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A phase I, dose-finding study of sunitinib in combination with irinotecan in patients with advanced solid tumours.

ABSTRACT: Sunitinib is a multitargeted, oral tyrosine kinase inhibitor with antitumour and antiangiogenic activity. We investigated the safety and pharmacokinetics of sunitinib in combination with irinotecan in patients with advanced, refractory solid tumours.Sunitinib was initially administered once daily at 37.5 mg per day on days 1-14 of a 21-day cycle, in which irinotecan 250 mg m(-2) was given on day 1. In a second cohort, the sunitinib dose was reduced to 25 mg per day. Blood samples were collected for pharmacokinetic studies.In the sunitinib 37.5 mg per day cohort, 3 out of 10 evaluable patients had objective responses, but dose-limiting toxicities (DLTs) of neutropenia, pneumococcal sepsis, and fatigue were observed. There were no DLTs in the sunitinib 25 mg per day cohort. Paired observations of pharmacokinetic parameter values of sunitinib and irinotecan alone vs the combination did not reveal significant drug-drug interactions. The maximum tolerated dose was defined as sunitinib 25 mg per day (days 1-14) with irinotecan 250 mg m(-2) (day 1), but no activity was observed at this dose.Although a higher sunitinib dose of 37.5 mg per day (days 1-14) with irinotecan showed preliminary evidence of antitumour activity, this dose was poorly tolerated. Therefore, this particular combination will not be pursued for further studies.

SUBMITTER: Boven E

PROVIDER: S-EPMC2965864 | biostudies-other | 2010 Sep

REPOSITORIES: biostudies-other

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Project description:BACKGROUND:We previously reported that low-dose, short-course sunitinib prior to neoadjuvant doxorubicin-cyclophosphamide (AC) normalised tumour vasculature and improved perfusion, but resulted in neutropenia and delayed subsequent cycles in breast cancer patients. This study combined sunitinib with docetaxel, which has an earlier neutrophil nadir than AC. METHODS:Patients with advanced solid cancers were randomized 1:1 to 3-weekly docetaxel 75?mg/m2, with or without sunitinib 12.5?mg daily for 7?days prior to docetaxel, stratified by primary tumour site. Primary endpoints were objective-response (ORR:CR?+?PR) and clinical-benefit rate (CBR:CR?+?PR?+?SD); secondary endpoints were toxicity and progression-free-survival (PFS). RESULTS:We enrolled 68 patients from 2 study sites; 33 received docetaxel-sunitinib and 35 docetaxel alone, with 33 breast, 25 lung and 10 patients with other cancers. There was no difference in ORR (30.3% vs 28.6%, p =?0.432, odds-ratio [OR] 1.10, 95% CI 0.38-3.18); CBR was lower in the docetaxel-sunitinib arm (48.5% vs 71.4%, p =?0.027 OR 0.37, 95% CI 0.14-1.01). Median PFS was shorter in the docetaxel-sunitinib arm (2.9 vs 4.9?months, hazard-ratio [HR] 2.00, 95% CI 1.15-3.48, p =?0.014) overall, as well as in breast (4.2 vs 5.6?months, p =?0.048) and other cancers (2.0 vs 5.3?months, p =?0.009), but not in lung cancers (2.9 vs 4.1?months, p =?0.597). Median OS was similar in both arms overall (9.9 vs 10.5?months, HR 0.92, 95% CI 0.51-1.67, p =?0.789), and in the breast (18.9 vs 25.8?months, p =?0.354), lung (7.0 vs 6.7?months, p =?0.970) and other cancers (4.5 vs 8.8?months, p =?0.449) subgroups. Grade 3/4 haematological toxicities were lower with docetaxel-sunitinib (18.2% vs 34.3%, p =?0.132), attributed to greater discretionary use of prophylactic G-CSF (90.9% vs 63.0%, p =?0.024). Grade 3/4 non-haematological toxicities were similar (12.1% vs 14.3%, p =?0.792). CONCLUSIONS:The addition of sunitinib to docetaxel was well-tolerated but did not improve outcomes. The possible negative impact in metastatic breast cancer patients is contrary to results of adding sunitinib to neoadjuvant AC. These negative results suggest that the intermittent administration of sunitinib in the current dose and schedule with docetaxel in advanced solid tumours, particularly breast cancers, is not beneficial. TRIAL REGISTRATION:The study was registered ( NCT01803503 ) prospectively on clinicaltrials.gov on 4th March 2013.

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A phase I, dose-finding study of sunitinib in combination with irinotecan in patients with advanced solid tumours.

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