I. Determine the recommended phase II dose (RP2D) of temozolomide in combination with
niraparib. (Phase Ib) II. Evaluate the efficacy of niraparib plus temozolomide (Arm A)
compared with best supportive care (Arm B) as measured by progression-free survival (PFS).
I. To evaluate the efficacy of niraparib plus temozolomide compared with best supportive care
as measured by overall survival (OS).
II. To evaluate the safety of niraparib plus temozolomide compared with best supportive care
as measured by adverse events (AEs).
I. To assess patient-reported outcomes on health-related quality of life and adverse events.
OUTLINE: This is a dose-escalation study of temozolomide. Patients are randomized to 1 of 2
ARM A: Patients receive temozolomide orally (PO) once daily (QD) on days 1-5 and niraparib PO
QD on days 1-28. Treatment repeats every 28 days in the absence of disease progression or
ARM B: Patients receive best supportive care.
After completion of study treatment, patients are followed up at 30 days, every 8 weeks for
24 weeks, and then every 12 weeks for up to 1 year.
- Willing and able to provide informed consent.
- Cytologically or histologically confirmed advanced and incurable solid malignancy. For
the randomized phase 2 portion of the trial, cytologically or histologically confirmed
small cell lung carcinoma (SCLC) with extensive-stage disease is required.
- For the phase 2 portion of the trial, complete response (CR) or partial response (PR)
(per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) following 4 to 6
cycles of platinum-based chemotherapy.
- Thoracic irradiation received as part of the treatment regimen and prophylactic
cranial irradiation with a washout period of 14 days are allowed. Participants
with limited stage disease receiving thoracic irradiation are excluded.
- For the phase 2 portion of the trial, able to proceed to randomization within 7 weeks
after day 1 of the last cycle of prior chemotherapy.
- Eastern Cooperative Oncology Group (ECOG) performance status of =< 1.
- Able to swallow the study drugs, has no known intolerance of study drugs or
excipients, and able to comply with study requirements.
- Absolute neutrophil count (ANC) >= 1,500 /mcL.
- Platelets >= 100,000 / mcL.
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO)
dependency (within 4 weeks of first dose).
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated
creatinine clearance >= 30 mL/min for participants with creatinine levels > 1.5 X
institutional ULN. (Glomerular filtration rate [GFR] can also be used in place of
creatinine or creatinine clearance [CrCl]).
- Creatinine clearance should be calculated using the standard Cockcroft and Gault
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN.
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X
ULN OR =< 5 X ULN for participants with liver metastases.
- Albumin >= 2.2 mg/dL.
- International Normalized Ratio (INR) or Prothrombin Time (PT) =< 1.5 X ULN unless
participant is receiving anticoagulant therapy, and then only as long as PT or Partial
Thromboplastin Time (PTT) is within therapeutic range of intended use of
- Activated Partial Thromboplastin Time (aPTT) =< 1.5 X ULN unless participant is
receiving anticoagulant therapy, and then only as long as PT or PTT is within
therapeutic range of intended use of anticoagulants.
- Female participants of childbearing potential must have a negative urine or serum
pregnancy test. If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required. The serum pregnancy test must be negative for
the participant to be eligible, and if assigned to Arm A (niraparib plus temozolomide)
the participant must agree to use a highly-effective birth control method from the
time of the first study drug treatment through 180 days after the last study drug
treatment, or be 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
- Participants 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.
- Male participants assigned to Arm A must use a condom when having sex with a pregnant
woman and when having sex with a woman of childbearing potential from the time of the
first study-drug treatment through 180 days after the last study drug treatment.
Contraception should be considered for a non-pregnant female partner of childbearing
- Male and female participants assigned to Arm A must agree not to donate sperm or eggs,
respectively, from the first study-drug treatment through 180 days after the last
study drug treatment.
- Female participants must agree to not breastfeed during the study or for 180 days
after the last dose of study treatment.
- Participants must agree to not donate blood during the study or for 90 days after the
last dose of study treatment.
- Has not recovered [recovery is defined as National Cancer Institute Common Terminology
Criteria for Adverse Events (CTCAE), version 4.0, grade =< 1] from the acute
toxicities of previous therapy, except treatment-related alopecia or laboratory
abnormalities otherwise meeting eligibility requirements.
- Prior treatment with a poly [ADP-ribose] polymerase (PARP) inhibitor (not including
- Use of antineoplastic therapies within 21 days before randomization. Use of
prophylactic cranial irradiation or thoracic irradiation within 14 days before
randomization. Palliative radiation to bone lesions must be completed 7 days before
- Use of any other investigational agent within 21 days before randomization.
- Progressive or symptomatic brain metastases. Brain metastases that have been radiated,
are asymptomatic, and on a stable or decreasing dose of steroids are allowed.
Leptomeningeal disease is excluded.
- Serious accompanying disorder or impaired organ function, including the following:
- Cardiac (within 3 months before randomization): any unstable ischemic disease,
heart failure, or untreated arrhythmia.
- Major surgery within 3 weeks before randomization.
- Requirement for IV alimentation (at the time of randomization).
- Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
- History of another cancer within 3 years before randomization, with the exception of
basal or squamous cell carcinoma of the skin that has been definitively treated. A
history of other malignancies with a low risk of recurrence, including appropriately
treated ductal carcinoma in situ (DCIS) of the breast and prostate cancer with a
Gleason score less than or equal to 6, are also not excluded.
- Gastrointestinal disorder affecting absorption.
- Participants must not have had radiotherapy encompassing > 20% of the bone marrow
within 2 weeks of the first dose or any radiation therapy within 1 week prior to day 1
of protocol therapy.
- Participants must not have a known hypersensitivity to the components of niraparib or
- Participants must not be considered a 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, or any psychiatric disorder that
prohibits obtaining informed consent.
- Participants 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.
- Participants must not be pregnant.
- Participants must not have progressed following first-line chemotherapy.