Phase I study of sunitinib malate continuously dosed and standard-infusion gemcitabine in solid tumors.

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2008 ASCO Annual Meeting

Abstract No: 13533
J Clin Oncol 26: 2008 (May 20 suppl; abstr 13533
J. M. Brell, J. A. Bokar, M. M. Cooney, S. S. Krishnamurthi, J.
Gibbons, C. J. Nock, P. Savvides, E. Batts, S. P. Ivy, A. Dowlati
Sunitinib malate (S) is an oral multi-targeted tyrosine kinase
inhibitor (TKIs) with affinity for VEGFRs, PDGFRs, KIT, RET, and Flt3.
These targets are significant in several malignancies based on
pre-clinical and clinical data. Cytotoxic chemotherapy and targeted
angiogenesis inhibition concomitently may enhance tumor control. In
this phase I trial gemcitabine (G) was combined with S in a continuous
dosing schema to assess maximum tolerated dose (MTD), dose-limiting
toxicity (DLT), and tumor response.
Methods: Eligible patients
had no curative therapy options, adequate organ function, and no prior
anti-angiogenic treatments. The first dose level administered G 800 mg/m2
intravenously (IV) weekly x 3 every 28 days and S 25 mg orally every
day. Any treatment-related grade 4 toxicity, grade 3 cardiac or venous
thrombosis, unresolved non-cardiac grade 3 event, or uncontrolled
hypertension was defined as DLT.
Results: Six patients (3
unresectable pancreas,1 metastatic pancreas, 1 pleural mesothelioma, 1
germ cell) with a median age of 65 years (range 39 to 73) and ECOG
performance status of 0 - 2 were treated on dose level one. Only the
mesothelioma and germ cell patients had prior therapy. Patient 2
experienced DLT of asymptomatic neutropenia, requiring expansion of the
cohort; no further DLTs were seen at this dose level. Other toxicities
included grade 4 dyspnea due to progressive disease and grade 3
hyponatremia, hypokalemia, and neutropenia, experienced by one pateint
each. Two patients had grade 3 leucopenia. Two of the unresectable
pancreas patients experienced confirmed partial responses (PRs).
Patients are accrued to dose level two (S 37.5 mg orally per day and G
800 mg/m2 IV weekly x 3 every 28 days ).
Continuous dosing of S with G appears tolerable. Safety monitoring
continues; it is anticipated that higher dose levels will have greater
myelosuppression based on known mechanisms of action. Two unresectable
pancreas cancer patients have confirmed PRs; the regimen merits
continued assessment in this population. Supported by NIH/Cancer
Therapy Evaluation Program U01 CA62502.