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DNA Methyltransferase Inhibitor Under Study in Cisplatin-Resistant Urothelial Carcinoma

By: Jenna Carter, PhD
Posted: Friday, May 14, 2021

A recent article published in Clinical Cancer Research highlighted the findings from a phase Ib/IIa clinical trial (SPIRE) examining the DNA methyltransferase inhibitor guadecitabine combined with cisplatin and gemcitabine for cisplatin-resistant urothelial cancer. Gareth Griffiths, PhD, of the University of Southampton, England, United Kingdom, and colleagues hypothesized that it might be possible to reverse cisplatin resistance if this novel agent was given simultaneously with a DNA-hypomethylating agent. The findings of this study established a recommended dose and schedule for guadecitabine with cisplatin.

“Treatment options for a cisplatin-resistant phenotype remain an important unmet clinical need. This…trial…provides a basis to undertake prospective randomized trials of this therapeutic approach…,” stated Dr. Griffiths and colleagues.

A total of 40 eligible patients were enrolled in this two-phase study: dose escalation (n = 17) and dose expansion (n = 20). Three patients were excluded from the first phase due to disease escalation and death. The primary objective was to establish the recommended phase II dose for guadecitabine combined with gemcitabine and cisplatin. The secondary endpoint was establishing the toxicity profile, pharmacokinetics of guadecitabine, and pathologic complete response rate.

Overall findings of the dose-escalation phase revealed that the guadecitabine recommended phase II dose was 20 mg/m2 on days 1 to 5, combined with gemcitabine and cisplatin and required granulocyte colony-stimulating factor prophylaxis. Findings from the dose-expansion phase revealed the trial did not meet its progression-free survival primary endpoint (16.3 vs. 9.1 weeks, for chemotherapy of choice control arm; P = .07). However, the 6-month progression-free rate was significantly higher with guadecitabine plus carboplatin (37% vs. 11%; P = .003). Based on these findings, Dr. Griffiths and colleagues concluded that despite increased adverse events, the addition of guadecitabine to gemcitabine and cisplatin was tolerable and warrants further investigation to assess its efficacy.

Disclosure: For full disclosure of the study authors, visit

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