Phase 2 clinical trial of VAL-083 as first-line treatment in newly-diagnosed MGMT-unmethylated glioblastoma multiforme (GBM): Halfway report
Chengcheng Guo1, Qunying Yang1, Jiawei Li1, Shaoxiong Wu2, Meiling Deng2, Xiaojing Du2, Ke Sai1, Xiaobing Jiang1, Zhenghe Chen1, Ji Zhang1, Fuhua Lin1, Jian Wang1, Yinsheng Chen1, Chao Ke1, Xiangheng Zhang1, Xue Ju1, Yonggao Mou1, Jeffrey Bacha3, Anne Steino3, Sarath Kanekal3, Claire Kwan3, Gregory Johnson3, Richard Schwartz3, John Langlands3, Dennis Brown3, Zhong-ping Chen1
1 Department of Neurosurgery/Neuro-Oncology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong Province, China
2 Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong Province, China
3 Delmar Pharmaceuticals, Inc., Vancouver, Canada; Delmar Pharmaceuticals, Inc., Menlo Park, CA, USA
Dr. Dennis Brown
DelMar Pharmaceuticals, Inc., Vancouver, Canada
Prof. Zhong-ping Chen
Department of Neurosurgery/Neuro-Oncology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou 510060, Guangdong Province
Source of Support: None, Conflict of Interest: Jeffrey Bacha was not affiliated with DelMar Pharmaceuticals Ltd. when submitting this article for publication.
Background and Aim: Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) gene, which confers a limited response to standard-of-care treatment with temozolomide (TMZ), resulting in a lower survival. Dianhydrogalactitol (VAL-083) is a novel bi-functional DNA-targeting agent that induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated repair of the O6 guanine alkylator TMZ. A Phase 2 study has been initiated for VAL-083 in newly diagnosed MGMT unmethylated GBM. Subjects and Methods: The study has two parts: part 1 is a dose–escalation and induction format to enroll up to ten patients in which they received VAL-083 at 20, 30, or 40 mg/m2 per day for 3 days every 21 days concurrently with standard radiation treatment and VAL-083 for up to eight additional cycles. Part 2 comprises an expansion phase to enroll up to twenty additional patients. This study was performed with approval by the Institutional Review Board of Sun Yat-sen University Cancer Center (B2016-058-01) on January 13, 2017, and registered with the ClinicalTrials.gov (NCT03050736) on February 13, 2017. Results: After completion of dose escalation, VAL-083, 30 mg/m2 per day, in combination with radiation therapy, was generally safe and well tolerated. At the cutoff date, 23 patients had been enrolled, 14 of whom had been treated in the expansion phase. Consistent with prior studies, myelosuppression was the most common adverse event. Pharmacokinetic assessment indicated that the levels of VAL-083 were as high in the cerebrospinal fluid as in plasma, 2 h postinfusion. Of the 22 patients who had reached their four precycle magnetic resonance imaging assessments, 12 were assessed with disease progression, with a median progression-free survival of 9.9 (95% confidence interval 7.3–12.0) months for all the patients studied. Conclusion: These preliminary data support VAL-083 as a potentially valuable treatment option for newly diagnosed GBM.