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ABSTRACT: To determine the efficacy and toxicity of the protein kinase C inhibitor bryostatin-1 plus paclitaxel in patients with advanced pancreatic carcinoma.
Each treatment cycle consisted of paclitaxel 90 mg/m by intravenous infusion over 1 hour on days 1, 8, and 16, plus bryostatin 25 mcg/m as a 1-hour intravenous infusion on days 2, 9, and 15, given every 28 days. Patients were evaluated for response after every 2 treatment cycles, and continued therapy until disease progression or prohibitive toxicity. The primary objective was to determine whether the combination produced a response rate of at least 30%.
Nineteen patients with locally advanced or metastatic pancreatic adenocarcinoma received a total of 52 cycles of therapy (range: 1-10). Patients received the combination as first-line therapy for advanced disease (N = 5) or after prior chemotherapy used alone or in combination with local therapy. No patients had a confirmed objective response. The median time to treatment failure was 1.9 months (95% confidence intervals: 1.2, 2.6 months). Reasons for discontinuing therapy included progressive disease or death in 14 patients (74%) or because of adverse events or patient choice in 5 patients (26%). The most common grade 3 to 4 toxicities included leukopenia in 26%, anemia in 11%, myalgias in 11%, gastrointestinal bleeding in 11%, infection in 10%, and thrombosis in 10%.
The combination of weekly paclitaxel and bryostatin-1 is not an effective therapy for patients with advanced pancreatic carcinoma.
American journal of clinical oncology 10/2009; 33(2):121-4. · 2.21 Impact Factor
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ABSTRACT: To determine the maximum tolerated dose of oblimersen, an antisense oligonucleotide directed to the Bcl-2 mRNA, in combination with cisplatin and 5-flourouracil in patients with advanced gastric and esophageal carcinoma.
Patients were treated with escalating doses of oblimersen administered by continuous intravenous infusion (CIVI) days 1 to 7, CIVI 5-fluorouracil (5-FU) days 4 to 7, and cisplatin on day 4 every 3 weeks.
Fifteen patients received a total of 49 courses of oblimersen at doses of 3, 5, or 7 mg/kg/d given as a 7 day CIVI in combination with 4 or 5 day CIVI of 5-FU (1000 or 750 mg/m2/d) plus intravenous cisplatin (100 or 75 mg/m2 over 2 hours). The recommended phase II dose of oblimersen was 5 mg/kg/d in combination with 5-FU (750 mg/m2/d for 4 days) and cisplatin (75 mg/m). The most common grade 3 to 4 adverse events that occurred in at least 10% of patients at all dose levels included neutropenia (33%), hypokalemia (27%), infection (20%), and mucositis, fatigue, dizziness, thrombosis, and dehydration (in 13% for each category).
The combination of oblimersen with 5-FU and cisplatin chemotherapy is feasible in patients with advanced upper gastrointestinal cancer, with antitumor activity observed in gastric carcinoma.
American journal of clinical oncology 10/2009; 33(1):61-5. · 2.21 Impact Factor
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ABSTRACT: LY293111, a novel diaryl ether carboxylic acid derivative, is a potent and selective inhibitor of the lipoxygenase pathway either directly through 5'-lipoxygenase or via antagonism of the leukotriene B4 (LTB4) receptor. More recently it has been determined to have peroxisome proliferator activated receptor-gamma agonist (PPARgamma) activity. LY293111 has antineoplastic activity in a variety of preclinical models. The tolerability and pharmacokinetics of LY293111 administered continuously, by mouth, BID for repeat cycles of 21 days was evaluated.
Thirty-eight patients with advanced solid tumors were treated at five dose levels (200 to 800 mg BID) for a total of 102 cycles.
The most common toxicity was diarrhea (76%). One patient at 600 mg BID (n = 11) and two at 800 mg BID (n = 8), experienced dose-limiting grade 3 diarrhea. Dose reductions and/or delays were infrequent. Increases in steady-state maximum plasma concentration (Cmax,ss) and area under the steady-state plasma concentration time curve 0 to 12 hours (AUCtau,ss) on day 8 could be considered to be dose-proportional over the four-fold-dose range. Interpatient variability in Cmax,ss and AUCtau,ss was estimated to be 65% and 71% respectively. There was a small increase in AUC (1.37; 90% CI, 0.85 to 2.21) between single and multiple doses. Two patients with progressive chondrosarcoma and melanoma had stable disease lasting approximately 336 and 168 days, respectively.
LY293111 can be administered safely by continuous oral therapy with mild toxicities. Diarrhea is dose-limiting. The recommended phase II dose will be 600 mg BID. The steady-state concentrations in humans exceed relevant levels observed in preclinical models.
Journal of Clinical Oncology 09/2005; 23(23):5365-73. · 18.37 Impact Factor
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Carmela Gurrieri,
Peter McGuire,
Hong Zan,
Xiao-Jie Yan,
Andrea Cerutti,
Emilia Albesiano,
Steven L Allen, Vincent Vinciguerra,
Kanti R Rai,
Manlio Ferrarini,
Paolo Casali,
Nicholas Chiorazzi
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ABSTRACT: Chronic lymphocytic leukemia (CLL) arises from the clonal expansion of a CD5(+) B lymphocyte that is thought not to undergo intraclonal diversification. Using V(H)DJ(H) cDNA single strand conformation polymorphism analyses, we detected intraclonal mobility variants in 11 of 18 CLL cases. cDNA sequence analyses indicated that these variants represented unique point-mutations (1-35/patient). In nine cases, these mutations were unique to individual submembers of the CLL clone, although in two cases they occurred in a large percentage of the clonal submembers and genealogical trees could be identified. The diversification process responsible for these changes led to single nucleotide changes that favored transitions over transversions, but did not target A nucleotides and did not have the replacement/silent nucleotide change characteristics of antigen-selected B cells. Intraclonal diversification did not correlate with the original mutational load of an individual CLL case in that diversification was as frequent in CLL cells with little or no somatic mutations as in those with considerable mutations. Finally, CLL B cells that did not exhibit intraclonal diversification in vivo could be induced to mutate their V(H)DJ(H) genes in vitro after stimulation. These data indicate that a somatic mutation mechanism remains functional in CLL cells and could play a role in the evolution of the clone.
Journal of Experimental Medicine 10/2002; 196(5):629-39. · 13.85 Impact Factor
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Carmela Gurrieri,
Peter McGuire,
Hong Zan,
Xiao-Jie Yan,
Andrea Cerutti,
Emilia Albesiano,
Steven L. Allen, Vincent Vinciguerra,
Kanti R. Rai,
Manlio Ferrarini,
Paolo Casali,
Nicholas Chiorazzi
[show abstract]
[hide abstract]
ABSTRACT: Chronic lymphocytic leukemia (CLL) arises from the clonal expansion of a CD5+ B lymphocyte that is thought not to undergo intraclonal diversification. Using VHDJH cDNA single strand conformation polymorphism analyses, we detected intraclonal mobility variants in 11 of 18 CLL cases. cDNA
sequence analyses indicated that these variants represented unique point-mutations (1–35/patient). In nine cases, these mutations
were unique to individual submembers of the CLL clone, although in two cases they occurred in a large percentage of the clonal
submembers and genealogical trees could be identified. The diversification process responsible for these changes led to single
nucleotide changes that favored transitions over transversions, but did not target A nucleotides and did not have the replacement/silent
nucleotide change characteristics of antigen-selected B cells. Intraclonal diversification did not correlate with the original
mutational load of an individual CLL case in that diversification was as frequent in CLL cells with little or no somatic mutations
as in those with considerable mutations. Finally, CLL B cells that did not exhibit intraclonal diversification in vivo could
be induced to mutate their VHDJH genes in vitro after stimulation. These data indicate that a somatic mutation mechanism remains functional in CLL cells and
could play a role in the evolution of the clone.
Journal of Experimental Medicine 09/2002; 196(5):629-639. · 13.85 Impact Factor
