Niraparib and Tumor-Treating Fields for the Treatment of Recurrent Glioblastoma
- Histopathologically or molecularly (per Consortium to Inform Molecular and Practical Approaches to central nervous system [CNS] Tumor Taxonomy [c-IMPACT NOW] criteria) proven diagnosis of glioblastoma which is recurrent following radiation therapy (prior dose must have been between 40 and 75 Gy), defined as meeting any one of the following criteria: * New contrast-enhancing lesion outside of the radiation field that was not present on the subject’s prior scan * Surgically proven recurrence of tumor * Per Response Assessment in Neuro-Oncology Criteria (RANO), an increase by >= 25% of the sum of the products of perpendicular diameters between the smallest tumor measurements previously obtained by the subject following radiation and a scan at least 12 weeks from completion of radiation therapy (on stable or increasing doses of corticosteroids) AND magnetic resonance imaging (MRI) performed at the University of Pennsylvania with advanced imaging (dynamic contrast-enhanced [DCE] and dynamic susceptibility contrast [DSC] perfusion imaging for perfusion and permeability data) that is favored by the University of Pennsylvania Brain Tumor Board, based on these advanced imaging metrics, to represent true tumor progression rather than pseudoprogression
- Tumor O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) methylation status must be available from any prior GBM tumor specimen; results of routinely used methods for MGMT methylation testing (e.g. mutagenically separated polymerase chain reaction [MSPCR] or quantitative polymerase chain reaction [PCR] are acceptable)
- Patients must have measurable contrast-enhancing disease (defined by at least 1cm x 1cm) by magnetic resonance imaging (MRI) imaging within 28 days of starting study treatment
- Patients may have had treatment for an unlimited number of prior relapses. Prior Gliadel wafers are only allowed if they were placed at time of patient’s first surgery for GBM at time of initial diagnosis. Prior bevacizumab is allowed for cohort A but not for cohort B. In cohort A, of the 24 total subjects enrolled, a minimum of 12 subjects must NOT have had prior bevacizumab
- Patients must have recovered from severe toxicity of prior therapy; the following intervals from previous treatments are required to be eligible: * 6 months from Optune treatment * 12 weeks from the completion of radiation * 6 weeks from a nitrosourea cytotoxic chemotherapy * 3 weeks from a non-nitrosourea cytotoxic chemotherapy * 3 weeks from bevacizumab * 3 weeks from any investigational (not Food and Drug Administration [FDA]-approved for glioblastoma) agents, or within a time interval less than at least 5 half-lives of the investigational agent whichever is shorter * 3 weeks from any major surgery, including brain surgery for recurrent tumor resection
- Patients must be able to swallow oral medications
- Karnofsky performance status >= 60
- Life expectancy > 3 months
- Absolute neutrophil count >= 1,500/ul
- Platelets >= 100,000/ul and without a platelet or red blood cell (RBC) transfusion within 4 weeks prior to initiating protocol therapy
- Hemoglobin >= 9 g/dl
- Total bilirubin (except patients with Gilbert’s Syndrome, who are eligible for the study but exempt from the total bilirubin eligibility criterion) =< 2.0 mg/dl (within 7 days prior to start of study treatment)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 X upper limit of normal (ULN) (within 7 days prior to start of study treatment)
- Serum creatinine =< 1.5 X institutional ULN OR calculated creatinine clearance (glomerular filtration rate can also be used in place of creatinine or CrCl) >= 50 mL/min for subjects with creatinine levels > 1.5 X institutional ULN (within 7 days prior to the start of study treatment)
- Reproductive status: * Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 7 days prior to the start of study drug * Women must agree to not breastfeed during the study or for 180 days after the last dose of study treatment * WOCBP must agree to use an adequate method to avoid pregnancy (as defined below) from the time of study screening through 180 days from last dose of study drug * Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception (as defined below) starting with the first dose of study drug through 180 days after the last dose of study * Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, these WOCBP must still undergo pregnancy testing as described in this section * At a minimum, participants of childbearing potential who are sexually active and their partners must agree to the use of a highly effective form of contraception (as defined below) throughout their participation beginning with the time of consent, during the study treatment, and for 180 days after last dose of study treatment(s)
- HIGHLY EFFECTIVE METHODS OF CONTRACEPTION: * Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) by WOCBP subject or male subject’s WOCBP partner. Female partners of male subjects participating in the study may use hormone-based contraceptives as one of the acceptable methods of contraception since they will not be receiving study drug * Non-hormonal intra-uterine devices (IUDs) * Bilateral tubal ligation * Vasectomy * Sexual abstinence ** It is not necessary to use any other method of contraception when complete abstinence is elected ** WOCBP participants who choose complete abstinence must continue to have pregnancy tests ** Acceptable alternate methods of highly effective contraception must be discussed in the event that the WOCBP participants chooses to forego complete abstinence
- Participant must agree to not donate blood during the study or for 90 days after the last dose of niraparib
- Participant must, in the opinion of the investigator, be able to comply with study procedures, including use of the Optune device
- Cohort B (surgical) patients only: patients must be undergoing surgery that is clinically indicated as determined by their care providers
- Cohort B (surgical) patients only: patients must have a tumor tissue form indicating availability of archived tissue from a previous surgery for glioblastoma, completed and signed by a pathologist
- Patients must be able to understand the study procedures and agree to participate in the study by providing written informed consent (or have legally authorized representative sign on patient’s behalf if patient physically unable to sign consent due to neurologic deficit)
- Prior treatment with tumor-treating fields therapy (Optune) within the past 6 months
- Prior treatment with a poly (adenosine phosphate [ADP]-ribose) polymerase (PARP) inhibitor
- Known history or current diagnosis of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). Patients with any other prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
- Patients with infratentorial tumor are excluded
- 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 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
- Implanted pacemaker, defibrillator or deep brain stimulator, other implanted electronic devices in the brain
- Skull defects such as missing bone flap, a shunt, or bullet fragments
- Known hypersensitivity to conductive hydrogels or known hypersensitivity to niraparib components or excipients
- Patients with gastrointestinal disorders or abnormalities that would interfere with absorption of study treatment
- Prisoners or subjects who are involuntarily incarcerated
- Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
- Participant must not be simultaneously enrolled in any interventional clinical trial
I. To determine the efficacy, as measured by the disease control rate (DCR), of the combination of niraparib and tumor-treating fields (TTFields) in recurrent glioblastoma multiforme (GBM).
I. To evaluate the safety and tolerability of the combination of niraparib and TTFields in recurrent GBM.
II. To determine objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with recurrent GBM treated with the combination of niraparib and TTFields.
I. To determine whether exposure to TTFields therapy induces homologous recombination deficiency (HRD) in GBM.
II. To identify predictive markers of clinical benefit from the combination of niraparib and TTFields in GBM using tumor genomics, transcriptomics, and proteomics.
III. To determine whether DCR, ORR, PFS, and OS associated with the study treatment differ in subjects who have received prior bevacizumab versus those who have not.
OUTLINE: Patients are assigned to 1 of 2 cohorts.
COHORT A: Patients wear Optune device continuously over 18 hours daily. Beginning 5-7 days after starting Optune therapy, patients receive niraparib orally (PO) once daily (QD). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
COHORT B: Beginning 5-7 days before planned surgery, patients wear Optune device continuously over 18 hours daily. Patients undergo standard of care brain surgery, and resume wearing Optune device within 35 days after surgery. Beginning 5-7 days after re-initiating Optune therapy, patients receive niraparib PO QD. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After the completion of study treatment, patients are followed up at 30 days, and then every 3 months afterwards up to 5 years.
Trial Phase Phase II
Trial Type Treatment
University of Pennsylvania / Abramson Cancer Center
Stephen Joseph Bagley
- Primary ID UPCC 03319
- Secondary IDs NCI-2020-00068
- Clinicaltrials.gov ID NCT04221503