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Hudes GR , Schol J
Phase I trial of oral R115777 in patients with refractory solid tumors: preliminary results
Farnesyltransferase inhibitors in cancer therapy. 2001 :251-4
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Several protein farnesyltransferase (FTase) inhibitors (FTI) are completing evaluation in Phase I clin. trials. RI115777, an orally bioavailable substituted quinone, is among the first FTI to undergo evaluation in humans. This chapter summarizes the preliminary results of a Phase I trial of R115777 administered orally, twice daily (bid) for 21 consecutive days, conducted at Fox Chase Cancer Center. Because continuous administration would be preferable for an agent with cytostatic rather than cytotoxic properties, a 21-d treatment schedule was selected for the second US Phase I trial, with cycles repeated every 28 d. The starting dose of R115777 was 60 mg/ m2 or approx 100 mg twice daily, based on the tolerability of this dose and five fold higher doses in the earlier NCl Phase I trial. A Bayesian dose escalation design, Escalation with Overdose Control (EWOC), provided rules for dose escalation or de-escalation, depending upon the overall toxicity experience in all patients (4). A total of 22 patients were enrolled and treated at doses ranging from 100 to 800 mg bid. All patients registered participated in pharmacokinetic studies. Of the initial 22 patients enrolled, 14 were male and 8 were female, with median age of 59 yr (range 35-73 yr). The tumor types represented were colorectal (7 patients), pancreatic carcinoma (4 patients), nonsmall cell lung cancer (2 patients), and one patient each (n = 9) with a variety of other tumors including renal, prostate, salivary gland, and hepatocellular cancers. None of these patients experienced grade 3 or 4 neutropenia or thrombocytopenia, including two patients treated for 7 and 8 cycles, resp., without toxicity. Other toxic effects were mild and uncommon. Plasma R115777 concn. data for all 22 patients were analyzed using noncompartmental methods. The preliminary findings of this Phase I trial indicate that R115777 can be administered safely for 21 consecutive days at doses that produce plasma concns. capable of inhibiting FTase. The wide interpatient pharmacokinetic variability of R115777 is similar to that obsd. with other orally administered agents. Fatigue, nausea, and diarrhea were common, but usually mild. Rash, creatinine elevation, and hyperbilirubinemia were sporadic, reversible toxicities. Considering all the Phase I trials together, the clin. toxicity of R115777 in humans has mirrored the preclin. toxicity profile in dogs. Phase II studies employing the 21-d, bid schedule of R115777 in a variety of tumor types will commence in the year 2000. [on SciFinder (R)]
edited by Saïd M. Sebti and Andrew D. Hamilton. ill. Includes bibliographical references and index.