Niraparib, Dostarlimab, and Radiation Therapy for the Treatment of Metastatic Pancreatic Cancer
- Histologically or cytologically confirmed metastatic adenocarcinoma of pancreatic origin
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1
- Life expectancy of greater than 3 months
- Leukocytes >= 2,000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Hemoglobin >= 9 g/dL
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (subjects with liver metastases can have an AST [SGOT] =< 5 x upper limit of normal [ULN])
- Creatinine =< 1.5 x ULN OR creatinine clearance >= 60 mL/min (if using the Cockcroft-Gault formula)
- Total bilirubin =< 1.5 x ULN (subjects with Gilbert syndrome can have a total bilirubin < 3 x ULN)
- International normalized ratio (INR), prothrombin time (PT), partial thromboplastin time (aPTT) =< 1.5 x ULN (subjects receiving anticoagulant therapy must have PT or PTT within therapeutic range)
- Women of childbearing potential (WoCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 7 days prior to initiating protocol therapy. Nonchildbearing potential is defined as follows (by other than medical reasons): * >= 45 years of age and has not had menses for > 1 year * Patients who have been amenorrheic for < 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation * Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must be willing to use 2 adequate barrier methods throughout the study, starting with the screening visit through 150 days after the last dose of study treatment. Information must be captured appropriately within the site’s source documents. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient
- Women of childbearing potential must agree to use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 6 months (30 days plus the time required for niraparib to undergo five half-lives/150 days) after the last dose of investigational drug
- Women must not be breastfeeding during the study or for 150 days after the last dose of investigational drug
- Men who are sexually active with WoCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving protocol therapy and who are sexually active with WoCBP will be instructed to adhere to contraception for a period of 6 months (150 days) after the last dose of investigational product. (Women who are not of childbearing potential, i.e. are postmenopausal as defined in the eligibility criteria or surgically sterile, as well as azoospermic men do not require contraception.)
- Ability to understand and the willingness to sign a written informed consent document
- If applicable, stable dose of dexamethasone of 10 mg or less for 4 weeks prior to initiation of investigational protocol therapy. Regimen must be completed > 14 days prior to treatment start
- One previously unirradiated lesion amenable to radiotherapy at a dose of 8 Gy x 3 and can meet dose constraints, and another unirradiated measurable lesion > 1 cm in size outside the radiation field that can be used as measurable disease
- Patients must have had at least one line of prior treatment. Any prior line of treatment is permitted, including adjuvant
- Systemic anticancer or biological therapy including prior chemotherapy, immunotherapy, targeted small molecule therapy within 14 days prior to investigational agent, or those who have not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 2 weeks earlier. Participants with =< grade 2 neuropathy are an exception to these criteria and may qualify for the study. If the participant received major surgery, then they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
- Received investigational therapy >= 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, prior initiating protocol therapy
- Major surgery =< 3 weeks prior to initiating protocol therapy and/or not recovered from any surgical effects
- Received radiation therapy encompassing > 20% of the bone marrow within 2 weeks; or any radiation therapy within 1 week prior to day 1 of protocol therapy
- Received a transfusion (platelets or red blood cells) =< 4 weeks prior to 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 initiating protocol therapy
- Known history of 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)
- Active, known or suspected autoimmune disease that has required systemic treatment within the past 2 years other than vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
- Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Participants are permitted to use topical, ocular, intraarticular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
- Known history of active TB (Bacillus Tuberculosis). Testing is not required for eligibility purposes
- Known hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. Testing is not required for eligibility purposes
- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). These participants are at increased risk of lethal infections when treated with marrow suppressive therapy. Testing is not required for eligibility purposes
- Known >= grade 3 immune-related adverse event (AE) with prior immunotherapy, with the exception of non-clinically significant lab abnormalities
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, recent (within 90 days) myocardial infarction or psychiatric illness/social situations that would limit compliance with study requirements.
- Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Known additional malignancy diagnosed, detected or treated =< 2 years prior to initiation of protocol therapy. Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
- Known history of, or any evidence of active, non-infectious pneumonitis or interstitial lung disease
- Active infection requiring systemic therapy
- Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
- Known hypersensitivity to niraparib and dostarlimab components or excipients
- History of severe hypersensitivity reaction to any monoclonal antibody
- Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Further imaging is not required for eligibility purposes
I. To estimate the disease control rate of the combination of niraparib tosylate monohydrate (niraparib) and dostarlimab with radiation in patients with metastatic pancreatic cancer by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
I. To estimate the disease control rate of the combination of niraparib and dostarlimab with radiation in patients with metastatic pancreatic cancer by Immune-related (ir)RECIST.
II. To estimate progression-free survival in patients with metastatic pancreatic cancer treated with niraparib and dostarlimab with radiation.
III. To estimate overall survival in patients with metastatic pancreatic cancer treated with niraparib and dostarlimab with radiation.
IV. To describe toxicity of niraparib and dostarlimab with radiation in patients with metastatic pancreatic cancer.
I. To explore the potential synergistic effect of anti-PD1 and PARP inhibition with radiation using multiplexed immune IF and ribonucleic acid sequencing (RNAseq), to assess the change in immune microenvironment between pre-treatment, post anti-PDI/PARP and post radiation biopsies.
II. To monitor response and define mechanisms of resistance to anti-PD1 and PARP inhibition with radiation using serial circulating cell-free deoxyribonucleic acid (cfDNA) analyses.
Patients receive niraparib orally (PO) once daily (QD) on days 1-21. Patients also receive dostarlimab intravenously (IV) over 30 minutes on day 1 of cycles 1-4, then on day 1 of odd number cycles starting cycle 5. Cycles repeat every 21 days in the absence of disease progression and unacceptable toxicity. Beginning cycle 2 day 1, patients also undergo radiation therapy every other weekday until the end of cycle 2 in the absence of disease progression and unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, every 12 weeks for 2 years, then every 6 months for 3 years.
Trial Phase Phase II
Trial Type Treatment
Dana-Farber Harvard Cancer Center
Theodore Sunki Hong
- Primary ID 19-538
- Secondary IDs NCI-2020-06745
- Clinicaltrials.gov ID NCT04409002