Article Text

  1. D. J. Moore,
  2. A. Bahrani,
  3. J. J. Hwang,
  4. P. Ramzi,
  5. J. L. Marshall
  1. Washington, DC., 1University of Louisville
  2. Louisville VAMC


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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