A new Phase 0 study will evaluate niraparib (Zejula®; GSK), an oral, once-daily poly (ADP-ribose) polymerase (PARP) inhibitor in patients with newly diagnosed glioblastoma (GBM) and recurrent glioma (grades II-IV).
The study is funded by the Ben and Catherine Ivy Foundation, in partnership with the Barrow Neurological Foundation.
Niraparib was approved in 2020 by the U.S. Food and Drug Administration as a monotherapy maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy, regardless of biomarker status.
As part of GSK’s aim of building a robust niraparib clinical development program, the drug is currently being evaluated in multiple pivotal trials to assess activity across multiple tumor types. The company is also evaluating several potential combinations of niraparib with other therapeutics.
How does a drug work
Phase 0 studies differ from other clinical trials. The purpose of a phase 0 study is to help speed up and streamline the drug approval process. This type of study may help researchers find out if the drugs do what they are expecting it to do. As a result, phase 0 studies may help save time and money that otherwise would have been spent on later (phase 1 – 3) studies.
One of the unique features of a phase 0 study is that it will only use a few small doses of a study drug to evaluate if the drug reaches the tumor, how the drug acts in the human body, and how cancer cells in the human body respond to the drug. Based on the results of the phase 0 study, a decision can be made if the drug should or should not be fast-tracked for further development.
The Phase 0 clinical trial designed to evaluate niraparib in the treatment of patients diagnosed with glioblastoma, to be conducted at The Ivy Brain Tumor Center at Barrow Neurological Institute in Phoenix, AZ, and the University of California (UCSF), San Francisco, CA, will enroll up to 42 participants divided into two groups, Arm A for newly diagnosed glioblastoma patients, and Arm B for patients with recurrent grade II-IV glioma with IDH mutation and ATRX loss. The Ivy Brain Tumor Center will accrue patients in both Arms, while UCSF will accrue patients only in Arm B.
The initial launch of the Phase 0 clinical trial with niraparib will begin by enrolling six Arm A participants to determine the Optimal Time Interval (OTI) – the time interval between the last dose of the drug and the tumor resection that can detect maximum unbound drug concentration in the gadolinium non-enhancing region of the tumor. After OTI is determined, the remaining 18 participants will enroll in Arm A and up to 18 participants will enroll in Arm B.
In both Arms, participants will receive niraparib once a day for four days before their scheduled surgery to test how much of the investigational drug is present in the tumor, blood, and cerebrospinal fluid (CSF). Arm A participants with tumors with a positive pharmacokinetics (PK) response will advance to a therapeutic expansion phase that combines therapeutic dosing of niraparib plus standard-of-care fractionated radiotherapy; Arm B participants with positive pharmacodynamics (PD) response will advance to a therapeutic expansion phase of niraparib monotherapy until progression of the disease. GSK’s niraparib has good bioavailability and shows strong synergy with temozolomide, as well as radiation in various preclinical studies.
“By evaluating PK- and PD-dependent endpoints in our Phase 0 clinical trials, brain tumor patients who advance to the expansion phase can feel confident that there is biological evidence suggesting their tumor can respond,” noted Nader Sanai, MD, director of the Ivy Brain Tumor Center and director of neurosurgical oncology at Barrow Neurological Institute.
“If the drug shows no effect on the brain tumor, patients can transition to another therapy or clinical trial without losing time,” he added.
“Our team at UCSF was instrumental in designing the PD assay for Arm B of this study and we’re proud to collaborate with the Ivy Brain Tumor Center to bring a potential new treatment option to the brain tumor community,” said Susan Chang, MD, professor of neurological surgery at UCSF.
“The Ivy Center’s innovative Phase 0 approach streamlines the drug testing and approval process and together we can swiftly evaluate niraparib for patients with newly diagnosed glioblastoma and recurrent gliomas.”
New treatment options needed
In the United States, about 6 to 8 per 100,000 people are diagnosed with a WHO grade III or IV primary brain tumor each year, with average survival after diagnosis ranging from 12-16 months. Recent observations have shown that the incidence of glioblastoma is on the rise in many countries. The reason for this rise is multifactorial, and possible contributing factors include an aging population, overdiagnosis, ionizing radiation, air pollution, and others.
The standard of care for treating high-grade gliomas consists of maximal resection, radiation, and a chemotherapy drug called temozolomide (TMZ), extending patient survival to a certain point, and then these tumors typically recur.
The Ivy Brain Tumor Center is singularly focused on discovering new therapies for brain tumor patients through a broad portfolio of pharmacodynamic- and pharmacokinetic-driven clinical trials, combining industry-partnered drug development with the nation’s largest operative brain tumor volume.
The niraparib study is one of seven clinical trials open at the center.
Trial of Niraparib in Participants With Newly-diagnosed Glioblastoma and Recurrent Glioma – NCT05076513
Highlights of prescribing information
Niraparib (Zejula®; GSK) [Prescribing Information]
 Grech N, Dalli T, Mizzi S, Meilak L, Calleja N, Zrinzo A. Rising Incidence of Glioblastoma Multiforme in a Well-Defined Population. Cureus. 2020 May 19;12(5):e8195. doi: 10.7759/cureus.8195. PMID: 32572354; PMCID: PMC7302718.
 Wen PY, Weller M, Lee EQ, Alexander BM, Barnholtz-Sloan JS, Barthel FP, Batchelor TT, Bindra RS, Chang SM, Chiocca EA, et al. Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro Oncol. 2020 Aug 17;22(8):1073-1113. doi: 10.1093/neuonc/noaa106. PMID: 32328653; PMCID: PMC7594557.
Featured Image: Nader Sanai, MD, (right) the director of the Ivy Brain Tumor Center and a neurosurgical oncologist who has been internationally recognized for his clinical expertise and research efforts dedicated to the treatment of brain tumors. Photo courtesy: ©2019 – 2021 The Ivy Brain Tumor Center at the Barrow Neurological Institute. Used with permission