A randomized phase II trial of ridaforolimus, dalotuzumab, and exemestane compared with ridaforolimus and exemestane in patients with advanced breast cancer.

PURPOSE: To evaluate whether adding humanized monoclonal insulin growth factor-1 receptor (IGF-1R) antibody (dalotuzumab) to mammalian target of rapamycin (mTOR) inhibitor (ridaforolimus) plus aromatase inhibitor (exemestane) improves outcomes in patients with estrogen receptor (ER)-positive advanced/metastatic breast cancer. METHODS: This randomized, open-label, phase II trial enrolled 80 postmenopausal women with high-proliferation (Ki67 index staining ≥15%), ER-positive breast cancer that progressed after a non-steroidal aromatase inhibitor (NCT01605396). Randomly assigned patients were given oral ridaforolimus 10 mg QD 5 ×/week, intravenous dalotuzumab 10 mg/kg/week, and oral exemestane 25 mg/day (R/D/E, n = 40), or ridaforolimus 30 mg QD 5 ×/week and exemestane 25 mg/day (R/E; n = 40). Primary end point was progression-free survival (PFS). RESULTS: Median PFS was 23.3 weeks for R/D/E versus 31.9 weeks for R/E (hazard ratio 1.18; 80% CI 0.81-1.72; P = 0.565). Grade 3-5 adverse events were reported in 67.5% of patients in the R/E arm and 59.0% in the R/D/E arm. Stomatitis (95.0 vs. 76.9%; P = 0.021) and pneumonitis (22.5 vs. 5.1%; P = 0.027) occurred more frequently in the R/E than the R/D/E arm; hyperglycemia (27.5 vs. 28.2%) occurred at a similar rate. CONCLUSIONS: R/D/E did not improve PFS compared with R/E. Because the PFS reported for R/E was similar to that reported for everolimus plus exemestane in patients with advanced breast cancer, it is possible that lower-dose ridaforolimus in the R/D/E arm (from overlapping toxicities with IGF1R inhibitor) contributed to lack of improved PFS.

A phase II study of combined ridaforolimus and dalotuzumab compared with exemestane in patients with estrogen receptor-positive breast cancer.

PURPOSE: Combining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67 > 15%). METHODS: This randomized, multicenter, international, phase II study enrolled postmenopausal women with advanced ER-positive breast cancer previously treated with a nonsteroidal aromatase inhibitor (NCT01234857). Patients were randomized to either oral ridaforolimus 30 mg daily for 5 of 7 days (once daily [qd] × 5 days/week) plus intravenous dalotuzumab 10 mg/kg/week or oral exemestane 25 mg/day, and stratified by Ki67 status. Due to a high incidence of stomatitis in the ridaforolimus-dalotuzumab group, two sequential, nonrandomized, reduced-dose cohorts were explored with ridaforolimus 20 and 10 mg qd × 5 days/week. The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS was 21.4 weeks for ridaforolimus 30 mg qd × 5 days/week plus dalotuzumab 10 mg/kg (n = 29) and 24.3 weeks for exemestane (n = 33; hazard ratio = 1.00; P = 0.5). Overall survival and objective response rates were similar between treatment arms. The incidence of drug-related, nonserious, and serious adverse events was higher with ridaforolimus/dalotuzumab (any ridaforolimus dose) than with exemestane. Lowering the ridaforolimus dose reduced the incidence of grade 3 stomatitis, but overall toxicity remained higher than acceptable at all doses without improved efficacy. CONCLUSIONS: The combination of ridaforolimus plus dalotuzumab was no more effective than exemestane in patients with advanced ER-positive breast cancer, and the incidence of adverse events was higher. Therefore, the combination is not being further pursued.

Exposure to antipsychotic medications over a 4-year period among children who initiated antipsychotic treatment before their sixth birthday.

PURPOSE: This study aims the following: (i) to describe the exposure to antipsychotic medications over a 4-year period experienced by a cohort of children who initiated antipsychotic treatment before their sixth birthday; and (ii) to identify variables associated with the risk of antipsychotic exposure. METHODS: Children were identified who initiated an index episode of antipsychotic treatment before their sixth birthday in Florida's fee for service Medicaid program. With the use of claims data, the medication utilization of these children was tracked during the year before and the 4 years following the start of their index episodes (pre-index and four post-index periods). Generalized estimating equations were used to identify variables associated with the risk of additional days of antipsychotic exposure. RESULTS: Five hundred twenty-eight children were included in the cohort. The mean total number of days of exposure was 821.9 (± 431.9), representing 56.3% of all days during the four post-index periods. The mean days of exposure to combinations of antipsychotics and other classes of psychotherapeutic medications were 623.8 ± 447.6 days. Children with primary diagnoses of pervasive developmental disorders and affective disorders were at greater risk of additional days of exposure than children with attention deficit/hyperactivity disorder. Exposure tended to be greater among children with indicators of clinical complexity including the presence of secondary diagnoses and the use of other classes of psychotherapeutic medications in addition to antipsychotics. CONCLUSIONS: Exposure to antipsychotic mediations was extensive. Although these children may have had complex and severe problems, additional research is urgently needed on the benefits and risks of long-term antipsychotic exposure among very young children.

Physical Health Outcomes in Preschoolers with Prior Authorization for Antipsychotics.

OBJECTIVE: To examine incidence of adverse health outcomes and associated factors among preschoolers (under age 6) who received antipsychotic treatment through the Florida Medicaid Prior Authorization (PA) program. METHODS: Using Florida's PA registry linked to the state's Medicaid claims data, we ascertained incident outcomes during PA-approved antipsychotic use between April 2008 and September 2015 (7.5 years). Six outcomes associated with use of antipsychotics included: diabetes, obesity, hyperlipidemia, hyperprolactinemia, cardiovascular disease (CVD) (including hypertension, ventricular arrhythmia, and other CVDs), and extrapyramidal symptoms (EPS) (including dystonia, akathisia, parkinsonism, and tardive dyskinesia). Outcome-specific incidences were stratified by short-term (≤1 year) and long-term (>1-7 years) antipsychotic use. We used multivariate modified Poisson regressions to determine factors associated with these outcomes among preschoolers. RESULTS: The overall crude incidence during PA-approved antipsychotic use was highest for EPS and obesity (57 and 19 cases/1000 children-years, respectively). The rate of these two outcomes differed by duration of antipsychotic use. We observed a higher obesity (23.8 vs. 9.6, p < 0.001) and dystonia incidence (7.2 vs. 2.5, p < 0.05), but lower akathisia incidence (44.4 vs. 60.6, p < 0.05) among long-term antipsychotic users compared with short-term users. Five outcomes-ventricular arrhythmia, other cardiovascular side effects, hyperprolactinemia, parkinsonism, and tardive dyskinesia-occurred rarely (<2.0/1000 children-years). Preschoolers who were younger at baseline (≤2 years old vs. 4-5 years old) and Black (vs. White) were at a higher risk of EPS. CONCLUSION: Risk for EPS and obesity deserves clinical attention during antipsychotic treatment among preschoolers. Controlled studies that allow interpretation of these incidence rates in the context of background risk and that formally quantify the incremental risk associated with antipsychotic initiation during early childhood are needed.

A phase I trial of the human double minute 2 inhibitor (MK-8242) in patients with refractory/recurrent acute myelogenous leukemia (AML).

OBJECTIVE: Evaluate safety/tolerability/efficacy of MK-8242 in subjects with refractory/recurrent AML. METHODS: MK-8242 was dosed p.o. QD (30-250mg) or BID (120-250mg) for 7on/7off in 28-day cycle. Dosing was modified to 7on/14off, in 21-day cycle (210 or 300mg BID). RESULTS: 26 subjects enrolled (24 evaluable for response); 5/26 discontinued due to AEs. There were 7 deaths; 1 (fungal pneumonia due to marrow aplasia) possibly drug-related. With the 7on/7off regimen, 2 subjects had DLTs in the 250mg BID group (both bone marrow failure and prolonged cytopenia). With the 7on/14off, no DLTs were observed in 210mg BID or 300mg BID (doses>300mg not tested). Best responses were: 1/24 PR (11 weeks;120mg QD, 7on/7off); 1/24 CRi (2 weeks;210mg BID, 7on/14off); 1/24 morphologic leukemia-free state (4 weeks; 250mg BID, 7on/7off). PK on Day7 at 210mg BID revealed AUC0-12h 8.7µM·h,Cmax 1.5µM (n=5,Tmax, 2-6h),T1/2 7.9h, CLss/F 28.8L/h, and Vss/F 317L. CONCLUSIONS: The 7on/14off regimen showed a more favorable safety profile; no MTD was established. Efficacy was seen using both regimens providing impetus for further study of HDM2 inhibitors in subjects with AML.