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Sunitinib in combination with gemcitabine for advanced solid tumours: a phase I dose-finding study.

ABSTRACT: This phase I, dose-finding study determined the maximum tolerated dose (MTD), safety, and pharmacokinetics of sunitinib plus gemcitabine in patients with advanced solid tumours.Two schedules with sunitinib (25-50 mg per day) and IV gemcitabine (750-1250 mg m(-2)) in escalating doses were studied. First, patients received sunitinib on a 4-weeks-on-2-weeks-off schedule (Schedule 4/2) plus gemcitabine on days 1, 8, 22, and 29. Second, patients received sunitinib on a 2-weeks-on-1-week-off schedule (Schedule 2/1) plus gemcitabine on days 1 and 8. The primary endpoint was determination of MTD and tolerability.Forty-four patients received the combination (Schedule 4/2, n=8; Schedule 2/1, n=36). With no dose-limiting toxicities (DLTs) at maximum dose levels on Schedule 2/1, MTD was not reached. Grade 4 treatment-related AEs and laboratory abnormalities included cerebrovascular accident, hypertension, and pulmonary embolism (n=1 each), and neutropenia (n=3), thrombocytopenia and increased uric acid (both n=2), and lymphopenia (n=1). There were no clinically significant drug-drug interactions. Antitumor activity occurred across dose levels and tumour types. In poor-risk and/or high-grade renal cell carcinoma patients (n=12), 5 had partial responses and 7 stable disease ? 6 weeks.Sunitinib plus gemcitabine on Schedule 2/1 with growth factor support was well tolerated and safely administered at maximum doses of each drug, without significant drug-drug interactions.

SUBMITTER: Michaelson MD

PROVIDER: S-EPMC3629436 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Sunitinib in combination with gemcitabine for advanced solid tumours: a phase I dose-finding study.

Michaelson M D MD Zhu A X AX Ryan D P DP McDermott D F DF Shapiro G I GI Tye L L Chen I I Stephenson P P Patyna S S Ruiz-Garcia A A Schwarzberg A B AB

British journal of cancer 20130319 7

<h4>Background</h4>This phase I, dose-finding study determined the maximum tolerated dose (MTD), safety, and pharmacokinetics of sunitinib plus gemcitabine in patients with advanced solid tumours.<h4>Methods</h4>Two schedules with sunitinib (25-50 mg per day) and IV gemcitabine (750-1250 mg m(-2)) in escalating doses were studied. First, patients received sunitinib on a 4-weeks-on-2-weeks-off schedule (Schedule 4/2) plus gemcitabine on days 1, 8, 22, and 29. Second, patients received sunitinib o ...[more]

PMID: 23511559

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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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Sunitinib in combination with gemcitabine for advanced solid tumours: a phase I dose-finding study.

Publications

Sunitinib in combination with gemcitabine for advanced solid tumours: a phase I dose-finding study.

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