Journal article
A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas
Investigational new drugs, Vol.26(4), pp.369-379
08/01/2008
DOI: 10.1007/s10637-008-9123-6
PMCID: PMC4461052
PMID: 18278438
Abstract
3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine (R)) is a novel small molecule inhibitor of ribonucleotide reductase (RR) with clinical signs of activity in pancreatic cancer. Therefore, the Phase 2 Consortium (P2C) initiated a trial (two single stage studies with planned interim analysis) of 3-AP at 96 mg/m(2) intravenously days 1-4 and 15-18 of a 28-day cycle in both chemotherapy-naive and gemcitabine-refractory (GR) patients with advanced pancreatic cancer. The primary endpoint was survival at six months (chemotherapy-naive) and four months (GR). Secondary endpoints were toxicity, response, overall survival, time to progression and mechanistic studies. Fifteen patients were enrolled including one chemotherapy-naive and 14 GR. The chemotherapy-naive patient progressed during cycle 1 with grade 3 and 4 toxicities. Of 14 GR patients, seven received two cycles, six received one cycle and one received eight cycles. Progression precluded further treatment in 11 GR patients. Additionally, one died of an ileus in cycle 1 considered related to treatment and two stopped treatment due to toxicity. Five GR patients had grade 4 toxicities possibly related to 3-AP and six GR patients had grade 3 fatigue. Toxicities and lack of meaningful clinical benefit prompted early study closure. Four-month survival in GR patients was 21% (95% CI: 8-58%). Correlative studies confirmed that 3-AP increased the percentage of S-phase buccal mucosal cells, the presence of multidrug resistance gene polymorphisms appeared to predict leukopenia, and baseline pancreatic tumor RR M2 expression was low relative to other tumors treated with 3-AP. In conclusion, this regimen appears inactive against predominantly GR pancreatic cancer. RR M2 protein may not have a critical role in the malignant potential of pancreatic cancer.
Details
- Title: Subtitle
- A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas
- Creators
- Steven Attia - University of Wisconsin Carbone Cancer CenterJill Kolesar - University of Wisconsin Carbone Cancer CenterMichelle R. Mahoney - Mayo ClinicHenry C. Pitot - Mayo ClinicDaniel Laheru - Johns Hopkins UniversityJames Heun - University of Wisconsin Carbone Cancer CenterWei Huang - University of Wisconsin Carbone Cancer CenterJens Eickhoff - University of Wisconsin Carbone Cancer CenterCharles Erlichman - Mayo ClinicKyle D. Holen - University of Wisconsin Carbone Cancer Center
- Resource Type
- Journal article
- Publication Details
- Investigational new drugs, Vol.26(4), pp.369-379
- DOI
- 10.1007/s10637-008-9123-6
- PMID
- 18278438
- PMCID
- PMC4461052
- NLM abbreviation
- Invest New Drugs
- ISSN
- 0167-6997
- eISSN
- 1573-0646
- Publisher
- Springer Nature
- Number of pages
- 11
- Grant note
- UL1RR025011 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) T32CA009614 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 24XS090; 1ULIRR025011 / PHS HHS; United States Department of Health & Human Services; United States Public Health Service P30 CA006973 / NCI NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 08/01/2008
- Academic Unit
- Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984695787402771
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