PRIMARY OBJECTIVE:
I. To determine antitumor activity as measured by disease control rate at 12 weeks (DCR12) as
assessed using immune-modified Response Evaluation Criteria in Solid Tumors (iRECIST) in
select homologous recombination repair (HRR) deficient pancreatic cancer patients with HRR
deficiency (defined as mutations in BRCA 1/ 2, or PALB2).
SECONDARY OBJECTIVES:
I. To assess adverse events according to the current National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE) and other safety parameters.
II. To assess the time to next treatment (TTNT), objective response rate (ORR), time to and
duration of response and duration of confirmed stable disease according to iRECIST.
III. To assess progression-free survival. IV. To assess overall survival.
CORRELATIVE RESEARCH OBJECTIVES:
I. To assess germline deoxyribonucleic acid (DNA) and serum markers of immune response.
II. To determine changes in circulating tumor DNA (ctDNA) profile after therapy with a PARP
inhibitor (i) and a PD-1 inhibitor.
III. To study mechanisms of resistance in ctDNA profile after therapy with a PARPi and a PD-1
inhibitor.
IV. To assess the tumor microenvironment for immune related changes (immune infiltration,
PD-L1 and PD-1 expression, tumor-infiltrating lymphocytes [TIL]).
V. To assess genetic profile of the tumor pre- and post-treatment. VI. To determine changes
in the cytokine profile pre- and post-treatment.
OUTLINE:
Patients receive niraparib orally (PO) once daily (QD) on days 1-21. Patients also receive
dostarlimab intravenously (IV) over 30 minutes on day 1 every 3 weeks (Q3W) for cycles 1-4
and every 6 weeks (Q6W) for subsequent cycles. Cycles repeat every 21 days for up to 2 years
in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, every 3 months
until progressive disease (PD), and then every 6 months for up to 5 years after registration.
Inclusion Criteria:
- Presence of either a germline deleterious mutation or somatic deleterious mutation in
any one of the genes in our proposed gene-panel as determined by any of the
commercially available or institutional testing platforms. Note: The somatic mutation
could be either on a tissue-based test or the circulating tumor DNA (ctDNA)-based
assay. The 6 genes that would determine eligibility would be: BRCA1/2, PALB2, BARD1,
RAD51c, RAD51d
- Provide written informed consent
- Histological/cytological confirmation of diagnosis of metastatic pancreatic ductal
adenocarcinoma
- At least one but no more than two prior lines of systemic therapy for metastatic
disease (maintenance therapy is not considered a line of treatment)
- Note: Patients who have not had any prior chemotherapy can refuse chemotherapy
and be considered eligible. This refusal and their reason for refusal would have
to be documented
- Received a platinum agent as part of first or second line treatment (unless
contraindicated)
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Serum creatinine =< 1.5 x upper limit of normal (ULN) or estimated glomerular
filtration rate (eGFR) >= 60 mL/min using the Cockcroft-Gault Equation (=< 14 days
prior to registration)
- Hemoglobin >= 9.0 g/dL (=< 14 days prior to registration)
- Absolute neutrophil count >= 1500/uL (=< 14 days prior to registration:)
- Platelets >= 100 x 10^9/L (=< 14 days prior to registration)
- Total bilirubin =< 1.5 x ULN, (2.0 x ULN for subjects with Gilbert's disease) (=< 14
days prior to registration:)
- Aspartate transaminase (AST) and alanine transaminase (ALT) =< 2.5 x ULN (for subjects
with hepatic metastases =< 5 x ULN) (=< 14 days prior to registration). Note: One time
repeat testing to meet eligibility is allowed. If more testing is required, discuss
with principal investigator (PI)
- 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 (=< 14 days prior to registration)
- Evaluable or measurable disease per iRECIST
- Life expectancy of >= 3 months
- Willingness to consent to translational studies
- Willingness to undergo repeat biopsies of tumor lesions amenable to biopsy
- Note: While biopsies are mandatory, subjects are allowed to participate if no
lesions are amenable to biopsy, or if biopsy is not possible due to safety
- Willingness to not donate blood during the study or for 90 days after the last dose of
study treatment
- Willingness to not breastfeed during the study or for 90 days after the last dose of
study treatment
- Negative pregnancy test done =< 7 days prior to registration, for persons of
childbearing potential only
Exclusion Criteria:
- Known hypersensitivity to any component of study treatments (either niraparib and/or
TSR-042 or similar medications)
- Prior treatment with the combination of PARP inhibition and immunotherapy (either
CTLA-4 or anti-PD1/PD-L1 therapies). Prior treatment consisting of monotherapy with
either PARP inhibitors and/or with immunotherapy are allowed. Treatment with PARPi or
PD1 inhibitor as the most recent treatment prior to enrollment is not allowed
- Patient experienced >= grade 3 immune-related adverse events (AE) with prior
immunotherapy, with the exception of non-clinically significant lab abnormalities
- Radiotherapy =< 2 weeks prior to first study treatment or radionuclide treatment =< 4
weeks of first study treatment
- Live attenuated vaccine administration within 30 days prior to registration and/or
expected during study period
- Known brain metastases, uncontrolled seizure disorder, or active neurologic disease
which in the opinion of the investigator would impede participation within the trial.
Subjects with treated brain metastases are allowed to enroll
- Allogeneic bone marrow transplantation or high-dose chemotherapy requiring
hematopoietic stem cell rescue
- Received a transfusion (platelets or red blood cells) =< 4 weeks prior to registration
- NOTE: patients are also deemed ineligible if they have received a transfusion =<
4 weeks prior to first dose of niraparib
- Received colony-stimulating factors (e.g., granulocyte colony-stimulating factor,
granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin) =< 4
weeks prior to registration
- NOTE: patients are also deemed ineligible if they have received
colony-stimulating factors =< 4 weeks prior to first dose of niraparib
- 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)
- =< 4 weeks since receiving treatment with another investigational drug, or anti-cancer
therapy, or within a time interval less than at least 5 half-lives of the
investigational agent (whichever is shorter), or insufficient recovery (to the
judgement of the investigator) from adverse events due to such a previously
administered agent, except for alopecia prior to initiating protocol therapy.
Bisphosphonate therapy and receptor activator of nuclear factor kappa-Β ligand (RANKL)
inhibitors are not considered anti-cancer therapy
- Inadequate recovery from toxicity and/or complications from previous interventions,
including due to major surgery to the judgement of the investigator. Minor surgery
allowed up to 3 weeks from registration
- Primary or secondary immunodeficiency, including immunosuppressive disease, and
immunosuppressive doses of corticosteroids (e.g., prednisone > 20 mg per day during 2
weeks prior to first study treatment) or other immunosuppressive medications at dose
levels that to the judgement of the investigator would preclude participation within
the past 4 weeks prior to registration. Subjects with human immunodeficiency virus
(HIV) who are stable on highly active antiretroviral therapy (HAART) will not be
excluded
- 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)
- Pregnant or lactating
- Clinically significant, active, bacterial infections that, to the judgement of the
investigator makes it undesirable for the subject to participate in the study
- Persons of childbearing potential (POCBP) or those capable of causing pregnancy whose
sexual partners are POCBP who are unwilling or unable to use an effective method of
contraception for at least 1 month prior to study entry, for the duration of the
study, and for at least 180 days after the last dose of study drug. 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 an adequate barrier method 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
- History or active TB (Bacillus tuberculosis) that in the investigators opinion would
preclude participation within the study
- Any gastro-intestinal conditions that to the judgement of the investigator would
interfere with the absorption of niraparib
- Active, known or suspected unstable auto-immune disease, are excluded from this study.
Exceptions to this criterion are all auto-immune disease that have remained stable
within the past 3 months on corticosteroids (=< prednisone 20 mg or equivalent) prior
to first study treatment are allowed to enroll. Patients with autoimmune diseases that
do not require active immunosuppression are also allowed to enroll
- Note: Paraneoplastic disease as a cause of auto-immune phenomenon will not be
considered as auto-immune disease and are allowed to enroll
- Evidence of serious uncontrolled medical disorder, active infection or mental disorder
that, to the judgement of the investigator, makes it undesirable for the subject to
participate in the study or that would jeopardize compliance with the protocol.
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
- Prior malignancy which required active systemic treatment within 2 years prior to
first study treatment. Exceptions are: successfully treated squamous cell carcinoma of
the skin, superficial bladder cancer, and in situ carcinoma of the cervix. Since
patients with BRCA 1/2 or PALB2 can have other tumors, as long as they have been
definitively treated, it would not be considered an exclusion
