ABSTRACT
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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Models, Statistical , Receptor, IGF Type 1/antagonists & inhibitors , Sarcoma/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Doxorubicin/administration & dosage , Female , Follow-Up Studies , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Staging , Prognosis , Receptor, IGF Type 1/genetics , Receptor, IGF Type 1/metabolism , Sarcoma/mortality , Sarcoma/pathology , Survival Rate , Young AdultABSTRACT
BACKGROUND: This study was conducted to determine the toxicity profile, maximum tolerated dose (MTD) and pharmacokinetics of the putative histone deacetylase inhibitor CI-994 in combination with capecitabine. PATIENTS AND METHODS: Fifty-four patients were treated according to three different dosing schemes in which the capecitabine dose was fixed and the CI-994 dose was escalated. Capecitabine was administered in twice daily divided doses, and CI-994 was given as a single daily dose. In schedule A, 26 patients were treated with capecitabine 1650 mg/m2/day and CI-994 for 2 weeks of a 3-week cycle. In schedule B, six patients received capecitabine 1650 mg/m2/day for two 3-week cycles and CI-994 for 5 of 6 weeks. In schedule C, 22 patients were treated with capecitabine 2000 mg/m2/day and CI-994 for 2 of 3 weeks. RESULTS: At the MTD, the principal dose-limiting toxicity was thrombocytopenia. The pharmacokinetics of CI-994 were unaltered by capecitabine, and there was no correlation between body surface area and major pharmacokinetic parameters. Platelet count nadir was best predicted by the observed maximal concentration (C(max)) of CI-994. CONCLUSIONS: The recommended phase II dose is 6 mg/m2 (or 10 mg) of CI-994 in combination with capecitabine 2000 mg/m2/day for 2 weeks of a 3-week cycle.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Deoxycytidine/analogs & derivatives , Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Benzamides , Capecitabine , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/pharmacokinetics , Diarrhea/chemically induced , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Fluorouracil/analogs & derivatives , Histone Deacetylase Inhibitors , Humans , Male , Metabolic Clearance Rate , Middle Aged , Nausea/chemically induced , Neoplasms/metabolism , Phenylenediamines/administration & dosage , Phenylenediamines/adverse effects , Phenylenediamines/pharmacokinetics , Stomatitis/chemically induced , Thrombocytopenia/chemically induced , Treatment OutcomeABSTRACT
Globoid cell leukodystrophy (GCL) or Krabbe disease is an autosomal recessive inherited disease caused by the deficiency of galactocerebrosidase, the lysosomal enzyme responsible for the degradation of galactocerebroside, a major component of myelin. An animal model homologue of GCL is the twitcher mouse. In the present work, using novel recombinant retroviruses harboring the SL3-3 LTR, we have been able to stably correct the galactocerebrosidase deficiency in twitcher mouse TM-2 cells and in primary human fibroblasts from a patient with globoid cell leukodystrophy. These results show the possibility of retroviral-mediated gene therapy for the treatment of GCL.
