cohort 2; 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; Niraparib is a drug FDA-approved for use in maintenance treatment of adults with advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.; Other Names: Zejula; Drug: Dostarlimab; Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody medication used for the treatment of endometrial cancer.; Other Names: Jemperli; Radiation: Short course radiation; 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.; Other Names: IMRT; VMAT

What is the study measuring?

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 up to 16 weeks.
Determination of the clinical complete response rate	Clinical evaluation of the tumor by both flexible sigmoidoscopy and pelvic MRI	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
Determination of the pathologic complete response	Absence of viable tumor in the primary tumor bed and all regional nodes in patients recommended to undergo surgical resection regardless of response to neoadjuvant therapy.	At surgery; up to 1 year post-treatment
Determination of the organ preservation rate	Organ perservation defined as day 1 therapy to receipt of rectal resection for any reason	From treatment day 1 up to 15 years post-treatment

Collaborators and Investigators

• Sponsor: Joseph Caster, Ph.D., M.D.
• Collaborators: GlaxoSmithKline
• Investigators: Principal Investigator: Joseph M. Caster, M.D., Ph.D., University of Iowa

Publications and helpful links

General Publications

• Seyedin SN, Hasibuzzaman MM, Pham V, Petronek MS, Callaghan C, Kalen AL, Mapuskar KA, Mott SL, Spitz DR, Allen BG, Caster JM. Combination Therapy with Radiation and PARP Inhibition Enhances Responsiveness to Anti-PD-1 Therapy in Colorectal Tumor Models. Int J Radiat Oncol Biol Phys. 2020 Sep 1;108(1):81-92. doi: 10.1016/j.ijrobp.2020.01.030. Epub 2020 Feb 6.

Study record dates

Study Major Dates

• Study Start (Actual): July 7, 2022
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: June 8, 2021
• First Submitted That Met QC Criteria: June 8, 2021
• First Posted (Actual): June 15, 2021

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 8, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: dostarlimab; radiation therapy; niraparib; total neoadjuvant therapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Neoplasms; Rectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Niraparib; Dostarlimab
• Other Study ID Numbers: 202103459

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be released publicly as per participant consent and IRB approval. Individual researchers should contact the research team for data sharing.
• IPD Sharing Time Frame: Study protocol and informed consent will be shared after primary completion. Statistical analysis plan will be shared with results reporting.
• IPD Sharing Access Criteria: An IRB-stamped signed usage agreement will be required in addition to a data sharing agreement between the academic centers.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No