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Article: Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer

TitlePhase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer
Authors
Issue Date2014
Citation
Investigational New Drugs, 2014, v. 32 n. 2, p. 330-339 How to Cite?
AbstractPurpose Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC). Methods Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a "3 + 3" design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m2 twice daily, days 1-14), oxaliplatin (130 mg/m2 on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (srcact) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28). Results Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of srcact expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high srcact expression (IHC ≥ 2), compared to 0 % (0/8) for patients with low srcact expression (IHC 0 or 1); (p = 0.007). Conclusions The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib. © 2013 Springer Science+Business Media New York.
Persistent Identifierhttp://hdl.handle.net/10722/194461
ISSN
2015 Impact Factor: 3.281
2015 SCImago Journal Rankings: 1.376
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorStrickler, JH-
dc.contributor.authorMcCall, S-
dc.contributor.authorNixon, AB-
dc.contributor.authorBrady, JC-
dc.contributor.authorPang, H-
dc.contributor.authorRushing, C-
dc.contributor.authorCohn, A-
dc.contributor.authorStarodub, A-
dc.contributor.authorArrowood, C-
dc.contributor.authorHaley, S-
dc.contributor.authorMeadows, KL-
dc.contributor.authorMorse, MA-
dc.contributor.authorUronis, HE-
dc.contributor.authorBlobe, GC-
dc.contributor.authorHsu, SD-
dc.contributor.authorZafar, SY-
dc.contributor.authorHurwitz, HI-
dc.date.accessioned2014-01-30T03:32:37Z-
dc.date.available2014-01-30T03:32:37Z-
dc.date.issued2014-
dc.identifier.citationInvestigational New Drugs, 2014, v. 32 n. 2, p. 330-339-
dc.identifier.issn0167-6997-
dc.identifier.urihttp://hdl.handle.net/10722/194461-
dc.description.abstractPurpose Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC). Methods Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a "3 + 3" design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m2 twice daily, days 1-14), oxaliplatin (130 mg/m2 on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (srcact) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28). Results Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of srcact expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high srcact expression (IHC ≥ 2), compared to 0 % (0/8) for patients with low srcact expression (IHC 0 or 1); (p = 0.007). Conclusions The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib. © 2013 Springer Science+Business Media New York.-
dc.languageeng-
dc.relation.ispartofInvestigational New Drugs-
dc.titlePhase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1007/s10637-013-0042-9-
dc.identifier.pmid24173967-
dc.identifier.scopuseid_2-s2.0-84896404476-
dc.identifier.spage330-
dc.identifier.epage339-
dc.identifier.isiWOS:000332715900014-

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