Phase 0 and window of opportunity clinical trial design in neuro-oncology: a RANO review

Abstract

Glioblastoma is a devastating disease with poor prognosis. Few effective chemotherapeutics are currently available, and much effort has been extended to identify new drugs capable of slowing tumor progression. The phase 0 trial design was developed to facilitate early identification of promising agents for cancer that should undergo accelerated approval. This design features an early in-human study that enrolls a small number of patients that receive sub-therapeutic doses of medication with the goals of describing pharmacokinetics through drug blood level measurements, and by determining intra-tumoral concentrations of the investigational compound as well as pharmacodynamics by studying the biochemical and physiological effects of drugs. In neuro-oncology, however, the presence of the blood-brain barrier and difficulty in obtaining brain tumor tissue warrant a separate set of considerations. In this manuscript, we critically reviewed the protocols used in all brain tumor related in-human phase 0 and phase 0-like (“window of opportunity”) studies between 1993 and 2018, as well as ongoing clinical trials, and identified major challenges in trial design as applied to central nervous system tumors that include surgical specimen collection and storage, brain tumor drug level analysis, and confirmation of drug action. We therefore propose that phase 0 trials in neuro-oncology should include 1) only patients in whom a resection of the tumor is planned, 2) use of clinical doses of an investigational agent, 3) tissue sampling from enhancing and non-enhancing portions of the tumor, and 4) assessment of drug-specific target effects. Standardization of clinical protocols for phase 0/window of opportunity studies can help accelerate the development of effective treatments for glioblastoma.

Glioblastoma: Emerging Treatments and Novel Trial Designs

“…One proposed type of trial that specifically aims to target agents is represented by ''phase 0 ' studies [97] (Figure 1).…”

“…Vogelbaum M.A. et al recently reviewed all phase 0 and phase 0-like studies carried out between 1993 and 2018, establishing that phase 0 study in neuro-oncology should include patients in which tumor resection is planned, and involve clinical doses of the investigational agent, a tissue sample from each part of the tumor (including enhancing and non-enhancing portions of the tumor), and the assessment of specific drug-related target effects [97]. Due to the protection offered by the blood-brain barrier (BBB) and the blood -tumorbrain barrier, several drugs failed to show a clinical effect on GBM.…”

The evolving role of neurosurgery for central nervous system metastases in the era of personalized cancer therapy

“…Apart from the clinical necessities described so far, surgical resection of brain metastases, in the setting of a clinical trial, may offer new, urgently needed pharmacodynamic information that will inform on the utility of systemically administered therapies. In 'window-of-opportunity' clinical trials the essential question as to whether a therapeutic reaches the brain metastasis at a sufficient concentration and whether there is enough of a biological impact to expect clinical efficacy may be answered [100]. Patients that are planned to undergo surgical of a metastasis can be enrolled in a such a trial where the therapeutic is given for days or hours before surgery and the subsequent surgical specimen is used to evaluate drug concentration and biological (Fig.…”

“…2). These assessments inform on whether the therapy can penetrate the bloodetumour barrier, and the extent of target coverage can be determined [100]. These evaluations may be complemented by molecular profiling of the tumour tissue to gather correlative information that will eventually guide treatment decisions for the administration of targeted agents [16].…”

World Cancer Day 2021 - Perspectives in Pediatric and Adult Neuro-Oncology

“…An increased TMB is one factor that may render the patient suitable for therapy with immune checkpoint inhibitors, discussed later in this Perspectives article. Furthermore, reoperation can facilitate eligibility to phase I/II clinical trials of novel targeted therapies or assessment of drug delivery and target inhibition in phase 0 or “window of opportunity” clinical trials ( 31 ).…”