CP-868,596 is a small-molecule tyrosine kinase inhibitor selective for PDGFR and is the only drug of this type to enter clinical trials to date. This report describes the safety and tolerability profile of CP-868,596 and its pharmacokinetic parameters and MTDs on three different dosing regimens (ie, empty stomach, with food, and with a film-coated formulation). Nausea and vomiting, which were prominent toxicities after dosing without food, were reported for the initial three patients treated on the study (with 100 mg once daily without food). These events occurred typically 30 to 40 minutes after ingestion of CP-868,596 and were self limiting. As a result, concomitant antiemetic prophylaxis with a 5-hydroxytryptamine3 receptor antagonist was allowed, and the prophylaxis nearly eliminated emesis during the without-food DEP. Other antiemetics appeared less effective. The MTD determined for once-daily dosing on an empty stomach was 200 mg, and the only significant toxicity was hematuria. It is notable, however, that the DLTs associated with the MAD of 340 mg once daily for dosing on an empty stomach were nausea, vomiting, and increased ALT. In an effort to mitigate nausea and vomiting without the need for daily 5-hydroxytryptamine3 receptor antagonist, the original protocol was amended to investigate the effects of food and a film-coated formulation on the adverse effect profile and pharmacokinetics of CP-869,596. The MAD for the film-coated formulation (ie, 140 mg twice daily) was associated with a DLT of nausea and vomiting, although this formulation was generally well tolerated. The maximum dosage administered with food (ie, 100 mg twice daily) was not associated with DLTs and was the best-tolerated dose and administration condition overall. It should be noted, however, that this dosage was associated with the highest AUC; for targeted agents, such as CP-868,596, it is possible that a concentration greater than the predicted effective concentration may be a more relevant pharmacokinetic parameter for establishing an effective dose and schedule. This hypothesis requires validation in trials intended to evaluate efficacy, which could possibly be designed to randomly assign patients across dose levels.10
Nausea and vomiting were the most frequently reported treatment-related AEs of any severity across the study. It was evident that food mitigated nausea and vomiting, which occurred at a severity of grade 1 or greater in only one patient of nine in the cohort who received CP-868,596 at a dosage of 100 mg twice daily with food. This suggests that nausea and vomiting probably result from local irritation of the gastrointestinal tract rather than from centrally mediated effects. This hypothesis is also supported by the effectiveness of 5-HT3
antagonists, which specifically target abdominal vagal afferent receptors, in mitigating this AE.11
A total of 110 treatment-related AEs were reported in 24 of 25 patients dosed without food, and 63 AEs occurred in 17 of 20 patients dosed with food. Furthermore, treatment-related permanent discontinuations, dose interruptions, and severe AEs were less frequent in patients who received CP-868,596 with food than in patients who received the drug without food. These data indicate that administration of CP-868,596 with food results in generally improved tolerability. The film-coated formula was associated with the lowest incidence of treatment-related AEs (n = 37; 11 of 14 patients) and dose reductions, but the film-coated cohort had a similar incidence of discontinuations to the cohort of dosing without food. Although additional development of the film-coated formulation remains a viable option, the uncoated formulation administered with food is preferred for phase II studies.
Other tyrosine kinase inhibitors, such as sunitinib, imatinib, sorafenib, motesanib and XL999, target PDGFR in tandem with other receptors, such as VEGFR, c-KIT, RET, FGFR, src, and ABL tyrosine kinases. Nausea, vomiting, and diarrhea also have been seen with many of these tyrosine kinase inhibitors,12–14
but the prominence of nausea and vomiting in our study is distinctive. Other than nausea and vomiting, however, we did not detect significant overlap with the AE profile of these other agents and the pattern of AEs seen with CP-868,596. Although it has been suggested previously that PDGFR inhibition results in AEs related to fluid retention,15
edema was not a prominent AE on this study.
Pharmacokinetic parameters of CP-868,596 were characterized. Although the number of patients was small (n = 3 to 7) and interpatient variability was high (CV%, 7% to 92%), systemic exposure parameters (Cmax and AUC) appeared to increase more than proportionally with dose (after a single dose and at steady-state), particularly at higher doses. Mean steady-state serum concentrations in all dose cohorts exceeded the preclinically predicted minimal efficacious concentration (ie, 16 ng/mL). At the recommended phase II dosage (ie, 100 mg twice daily with food), the steady-state serum concentrations were greater than 16 ng/mL for the entire dosing interval in all patients (n = 10). The mean terminal t1/2 (range, 12.3 to 18.5 hours) was similar across all dose levels and was independent of food or film coating. The mean AUC accumulation of CP-868,596 was 1.35-fold to 2.16-fold when given once daily, and it was 2.62-fold to 4.46-fold when given twice daily, which is consistent with the mean terminal t1/2. Food and film coating did not appear to affect the terminal t1/2, but they did delay tmax and increase interpatient variability in Cmax and AUC. The effect of food or film coating on Cmax and AUC was variable. However, the interpretation of both food and film-coated pharmacokinetic findings warrants caution, given the parallel cohort design and the small number of patients (n = three to 10) relative to the moderate-to-large interpatient variability (CV%, 24% to 130%). Reversible AST and ALT elevations appeared to be positively correlated to pharmacokinetic exposures of CP-868,596 (data not shown).
No objective responses (ie, complete or partial responses) were reported on this study. The population was, as expected, heavily pretreated, and the study was not designed with the primary objective of assessing efficacy. Nonetheless, eight patients had stable disease, and there were indications of antitumor activity. Of particular interest are the four patients with bronchoalveolar carcinoma (n = 1), spindle cell neoplasms (n = 1) and sarcoma (n = 2) who remained on study for longer than 170 days, which suggests a possible driving role for PDGFR signaling in these tumors. However, as bronchoalveolar carcinoma and well-differentiated retroperitoneal liposarcoma can be indolent tumors, it is difficult to draw conclusions from these data. Nonetheless, it is notable that the patient with liposarcoma had extensive disease that progressed through six prior treatment regimens, including imatinib. The patient with bronchoalveolar carcinoma had received three prior regimens and had actively progressive disease on gefitinib at the time of study entry. It will also be of interest to assess the activity of CP-868,596 in combination with cytotoxic agents, particularly as agents that target PDGFR may elevate intratumor concentrations of cytotoxic agents.
In summary, CP-868,596 demonstrated generally increasing pharmacokinetic exposures with dose. Twice-daily administration with an uncoated formulation was well tolerated, particularly at a recommended phase II dosage of 100 mg twice daily with food.