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).
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.
