Bacha, Jeffrey

Abstract On July 24, 2020, a workshop sponsored by the National Brain Tumor Society was held on innovating brain tumor clinical trials based on lessons learned from the COVID-19 experience. Various stakeholders from the brain tumor community participated including the US Food and Drug Administration (FDA), academic and community clinicians, researchers, industry, clinical research organizations, patients and patient advocates, and representatives from the Society for Neuro-Oncology and the National Cancer Institute. This report summarizes the workshop and proposes ways to incorporate lessons learned from COVID-19 to brain tumor clinical trials including the increased use of telemedicine and decentralized trial models as opportunities for practical innovation with potential long-term impact on clinical trial design and implementation.

Abstract Determination of therapeutic benefit in intracranial tumors is intimately dependent on serial assessment of radiographic images. The Response Assessment in Neuro-Oncology (RANO) criteria were established in 2010 to provide an updated framework to better characterize tumor response to contemporary treatments. Since this initial update a number of RANO criteria have provided some basic principles for the interpretation of changes on MR images; however, the details of how to operationalize RANO and other criteria for use in clinical trials are ambiguous and not standardized. In this review article designed for the neuro-oncologist or treating clinician, we outline essential steps for performing radiographic assessments by highlighting primary features of the Imaging Charter (referred to as the Charter for the remainder of this article), a document that describes the clinical trial imaging methodology and methods to ensure operationalization of the Charter into the workings of a clinical trial. Lastly, we provide recommendations for specific changes to optimize this methodology for neuro-oncology, including image registration, requirement of growing tumor for eligibility in trials of recurrent tumor, standardized image acquisition guidelines, and hybrid reader paradigms that allow for both unbiased measurements and more comprehensive interpretation.

Abstract Dysregulation of ErbB-mediated signaling is observed in up to 90% of solid tumors. ErbB family cross-talk is implicated in the development of resistance and metastasis, including CNS metastases. Inhibition of multiple ErbB receptors may result in improved patient outcomes. EO1001 is a novel, patented, oral, brain-penetrating, irreversible pan-ErbB inhibitor targeting EGFR (ErbB1), HER2 (ErbB2) and HER4 (ErbB4). METHODS: (1) In vitro testing. EO1001 demonstrates high specificity for the ErbB family of receptors with excellent, balanced equipotent activity against EGFR, HER2 and HER4 (0.4 to 7.4 nM). EO1001 inhibits signaling downstream of wild type EGFR, mutant EGFR (T790M, L858R and d746-750) and HER2. (2) PK and toxicity. In rodent studies in vivo, EO1001 exhibited a half-life of 16–20 hours. EO1001 rapidly enters the CNS and penetrates tumor tissue at higher concentrations relative to plasma. Safety of EO1001 was evaluated by repeat-dosing studies in SD rats and beagle dogs. Toxicities typical of the ErbB inhibitor class, including gastro-intestinal effects, weight loss and decreased activity were observed at higher dose groups in both species. Mortality was observed in SD rats at higher dose groups. (3) In vivo efficacy studies. EO1001 was studied following oral administration in several erbB-positive mouse xenograft models including N87 (Her2+), H1975 (EGFR/T790M), GBM12 (EGFR+), GBM39 (EGVRvIII+). Following oral administration, treatment with EO1001 resulted in a statistically significant improvement in outcomes compared to positive and negative controls in both CNS and systemic tumor models. EO1001 was well-tolerated with no gastrointestinal side effects observed at efficacious doses in these models. CONCLUSION: Based on research to date, EO1001 has the potential to be a best-in-class CNS-penetrating pan-ErbB inhibitor with a safety and pharmacokinetic profile amenable for use as a single agent and in combination with other agents. EO1001 is poised to enter phase 1-2a clinical testing in the second-half of 2019.

Abstract Glioblastoma (GBM) is the most common brain cancer. Front-line systemic therapy with temozolomide (TMZ) is often ineffective due to O6-methylguanine-DNA-methyltransferase (MGMT)-mediated resistance and patients with recurrent glioma have limited treatment options and very poor prognosis. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent that readily crosses the blood-brain barrier and has demonstrated activity against GBM in prior NCI-sponsored clinical trials. VAL-083 induces cross-links at N7 of guanine causing double-strand DNA breaks and apoptosis independent of MGMT expression against multiple GBM cell lines and cancer stem cells in vitro. VAL-083 cytotoxic activity also appears to be less dependent on wild type p53 compared to other alkylating agents. The main goal of this clinical trial was to determine an appropriate dose for VAL-083 for advancement to Phase II/III trials as a potential new treatment for refractory GBM. METHOD: Open-label, single-arm Phase I dose-escalation study (3+3 design) of IV treatment with VAL-083 on days 1, 2, 3 of a 21-day cycle, until MTD was reached. In Phase II, additional patients with GBM are treated at the MTD to gather further safety and outcomes data. Patients must have histologically confirmed GBM, previously treated with surgery and radiation and must have failed both TMZ and bevacizumab, unless contraindicated. RESULTS: Phase I has been completed and 40 mg/m2/d confirmed as the MTD. 29 GBM patients were enrolled in Phase I across 9 dose cohorts (1.5 - 50 mg/m2/d). Myelosuppression was mild; no drug-related serious adverse events were reported at doses ?40 mg/m2/d. Dose limiting toxicities (DLT), consisting of thrombocytopenia, were observed at 50 mg/m2/d and at an interim 45 mg/m2/d cohort. Platelet nadir occurred around day 20 and resolved rapidly and spontaneously. Pharmacokinetic analyses show dose-dependent linear systemic exposure with a short 1-2h plasma terminal half-life; average Cmax 781 ng/mL (5.3μM) at 40 mg/m2/d resulting in estimated CNS concentrations within the IC50 range observed for GBM cell-lines in vitro. A 14 patient Phase II expansion cohort was enrolled at 40 mg/m2/d. Safety observations in the Phase II expansion cohort to date are consistent with Phase I: Observed myelosuppression is mild, with the exception of 1 patient previously treated with CCNU who developed grade 4 thrombocytopenia. To date, 20 GBM patients (6 patients in Phase I and 14 patients in Phase II) have been treated with VAL-083 at therapeutic doses of 30 or 40 mg/m2/d. CONCLUSIONS: VAL-083 at 40 mg/m2/d on days 1, 2, 3 of a 21-day cycle exhibits a favorable safety profile and the Phase I part of the study showed a trend toward clinically meaningful improved survival in refractory GBM patients. Updated safety and outcomes data from the Phase II expansion cohort will be presented. ClinicalTrials.gov Identifier NCT01478178. Citation Format: Kent C. Shih, Manish R. Patel, Nicholas Butowski, Gerald S. Falchook, Sani H. Kizilbash, Jeffrey A. Bacha, Dennis M. Brown, Anne Steino, Richard Schwartz, Sarath Kanekal, Lorena M. Lopez, Howard A. Burris. Phase I/II study of VAL-083 in patients with recurrent glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT074.