Background By inhibiting PDGF-R, imatinib (Im) decreases the interstitial fluid pressure in tumors, increases cytotoxic drug uptake in preclinical studies, and thus may improve the efficacy of chemotherapy. The combination of Im with P enhances P activity in SCID mice bearing tumor xenografts. Similarly, myelosupression from Im has prevented successful combination with gemcitabine and doxorubicin. In our initial phase I patient (pt) cohort with continuous Im, neutropenia was the main obstacle to dose escalation; thus, the amended protocol switched to a 4-day Im pulse q week.
Methods A dose escalation phase I trial was initiated to study the pharmacokinetics (PK), toxicities, and maximum tolerated doses (MTD) of Im and P in patients (pts) with advanced solid tumors. See table. Non-heme dose limiting toxicity (DLT) was defined as grade (gr) 3 or 4 toxicity. Heme DLT was defined as any gr 4 cytopenia. MTD = dose level at which 1/3 of evaluable patients have DLT. As of 6/1/04, 14 pts have enrolled. Pts received an average of 3 prior chemo regimens.
Results 4/6 pts enrolled at DL1 developed a DLT with gr 3 neutropenia; accrual was stopped. 5 pts accrued to DL-1; only 1/5 developed a gr 3 neutropenia DLT. No non-heme DLTs were observed. Since dose escalation of Im was not feasible, the protocol was amended to give Im as a 4-d pulse q week (DL1A-5A) to avoid significant cytopenias. 3 pts have been treated on DL1A. There were no DLT or grade 2+ neutropenia. Accrual to the next dose levels is ongoing. Overall, the gr 3 toxicities were neutropenia (5/14 only in DL1 and DL-1) and fatigue (1/14 in DL-1). Gr 2 toxicities observed were anemia (5/14 pts), diarrhea (4/14), fatigue (4/14), allergic reaction to Taxol (4/14), neutropenia (2/14), and neuropathy (1/14). 12/14 patients completed 2 cycles (C) with 2 PR, 4 SD, and 6 PD. The 2 pts with PR (colon and esophageal cancers) were able to complete 6C, but later stopped due to PD or pt refusal. PK data indicate that P does not exert a substantial effect on Im.
Conclusions Neutropenia is the main obstacle in combining daily Im with P. Pulse administration of Im with weekly P does not appear to cause significant neutropenia and should allow dose escalation while allowing significant clinical activity.
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