Niraparib and TSR-042 for the Treatment of BRCA-Mutated Unresectable or Metastatic Breast, Pancreas, Ovary, Fallopian Tube, or Primary Peritoneal Cancer
Niraparib and TSR-042 for the Treatment of BRCA-Mutated Unresectable or Metastatic Breast, Pancreas, Ovary, Fallopian Tube, or Primary Peritoneal Cancer
This phase IB trial evaluates the effect of niraparib and TSR-042 in treating patients with
 BRCA-mutated breast, pancreas, ovary, fallopian tube, or primary peritoneal cancer that
 cannot be removed by surgery (unresectable) or has spread to other places in the body
 (metastatic). Niraparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic
 acid (DNA) when it becomes damaged. Blocking PARP may help keep cancer cells from repairing
 their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy.
 Immunotherapy with monoclonal antibodies, such as TSR-042, may help the body's immune system
 attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
 Giving niraparib and TSR-042 may kill more cancer cells.
OUTLINE:

 Patients receive niraparib orally (PO) once daily (QD) on days 1-28 of cycle 1. Beginning
 cycle 2, patients receive niraparib PO QD on days 1-21 and dostarlimab intravenously (IV) on
 day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or
 unacceptable toxicity. Beginning cycle 6, patients receive niraparib PO QD on days 1-42 and
 dostarlimab IV on day 1. Cycles repeat every 42 days for up to 24 months in the absence of
 disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up for 30 days, every 6 months for
 2 years, and then annually for up to 5 years.
Inclusion Criteria:

 -  Participant must have breast, pancreas, ovary, fallopian tube or primary peritoneal
 cancer that is unresectable or metastatic, with a pathogenic mutation in BRCA1 or
 BRCA2 (either germline or somatic) as confirmed by next generation gene sequencing
 such as University of Washington (UW) OncoPlex assay or equivalent, and who have
 experienced progression or been intolerant to standard therapies for their disease.

 -  Breast cancer patients with or without HER2+, estrogen receptor (ER)+, and/or
 progesterone receptor (PR)+ disease, as determined by pathological report, are
 allowed

 -  Participant must be able and willing to undergo pre-treatment and on-treatment biopsy

 -  Participant must have life expectancy of 4 months or greater

 -  Tumor must be measurable according to Response Evaluation Criteria in Solid Tumors
 (RECIST)1.1 criteria

 -  Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status
 of =< 1

 -  Participant must be >= 18 years of age

 -  Patient must be able to tolerate oral medication

 -  Absolute neutrophil count >= 1,500/uL

 -  Platelets >= 100,000/uL

 -  Hemoglobin >= 9 g/dL

 -  Serum creatinine =< 1.5 x upper limit of normal (ULN) or calculated creatinine
 clearance >= 60 mL/min using the Cockcroft-Gault equation

 -  Total bilirubin =< 1.5 x ULN (=< 2.0 in patients with known Gilberts syndrome) OR
 direct bilirubin =< 1 x ULN

 -  Aspartate aminotransferase and alanine aminotransferase =< 2.5 x ULN unless liver
 metastases are present, in which case they must be =< 5 x ULN

 -  International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x 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 x ULN unless patient is receiving anticoagulant
 therapy as long as PT or PTT is within therapeutic range of intended use of
 anticoagulants

 -  Asymptomatic patients with stable brain metastases must have no evidence of bleeding
 and no need for steroids or anti-epileptic medications for at least 7 days prior to
 day 1

 -  Participants receiving corticosteroids may continue as long as their dose is stable
 for at least 4 weeks prior to initiating protocol therapy

 -  Female participant has a negative urine or serum pregnancy test within 7 days prior to
 taking study treatment if of childbearing potential and agrees to abstain from
 activities that could result in pregnancy from screening through 180 days after the
 last dose of study treatment or is of nonchildbearing potential. 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 amenorrhoeic 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 180 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

 -  Participant must agree to not breastfeed during the study or for 180 days after the
 last dose of study treatment

 -  Male participant agrees to use an adequate method of contraception starting with the
 first dose of study treatment through 180 days after the last dose of study treatment.
 Note: Abstinence is acceptable if this is the established and preferred contraception
 for the patient

 -  Participant must be able to understand the study procedures and agree to participate
 in the study by providing written informed consent

 -  Participant must agree to not donate blood during the study or for 90 days after the
 last dose of study treatment

 -  Prior treatment with a PARP inhibitor is allowed as long as patient has not had
 previous exposure to immune checkpoint inhibitor including inhibitors of PD1, PD-L1 or
 CTLA4

 -  Prior treatment with immune checkpoint inhibitor including inhibitors of PD1, PD-L1 or
 CTLA4 is allowed as long as patient has not had previous exposure to PARP inhibitor

 Exclusion Criteria:

 -  Participant must not be simultaneously enrolled in any interventional clinical trial

 -  Participant must not have had major surgery =< 3 weeks prior to initiating protocol
 therapy and participant must have recovered from any surgical effects

 -  Prior treatment with both PARP inhibitor and immune checkpoint inhibitor blockade
 either sequentially or together including inhibitors of PD1, PD-L1 or CTLA4 is not
 allowed. Patients may have had either PARP inhibitor or Immune checkpoint inhibitor
 previously but not within 3 months of starting treatment

 -  Participant must not have 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

 -  Participant must not have had 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

 -  Participant must not have a known hypersensitivity to niraparib and dostarlimab
 (TSR-042) components or excipients

 -  Participant must not have received a transfusion (platelets or red blood cells) =< 4
 weeks prior to initiating protocol therapy

 -  Participant must not have received colony stimulating factors (e.g., granulocyte
 colony-stimulating factor, granulocyte macrophage colony stimulating factor, or
 recombinant erythropoietin) within 4 weeks prior initiating protocol therapy

 -  Participant has had any 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

 -  Participant must not have any known history of myelodysplastic syndrome (MDS) or acute
 myeloid leukemia (AML)

 -  Participant must not have a serious, uncontrolled medical disorder, nonmalignant
 systemic disease, or active, uncontrolled infection. 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, or any psychiatric disorder that prohibits obtaining
 informed consent

 -  Participant must not have had 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 in situ cervical cancer that has been definitively treated
 or a BRCA-related cancer (i.e., breast, prostate, pancreas or ovarian)

 -  Participant must not have a known partial or complete bowel obstruction that is
 incompatible with oral feeding and/or absorption of oral medications

 -  Patient experienced >= grade 3 immune-related adverse event (AE) with prior
 immunotherapy, with the exception of non-clinically significant lab abnormalities

 -  Participant has a diagnosis of immunodeficiency or has received systemic steroid
 therapy or any other form of immunosuppressive therapy within 7 days prior to
 initiating protocol therapy

 -  Participant has a known history of human immunodeficiency virus (type 1 or 2
 antibodies)

 -  Participant has 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)

 -  Participant has an 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

 -  Participant must not have a history of interstitial lung disease

 -  Participant has received a live vaccine within 14 days of initiating protocol therapy