James Battiste's research while affiliated with Moffitt Cancer Center and other places

2068 Background: Epidermal growth factor receptor ( EGFR) gene is the most frequently altered oncogenic driver in glioblastoma (GBM). In-frame deletion alterations (e.g., EGFRvIII) and missense mutations co-occur in the setting of EGFR gene amplification and are characterized as a hallmark of disease pathogenesis in GBM. BDTX-1535 is an oral, highly potent, brain penetrant, selective, irreversible 4 th generation tyrosine kinase inhibitor that targets EGFR alterations in GBM and NSCLC. Preliminary results of the Phase 1 dose escalation study (NCT05256290) of patients with recurrent GBM (rGBM) are presented here. Methods: BDTX-1535-101 is a first-in-human study that enrolled patients with either rGBM harboring EGFR alterations following standard of care or patients with locally advanced or metastatic EGFR mutated NSCLC that progressed on prior EGFR TKIs. Using an adaptive Bayesian optimal interval design in the Phase 1 part, patients were enrolled at increasing dose cohorts and were treated daily for 21-day cycles until treatment discontinuation. The primary objective was to determine the BDTX-1535 recommended Phase 2 dose based on the overall safety, PK, pharmacodynamics, and preliminary antitumor activity. Results: Twenty-seven patients with rGBM were enrolled in the Phase 1 cohort that consisted of 54 patients in total including 27 patients with NSCLC. Patients were treated across seven dose levels (15mg – 400mg QD). The mean age of patients with rGBM was 58.7 years (range 41-85) with 96% of patients with previous temozolomide (TMZ) treatment and a median of 2 lines of prior therapy (range 1-4). The most common all-grade treatment-related AEs across all cohorts were rash (78%), diarrhea (41%), fatigue (15%), stomatitis (11%), decreased appetite (11%), nausea (11%) and paronychia (11%). Gr 3 TRAEs ≥ 10% included rash (19%) reported at 300 or 400 mg QD doses. Plasma exposure of BDTX-1535 increased dose proportionally and had a half-life of ~15h, supporting once daily dosing. The maximum tolerated dose (MTD) is 300 mg QD. Among 19 evaluable patients for response based on RANO criteria, 1 confirmed partial response was observed and 8 patients achieved stable disease. Five patients remained on BDTX-1535 with stable disease for an extended period (>5 months) who previously performed poorly on TMZ with short treatment duration, and 1 patient continues on BDTX-1535 after 16 months of treatment. Conclusions: BDTX-1535 was well-tolerated up to 300mg daily, which is the MTD, and promising preliminary clinical activity was observed in patients with rGBM after relapse on standard of care treatment. Given the inability to reconfirm EGFR status at the time of treatment with BDTX-1535 in this Phase 1 trial, further exploration of BDTX-1535 in a “window of opportunity” study is ongoing (NCT06072586). Clinical trial information: NCT05256290 .

The quality of radiation therapy (RT) treatment plans directly affects the outcomes of clinical trials. KBP solutions have been utilized in RT plan quality assurance (QA). In this study, we evaluated the quality of RT plans for brain and head/neck cancers enrolled in multi-institutional clinical trials utilizing a KBP approach. The evaluation was conducted on 203 glioblastoma (GBM) patients enrolled in NRG-BN001 and 70 nasopharyngeal carcinoma (NPC) patients enrolled in NRG-HN001. For each trial, fifty high-quality photon plans were utilized to build a KBP photon model. A KBP proton model was generated using intensity-modulated proton therapy (IMPT) plans generated on 50 patients originally treated with photon RT. These models were then applied to generate KBP plans for the remaining patients, which were compared against the submitted plans for quality evaluation, including in terms of protocol compliance, target coverage, and organ-at-risk (OAR) doses. RT plans generated by the KBP models were demonstrated to have superior quality compared to the submitted plans. KBP IMPT plans can decrease the variation of proton plan quality and could possibly be used as a tool for developing improved plans in the future. Additionally, the KBP tool proved to be an effective instrument for RT plan QA in multi-center clinical trials.

Background Preclinical studies have demonstrated that VT1021, a first-in-class therapeutic agent, inhibits tumor growth via stimulation of thrombospondin-1 (TSP-1) and reprograms the tumor microenvironment. We recently reported data from the dose escalation part of a phase I study of VT1021 in solid tumors. Here, we report findings from the dose expansion phase of the same study. Methods We analyzed the safety and tolerability, clinical response, and biomarker profile of VT1021 in the expansion portion of the phase I study (NCT03364400). Safety/tolerability is determined by adverse events related to the treatment. Clinical response is determined by RECIST v1.1 and iRECIST. Biomarkers are measured by multiplexed ion beam imaging and enzyme-linked immunoassay (ELISA). Results First, we report the safety and tolerability data as the primary outcome of this study. Adverse events (AE) suspected to be related to the study treatment (RTEAEs) are mostly grade 1–2. There are no grade 4 or 5 adverse events. VT1021 is safe and well tolerated in patients with solid tumors in this study. We report clinical responses as a secondary efficacy outcome. VT1021 demonstrates promising single-agent clinical activity in recurrent GBM (rGBM) in this study. Among 22 patients with rGBM, the overall disease control rate (DCR) is 45% (95% confidence interval, 0.24-0.67). Finally, we report the exploratory outcomes of this study. We show the clinical confirmation of TSP-1 induction and TME remodeling by VT1021. Our biomarker analysis identifies several plasmatic cytokines as potential biomarkers for future clinical studies. Conclusions VT1021 is safe and well-tolerated in patients with solid tumors in a phase I expansion study. VT1021 has advanced to a phase II/III clinical study in glioblastoma (NCT03970447).

Background: OKN-007 is a novel nitrone anti-cancer agent. OKN-007 plus Temozolomide (TMZ) increased survival in glioma-bearing mice compared to TMZ alone. Furthermore, OKN-007 increased TMZ sensitivity in both TMZ-sensitive and TMZ-resistant cell lines. Following a phase I study in recurrent glioblastoma (rGBM), we initiated a phase 2 clinical trial (NCT04388475) of OKN-007 combined with TMZ to examine the efficacy, safety, and pharmacokinetic properties of OKN-007 combined with TMZ. Here, we report the safety and efficacy findings of this ongoing trial. Methods: This is a multi-center, open label phase 2 clinical trial in first or second rGBM WHO Grade (Gr) IV. Adult patients with rGBM previously treated with standard radiation and chemotherapy (Stupp regimen) were eligible. Any second-line therapy was acceptable, excluding bevacizumab. Patients were treated with OKN-007, administered intravenously, at 60 mg/kg, three times weekly for 12 weeks, then twice weekly for 12 weeks, then once weekly until progression. TMZ was administered orally, at a dose of 150 mg/m2 (Cycle 1) or 200 mg/m2 (subsequent cycles). An initial 3-patient safety lead-In cohort established the safety of the OKN-007 and TMZ combination in this patient population. Kaplan-Meier analysis was used to determine progression-free (PFS) and overall survival (OS). Additionally, a comparative analysis of PFS and OS for a matched external control rGBM population treated with lomustine in other formal randomized clinical trials was performed. Results: 57 patients were enrolled at study completion. Of 57 patients enrolled, there were no adverse events (AEs) deemed as a dose-limiting toxicity in the safety Lead-In cohort with 3 patients. Median age was 56 years (range, 29-82), and 41 patients were treated with one line of prior anti-cancer therapy and 15 were treated with two prior lines. Eighteen patients experienced 46 SAEs and of these 9 (Gr3 nausea, Gr2 vomiting, Gr3 fatigue, Gr2 infusion related reaction, Gr3 acute liver injury, Gr3 generalized weakening upper and lower extremities, Gr3 bilirubin increase, Gr3 AST and ALT increase) were deemed to be possibly related to administration of OKN-007. For 56 patients receiving the combination of OKN-007 and TMZ, median PFS was 2.2 (95% CI, 1.6-3.6) months vs. 1.8 (95% CI, 1.7-1.9) months in control patients. Median OS was 9.7 (95% CI 7.6-12.5) months vs. 7.2 (95% CI, 6.8-7.8) months (Cox hazard ratio (HR) = 0.68, p = 0.034). 6-month PFS rate was 23.6% (95% CI, 13.5-35.4) vs. 13.0% (95% CI, 10.0-16.4) and 12-month OS rate was 38.1% (95% CI, 25.1-50.9) vs. 26.3% (95% CI, 22.0-30.8), respectively. Conclusions: Our data indicate that the combination therapy of OKN-007 and TMZ appears safe and, compared to standard lomustine therapy, may prolong OS in rGBM. Citation Format: James Battiste, Glenn Lesser, Santosh Kesari, Varun Monga, Tobias Walbert, Kaylyn Sinicrope, Burt Nabors, Jason Schroeder, Eric Wong, Barry D. Anderson, Hyun Sook Kim, Shinwook Kang. Phase 2 clinical trial of OKN-007 in recurrent malignant glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT201.

Background Glioblastoma exhibits aggressive growth and poor outcomes despite treatment, and its marked variability renders therapeutic design and prognostication challenging. The Oncology Research Information Exchange Network (ORIEN) database contains complementary clinical, genomic, and transcriptomic profiling of 206 glioblastoma patients, providing opportunities to identify novel associations between molecular features and clinical outcomes. Methods Survival analyses were performed using the Logrank test, and clinical features were evaluated using Wilcoxon and chi-squared tests with q-values derived via Benjamini-Hochberg correction. Mutational analyses utilized sample-level enrichments from whole exome sequencing data, and statistical tests were performed using the one-sided Fisher Exact test with Benjamini-Hochberg correction. Transcriptomic analyses utilized a student’s t-test with Benjamini-Hochberg correction. Expression fold changes were processed with Ingenuity Pathway Analysis to determine pathway-level alterations between groups. Results Key findings include an association of MUC17, SYNE1, and TENM1 mutations with prolonged overall survival (OS); decreased OS associated with higher epithelial growth factor receptor (EGFR) mRNA expression, but not with EGFR amplification or mutation; a 14-transcript signature associated with OS > 2 years; and 2 transcripts associated with OS < 1 year. Conclusions Herein, we report the first clinical, genomic, and transcriptomic analysis of ORIEN glioblastoma cases, incorporating sample reclassification under updated 2021 diagnostic criteria. These findings create multiple avenues for further investigation and reinforce the value of multi-institutional consortia such as ORIEN in deepening our knowledge of intractable diseases such as glioblastoma.

INTRODUCTION Headaches are one of the most common morbidities in glioma reported in 36 to 62% of patients along the course of their disease. Gliomas represent 27% of primary CNS neoplasms and accounted for an average annual age-adjusted incidence rate of 6.0 per 100 000 population according to data collected between 2010 and 2014. OBJECTIVES: The goal of this review was to evaluate current treatment options for glioma patients presenting with headaches and identify current headache treatment methods that could play a role in those patients. METHODS A systematic review of studies involving headaches in patients with gliomas was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The search was conducted on PubMed, Ovid Medline, and Embase databases through January 3rd, 2023, with the following search terms: (analgesic OR anti-inflammatory OR prophylaxis OR steroids) AND (headache) AND (glioma or glioblastoma) AND (treatment). For each patient, we extracted: the therapy used, its outcome, and any side effects. RESULTS There were 11 out of 195 articles included in the review. For the articles that were fully reviewed (n =93), the majority of the exclusions 49% (n=40) were due to lack treatment method for patients’ headache. The most reported treatment options were Analgesics (n=211), steroids (dexamethasone, n=116), Surgical resection (n=2), and CGRP inhibitor (Fremanezumab, n=1). Most of the included studies 55% (n=6) only discussed headache treatment in 1 patient with 67% (n=4) of them being case report highlighting the lack of evidence covering this topic. CONCLUSION Headache treatment in patients with gliomas is an area of neuro-oncology with much to be learned. There is a need to further study the etiology of headaches in order to provide effective treatment plans that could improve the quality of life in this patient population.

TPS9156 Background: The epidermal growth factor receptor (EGFR) is a potent oncogene commonly altered in many cancers, including glioblastoma (GBM) and non-small cell lung cancer (NSCLC). EGFR tyrosine kinase activity driven by common EGFR mutations can be inhibited by small molecules, however, resistance to available agents may be driven by mutations in the EGFR active kinase site or other regions. BDTX-1535 is an orally available, highly potent, selective, irreversible inhibitor of EGFR mutations, including extracellular variants and amplifications commonly expressed in GBM and inhibits the common and uncommon EGFR mutations found in NSCLC, including the C797S mutation acquired following 3 rd generation EGFR inhibitor therapy. Preclinical data demonstrated the ability of BDTX-1535 to cross the blood-brain barrier and produce sustained inhibition of EGFR signaling. Preclinical studies suggest that BDTX-1535 has the potential to be clinically active in suppressing tumor growth in patients with GBM and NSCLC with or without CNS metastases, including a potential survival benefit. Methods: BDTX-1535-101 (NCT05256290) is Phase 1, open-label, multicenter study to assess the safety, tolerability, PK, CNS activity, and preliminary antitumor activity of BDTX-1535 in recurrent GBM (rGBM) or locally advanced or metastatic NSCLC with or without CNS disease. The Monotherapy Dose Escalation portion will evaluate BDTX-1535 in patients with either rGBM expressing EGFR alterations or locally advanced/metastatic NSCLC harboring sensitizing EGFR mutations with or without CNS disease. Patients with rGBM must have previously received available standard therapy of surgical resection followed by chemoradiotherapy and/or temozolomide (TMZ). Eligible NSCLC patients must have EGFR mutated NSCLC that has progressed following standard of care EGFR inhibitor therapy. Once a provisional recommended Phase 2 dose (RP2D) has been established, BDTX-1535 monotherapy will be explored in the following Dose Expansion cohorts to further evaluate safety, PK, and preliminary assessment of efficacy: 1) rGBM with confirmed EGFR alterations, 2) NSCLC with uncommon EGFR mutations following EGFR inhibitor therapy; 3) NSCLC with acquired EGFR resistance mutation following a 3rd generation EGFR inhibitor in 1L setting. NSCLC patients may enroll with or without CNS metastases and must not be known to express excluded resistance mutations such as EGFR T790M or MET. BDTX-1535 will also be studied in combination with TMZ to assess safety, tolerability, and a recommended combination dose for the treatment of patients with rGBM harboring EGFR mutations or variants. Enrollment was initiated in 2022 and dose escalation is ongoing. Dose Expansion cohorts are expected to open in 2023. For additional information, please contact BDTX_1535_101_Study@bdtx.com . Clinical trial information: NCT05256290 .

Background: The epidermal growth factor receptor (EGFR) is a potent oncogene commonly altered in many cancers, including glioblastoma (GBM) and non-small cell lung cancer (NSCLC). EGFR tyrosine kinase activity driven by common EGFR mutations can be inhibited by small molecules, however, resistance to available agents may be driven by mutations in the EGFR active kinase site or other regions. BDTX-1535 is an orally available, highly potent, selective, irreversible inhibitor of EGFR mutations, including extracellular variants and amplifications commonly expressed in GBM and inhibits the uncommon EGFR mutations found in NSCLC, including the C797S mutation acquired following 3rd generation EGFR inhibitor therapy. Preclinical data demonstrated the ability of BDTX-1535 to cross the blood-brain barrier and produce sustained inhibition of EGFR signaling. Preclinical studies suggest that BDTX-1535 has potential to be clinically active in suppressing tumor growth in patients with GBM and NSCLC with or without CNS metastases, including a potential survival benefit. Methods: BDTX-1535-101 (NCT05256290) is Phase 1, open-label, multicenter study to assess the safety, tolerability, PK, CNS penetrance, and preliminary antitumor activity of BDTX-1535 in recurrent GBM (rGBM) or locally advanced or metastatic NSCLC with or without CNS disease. The Monotherapy Dose Escalation portion will evaluate BDTX-1535 in patients with either rGBM expressing EGFR alterations or locally advanced/metastatic NSCLC harboring sensitizing EGFR mutations with or without CNS disease. Patients with rGBM must have previously received available standard therapy of surgical resection followed by chemoradiotherapy and/or temozolomide (TMZ). Eligible NSCLC patients must have EGFR mutated NSCLC that has progressed following standard of care EGFR inhibitor therapy. Once a provisional recommended Phase 2 dose (RP2D) has been established, BDTX-1535 monotherapy will be explored in the following Dose Expansion cohorts to further evaluate safety, PK, and preliminary assessment of efficacy: 1) rGBM with confirmed EGFR alterations, 2) NSCLC with uncommon EGFR mutations following EGFR inhibitor therapy; 3) NSCLC with acquired EGFR resistance mutation following a 3rd generation EGFR inhibitor in 1L setting. NSCLC patients may enroll with or without CNS metastases and must not be known to express excluded resistance mutations such as EGFR T790M or MET. BDTX-1535 will also be studied in combination with TMZ to assess safety, tolerability, and a recommended combination dose for the treatment of patients with rGBM harboring EGFR mutations or variants. Enrollment was initiated in 2022 and dose escalation is ongoing. Dose Expansion cohorts are expected to open in 2023. For additional information, please contact BDTX_1535_101_Study@bdtx.com Citation Format: Melissa Johnson, Jason Henry, Alex Spira, James Battiste, Iyad Alnahhas, Manmeet Ahluwalia, Minal Barve, Jeffrey Edenfield, DoHyun Nam, Sudharshan Eathiraj, Julio Hajdenberg, Sergey Yurasov, Helena Yu, Patrick Wen. A phase 1 study to assess BDTX-1535, an oral EGFR inhibitor, in patients with glioblastoma or non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT127.

We previously reported on the experimental validation of several in silico-predicted glioma biomarkers (e.g., Plexin-B2 (PLXNB2), SLIT3, and Spondin-1 (SPON1)) that were found to be higher in human high-grade gliomas (HGGs). In this study, we validated their therapeutic potential by investigating antibody therapies against these three biomarkers in a preclinical mouse GL261 high-grade glioma model. Efficacies for antibody therapies against these biomarkers were assessed by survival and tumor volumes, biomarker expressions, cell invasion and proliferation, and bioinformatics gene/protein associations. Antibodies against PLXNB2, SLIT3, or SPON1 were effective in significantly reducing tumor volumes and increasing animal survival. With immunohistochemistry (IHC), these biomarkers were highly expressed in human HGGs, as well as in mice tumors. From IHC, CD44v6 was significantly decreased for all three antibody treatments, compared to UT GL261 tumors. Bioinformatics suggested that targeting either PLXNB2 or SPON1 may have a major effect on HGG cell migration and invasion (validated with CD44v6 IHC), whereas targeting SLIT3, in addition to affecting cell invasion, may also affect cell proliferation (not validated with Ki67 IHC). These results indicate that targeting these three biomarkers could add to the therapeutic arsenal against high-grade gliomas and that antibodies against them could be considered for clinical translation.