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

Primary Purpose

Rectal Neoplasms, Rectal Neoplasm Malignant

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Niraparib
Dostarlimab
Short course radiation
Sponsored by
Joseph Caster, Ph.D., M.D.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rectal Neoplasms focused on measuring niraparib, dostarlimab, radiation therapy, surgery

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Holden Comprehensive Cancer Center at the University of IowaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Cohort 1 (starting)

Cohort 2

Arm Description

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

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

Outcomes

Primary Outcome Measures

Determination of recommended phase 2 niraparib dose
The recommended dose will be determined by incidence of dose limiting toxicities.
Determination of the pathologic complete response
Pathologic evaluation of the excised tumor from surgery will determine the pathologic response
Determination of the clinical complete response rate
Clinical evaluation of the tumor by both flexible sigmoidoscopy and pelvic MRI

Secondary Outcome Measures

Determine overall survival (OS)
Time from treatment day 1 to death from any cause
Determine progression free survival (PFS)
Time (measured in days) to documented disease progression in imaging as described by the RECIST criteria.
Determine metastasis free survival
Time (measured in days) to documented disease progression outside of the pelvis or death from any cause.
Determine local recurrence free survival
Time (measured in days) to disease progression within the pelvis or death from any cause.
Determine ostomy free survival
Time (measured in days) to receipt of permanent ostomy or death from any cause.
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

Full Information

First Posted
June 8, 2021
Last Updated
February 16, 2023
Sponsor
Joseph Caster, Ph.D., M.D.
Collaborators
GlaxoSmithKline
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1. Study Identification

Unique Protocol Identification Number
NCT04926324
Brief Title
A Safety Study Adding Niraparib and Dostarlimab to Radiation Therapy for Rectal Cancers
Official Title
A Phase 1b/2 Trial of Preoperative Niraparib, Dostarlimab, and Hypofractionated Radiotherapy for the Treatment of Locally-advanced Rectal Cancers.
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 7, 2022 (Actual)
Primary Completion Date
December 31, 2024 (Anticipated)
Study Completion Date
December 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Joseph Caster, Ph.D., M.D.
Collaborators
GlaxoSmithKline

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rectal Neoplasms, Rectal Neoplasm Malignant
Keywords
niraparib, dostarlimab, radiation therapy, surgery

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
38 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1 (starting)
Arm Type
Experimental
Arm Description
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
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Niraparib
Other Intervention Name(s)
Zejula
Intervention Description
Niraparib is a drug FDA-approved for use in maintenance treatment of adults with advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
Intervention Type
Drug
Intervention Name(s)
Dostarlimab
Other Intervention Name(s)
Jemperli
Intervention Description
Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody medication used for the treatment of endometrial cancer.
Intervention Type
Radiation
Intervention Name(s)
Short course radiation
Other Intervention Name(s)
IMRT, VMAT
Intervention Description
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.
Primary Outcome Measure Information:
Title
Determination of recommended phase 2 niraparib dose
Description
The recommended dose will be determined by incidence of dose limiting toxicities.
Time Frame
From treatment day 1 for 21 weeks.
Title
Determination of the pathologic complete response
Description
Pathologic evaluation of the excised tumor from surgery will determine the pathologic response
Time Frame
Study week 13
Title
Determination of the clinical complete response rate
Description
Clinical evaluation of the tumor by both flexible sigmoidoscopy and pelvic MRI
Time Frame
Study week 8
Secondary Outcome Measure Information:
Title
Determine overall survival (OS)
Description
Time from treatment day 1 to death from any cause
Time Frame
Time (measured in days) until death from any cause, up to 20 years post-treatment.
Title
Determine progression free survival (PFS)
Description
Time (measured in days) to documented disease progression in imaging as described by the RECIST criteria.
Time Frame
From treatment day 1 to disease progression, up to 15 years post-treatment
Title
Determine metastasis free survival
Description
Time (measured in days) to documented disease progression outside of the pelvis or death from any cause.
Time Frame
From treatment day 1 to disease progression or death, up to 20 years post-treatment.
Title
Determine local recurrence free survival
Description
Time (measured in days) to disease progression within the pelvis or death from any cause.
Time Frame
From treatment day 1 to disease progression or death, up to 20 years post-treatment.
Title
Determine ostomy free survival
Description
Time (measured in days) to receipt of permanent ostomy or death from any cause.
Time Frame
From treatment day 1 up to 20 years post-treatment.
Title
Determine objective response rate
Description
Objective response rate, measured using the standardized RECIST criteria, is a reflection of complete tumor response and partial tumor response. The
Time Frame
3 months post-radiation

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Joseph M. Caster, M.D., Ph.D.
Phone
319-353-8836
Email
joseph-caster@uiowa.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Saima Sharif, M.D.
Email
saima-sharif@uiowa.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joseph M. Caster, M.D., Ph.D.
Organizational Affiliation
University of Iowa
Official's Role
Principal Investigator
Facility Information:
Facility Name
Holden Comprehensive Cancer Center at the University of Iowa
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sandy Vollstedt, RN, BSN, OCN
Phone
319-353-7143
Email
sandy-vollstedt@uiowa.edu
First Name & Middle Initial & Last Name & Degree
Heather Brown, RN, BAN, OCN
Phone
(319) 384-7912
Email
heather-brown@uiowa.edu
First Name & Middle Initial & Last Name & Degree
Joseph M Caster, MD, PhD
First Name & Middle Initial & Last Name & Degree
Saima Sharif, MD
First Name & Middle Initial & Last Name & Degree
Joseph Cullen, MD, FACS

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
Citations:
PubMed Identifier
32036006
Citation
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.
Results Reference
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A Safety Study Adding Niraparib and Dostarlimab to Radiation Therapy for Rectal Cancers

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