Porter, Alyx B.

Abstract Introduction: Participation in a clinical trial offers the promise for high-quality medical care for patients with cancer, particularly glioma; however, disparities exist in the accrual of underserved patient populations, including minority patients. A multi-pronged approach for increasing the accrual of underrepresented patients to meet NIH-defined benchmarks includes optimizing patient trial education and counseling. This study seeks to assess the perceptions of the trial counseling process and barriers to trial enrollment among a diverse population of patients with low-and high-grade glioma. Methods: Adult glioma patients who received care from the UCSF Brain Tumor Center from 2020 to 2022 participated in supervised interviews and completed a validated survey, Service Evaluation of Patient Experience of Clinical Trials and Factors Influencing Clinical Trial Entry (SPECIFIC). Thematic analysis, descriptive statistics, and Chi-square tests were used for analysis. Results: One hundred and thirty-six patients completed the SPECIFC questionnaire. There were 44 trial participants (TPs), and 92 non-trial participants (NTPs). Compared to NTPs, TPs were on average 49.8 years old (NTPs 54.6, p=.11) and white (86.3% v. 70%, p=.009). Four core themes emerged from patient perspectives, either as facilitators or barriers to clinical trial participation: 1) Cancer Awareness/Knowledge of Scientific Research 2) Flexible Lifestyle/Affordability 3) Consistency with Values/Faith/Belief System 4) Existing Family/Community Support. Both TPs and NTPs overwhelmingly agreed that clinical trials help improve treatments for cancer. However, compared to 100% of TPs, only 57% of NTPs believed trials offered the best treatment available (p=.001). TPs were more likely to be referred to our institution specifically to enroll in a trial (p=.003), have done prior research on specific experimental treatments (p=.002), have had more than two appointments with the neurosurgeon/neuro-oncologist, and report receiving the most counseling directly from an MD level provider (p=.01). When evaluating the trial counseling process, 93% of TPs reported willingness to consent the same day, but 5% endorsed feeling pressure to participate. TPs were satisfied with the quality of the patient information sheet, with 88% rating the information sheet as good or excellent and 88% reporting that the information sheet was easy to understand. While 14% of TPs believed the information sheet was too long, 27% and 41% desired more information about the trial therapeutic and participation requirements, respectively. Conclusion: Overwhelmingly, trial participants were confident in the information they received and were willing to begin clinical trial enrollment on the same day of receiving information. Interventions to improve the quality and equitable delivery of patient trial education must be paired with other validated multi-dimensional strategies to reach target accrual benchmarks of underserved patient populations to therapeutic clinical trials. Citation Format: Mulki Mehari, Sheantel Reihl, Ramin Morshed, Jasleen Kaur, Mikias Negussie, Ugomma Chukwueke, Alyx Porter, Valy Fontil, Shawn Hervey-Jumper. Engagement and experience with clinical trial counseling in adult glioma patients: A single institution, mixed-methods study [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A080.

Abstract Sequencing efforts have identified key oncogenic drivers and transcriptomic subtypes of high-grade gliomas (HGGs), but this knowledge has not resulted in individualized therapy or improved patient outcomes. Here, we used a functional genomics approach combining integrated genomic/transcriptomic analyses with patient-derived 3D micro-cancers (mCancers) to rapidly identify individualized therapeutic vulnerabilities and determine predictive response biomarkers. 30 primary/recurrent HGGs, including 20 glioblastomas, 5 astrocytomas, and 5 oligodendrogliomas, were included for drug testing. mCancers recapitulated the structural and molecular alterations, cellularity, and heterogeneity, of parental patient tumors. A total of 119 single-agent drugs and 183 drug combinations were tested, while a pre-selected drug panel comprising 25 glioma-relevant treatment strategies was tested across all cases. In general, mCancer efficacy corresponded well to historical responses to previously tested agents (EGFR, HDAC inhibitors, etc.). Combined, strong efficacy (i.e. >70% growth inhibition at Cmax) of single treatments targeting deregulated receptor tyrosine kinase (RTK), p53/apoptosis, cell cycle, DNA damage repair, IDH, or telomere maintainance pathways, was observed in 14 out of 30 cases. Surprisingly, transcriptional signatures, but not specific genetic alterations, were found to stratify drug responses. For example, mCancers enriched for the most aggressive mesenchymal (MES) and glycolytic/plurimetabolic (GPM) transcriptional subtypes exhibited stronger response to the BET inhibitor JQ1 (and other clinical BET inhibitors) and the DNA-PKcs/mTOR dual inhibitor CC-115. This therapeutic vulnerability was associated with enrichment of YAP/TAZ signaling, and the glioblastoma stem cell G-STEM signature. Notably, individual combination strategies were effective across tumors, with strong responses ranging from 38% to 77% of all tumors tested. Overall, this study underscores the value of functional genomics in identifying novel vulnerabilities of HGGs and associated response biomarkers. It also highlights the need for further clinical validation of several novel therapies and especially drug combination strategies with strong efficacy in the ex vivo setting.

Abstract BACKGROUND Treatment of high-grade glioma (HGG) remains a challenge. Several groups have developed ex vivo drug sensitivity assays to evaluate susceptibility of the tumor tissue to specific chemotherapeutics. This tool, in addition to molecular analysis of tumors might provide another layer of confidence in choosing treatments for patients with high-grade gliomas. METHODS 3D PredictTM platform (Kiyatec, Greenville, SC, USA) was tested at three academic medical centers in the United States. Twelve patients with newly diagnosed and recurrent HGGs were included. Tumor spheroids created ex vivo were exposed to twelve pre-selected drugs. Responses were reported as: no response, moderate response and response. We analyzed: demographics, histopathology, stage of disease, success rate and results of the ex vivo assay and clinical implications. RESULTS Majority of patients were women (67%). Median age was 58.5. Histology: GBM-83%, HGGs-17%. Eighty three percent of the samples represented recurrent disease. Sixty percent represented first recurrence while the remaining 40% represented 2nd or 3rd recurrence. Eight out of 12 tissue samples (67%) were successfully tested ex vivo. In six cases (75%), the information was used for immediate clinical decision making. In 2 cases, the decision was deferred until the next progression of the disease. The drugs chosen for treatment based on assay results included: olaparib (the assay was positive for response to rucaparib), temozolomide, lomustine, carboplatin and irinotecan. CONCLUSIONS This platform is easy to use in a standard clinical setting, the success rate for creating viable spheroids for drug sensitivity testing is high and the information obtained can be useful in clinical practice. Addition of other agents to the assay, correlation with molecular testing of the tumor tissue and attempt to assess response to drug combinations should be considered in further development of this technology. Prospective clinical trial is needed to validate this approach for routine clinical use.

Abstract BACKGROUND Selinexor (SEL) is a first-in-class XPO1 inhibitor with potent antitumor activity via tumor suppressor protein nuclear localization and reactivation, oncoprotein translation suppression, and DNA repair inhibition. As a single agent, SEL has demonstrated adequate brain penetration and clinically relevant responses in glioblastoma. We seek to enhance the effect and benefit of SEL by priming with temozolomide (TMZ). METHODS We developed in vitro and in vivo studies to rationally design a phase I/II trial to evaluate the safety and efficacy of the sequential combination of SEL+TMZ. Sequential treatment of U87 cells and intracranial mouse xenografts demonstrated superior DNA damage (ɣH2A.X, cleaved PARP) and overall survival compared to combination or single-agent therapy (HR 0.25 [95% CI, 0.07-0.84]; p = 0.01, log-rank). We used the top-scoring pair method to identify a 6 gene-pair RNAseq signature associated with response to SEL. RESULTS Based on preclinical findings, we developed and opened a multi-institutional phase I/II clinical trial in October 2022. Eligibility includes histologically confirmed 1st recurrent MGMT promoter methylated glioblastoma. Primary objectives are safety and preliminary efficacy. Secondary objectives are overall response rate, efficacy, and prospective validation of a molecular signature of response. Phase I dose finding by IQ 3 + 3 (n = 12) involves TMZ 150mg/m2 on days 1-5 of a 28-day cycle plus SEL on days 8 and 15. Phase II will involve randomization (n = 72) to the RP2D of SEL+TMZ versus monotherapy TMZ. Using proportional hazards regression, RHR 0.5 with p < 0.1 will demonstrate sufficient efficacy. We have enrolled 3 participants in dose level 1 (SEL 60mg) with no dose-limiting toxicities (DLTs) observed. Additional preliminary results will be presented. CONCLUSION Preliminary results suggest that a sequential dosing regimen of SEL+TMZ is feasible and initial dose is well-tolerated and may minimize the cumulative toxicity of SEL. The trial is currently enrolling nationwide (NCI #10505, NCT05432804).