Phase I Trial of DNA Methyltransferase Inhibitor Guadecitabine Combined with Cisplatin and Gemcitabine for Solid Malignancies Including Urothelial Carcinoma (SPIRE).
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Embargo End Date
ICR Authors
Authors
Crabb, SJ
Danson, S
Catto, JWF
Hussain, S
Chan, D
Dunkley, D
Downs, N
Marwood, E
Day, L
Saunders, G
Light, M
Whitehead, A
Ellis, D
Sarwar, N
Enting, D
Birtle, A
Johnson, B
Huddart, R
Griffiths, G
Danson, S
Catto, JWF
Hussain, S
Chan, D
Dunkley, D
Downs, N
Marwood, E
Day, L
Saunders, G
Light, M
Whitehead, A
Ellis, D
Sarwar, N
Enting, D
Birtle, A
Johnson, B
Huddart, R
Griffiths, G
Document Type
Journal Article
Date
2021-04-01
Date Accepted
2021-01-15
Abstract
PURPOSE: Preclinical data indicate that DNA methyltransferase inhibition will circumvent cisplatin resistance in various cancers. PATIENT AND METHODS: SPIRE comprised a dose-escalation phase for incurable metastatic solid cancers, followed by a randomized dose expansion phase for neoadjuvant treatment of T2-4a N0 M0 bladder urothelial carcinoma. The primary objective was a recommended phase II dose (RP2D) for guadecitabine combined with gemcitabine and cisplatin. Treatment comprised 21-day gemcitabine and cisplatin cycles (cisplatin 70 mg/m2, i.v., day 8 and gemcitabine 1,000 mg/m2, i.v., days 8 + 15). Guadecitabine was injected subcutaneously on days 1-5, within escalation phase cohorts, and to half of 20 patients in the expansion phase. Registration ID: ISRCTN 16332228. RESULTS: Within the escalation phase, dose-limiting toxicities related predominantly to myelosuppression requiring G-CSF prophylaxis from cohort 2 (guadecitabine 20 mg/m2, days 1-5). The most common grade ≥3 adverse events in 17 patients in the dose-escalation phase were neutropenia (76.5%), thrombocytopenia (64.7%), leukopenia (29.4%), and anemia (29.4%). Addition of guadecitabine to gemcitabine and cisplatin in the expansion phase resulted in similar rates of severe hematologic adverse events, similar cisplatin dose intensity, but modestly reduced gemcitabine dose intensity. Radical treatment options after chemotherapy were not compromised. Pharmacodynamics evaluations indicated guadecitabine maximal target effect at the point of cisplatin administration. Pharmacokinetics were consistent with prior data. No treatment-related deaths occurred. CONCLUSIONS: The guadecitabine RP2D was 20 mg/m2, days 1-5, in combination with gemcitabine and cisplatin and required GCSF prophylaxis. Gene promoter methylation pharmacodynamics are optimal with this schedule. Addition of guadecitabine to gemcitabine and cisplatin was tolerable, despite some additional myelosuppression, and warrants further investigation to assess efficacy.
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2021
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Collections
Research Team
Clinical Academic Radiotherapy (Huddart)
Clinical Academic Radiotherapy (Huddart)
Clinical Academic Radiotherapy (Huddart)