A Phase I Trial of the IGF-1R Antibody Ganitumab (AMG 479) in Combination with Everolimus (RAD001) and Panitumumab in Patients with Advanced Cancer.

PURPOSE: This study evaluated the maximum tolerated dose or recommended phase II dose (RPTD) and safety and tolerability of the ganitumab and everolimus doublet regimen followed by the ganitumab, everolimus, and panitumumab triplet regimen. MATERIALS AND METHODS: This was a standard 3 + 3 dose escalation trial. Doublet therapy consisted of ganitumab at 12 mg/kg every 2 weeks; doses of everolimus were adjusted according to dose-limiting toxicities (DLTs). Panitumumab at 4.8 mg/kg every 2 weeks was added to the RPTD of ganitumab and everolimus. DLTs were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Pretreatment and on-treatment skin biopsies were collected to assess insulin-like growth factor 1 receptor and mammalian target of rapamycin (mTOR) target modulation. RESULTS: Forty-three subjects were enrolled. In the doublet regimen, two DLTs were observed in cohort 1, no DLTs in cohort -1, and one in cohort -1B. The triplet combination was discontinued because of unacceptable toxicity. Common adverse events were thrombocytopenia/neutropenia, skin rash, mucositis, fatigue, and hyperglycemia. In the doublet regimen, two patients with refractory non-small cell lung cancer (NSCLC) achieved prolonged complete responses ranging from 18 to >60 months; one treatment-naïve patient with chondrosarcoma achieved prolonged stable disease >24 months. In dermal granulation tissue, the insulin-like growth factor receptor and mTOR pathways were potently and specifically inhibited by ganitumab and everolimus, respectively. CONCLUSION: The triplet regimen of ganitumab, everolimus, and panitumumab was associated with unacceptable toxicity. However, the doublet of ganitumab at 12 mg/kg every 2 weeks and everolimus five times weekly had an acceptable safety profile and demonstrated notable clinical activity in patients with refractory NSCLC and sarcoma. IMPLICATIONS FOR PRACTICE: This trial evaluated the maximum tolerated dose or recommended phase II dose and safety and tolerability of the ganitumab and everolimus doublet regimen followed by the ganitumab, everolimus, and panitumumab triplet regimen. Although the triplet regimen of ganitumab, everolimus, and panitumumab was associated with unacceptable toxicity, the doublet of ganitumab at 12 mg/kg every 2 weeks and everolimus at five times weekly had an acceptable safety profile and demonstrated notable clinical activity in patients with refractory non-small cell lung cancer and sarcoma.

Metastatic ampullary adenocarcinoma presenting as a hydrocele: a case report.

CONTEXT: Metastases from ampullary malignancies are common, but spread to the testicle and paratesticular tissue is exceedingly rare with only 2 reported cases in the literature. CASE REPORT: We report a case of a 70 year-old male with a history of ampullary adenocarcinoma status post pancreaticoduodenectomy who presented with a symptomatic right-sided hydrocele. Subsequent pathology revealed metastatic ampullary adenocarcinoma. CONCLUSIONS: Metastasis to the testicle and paratesticular tissue from ampullary malignancies is rare, but must be considered in the evaluation of scrotal masses in patients with a history of ampullary malignancy.

Thrombocytosis in 158 cats (2011-2018).

OBJECTIVES: Thrombocytosis is an uncommon hematologic abnormality that is associated with various physiologic, metabolic, inflammatory and neoplastic conditions in people and dogs. Thrombocytosis is not a well-described abnormality in cats. The objective of this study was to classify thrombocytosis in cats based on underlying disease processes and severity, and to compare this with a control population of cats. METHODS: A retrospective study was conducted by reviewing the medical records of cats with increased (>600 × 103/µl; thrombocytosis group) and normal (200-600 × 103/µl; 2:1 age-matched control group) platelet counts between 2011 and 2018. Platelet counts were estimated based on blood smear assessment in all cats. Cats were classified by the severity (mild, moderate or marked) of thrombocytosis. Diagnoses were recorded for all cases, and were classified broadly into either neoplasia, endocrine or inflammatory disease. RESULTS: In total, 158 cats were identified with thrombocytosis, with 315 cats in the control group. Non-neoplastic inflammatory disease was the most common diagnosis in both groups (54.4% in cats with thrombocytosis and 56.2% in controls; P = 0.77); however, gastrointestinal diseases were more common in cats with thrombocytosis (75.6%) when compared with controls (34.5%; P <0.0001). Neoplasia was diagnosed more frequently in cats with thrombocytosis (44.3%) compared with the control group (25.4%; P <0.0001). Round cell tumor was the most common neoplasia diagnosis in both groups, but gastrointestinal and multicentric lymphoma were diagnosed more frequently in cats with thrombocytosis compared with control cats. No association between the severity of thrombocytosis and etiology was identified. CONCLUSIONS AND RELEVANCE: Thrombocytosis in cats is more commonly associated with gastrointestinal, hepatobiliary or immune-mediated diseases when compared with a control population. Neoplasia, especially multicentric and gastrointestinal lymphoma, was more commonly diagnosed in cats with thrombocytosis when compared with control cats.

Evaluation of a flash glucose monitoring system in nondiabetic dogs with rapidly changing blood glucose concentrations.

BACKGROUND: A flash glucose monitoring system (FGMS; FreeStyle Libre) is useful for monitoring hypoglycemic dogs with diabetes. OBJECTIVE: To assess the utility of this FGMS in dogs with induced hypoglycemia and rapid fluctuations in blood glucose (BG) concentrations. ANIMALS: Twenty-four apparently healthy research (n = 10) and teaching (n = 14) dogs. METHODS: Prospective, observational study performed in tandem with a teaching laboratory. Regular insulin was administered to dogs and resulting hypoglycemia was corrected. Before insulin administration and every 10 minutes over a 90-minute period, serial measurements of interstitial glucose (IG) with FGMS and BG with a portable blood glucose meter (PBGM) and clinical chemistry analyzer concentrations were made. Portable blood glucose meter and FGMS readings were compared to that of the clinical chemistry analyzer. Analytical and clinical accuracy were assessed using ISO 15197:2013 criteria, including Parkes error grid analysis. RESULTS: The proportions of readings in the low BG range (BG <100 mg/dL) for which the test method measurement was within ±15 mg/dL of the reference BG for the PBGM and FGMS were 81.7% (161/197) and 39.1% (72/184), respectively. The proportions of readings for the PBGM and FGMS, which were not likely to affect clinical outcome according to Parkes error grid analysis, were 97.9% (233/238) and 80.1% (177/221), respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: In this model, there was limited agreement between the FGMS and reference standard BG measurements. The FGMS (measuring IG concentrations) was compared to peripheral BG concentrations, not brain-tissue glucose concentrations, and failed to reliably detect hypoglycemia.

Direct Evidence of Target Inhibition with Anti-VEGF, EGFR, and mTOR Therapies in a Clinical Model of Wound Healing.

PURPOSE: In early clinical testing, most novel targeted anticancer therapies have limited toxicities and limited efficacy, which complicates dose and schedule selection for these agents. Confirmation of target inhibition is critical for rational drug development; however, repeated tumor biopsies are often impractical and peripheral blood mononuclear cells and normal skin are often inadequate surrogates for tumor tissue. Based upon the similarities of tumor and wound stroma, we have developed a clinical dermal granulation tissue model to evaluate novel targeted therapies. EXPERIMENTAL DESIGN: A 4-mm skin punch biopsy was used to stimulate wound healing and a repeat 5-mm punch biopsy was used to harvest the resulting granulation tissue. This assay was performed at pretreatment and on-treatment evaluating four targeted therapies, bevacizumab, everolimus, erlotinib, and panitumumab, in the context of three different clinical trials. Total and phosphorylated levels VEGFR2, S6RP, and EGFR were evaluated using ELISA-based methodologies. RESULTS: Significant and consistent inhibition of the VEGF pathway (using VEGFR2 as the readout) was observed in granulation tissue biopsies from patients treated with bevacizumab and everolimus. In addition, significant and consistent inhibition of the mTOR pathway (using S6RP as the readout) was observed in patients treated with everolimus. Finally, significant inhibition of the EGFR pathway (using EGFR as the readout) was observed in patients treated with panitumumab, but this was not observed in patients treated with erlotinib. CONCLUSIONS: Molecular analyses of dermal granulation tissue can be used as a convenient and quantitative pharmacodynamic biomarker platform for multiple classes of targeted therapies.

A phase I study of bevacizumab (B) in combination with everolimus (E) and erlotinib (E) in advanced cancer (BEE).

PURPOSE: VEGF, mTOR, and EGFR inhibitors have demonstrated anti-tumor and anti-angiogenic effects alone and in combination with each other. This study evaluated the safety, tolerability, and pharmacokinetics of bevacizumab, everolimus, and erlotinib combination. METHODS: Doublet therapy consisted of bevacizumab at 10 mg/kg every 14 days and everolimus 5 mg daily which escalated to 10 mg daily. Erlotinib 75 mg daily was added to the phase II dose recommended phase II dose (RPTD) of bevacizumab and everolimus. Dose-limiting toxicity (DLT) was assessed in cycle 1. RESULTS: Forty-eight patients with advanced solid malignancies were evaluable for DLT and efficacy. No DLTs were observed in the doublet dose escalation. Two DLTs (grade 3 mucositis and grade 3 rash) were observed with the addition of erlotinib 75 mg daily. Consequently, triplet doses were adjusted and were better tolerated. Four patients had a partial response. Median progression-free survival (PFS) for the doublet therapy was 6.0 months (0.5 to 32+ months) and 5.5 months (0.8 to 27+ months) for the triplet therapy. Systemic exposure of everolimus was significantly higher in combination with erlotinib (476 ± 161 ng h/mL) compared to when given alone (393 ± 156 ng h/mL; P = 0.020). CONCLUSIONS: The RPTD for the doublet therapy is bevacizumab 10 mg/kg every 14 days and everolimus 10 mg daily, and the RPTD for the triplet therapy is bevacizumab 5 mg/kg every 14 days, everolimus 5 mg and erlotinib 75 mg daily. Prolonged disease stability was demonstrated in tumors known to respond to mTOR inhibition and potentially resistant to VEGF blockade.