The combination of the MET inhibitor tivantinib and erlotinib is well-tolerated. Although the study did not meet its primary end point, evidence of activity was demonstrated, especially among patients with KRAS mutations. Additional study of tivantinib and erlotinib in patients with NSCLC is planned.

A B S T R A C T PurposeWe examined the rate of increase in the body mass index (BMI; kg/m 2 ) after final height attainment in survivors of acute lymphoblastic leukemia (ALL) and a noncancer comparison group. MethodsChildhood Cancer Survivor Study (CCSS) is a retrospectively ascertained cohort study that prospectively tracks the health status of adults who were diagnosed with childhood cancer between 1970 and 1986 and a comparison group of siblings. Changes in BMI from baseline enrollment to time of completion of follow-up (mean interval, 7.8 years) were calculated for 1,451 ALL survivors (mean age, 32.3 years at follow-up) and 2,167 siblings of childhood cancer survivors (mean age, 35.9 years). ResultsThe mean BMI of the CCSS sibling comparison group increased with age (women, 0.25 units/yr, 95% CI, 0.22 to 0.28 units; men, 0.23 units/yr, 95% CI, 0.20 to 0.25 units). Compared with CCSS siblings, ALL survivors who were treated with cranial radiation therapy (CRT) had a significantly greater increase in BMI (women, 0.41 units/yr, 95% CI, 0.37 to 0.45 units; men, 0.29 units/yr; 95% CI, 0.26 to 0.32 units). The rate of BMI increase was not significantly increased for ALL survivors who were treated with chemotherapy alone. Younger age at CRT exposure significantly modified risk. ConclusionCRT used in the treatment of childhood ALL is associated with a greater rate of increasing BMI, particularly among women treated with CRT during the first decade of life. Health care professionals should be aware of this risk and interventions to reduce or manage weight gain are essential in this high-risk population.

ARQ 197 safely inhibited intratumoral c-MET signaling. Further clinical evaluation focusing on combination approaches, including an erlotinib combination in non-small-cell lung cancer, is ongoing.

Summary Patients with advanced solid malignancies were enrolled to an open-label, single-arm, dose-escalation study, in which CRLX101 was administered intravenously over 60 min among two dosing schedules, initially weekly at 6, 12, and 18 mg/m2 and later bi-weekly at 12, 15, and 18 mg/m2. The maximum tolerated dose (MTD) was determined at 15 mg/m2 bi-weekly, and an expansion phase 2a study was completed. Patient samples were obtained for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Response was evaluated per RECIST criteria v1.0 every 8 weeks. Sixty-two patients (31 male; median age 63 years, range 39-79) received treatment. Bi-weekly dosing was generally well tolerated with myelosuppression being the dose-limiting toxicity. Among all phase 1/2a patients receiving the MTD (n=44), most common grade 3/4 adverse events were neutropenia and fatigue. Evidence of systemic plasma exposure to both the polymer-conjugated and unconjugated CPT was observed in all treated patients. Mean elimination unconjugated CPT Tmax values ranged from 17.7 to 24.5 h, and maximum plasma concentrations and areas under the curve were generally proportional to dose for both polymer-conjugated and unconjugated CPT. Best overall response was stable disease in 28 patients (64 %) treated at the MTD and 16 (73 %) of a subset of NSCLC patients. Median progression-free survival (PFS) for patients treated at the MTD was 3.7 months and for the subset of NSCLC patients was 4.4 months. These combined phase 1/2a data demonstrate encouraging safety, pharmacokinetic, and efficacy results. Multinational phase 2 clinical development of CRLX101 across multiple tumor types is ongoing.

LBA7502 Background: Orally administered ARQ197 is a selective, non-ATP competitive inhibitor of c-MET (MET), a receptor TK implicated in cancer cell migration, invasion, and proliferation. Dual EGFR-MET inhibition is a promising strategy for overcoming MET-mediated resistance to EGFR inhibitors. A prior phase I trial demonstrated the safety of ARQ197 plus erlotinib and suggested activity in patients (pts) with advanced NSCLC. Methods: This is a global, randomized, placebo-controlled, double-blind trial comparing erlotinib plus ARQ197 (E+A) versus erlotinib plus placebo (E+P). Archival tissue was collected for all pts for k-RAS, EGFR, and MET analyses. The primary endpoint was PFS; secondary endpoints included safety, ORR, OS, and subgroup analyses. Results: 167 pts were randomized to E+A (84 pts) or E+P (83 pts). Mean age was 63 yrs and baseline characteristics were well balanced for sex (39%/41% F); race (93%/96% white) and smoking history (20%/22% never smoker). Imbalances were seen among treatment arms in NSCLC histology (54%/64% adeno) and predictive molecular genotypes: EGFR mutations (7%/13%) and k-RAS mutations (12%/6%). Final PFS was prolonged with E+A (median = 16.1 wks) vs E+P (9.7 wks) among ITT pts (HR 0.81 [95% CI 0.57, 1.15]; p=0.23). Planned multivariable Cox regression model adjusting for prognostic factors (including histology, genotype) yielded PFS HR 0.68 (95% CI 0.47, 0.98; p<0.05). PFS improvement was particularly prominent among pts with nonsquamous histology, EGFR wild-type status, and k-RAS mutations. Preliminary safety analysis revealed no major differences between arms with AEs (≥10% of pts; all grades) including rash (64%/52%); diarrhea (48%/53%); fatigue (33%/37%); nausea (26%/26%); and anemia (14%/13%). OS, ORR, and final safety data will be analyzed at study conclusion. Conclusions: Combined with erlotinib in the treatment of second/third-line EGFR-inhibitor naïve NSCLC, ARQ-197 is well-tolerated and prolongs PFS. Particular benefit is observed among pts with non-squamous histology, k-RAS mutations, and EGFR wild-type status. [Table: see text]

ABSTRACT

Background Catheter-related bloodstream infections remain costly with no simple prevention. We report preliminary results of a phase I trial of ethanol-lock administration to prevent mediport catheter-related bloodstream infections in children. Methods Twelve patients receiving intravenous antibody treatments for neuroblastoma were enrolled. On 4 days of each 5-day antibody cycle, 70% ethanol was administered instead of heparin to dwell in each patient’s mediport overnight. We used clinical monitoring/questionnaires to assess symptoms; and measured blood ethanol levels and liver functions. Patients were tracked for positive blood cultures. Time-to-infection for ethanol-lock treated patients was compared with historical controls. Results We administered 123 ethanol-locks. No adverse symptoms attributable to ethanol occurred; one patient’s urticaria worsened. Blood ethanol levels averaged 11 mg/dL. The study was voluntarily suspended after 3 patients’ catheters became occluded, 1 of which fractured. A positive blood culture occurred in 1 of 12 patients (8%), but suspension of the study precluded statistical power to detect impact on time-to-infection. Conclusions Although children with mediport catheters exhibited nontoxic blood ethanol levels and a low rate of bloodstream infections following prophylactic ethanol-lock use, there was a high incidence of catheter occlusion. Adjustments are necessary before adopting ethanol-locks for routine prophylaxis against catheter infections in children.

BACKGROUND: Amplification of the mesenchymal‐epithelial transition factor (MET) gene can promote tumor resistance to epidermal growth factor receptor (EGFR) inhibition. Dual EGFR‐MET inhibition may overcome this resistance. Tivantinib (ARQ 197) is a selective, oral, non–ATP‐competitive, small‐molecule inhibitor of the MET receptor tyrosine kinase. This phase 1 trial assessed the safety, pharmacokinetics, and preliminary antitumor activity of tivantinib combined with the EGFR inhibitor erlotinib. METHODS: Patients with advanced solid malignancies were administered oral tivantinib at escalating doses of 120, 240, 360, and 480 mg twice daily (BID) plus 150 mg erlotinib once daily (QD). Single or multiple intrapatient dose escalation was planned in the absence of dose‐limiting toxicity in the first cycle of therapy (21 days). RESULTS: Thirty‐two patients received combination treatment. Tivantinib serum concentrations were not dose‐proportional. The most common (≥20%) adverse events (AEs) regardless of causality included rash (n = 17), fatigue (n = 12), nausea (n = 10), abdominal pain (n = 10), diarrhea (n = 9), bradycardia (n = 9), and anemia (n = 7). AEs considered related to study treatment occurred in 28 patients (87.5%), and 5 patients (15.6%) had treatment‐related serious AEs, including neutropenia, leukopenia, syncope, sinus bradycardia, and sick sinus syndrome. Fifteen of 32 patients (46.8%) had a partial response (n = 1) or stable disease (n = 14) as assessed by Response Evaluation Criteria in Solid Tumors. Six of 8 patients with nonsmall cell lung cancer achieved stable disease. The recommended phase 2 dose is tivantinib 360 mg BID plus erlotinib 150 mg QD. CONCLUSIONS: Tivantinib plus erlotinib was well tolerated with encouraging clinical activity, especially in patients with nonsmall cell lung cancer. Cancer 2012. © 2012 American Cancer Society.