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
 
 
Background:
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 ).
Conclusions:
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.