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About
The second line of therapy for patients with MSI-H CRC who experience disease progression on anti-PD1 based therapies is not well defined and there is an unmet need for research for patients with anti-PD1 refractory MSI-H CRC. This study will examine the combination of niraparib and dostarlimab for a synergistic antitumor effect for patients with MSI-H CRC.
Full description
In this single-arm phase II study, the clinical effectiveness of niraparib in combination with dostarlimab will be investigated for patients with MSI-H colorectal cancer who had disease progression on anti-PD1-based therapy. This study aims to leverage MRE11 deficiency and other HR pathway alterations by using Niraparib and also aims to create potential synergetic effect between dostarlimab with niraparib combination to induce clinically meaningful antitumor benefit. Patients with advanced stage MSI-H CRC who progressed on first line anti-PD1 +/- anti-CTLA4 based therapy will be eligible for this study.
Enrollment
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Volunteers
Inclusion criteria
Histologically confirmed mismatch repair deficient or microsatellite instability high advanced stage colorectal cancer
Measurable disease per RECIST v1.1
ECOG 0 to 2
Age ≥ 18 years
Able to swallow oral medication (tablets).
Progression on prior anti-PD1 ± anti-CTLA4 therapy.
Adequate organ function based on the following lab assessments:
Patient who experienced progression of disease on prior anti-PD1 ± Anti-CTLA in the adjuvant and neoadjuvant settings are eligible to be enrolled in this trial without requirement of a second line of immunotherapy for advanced stage disease.
Women of childbearing potentials must use a contraceptive method that is highly effective (with a failure rate of <1% per year), from the screening visit through at least 120 days after the last dose of study treatment and agree not to donate eggs (ova, oocytes) for the purpose of reproduction during this period.
Men must agree to use adequate contraception for the duration of trial participation and for 4 months after the last dose of study drugs. Men must also agree to not donate sperm. Men must agree to use adequate contraception for the duration of trial participation and for 4 months after the last dose of study drugs. Men must also agree to not donate sperm.
Exclusion criteria
More than 2 lines of systemic therapy (excluding adjuvant therapy)
Prior oxaliplatin based chemotherapy for metastatic disease. This excludes adjuvant oxaliplatin. Patients who received oxaliplatin based chemotherapy for metastatic disease before determination of MMR-D/MSI-H status (due to test turn-around time) can be enrolled if they received 4 or less cycle of oxaliplatin treatment (each cycle is one dose).
More than 1 line of anti-PD1 based therapy.
History of severe hypersensitivity to anti-PD1 monoclonal antibodies
Prior PARPi
Progression on platinum-based chemotherapy
Active autoimmune disease requiring immune suppression except following conditions:
Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone without an active complication are eligible for the study.
Patients with well controlled Type 1 diabetes mellitus who are actively on an insulin regimen are eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
Active untreated brain metastasis (patients treated brain metastasis within 4 weeks can be enrolled)
Any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels.
Received colony-stimulating factors (e.g., granulocyte macrophage colony-stimulating factor or recombinant erythropoietin) within 4 weeks.
Previously or are currently participating in a treatment study of an investigational agent within 4 weeks of the first dose of therapy preceding the study.
Received live vaccine within 30 days of planned start of study randomization. Study patients can be vaccinated against Corona virus disease 2019 (COVID-19) using vaccines authorized via the appropriate regulatory mechanisms. Note: messenger ribonucleic acid (mRNA) and adenoviral-based COVID-19 vaccines are considered nonlive. If COVID-19 vaccine is administered at any time, the date, name of the COVID-19 vaccine anatomic location, must be entered in the eCRF.
Hypersensitivity to the components of niraparib or the formulation excipients.
Undergone major surgery within 4 weeks of starting the first dose of study treatment or have not recovered from any effects of any major surgery.
Have a second primary malignancy. Exceptions are the following:
Current active pneumonitis or any history of pneumonitis requiring steroids (any dose) or immunomodulatory treatment within 90 days of planned start of the study.
Any clinically significant concomitant disease or condition (such as transfusion-dependent anemia or thrombocytopenia) that could interfere with, or for which the treatment might interfere with, the conduct of the study or that would, in the opinion of the Investigator, pose an unacceptable risk to the patients in this study.
Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study requirements and/or follow-up procedures. Those conditions should be discussed with the patients before study entry.
High medical risk due to a serious, uncontrolled medical disorder; nonmalignant systemic disease; or active, uncontrolled infection (including COVID-19). Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, active uncontrolled coagulopathy, bleeding disorder, or any psychiatric disorder that prohibits obtaining informed consent.
Uncontrolled hypertension defined as SBP>180 and DBP>100 should receive antihypertensive medical therapy for blood pressure control (to achieve SBP<160 and DBP <90) before being enrolled in the study.
Is pregnant, breastfeeding, or expecting to conceive children while receiving study treatment and/or for up to 180 days after the last dose of study treatment.
Presence of hepatitis B surface antigen or a positive hepatitis C virus (HCV) antibody test result at Screening or within 3 months prior to first dose of study treatment. Patients with presence of hepatitis B core antibody should also be excluded.
Known history of MDS or AML
Are immunocompromised. Patients with splenectomy are allowed. Patients with known human immunodeficiency virus (HIV) are allowed if they meet the following criteria:
Prior immunotherapy toxicities (until resolution to Grade 1 or better)
Primary purpose
Allocation
Interventional model
Masking
20 participants in 1 patient group
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Central trial contact
Debra Diecks, MSN
Data sourced from clinicaltrials.gov
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