A phase II study of everolimus in combination with imatinib for previously treated advanced renal carcinoma.

PURPOSE: This phase II study evaluated the activity of combined treatment with the mTOR inhibitor everolimus and the PDGFR inhibitor imatinib in patients with previously-treated, advanced renal carcinoma. The primary endpoint was estimation of the 3-month progression-free rate. PATIENTS AND METHODS: Eligible patients had metastatic or unresectable clear cell renal carcinoma, at least one prior systemic therapy, no prior mTOR inhibitor therapy, performance status 0-2, and measurable disease. Treatment consisted of everolimus 2.5 mg p.o. daily and imatinib 600 mg p.o. daily. The primary endpoint was the 3-month progression-free rate. RESULTS: The study was closed after the first 19 patients because of an insufficient number of patients who were progression-free at 3 months. The 3-month progression-free rate was 49% (95% C.I. 23%, 72%) and the median progression-free survival was 2.9 months (95% C.I. 1.9, 6.2). Toxicities with an incidence of > 50% included nausea, elevated serum creatinine, edema, anemia, hypocalcemia, fatigue, diarrhea, vomiting, and dyspnea, and leukopenia. CONCLUSION: The combination of everolimus with imatinib in previously treated patients with advanced renal carcinoma did not result in a sufficient 3-month progression-free rate to warrant further investigation of this combination.

A phase II study of high-dose calcitriol combined with mitoxantrone and prednisone for androgen-independent prostate cancer.

OBJECTIVE: To evaluate the preliminary efficacy, safety, and impact on quality of life (QoL) of high-dose calcitriol (DN-101) combined with mitoxantrone and glucocorticoids in androgen-independent prostate cancer (AIPC). PATIENTS AND METHODS: Nineteen patients with metastatic AIPC and no previous chemotherapy received DN-101 180 microg orally on day 1 and mitoxantrone 12 mg/m(2) intravenously on day 2 every 21 days with continuous daily prednisone 10 mg orally for a maximum of 12 cycles. A confirmed decline in prostate-specific antigen (PSA) levels by half was the primary endpoint. QoL was evaluated using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire, and pain and analgesic use were evaluated. RESULTS: Five of 19 patients (26%; 95% confidence interval, CI, 9-51) achieved a >/=50% decline in PSA level. The median (95% CI) time to PSA progression was 16 (6-26) weeks. The overall median (95% CI) survival was 16 (6-26) months; 47 (21-73)% of patients achieved an analgesic response. Toxicity was similar to that expected with mitoxantrone and prednisone alone. The QoL analysis suggested a decrease in physical functioning and increase in fatigue, insomnia, and diarrhoea. CONCLUSIONS: DN-101 given every 3 weeks does not add significant activity to mitoxantrone and prednisone in AIPC, as measured by the PSA decline. The high rate of analgesic response is encouraging. The addition of DN-101 does not appear to increase the toxicity of mitoxantrone.

Postchemotherapy hyperammonemic encephalopathy emulating ornithine transcarbamoylase (OTC) deficiency.

A young patient with hepatocellular carcinoma receiving chemotherapy presented with encephalopathy. Evaluation of the patient revealed a metabolic profile consistent with ornithine transcarbamoylase (OTC) deficiency, an inherited disorder of the urea cycle. The evaluation yielded a plasma amino acid analysis consistent with OTC deficiency. However, genetic analysis did not reveal a somatic mutation of the OTC gene in this patient. The hyperammonemic encephalopathy was reversed by the infusion of arginine, a common treatment for hereditary OTC deficiency. This case may represent a distinct syndrome of reversible hyperammonemia in patients with hepatocellular carcinoma.