Barbara Jane O'Brien

Profiles of brain metastases: Prioritization of therapeutic targets: Profiling brain metastases

We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next‐generation sequencing with a targeted 47‐gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.

Abstract CT054: Phase II study of dianhydrogalactitol in patients withMGMT-unmethylated bevacizumab-naive recurrent glioblastoma

Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard of care includes surgery, radiation and treatment with temozolomide (TMZ), however nearly all tumors recur and the prognosis for recurrent GBM is dismal. Most GBM tumors have unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT); a validated biomarker for TMZ-resistance. Second-line treatment with anti-angiogenic agent bevacizumab has not improved overall survival (OS) and 5-year survival is less than 3%. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent targeting N7-Guanine and inducing interstrand cross-links, DNA double-strand breaks and cell-death in GBM cell-lines and GBM cancer stem cells. VAL-083’s cytotoxicity is independent of MGMT status and VAL-083 overcomes TMZ-resistance in vitro. Our recent phase I/II clinical trial in recurrent GBM patients failing both TMZ and bevacizumab, suggested VAL-083 offers clinically meaningful survival benefits for patients with recurrent GBM and pinpointing a new dosing regimen (40 mg/m2/d on days 1,2,3 of a 21-day cycle). A pivotal Phase 3 study in recurrent GBM after failing both TMZ and bevacizumab is being planned. If successful, this study will serve as the basis for a New Drug Application (NDA) submission for VAL-083. In addition, a single-arm Phase 2 study to confirm the tolerability of the new dosing regimen in combination with radiotherapy and to explore the activity of VAL-083 in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high MGMT levels is proceeding. In the present Phase 2 clinical trial, the main goal is to assess the overall survival (OS) in MGMT-unmethylated, recurrent, bevacizumab-naive GBM. RATIONALE: The vast majority of GBM patients experience recurrent/progressive disease within a year from initial diagnosis and median survival after recurrence is 3-9 months. Chemotherapy regimens for these patients are lacking and there is a significant unmet medical need. Given VAL-083’s novel alkylating mechanism, promising clinical benefit, and favorable safety profile, a trial studying VAL-083 in MGMT-unmethylated recurrent GBM is warranted. METHOD: Open label, single-arm, biomarker-driven Phase 2 clinical trial in MGMT-unmethylated adult GBM patients at first recurrence/progression, prior to bevacizumab. 48 patients will be enrolled to determine if treatment with VAL-083 will improve OS at 9-months compared to historical control with lomustine. The patients will receive VAL-083 40mg/m2/day on days 1,2,3 of a 21-day cycle. Patients will be followed until death or for at least 9 months from enrollment, whichever occurs earlier. Survival will be compared to recently published EORTC26101 for recurrent MGMT-unmethylated GBM patients treated with lomustine. Secondary outcome measures include progression-free survival and overall response rate. Clinicaltrials.gov identifier: NCT02717962. Citation Format: Barbara J. O9Brien, Jeffrey A. Bacha, Dennis M. Brown, Anne Steino, Richard Schwartz, Sarath Kanekal, Lorena Lopez, Marta Penas-Prado. Phase II study of dianhydrogalactitol in patients with MGMT-unmethylated bevacizumab-naive recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT054. doi:10.1158/1538-7445.AM2017-CT054