Weekly paclitaxel and concurrent pazopanib following doxorubicin and cyclophosphamide as neoadjuvant therapy for HER-negative locally advanced breast cancer: NSABP Foundation FB-6, a phase II study.

This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple-negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre-specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer.

Expression of an activation antigen, Mo3e, associated with the cellular response to migration inhibitory factor by HL-60 promyelocytes undergoing monocyte-macrophage differentiation.

HL-60 promyelocytic cells acquire the surface expression of the Mo3e antigenic determinant after exposure to PMA or compounds that raise intracellular concentrations of cyclic AMP (dibutyryl cyclic AMP or a combination of cholera toxin and IBMX). The expression of Mo3e by these stimulated HL-60 cells coincides with the development of features of monocyte-macrophage differentiation (characteristic morphology, nonspecific esterase activity, and respiratory burst activity). During in vitro monocyte-macrophage differentiation, HL-60 cells become responsive to migration inhibitory factor (MIF); the MIF responsiveness of differentiated HL-60 cells is blocked by anti-Mo3e monoclonal antibody. These findings further support the relationship between the expression of Mo3e and the cellular response to MIF.

Hybrid high-dose bolus/continuous infusion interleukin-2 in patients with metastatic renal cell carcinoma: a phase II trial of the National Biotherapy Study Group.

BACKGROUND: Interleukin-2 (IL-2) is an active agent for the treatment of renal cell carcinoma. In animal studies, polyethylene glycol conjugated (PEG) IL-2 was found to be effective in certain IL-2-resistant models. When bolus/infusion IL-2 was administered to approximate the pharmacokinetics of PEG-IL-2, resistance was also overcome in these models. Based on these observations, the National Bio-therapy Study Group (NBSG) previously had conducted a pilot study (NBSG 90-01) and then a phase I trial of a hybrid regimen of bolus IL-2 followed by continuous IL-2 (NBSG 91-04). METHODS: In the current study, NBSG 92-09, a phase II trial was conducted in patients with metastatic renal cell carcinoma using IL-2 at a dose of 36 MIU/m2 followed by a 72-hour continuous infusion of IL-2 at 18 MIU/m2 per day, so that over 3 days a total of 90 MIU/m2 of IL-2 were delivered; the same amount as previously given during 5 days of continuous intravenous (i.v.) IL-2 at 18 MIU/m2 per day. This was repeated every 2 weeks for 2 months, and then monthly for up to 4 months. RESULTS: Thirty-one patients with a median age of 62 years were enrolled in this trial. During the first 4 biweekly treatments, the percentages of planned IL-2 administered were 98% for 31 patients, 99% for 27, 98% for 23, and 99% for 20 patients. Toxicities were qualitatively the same as those seen with other IL-2 regimens. During the first 2 months, 4 patients ceased treatment because of rapidly progressive disease while 7 patients stopped because of toxicity; 5 of the 7 were > 65 years of age. At the time of formal reassessment after 2 months of treatment, 7 additional patients had progressive disease for a treatment failure rate of 55% prior to monthly maintenance therapy. There were two partial responses among 22 patients who had measurable disease for a response rate of 9% (1 to 29%, 95% CI). Median survival was 10.2 months and failure-free survival (FFS) 3.4 months for the entire group. CONCLUSION: The response rate seen with this regimen is similar to those of other schedules of IL-2 requiring more prolonged hospitalization. This hybrid bolus/continuous infusion IL-2 schedule appears to be an equally effective and less expensive schedule of IL-2 administration than previously reported inpatient regimens. However, it is not likely that this regimen is superior to outpatient combination biotherapy regimens which are currently under investigation.

Hybrid high-dose bolus/continuous infusion interleukin-2 in patients with metastatic melanoma: a phase II trial of the Cancer Biotherapy Research Group (formerly the National Biotherapy Study Group).

PURPOSE: Interleukin-2 (IL-2) is an active agent for the treatment of melanoma. In animal studies, polyethylene glycol conjugated (PEG) IL-2 was found to be effective in certain IL-2-resistant models. Bolus/infusional IL-2 administered to approximate the pharmacokinetics of PEG-IL-2 also overcame resistance in these models. Based on these observations, the Cancer Biotherapy Research Group (CBRG) [formerly the National Biotherapy Study Group (NBSG)] previously had conducted a pilot study and then a phase I trial of bolus IL-2 followed by continuous IL-2 (NBSG 90-01). METHODS: In the current study, NBSG 92-09, a phase II trial was conducted using IL-2 at a dose of 36 MIU/m2 followed by a 72-hour continuous infusion of IL-2 at 18 MIU/m2/day, so that over 3 days a total of 90 MIU/m2 of IL-2 were delivered; the same amount as previously given during 5 days of continuous i.v. IL-2 at 18 MIU/m2/day. This schedule was repeated every 2 weeks for 2 months, and then monthly for up to 6 months. RESULTS: Twenty-two patients with metastatic melanoma were enrolled in this trial. Toxicities were qualitatively similar to those seen with other IL-2 regimens, but grade 3 and 4 toxicities were observed only in patients who received at least four cycles of treatment; only one patient went off study because of toxicity. For 18 patients with measurable disease, there were two complete and two partial responses in patients ages 32, 66, 72 and 83 years, for a response rate of 22% (6% to 48%; 95% confidence interval [Ci]). The median survival for all 21 evaluable patients enrolled in the trial was 8.5 months. CONCLUSION: The hybrid schedule of drug delivery in NBSG 92-09 allowed the same dose and intensity of IL-2 to be delivered over 3 days instead of 5 days, which resulted in fewer days of hospitalization and therefore decreased cost; but with no increase in toxicity and no decrease in efficacy in patients with metastatic melanoma.

Chemo-biotherapy with 5-fluorouracil, leucovorin, and alpha interferon in metastatic carcinoma of the colon--a Cancer Biotherapy Research Group [CBRG] phase II study.

BACKGROUND: Biochemical modulation of 5-Fluorouracil activity with Leucovorin has been well documented in colorectal cancer. Several studies have shown increased efficacy of 5-fluorouracil in combination with alpha interferon. We therefore initiated a phase II trial of dual modulation of 5-fluorouracil with leucovorin and alpha interferon to evaluate outcomes in patients with metastatic carcinoma of the colon. METHODS: Patients with metastatic colon carcinoma with expected survival > 4 months and performance status of ECOG < or = 2 were treated weekly with Leucovorin 400 mg i.v. followed by 5-FU 600 mg/m2 i.v. bolus. Alpha interferon 3-9 million units was administered subcutaneously every Monday, Wednesday and Friday. Patients were analyzed for toxicity, tumor response and survival. RESULTS: Sixteen patients with a median age of 66 years were treated. Three patients were not evaluable for response but were evaluable for toxicity. Grades 3 and 4 toxicities were neutropenia, diarrhea, mucositis, nausea and vomiting, fatigue, fever, asthenia and elevated hepatic enzymes. One patient died from complications associated with diverticulitis and neutropenia. Objective response rate was 23% (95% confidence interval 4-46%) and median survival was 11.5 months (95% confidence interval 6.3-19 months). Thirty-eight percent of the patients were alive at one year and 19% at two years. CONCLUSION: The combination of 5-fluorouracil, leucovorin and alpha interferon as administered in this phase II study did not result in enhanced response rate or survival. However this regimen was associated with considerable toxicity.

Regulation of human monocyte surface antigen expression. I. Up-modulation of Mo3e antigen expression on U-937 and HL-60 cells stimulated by pharmacologic activators of protein kinase C.

Mo3e is a protein (p 50,80) that is expressed on the surface of human monocytic cells after exposure in vitro to soluble activating factors that include bacterial lipopolysaccharide, muramyl dipeptide, and phorbol myristate acetate (PMA). The surface expression of Mo3e may represent a cellular event that occurs in response to the formation of "secondary messengers" that include diacylglycerol, inositol trisphosphate, and calcium ions. This postulate is based on the stimulatory effect of agents that can mimic the activity of endogenous diacylglycerol (PMA and other biologically active phorbol compounds, mezerein, and L-alpha-1,2 dioctanoylglycerol) and inositol trisphosphate (ionomycin) on Mo3e expression by U-937 and HL-60 cells. The inhibitory effect of phospholipid-active calmodulin inhibitors (trifluoperazine, chlorpromazine, and dibucaine), calcium antagonists (nicardipine and TMB-8), and EGTA further support the involvement of phospholipid- and calcium-dependent protein kinase (protein kinase C) and calcium ions in the up-modulation of Mo3e surface expression.