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
