The concurrent modulation of TIH together with tumoural angiogenesis may be an approach to achieve adequate cytotoxic drug exposure and increase therapeutic efficacy. In order to understand the clincial effects of combining PDGFR inhibition with chemotherapy, this phase Ib trial investigated the combination of CP-868,596 and docetaxel in cancer patients. Also explored was the effect of concurrently inhibiting PDGFR and VEGFRs by adding axitinib, a potent inhibitor of VEGFR, to this combination.
The tested regimens were well tolerated and the combination of the recommended phase II dose of CP-868,596 (100
mg BID with food) (Lewis et al, 2009
) with docetaxel (100
every 3 weeks) was feasible. However, dose escalation was limited for the triple combination because of the increased incidence of concurrent mucositis-like AEs and neutropenia relative to that expected for docetaxel alone.
The most common toxicities to date for CP-868,596 are nausea, vomiting, diarrhoea, and transaminitis (Lewis et al, 2009
). For axitinib, the main toxicities are fatigue, nausea, diarrhoea, and hypertension (Rugo et al, 2005
). Hence, together with the toxicities of docetaxel (Sanofi-Aventis U.S.LLC, 2008
), none of the frequently observed treatment-related AEs in this study were unexpected in type. As the toxicity profiles of CP-868,596 and axitinib are largely non-overlapping, it was, therefore, assumed that they might be co-administered without additive toxicity. Unexpectedly, the incidence of concurrent mucositis-like AEs and neutropenia was elevated as noted above.
None of the patients entered in this trial achieved a major radiological response, an observation similar to that reported for the single-agent phase I study of CP-868,596 (Lewis et al, 2009
). Nevertheless, it was unanticipated given that docetaxel is an active agent for the majority of advanced malignancy types entered into this trial (Burris et al, 1993
; Extra et al, 1993
; Tomiak et al, 1994
). The lack of radiological response was also unanticipated as CP-868,596 was expected to increase the intratumoural docetaxel concentration. The effects of PDGFR inhibition on intratumoural IFP and intratumour drug concentrations were not measured in this study. However, in preclinical xenograft models, concomitant administration of PDGFR antagonists increased the tumoural uptake of paclitaxel (Pietras et al, 2002
), and liposomal doxorubicin (Vlahovic et al, 2007
), with increased antitumour efficacy (Vlahovic et al, 2007
The lack of objective radiological response may reflect the small sample size given that the study's major end point was safety and toxicity based. It may also reflect the extent of prior chemotherapy undergone by patients entered and the heterogeneity of their disease. A recent phase II study treated patients with NSCLC (n
=18) with second-line imatinib (a non-selective PDGFR inhibitor) plus docetaxel and reported a partial response rate of 5.5% and stable disease in 27.8% of patients (Huang et al, 2008
). Similarly, low response rates were observed in which imatinib was combined with capecitabine in metastatic breast cancer (Chew et al, 2008
). The selection of patients whose tumours are known to be driven by PDGFR may optimise response rates. In an in vitro
study of PDGFR-β
overexpressing mesothelioma cell lines, imatinib induced cytotoxicity and apoptosis, probably because of PDGFR-β
inactivation and downstream AKT pathway inhibition (Wilmink and Richel, 2008
The triple combination cohort was notable in that all seven evaluable patients achieved stable disease and all nine remained on therapy for a median of six cycles (range 3–16). Phase I trials of comparable doses of single-agent docetaxel reported a median of three–four cycles of administered therapy (Bissett et al, 1993
; Tomiak et al, 1994
). Thus, this study suggests that the combination of docetaxel with CP-868,596 and axitinib resulted in a regimen with improved disease control and tolerability. However, improved disease control may be due to the combination of axitinib with docetaxel.
Pharmacokinetic and pharmacodynamic parameters were also assessed. Pharmacokinetic data showed a lack of drug–drug interactions; indicating the feasibility of both the double and triple combinations from a pharmacokinetic perspective. Preliminary DCE-MRI data for eight patients who received CP-868,596 plus docetaxel showed no evidence of a treatment effect: this is not surprising given the lack of response observed. It may also, however, reflect the small sample size and the heterogeneity of tumour types in the study population. These findings do not corroborate the DCE-MRI changes observed on treatment with CDP860, a di-Fab anti-PGDF antibody, although the MRI parameter assessments were not identical (Jayson et al, 2005
). In the study reported here, it is possible that tumoural CP-868,596 exposure was sub-optimal or that the MRI parameters assessed failed to detect vascular changes arising from PDGFR inhibition. Further studies are required to determine whether CP-868,596 can be combined with other anticancer drugs and whether efficacy can be improved with the use of potential biomarkers of response such as PDGFR expression.
In conclusion, combination therapy with CP-868,596 and docetaxel was well tolerated and no unfavourable drug–drug interactions were shown. The expected additive clinical efficacy was not observed and may not support the clinical development of this combination in non-selected patient populations. However, the addition of axitinib to the combination resulted in greater-than-expected benefits in terms of prolonged stable disease and tolerability. The separate inhibition of individual receptor targets in this study resulted in unexpected findings, suggesting that this approach may be worthy of further study.