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1.  Clinical activity and safety of combination therapy with temsirolimus and bevacizumab for advanced melanoma: A Phase II trial (CTEP 7190/Mel47) 
Purpose
A CTEP-sponsored phase II trial was performed to evaluate safety and clinical activity of combination therapy with CCI-779 (temsirolimus) and bevacizumab in patients with advanced melanoma.
Experimental Design
Patients with unresectable stage III to IV melanoma were treated intravenously with temsirolimus 25mg weekly and bevacizumab 10mg every 2 weeks. Adverse events were recorded using CTCAE v3.0. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors, and overall survival was recorded. Correlative studies measured protein kinases and histology of tumor biopsies, and immune function in peripheral blood.
Results
Seventeen patients were treated. Most patients tolerated treatment well, but two had grade 4 lymphopenia and one developed reversible grade 2 leukoencephalopathy. Best clinical response was partial response (PR) in three patients (17.7%, 90%CI 5,0–39.6), stable disease at 8 weeks (SD) in 9 patients, progressive disease (PD) in 4 patients, and not evaluable in 1 patient. Maximal response duration for PR was 35 months. Ten evaluable patients had BRAFWT tumors, among whom 3 had PRs, 5 had SD, and 2 had PD. Correlative studies of tumor biopsies revealed decreased phospho-S6K (d2 and d23 vs d1, p<0.001), and decreased mitotic rate (Ki67+) among melanoma cells by d23 (p=0.007). Effects on immune functions were mixed, with decreased alloreactive T cell responses and decreased circulating CD4+FoxP3+ cells.
Conclusion
These data provide preliminary evidence for clinical activity of combination therapy with temsirolimus and bevacizumab, which may be greater in patients with BRAFwt melanoma. Mixed effects on immunologic function also support combination with immune therapies.
doi:10.1158/1078-0432.CCR-12-3919
PMCID: PMC3700572  PMID: 23620404
melanoma; mTOR; VEGF; targeted therapy; biomarkers; BRAF; clinical outcome
2.  Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Oral CP-868,596, a Highly Specific Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor in Patients With Advanced Cancers 
Journal of Clinical Oncology  2009;27(31):5262-5269.
Purpose
This phase I, first-in-human study evaluated the safety, tolerability, pharmacokinetics, and maximum-tolerated dose (MTD) of an oral platelet-derived growth factor receptor inhibitor, CP-868,596.
Patients and Methods
Patients with advanced solid tumors were eligible. Dose escalations were performed in three groups with two formulations: uncoated on an empty stomach (UES), uncoated with food (UFED), and film-coated (FC) without food. Initial dose escalation in the UES group was followed by parallel escalations in the UFED and FC groups.
Results
Fifty-nine patients enrolled. CP-868,596 was escalated from 100 mg to 340 mg daily in the UES group, from 60 mg to 100 mg twice daily in the UFED group, and from 100 mg once daily to 140 mg twice daily in the FC group. MTDs were 200 mg daily in the UES group and 100 mg twice daily in the FC group; MTD was not reached at 100 mg twice daily in the UFED group. Dose-limiting toxicities included hematuria, increased γ-glutamyltransferase or ALT, insomnia, and nausea/vomiting. Most treatment-related AEs were of grades 1 to 2 severity; nausea, vomiting, and diarrhea were reported most frequently. Administration with food generally improved tolerability. CP-868,596 was absorbed slowly; systemic exposure parameters appeared to increase greater than proportionally with dose. Mean serum concentrations exceeded the preclinically predicted minimal efficacious concentration (ie, 16 ng/mL) at all dosages. Food and film coating apparently increased interpatient variability of the maximum observed plasma concentration and the area under the concentration-time curve. No objective responses were reported, and eight patients achieved stable disease (mean duration, 5.7 months).
Conclusion
CP-868,596 potentially demonstrated greater than dose-proportional pharmacokinetics. The recommended dosage of 100 mg twice daily with food was well tolerated. Additional development as a single agent in selected populations or in combination with chemotherapy in broader populations is warranted.
doi:10.1200/JCO.2009.21.8487
PMCID: PMC2773478  PMID: 19738123

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