Doxorubicin plus the IGF-1R antibody cixutumumab in soft tissue sarcoma: a phase I study using the TITE-CRM model |
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| Institution: | 1. Departments of Internal Medicine, University of Michigan, Ann Arbor;2. Biostatistics, University of Michigan, Ann Arbor;3. Pathology, University of Michigan, Ann Arbor;4. Cancer Clinical Trials Office, University of Chicago, Chicago;5. Clinical Trials Office, University of Michigan, Ann Arbor;6. NorthShore University Health System, Evanston;7. Department of Medicine, University of Chicago, Chicago, USA |
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| Abstract: | BackgroundInsulin-like growth factor receptor (IGF-1R) has been studied as an oncologic target in soft tissue sarcoma (STS), but its role in sarcoma biology is unclear. Anti-IGF-1R antibody cixutumumab demonstrated acceptable toxicity but limited activity as a single agent in STS. We carried out a dose-escalation study of cixutumumab with doxorubicin to evaluate safety and dosing of the combination.Patients and methodsEligible patients with advanced STS were treated with cixutumumab intravenously on days 1/8/15 at one of three dose levels (A: 1 mg/kg, B: 3 mg/kg, C: 6 mg/kg) with doxorubicin at 75 mg/m2 as a 48 h infusion on day 1 of a 21 day cycle. After six cycles of the combination, patients could receive cixutumumab alone. The Time-to-Event Continual Reassessment Method was used to estimate the probability of dose-limiting toxicity (DLT) and to assign patients to the dose with an estimated probability of DLT≤20%.ResultsBetween September 2008 and January 2012, 30 patients with advanced STS received a median of six cycles of therapy (range <1–22). Two DLTs were observed, grade 3 mucositis (dose level B) and grade 4 hyperglycemia (dose level C). Grade 2 and 3 reduced left ventricular ejection fraction was seen in three and two patients, respectively. Five partial responses were observed, and estimated progression-free survival was 5.3 months (95% confidence interval 3.0–6.3) in 26 response-assessable patients. Immunohistochemical staining of 11 available tumor samples for IGF-1R and phospho-IGF-1R was not significantly different among responders and non-responders, and serum analysis of select single-nucleotide polymorphisms did not predict for cardiotoxicity.ConclusionThe maximum tolerated dose was doxorubicin 75 mg/m2 on day 1 and cixitumumab 6 mg/kg on days 1/8/15 of a 21 day cycle. Cardiac toxicity was observed and should be monitored in subsequent studies, which should be considered in STS only if a predictive biomarker of benefit to anti-IGF-1R therapy is identified.Trial registrationClinicalTrials.gov:NCT00789633. |
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