Effects of Single Agent Niraparib and Niraparib Plus Programmed Cell Death-1 (PD-1) Inhibitors in Non-Small Cell Lung Cancer Participants
Condition: Neoplasms
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: Niraparib; Pembrolizumab; TSR-042 (Dostarlimab)
Intervention description: Niraparib is an orally available, potent, highly selective poly adenosine diphosphate- ribose (poly ADP-ribose) polymerase-1 (PARP-1) and PARP-2 inhibitor. It will be available as 100 milligrams (mg) capsules and will be administered as 2 X 100 mg capsules (200 mg per day) orally once daily (QD).; Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the immunoglobulin G-4 (IgG4)/kappa isotype designed to directly block the interaction between PD-1 and its ligands (PD-L1 and PD-L2). It will be available as 50 mg lyophilized powder single-use vials or 100 mg/4 milliliters (mL) (25 mg/mL) solution in a single-dose vial. It will be administered at a dose of 200 mg intravenous (IV) using a 30-minute IV infusion; TSR-042 (Dostarlimab) is a humanized mAb of the IgG4/kappa isotype that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. It will be administered at a dose of 500 mg for every 3 weeks (Q3W) for first 4 cycles followed by 1000 mg for every 6 weeks (Q6W) for all subsequent cycles using a 30-minute IV infusion. TSR-042 (dostarlimab) will be supplied as a solution of 160 mg (20 mg/mL) or 500 mg (50 mg/mL) in a single-dose vial.
Intervention MeSH terms: Pembrolizumab; Niraparib; Dostarlimab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Participants will receive niraparib either as monotherapy or in combination with pembrolizumab during Stage 1 of the study. Participants will receive niraparib in combination with TSR-042 (dostarlimab) during Stage 2 of the study.
Masking: None (Open Label)
Masking description: This will be an open-label study.
Enrollment: 53.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Niraparib; NSCLC; Pembrolizumab; Dostarlimab; TSR-042

Summary:

      This is a multicenter, open-label, phase 2 study to evaluate the efficacy and safety of
      niraparib alone and in combination with PD-1 inhibitors in participants with locally advanced
      and metastatic non-small cell lung cancer (NSCLC). The study will consist of 2 stages. In
      stage 1, participants from Cohorts 1 and 2 will receive niraparib plus PD-1 inhibitor;
      pembrolizumab and participants from Cohort 3 will receive niraparib alone. In Stage 2,
      participants from Cohorts 1A and 2A will receive niraparib plus the PD-1 inhibitor, TSR-042
      (Dostarlimab).
    

Eligibility criteria:

        General Inclusion Criteria:

          -  Male or female participants at least 18 years of age.

          -  Histological or cytological proven advanced (unresectable) or metastatic NSCLC as
             defined as stage IIIB (positive supraclavicular lymph nodes) not amenable to
             definitive chemoradiotherapy or stage IV NSCLC.

          -  Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version
             (v) 1.1.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

          -  Adequate organ function, defined as:

               1. Absolute neutrophil count (ANC) >= 1500 per microliter (/µL).

               2. Platelets >= 100,000/µL.

               3. Hemoglobin >= 9 grams per deciliter (g/dL) or >= 5.6 millimoles per liter
                  (mmol/L).

               4. Serum creatinine <= 1.5 times upper limit of normal (ULN) or creatinine clearance
                  >= 50 milliliters per minute (mL/min) (as calculated using the Cockcroft Gault
                  equation or measured using 24-hour urine creatinine clearance) for participants
                  with creatinine levels > 1.5 times institutional ULN.

               5. Total bilirubin <= 1.5 times ULN except in participants with Gilbert's syndrome.
                  Participants with Gilbert's syndrome may enroll if direct bilirubin <= 1.5 times
                  ULN of the direct bilirubin.

               6. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 2.5 times
                  ULN unless liver metastases are present, in which case they must be <= 5 times
                  ULN.

          -  Participant must have recovered to Grade 1 toxicity from prior cancer therapy (a
             participant with Grade 2 neuropathy or Grade 2 alopecia is an exception to this
             criterion and may qualify for this study).

          -  Participant agrees to submit formalin fixed paraffin embedded (FFPE) tumor tissue
             specimen, which may have been collected at any time prior to screening. If no archival
             FFPE tumor tissue is available, participant agrees to undergo a tumor tissue biopsy
             before Cycle 1/Day 1. (For Cohort 3 only: if diagnosis was made by cytology and
             archival tissue is not available, participant will not need to provide tumor tissue).

          -  Participants is able to take oral medications.

          -  Female participant meets the following criteria:

             a) Female participant (of childbearing potential) is not breastfeeding, has a negative
             serum pregnancy test within 72 hours prior to taking study drug, and agrees to abstain
             from activities that could result in pregnancy from enrollment through 180 days after
             the last dose of study treatment or is of nonchildbearing potential; or b) Female
             participant is of nonchildbearing potential, other than medical reasons, defined as
             follows: i) >=45 years of age and has not had menses for > 1 year. ii) Amenorrheic for
             < 2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone
             (FSH) value in the postmenopausal range upon screening evaluation.

        iii) Post hysterectomy, bilateral oophorectomy, or 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 participant must be willing to use 2 highly effective
        contraception methods throughout the study, starting with the screening visit through 180
        days after the last dose of study therapy.

          -  Male participant agrees to use an adequate method of contraception and not donate
             sperm starting with the first dose of study therapy through 120 days after the last
             dose of study therapy.

          -  Participant is able to understand the study procedures and agree to participate in the
             study by providing written informed consent.

        Cohort Specific Inclusion Criteria:

          -  Cohorts 1 and 1A (combination of niraparib and PD-1 inhibitor): participants must have
             tumors with high PD-L1 expression (TPS >= 50%) per local assessment; with no known
             Epidermal Growth Factor Receptor (EGFR)-sensitizing mutation and/or ROS -1 or
             anaplastic lymphoma kinase (ALK) translocation, and no prior systemic chemotherapy or
             PD-1/PD-L1 inhibitor treatment for metastatic NSCLC.

          -  Cohorts 2 and 2A (combination of niraparib and PD-1 inhibitor): participants must have
             tumors with PD-L1 expression (TPS between 1% and 49%) per local assessment, with no
             known EGFR-sensitizing mutation and/or ROS-1 or ALK translocation, and no prior
             systemic chemotherapy or PD-1/PD-L1 inhibitor treatment for metastatic NSCLC.

          -  Cohort 3 (single agent niraparib): participants must have metastatic squamous
             non-small cell lung cancer (sqNSCLC) and have progressed after both prior
             platinum-based chemotherapy and prior PD-1 or PD-L1 inhibitor treatment.

        Exclusion Criteria for Cohorts 1, 1A , 2 and 2A:

          -  Participant has received systemic therapy for the treatment of advanced stage NSCLC.
             Completion of treatment with chemotherapy and/or radiation as part of
             neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6
             months prior to the diagnosis of metastatic disease.

          -  Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

          -  Known hypersensitivity to the components of niraparib, pembrolizumab, TSR-042
             (Dostarlimab), or their excipients.

          -  Known EGFR (exon 19 and 21) mutations, ALK translocations, and/or ROS-1
             translocations.

          -  Participant has a history or current condition (such as transfusion-dependent anemia
             or thrombocytopenia), therapy, or laboratory abnormality that might confound the study
             results, or interfere with the participant's participation for the full duration of
             the study treatment.

          -  Known diagnosis of immunodeficiency or receiving systemic steroid therapy or any other
             form of immunosuppressive therapy within 7 days prior to the first dose of study
             treatment.

          -  Participant is immunocompromised, in the opinion of the Investigator.

          -  Current participation in a treatment study or past participation in a study of an
             investigational agent within 4 weeks before the first dose of study treatment.

          -  Symptomatic uncontrolled brain or leptomeningeal metastases. (To be considered
             "controlled," central nervous system [CNS] disease must have undergone treatment
             [example, radiation or chemotherapy] at least 1 month prior to study entry. The
             participant must not have any new or progressive signs or symptoms related to the CNS
             disease and must be taking <= 10 mg of prednisone or equivalent per day or no
             steroids.) Participants who have untreated brain metastases and who are not
             symptomatic may enroll if the Investigator feels that treatment of these metastases is
             not indicated. A scan to confirm the absence of brain metastases is not required.
             Participants with spinal cord compression may be considered if they have received
             definitive treatment for this and evidence of clinically SD for 28 days.

          -  Active autoimmune disease that required systemic treatment in the past 2 years (with
             use of disease-modifying agents, corticosteroids, or immunosuppressive drugs).
             Replacement therapy (examples, thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency) is not considered a form
             of systemic treatment.

          -  Major surgery within 3 weeks of starting the study or participant has not recovered
             from any effects of any major surgery.

          -  Other active concomitant malignancy that warrants systemic therapy.

          -  Poor medical risk due to 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, uncontrolled hypertension, active uncontrolled
             coagulopathy or any psychiatric disorder that prohibits obtaining informed consent.

          -  Known history of interstitial lung disease, drug-related pneumonitis, or radiation
             pneumonitis requiring steroid treatment.

          -  Participant is pregnant, breastfeeding, or expecting to conceive children while
             receiving study treatment and for 180 days (for pregnancy or conception) or 30 days
             (for breastfeeding) after the last dose of study treatment.

          -  Male participant is expecting to donate sperm or father children while receiving study
             drug or for 120 days after the last dose of study treatment.

          -  Known active hepatic disease (known hepatic cirrhosis, hepatitis B surface
             antigen-positive status, or suspected active hepatitis C infection).

          -  Prior treatment with a known poly adenosine diphosphate-ribose (ADP-ribose) polymerase
             (PARP) inhibitor.

          -  Participant received a live vaccine within 30 days of planned start of study therapy.

          -  Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

        Exclusion criteria for Cohort 3:

          -  Platinum-treated participant who progressed while on or within less than 8 weeks from
             the last day of platinum administration.

          -  Known hypersensitivity to the components of niraparib or excipients.

          -  Participant has a history or current condition (such as transfusion dependent anemia
             or thrombocytopenia), therapy, or laboratory abnormality that might confound the study
             results, or interfere with the participant's participation for the full duration of
             the study treatment.

          -  Known diagnosis of immunodeficiency or receiving systemic steroid therapy or any other
             form of immunosuppressive therapy within 7 days prior to the first dose of study
             treatment.

          -  Current participation in a treatment study or past participation in a study of an
             investigational agent within 4 weeks before the first dose of study treatment.

          -  Symptomatic uncontrolled brain or leptomeningeal metastases. (To be considered
             "controlled," CNS disease must have undergone treatment [example, radiation or
             chemotherapy] at least 1 month prior to study entry. The participant must not have any
             new or progressive signs or symptoms related to the CNS disease and must be taking <=
             10 mg of prednisone or equivalent per day or no steroids.) Participants who have
             untreated brain metastases and who are not symptomatic may enroll if the investigator
             feels that treatment of these metastases is not indicated. A scan to confirm the
             absence of brain metastases is not required. Participants with spinal cord compression
             may be considered if they have received definitive treatment for this and evidence of
             clinically SD for 28 days.

          -  Major surgery within 3 weeks of starting the study or participant has not recovered
             from any effects of any major surgery.

          -  Other active concomitant malignancy that warrants systemic therapy.

          -  Poor medical risk due to 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, uncontrolled hypertension, active uncontrolled
             coagulopathy, or any psychiatric disorder that prohibits obtaining informed consent.

          -  Known history of interstitial lung disease, drug-related pneumonitis, or radiation
             pneumonitis requiring steroid treatment.

          -  Participant is pregnant, breastfeeding, or expecting to conceive children, while
             receiving study treatment and for 180 days (for pregnancy or conception) or 30 days
             (for breastfeeding) after the last dose of study treatment.

          -  Male participant is expecting to donate sperm or father children while receiving study
             drug or for 120 days after the last dose of study treatment.

          -  Participant is immunocompromised, in the opinion of the Investigator.

          -  Known active hepatic disease (known hepatic cirrhosis, hepatitis B surface
             antigen-positive status, or suspected active hepatitis C infection).

          -  Prior treatment with a known PARP inhibitor.

          -  Known history of MDS or AML.