Novel Alkylating Agent Defies Mechanisms of Resistance in GBM Tumors

Nicholas Butowski, MD

VAL-083, a novel alkylating agent that has demonstrated potency against brain tumor cells and can overcome resistance associated with methylguanine methyltransferase (MGMT), is being investigated in patients with glioblastoma multiforme (GBM) or gliosarcoma (GS) who had progressive disease during or after treatment with bevacizumab (Avastin). The drug will be tested in the phase III randomized STAR-3 trial (NCT03149575).

GBM, considered a grade 4 tumor, is the most aggressive and infiltrative form of brain cancer. Median survival in patients with a new diagnosis is just 14.6 months. Additionally, the 5-year survival rate for patients with GBM is less than 5%.¹ These statistics illustrate the need for effective novel therapies in the advanced setting. “There aren’t many, if any, current standard-of-care options for recurrent glioblastoma patients,” said Nicholas Butowski, MD, professor of neurological surgery and director of translational research at University of California, San Francisco. “Most trials exclude these patients after failure with bevacizumab (Avastin). At that point, GBM becomes more invasive and harder to control, based on preclinical evidence,” Butowski said.

VAL-083 could be the answer to this unmet need for GBM therapy because it is an alkylating agent with a unique mechanism of action. Most agents in this class, such as temozolomide (Temodar), methylate the purine bases of DNA (O6-guanine, N7-guanine, and N3-adenine),² damaging tumor cell DNA and triggering cell death, although the outcome is dependent on MGMT-mediated resistance. Conversely, VAL-083, causes highly toxic DNA lesions specifically at the N7 position of guanine in growing cells and is less affected by MGMT resistance. This more targeted approach results in double-strand DNA breaks, cell cycle arrest, and—ultimately—cell death.³ Butowski, who is the principal investigator for STAR-3, said preclinical evidence suggests that VAL-083 also succeeds against other major resistance mechanisms that have defeated alkylating agents.

Figure. VAL-083 in Patients With Recurrent GBM

Prior Success in Refractory GBM

The investigators for the STAR-3 trial are seeking to recruit approximately 180 patients with GBM or GS who were previously treated with surgery (when appropriate) plus standard-of-care chemoradiation, including temozolomide, and were refractory after treatment with bevacizumab (Figure). Eligible participants must also have a Karnofsky-scale performance status of ≥70%. The participants will be randomized in a 2:1 fashion to either receive VAL-083 or an investigator’s choice of salvage therapy—either temozolomide, lomustine, or carboplatin—based on the patient’s prior history.A previous, phase I/II study of VAL-083 found that the drug was well tolerated in patients with refractory GBM, and that it had the potential to offer a clinically meaningful survival benefit.⁵ This study also determined the best dose of VAL-083, which was 40 mg/m² administered through IV once per day. In a survival analysis, 5 out of 48 patients enrolled in the study achieved stable disease as their best response following treatment with VAL-083, and 43 patients experienced progressive disease. A preliminary analysis of all patients receiving the therapeutic dose of VAL-083 also suggests that it may offer improved survival for patients with GBM following bevacizumab failure.⁵

According to Butowski, the most common adverse events (AEs) were nausea, vomiting, myelosuppression, low platelet count, and fatigue. In the safety and efficacy study, 12% of patients experienced grade 2 or lower anemia, 12% experienced leukopenia, and 18% experienced thrombocytopenia. Only 1 patient experienced a grade 3 or higher AE of thrombocytopenia.⁵

Among the treatment options available, no single one stands out as being preferred by a majority of physicians, so VAL-083 has potential to become a new standard of care. “At present, when a patient has recurrent GBM, although there are some commercially approved choices, there aren’t any that are by far a path that patients and physicians choose, so I would assume that if this were a positive study and [VAL-083 was] approved for GBM, it would become the default choice,” Butowski commented.

VAL-083 is currently approved as a cancer chemotherapeutic in China for the treatment of chronic leukemia and lung cancer. VAL-083 is under investigation in non—small cell lung cancer and ovarian cancer in the United States.⁶

The next steps for VAL-083 in GBM would be to determine its usefulness in patients given a new GBM diagnosis and whether it can be used earlier in the course of treatment, Butowski said.

References

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2. Zhang J, Stevens MF, Bradshaw TD. Temozolomide: mechanisms of action, repair and resistance. Curr Mol Pharmacol. 2012;5(1):102-114. doi: 10.2174/1874467211205010102
3. Zhai B, Gobielewska A, Steino A, et al. Distinct mechanism-of-action of dianhydrogalactitol (VAL-083) overcomes chemoresistance in glioblastoma. Neuro Oncol. 2017;19(suppl 3):iii66. doi: 10.1093/neuonc/nox036.246.
4. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003. doi: 10.1056/NEJMoa043331.
5. Shih KC, Patel MR, Butowski N, et al. Phase I/II study of dianhydrogalactitol in patients with recurrent glioblastoma. Poster presented at: 2016 ASCO Annual Meeting; June 3-7, 2016; Chicago, IL. delmarpharma.com/ ASCO%202016%20clinical%20-%2090(w)x45(h)_FINAL.pdf.
6. VAL-083 research and product development. DelMar Pharmaceuticals pipeline. delmarpharma.com/pipeline.html. Accessed September 19, 2017.