Samir D. Undevia

PURPOSE: Severe toxicity is commonly observed in cancer patients receiving irinotecan. UDP-glucuronosyltransferase 1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38. This study prospectively evaluated the association between the prevalence of severe toxicity and UGT1A1 genetic variation. PATIENTS AND METHODS: Sixty-six cancer patients with advanced disease refractory to other treatments received irinotecan 350 mg/m(2) every 3 weeks. Toxicity and pharmacokinetic data were measured during cycle 1. UGT1A1 variants (-3279G>T, -3156G>A, promoter TA indel, 211G>A, 686C>A) were genotyped. RESULTS: The prevalence of grade 4 neutropenia was 9.5%. Grade 4 neutropenia was much more common in patients with the TA indel 7/7 genotype (3 of 6 patients; 50%) compared with 6/7 (3 of 24 patients; 12.5%) and 6/6 (0 of 29 patients; 0%) (P =.001). The TA indel genotype was significantly associated with the absolute neutrophil count nadir (7/7 < 6/7 < 6/6, P =.02). The relative risk of grade 4 neutropenia was 9.3 (95% CI, 2.4 to 36.4) for the 7/7 patients versus the rest of the patients. Pretreatment total bilirubin levels (mean +/- standard deviation) were significantly higher in patients with grade 4 neutropenia (0.83 +/- 0.08 mg/dL) compared to those without grade 4 neutropenia (0.47 +/- 0.03 mg/dL; P <.001). The -3156G>A variant seemed to distinguish different phenotypes of total bilirubin within the TA indel genotypes. The -3156 genotype and the SN-38 area under the concentration versus time curve were significant predictors of ln(absolute neutrophil count nadir; r(2) = 0.51). CONCLUSION: UGT1A1 genotype and total bilirubin levels are strongly associated with severe neutropenia, and could be used to identify cancer patients predisposed to the severe toxicity of irinotecan. The hypothesis that the -3156G>A variant is a better predictor of UGT1A1 status than the previously reported TA indel requires further testing.

PURPOSE Since activity of sorafenib was observed in sarcoma patients in a phase I study, we performed a multicenter phase II study of daily oral sorafenib in patients with recurrent or metastatic sarcoma. PATIENTS AND METHODS We employed a multiarm study design, each representing a sarcoma subtype with its own Simon optimal two-stage design. In each arm, 12 patients who received 0 to 1 prior lines of therapy were treated (0 to 3 for angiosarcoma and malignant peripheral-nerve sheath tumor). If at least one Response Evaluation Criteria in Solid Tumors (RECIST) was observed, 25 further patients with that sarcoma subtype were accrued. Results Between October 2005 and November 2007, 145 patients were treated; 144 were eligible for toxicity and 122 for response. Median age was 55 years; female-male ratio was 1.8:1. The median number of cycles was 3. Five of 37 patients with angiosarcoma had a partial response (response rate, 14%). This was the only arm to meet the RECIST response rate primary end point. Median progression-free survival was 3.2 months; median overall survival was 14.3 months. Adverse events (typically dermatological) necessitated dose reduction for 61% of patients. Statistical modeling in this limited patient cohort indicated sorafenib toxicity was correlated inversely to patient height. There was no correlation between phosphorylated extracellular signal regulated kinase expression and response in six patients with angiosarcoma with paired pre- and post-therapy biopsies. CONCLUSION As a single agent, sorafenib has activity against angiosarcoma and minimal activity against other sarcomas. Further evaluation of sorafenib in these and possibly other sarcoma subtypes appears warranted, presumably in combination with cytotoxic or kinase-specific agents.

BACKGROUND: Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry. METHODS: We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015. FINDINGS: Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21-43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24-47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28-51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3-4. The most common grade 3-4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%). INTERPRETATION: The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination. FUNDING: National Cancer Institute and CycleforSurvival Fund, Memorial Sloan-Kettering Cancer Center.

PURPOSE: Hypertension is a mechanism-based toxicity of sorafenib and other cancer therapeutics that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. This prospective, single-center, cohort study characterized ambulatory blood pressure monitoring as an early pharmacodynamic biomarker of VEGF signaling pathway inhibition by sorafenib. EXPERIMENTAL DESIGN: Fifty-four normotensive advanced cancer patients underwent 24-hour ambulatory blood pressure monitoring before and between days 6 and 10 of sorafenib therapy. After blood pressure changes were detected among the first cohort within 10 days, ambulatory blood pressure monitoring was done during the first 24 hours of treatment for the second cohort. RESULTS: For the entire patient population, the blood pressure increase [mean systolic, +10.8 mm Hg; 95% confidence interval (95% CI), 8.6-13.0; range, -5.2 to +28.7 mm Hg; mean diastolic, +8.0 mm Hg; 95% CI, 6.3-9.7; range, -4.4 to +27.1 mm Hg] was detected between days 6 and 10 (P < 0.0001 for both) and plateaued thereafter. Variability in blood pressure change did not associate with: age, body size, sex, self-reported race, baseline blood pressure, or steady-state sorafenib plasma concentrations. In the second cohort, the blood pressure elevation was detected during the first 24 hours (mean systolic, +8.2 mm Hg; 95% CI, 5.0-11.3; mean diastolic, +6.5 mm Hg; 95% CI, 4.7-8.3; P < 0.0001 for both). CONCLUSIONS: Ambulatory blood pressure monitoring detects the blood pressure response to VEGF signaling pathway inhibition by sorafenib during the first 24 hours of treatment. The magnitude of blood pressure elevation is highly variable and unpredictable but could be important in optimizing the therapeutic index of VEGF signaling pathway inhibitor therapy.