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Establishment of a Primary Culture of Patient-derived Soft Tissue Sarcoma
Published on: April 11, 2018
Doxorubicin plus the IGF-1R antibody cixutumumab in soft tissue sarcoma: a phase I study using the TITE-CRM model
R Chugh1, K A Griffith2, E J Davis1
1Departments of Internal Medicine, University of Michigan, Ann Arbor.
Background:
Insulin-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 Methods:
Eligible 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/m(2) 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%.
Results:
Between 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.
Conclusion:
The maximum tolerated dose was doxorubicin 75 mg/m(2) 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 Registration:
ClinicalTrials.gov:NCT00720174.
Insights
This study combined cixutumumab with doxorubicin in advanced soft tissue sarcoma (STS) patients. The combination showed manageable toxicity, but further research needs predictive biomarkers for anti-IGF-1R therapy efficacy.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Insulin-like growth factor receptor (IGF-1R) is a potential oncologic target in soft tissue sarcoma (STS).
- Cixutumumab, an anti-IGF-1R antibody, showed limited efficacy as a single agent in STS.
- The role of IGF-1R in sarcoma biology requires further elucidation.
Purpose of the Study:
- To evaluate the safety and dosing of a combination therapy involving cixutumumab and doxorubicin in advanced STS.
- To determine the maximum tolerated dose (MTD) of the cixutumumab-doxorubicin combination.
- To assess preliminary efficacy and toxicity of the combination regimen.
Main Methods:
- A dose-escalation study was conducted using cixutumumab at three dose levels (1, 3, 6 mg/kg) combined with doxorubicin (75 mg/m²) over a 48-hour infusion.
- The Time-to-Event Continual Reassessment Method was employed to estimate dose-limiting toxicity (DLT) and guide dose selection.
- Patients received up to six cycles of combination therapy, followed by cixutumumab monotherapy if eligible.
Main Results:
- Two DLTs were observed: grade 3 mucositis at dose level B and grade 4 hyperglycemia at dose level C.
- Cardiac toxicity, including reduced left ventricular ejection fraction, was noted in several patients.
- Five partial responses were observed, with a median progression-free survival of 5.3 months in response-assessable patients.
Conclusions:
- The maximum tolerated dose was determined to be doxorubicin 75 mg/m² with cixutumumab 6 mg/kg.
- Cardiac toxicity necessitates careful monitoring in future studies.
- Anti-IGF-1R therapy in STS should be considered only if a predictive biomarker for treatment benefit is identified.
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