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1.
Clin Cancer Res ; 13(14): 4178-84, 2007 Jul 15.
Article in English | MEDLINE | ID: mdl-17634546

ABSTRACT

PURPOSE: Patupilone is a microtubule-targeting chemotherapeutic agent with clinical activity in a broad range of taxane-sensitive/resistant tumor types. The present phase Ib study examined the safety/tolerability and pharmacokinetics of patupilone in combination with carboplatin in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients with advanced cancer received patupilone via a 5- to 10-min i.v. infusion at doses of 3.6 to 6.0 mg/m(2) q3w, immediately followed by carboplatin area under the curve (AUC) 5 or 6 mg/mL/min. RESULTS: Of the 37 patients enrolled, the majority previously received taxanes (81%) and/or platinum-containing drugs (97.3%). The maximum tolerated dose (MTD) of patupilone with carboplatin AUC 6 was 4.8 mg/m(2); additional patients were enrolled to consolidate experience at this dose. Of the 22 patients who received the MTD, the most common nonhematologic adverse events were fatigue in six (27.3%) and diarrhea, nausea, vomiting, abdominal pain, and neuropathy in one each (4.5%; all grade 3); hematologic toxicities included two patients (9.1%) with grade 3 neutropenia. The pharmacokinetics of patupilone were similar to those in a previous study of patupilone monotherapy. Of the 26 patients with recurrent platinum-sensitive ovarian cancer, tumor response was assessable by response evaluation criteria in solid tumors in 17; 1 patient (6%) achieved a complete response, and 10 (59%) achieved a partial response. CONCLUSIONS: The combination of patupilone 4.8 mg/m(2)/carboplatin AUC 6 was well tolerated and showed antitumor activity similar to established regimens in patients with recurrent platinum-sensitive ovarian cancer. The optimal dose for this regimen is currently being further refined in phase II trials.


Subject(s)
Antineoplastic Agents/toxicity , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/therapeutic use , Epothilones/toxicity , Neoplasms/drug therapy , Adult , Aged , Antineoplastic Agents/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/toxicity , Carboplatin/pharmacokinetics , Epothilones/pharmacokinetics , Female , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Neoplasms/pathology , Humans , Male , Middle Aged , Neoplasm Staging , Neoplasms/pathology , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/pathology , Uterine Neoplasms/drug therapy , Uterine Neoplasms/pathology
2.
Clin Cancer Res ; 10(6): 1949-55, 2004 Mar 15.
Article in English | MEDLINE | ID: mdl-15041711

ABSTRACT

PURPOSE: The purpose of our study was to determine the maximum-tolerated dose, dose-limiting toxicity, safety profile, and pharmacokinetics of the polyamine synthesis inhibitor SAM486A given in combination with 5-fluorouracil/leucovorin (5-FU/LV) in cancer patients. EXPERIMENTAL DESIGN: Patients with advanced colorectal cancer were treated with 5-FU [bolus (400 mg/m(2)) followed by a 22-h infusion (600 mg/m(2))] and LV (200 mg/m(2)) and escalating doses of SAM486A, 1-3-h infusion daily for 3 days. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of the combination RESULTS: Twenty-seven patients with metastatic colorectal cancer and 1 with pseudomyxoma peritonei were treated. Twenty-six patients received SAM486A in the combination at doses ranging from 25 to 150 mg/m(2)/day. Dose-limiting toxicity consisting of fatigue grade 3 was seen at 150 mg/m(2)/day. Other adverse events included neutropenia, hand and foot syndrome, nausea, vomiting, diarrhea, and constipation. Fifteen of 26 patients evaluable for best response according to the Southwest Oncology Group criteria achieved a partial response [8 (30%) of 26] or stable disease [9 (35%) of 26]. SAM486A did not influence the pharmacokinetics of 5-FU, and SAM486A clearance was similar to that when used as a single agent. CONCLUSIONS: The novel molecular agent SAM486A is tolerable and safe in combination with a standard 5-FU regimen in patients with advanced colorectal cancer. The dose of SAM486A recommended for additional studies with this combination is 125 mg/m(2)/day. A disease-directed evaluation of SAM486A using this regimen is warranted.


Subject(s)
Amidines/pharmacokinetics , Amidines/toxicity , Antineoplastic Agents/toxicity , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Indans/pharmacokinetics , Indans/toxicity , Adult , Aged , Amidines/administration & dosage , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/toxicity , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Colorectal Neoplasms/parasitology , Female , Fluorouracil/administration & dosage , Humans , Indans/administration & dosage , Infusions, Intravenous , Leucovorin/administration & dosage , Male , Middle Aged , Neoplasm Metastasis , Pseudomyxoma Peritonei/drug therapy , Pseudomyxoma Peritonei/pathology , Rectal Neoplasms/drug therapy , Rectal Neoplasms/pathology , Treatment Outcome
3.
Clin Cancer Res ; 10(4): 1299-305, 2004 Feb 15.
Article in English | MEDLINE | ID: mdl-14977828

ABSTRACT

PURPOSE: SAM486A is a new inhibitor of S-adenosyl-methionine-decarboxylase, a key enzyme for polyamine biosynthesis. It is more potent than the first generation S-adenosyl-methionine-decarboxylase inhibitor methylglyoxal bis-guanylhydrazone. This Phase IIa study reports the findings of SAM486A monotherapy in patients with refractory or relapsed non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Forty-one previously treated patients with either diffuse large cell, follicular, or peripheral T-cell NHL were treated i.v. with 100 mg/m(2) SAM486A as a daily 1-h infusion for 5 days repeated every 3 weeks. Treatment was continued for a total of eight cycles or until disease progression. RESULTS: Two patients, both with large B-cell lymphoma, showed a complete response at cycle 3 that was maintained for >or=13 and >or=28 months. Five patients had a partial response, and 3 had stable disease at last follow-up. The overall response rate (complete response plus partial response) was 18.9% for evaluable patients (7 patients). Anemia was the primary hematological toxicity and observed in 7 (17.1%) patients. Five patients experienced grade 3/4 anemia. Four patients (9.8%) experienced grade 3/4 febrile neutropenia and grade 3/4 thrombocytopenia, respectively. Nonhematological toxicities were mild to moderate in intensity. The most frequent side effects were nausea (39%), vomiting (22%), diarrhea (19.5%), asthenia (17.1%), abdominal pain (14.6%), and flushing (9.8%). CONCLUSION: SAM486A has a promising clinical activity in patients with poor prognosis NHL and manageable safety profile. To further define the role of SAM486A, in the treatment of NHL, additional studies are warranted.


Subject(s)
Amidines/pharmacology , Antineoplastic Agents/pharmacology , Indans/pharmacology , Lymphoma, Non-Hodgkin/drug therapy , Polyamines/antagonists & inhibitors , Adenosylmethionine Decarboxylase/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Disease Progression , Disease-Free Survival , Female , Humans , Lymphoma, Non-Hodgkin/pathology , Male , Middle Aged , Prognosis , Recurrence , Time Factors , Treatment Outcome
4.
Clin Cancer Res ; 8(7): 2157-66, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12114416

ABSTRACT

PURPOSE: SAM486A is a novel inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (SAMDC). This study was performed to characterize the toxicity profile and the pharmacological behavior and to determine the maximum tolerated dose (MTD) of SAM486A administered by a 1-h i.v. infusion daily for 5 days every 3 weeks in patients with advanced cancer. EXPERIMENTAL DESIGN: Twenty-three patients received 46 cycles of SAM486A at dose levels ranging from 3.6 to 202.8 mg/m(2)/day. SAM486A plasma concentrations were measured during the first cycle for pharmacokinetic and pharmacodynamic evaluations. Paired tumor biopsy specimens pre- and posttreatment were obtained in 1 patient to assess the impact of SAM486A on intratumoral enzymes and metabolites involved in the polyamine biosynthetic pathway. RESULTS: The dose-limiting toxicity of SAM486A on this schedule was myelosuppression. Nonhematological toxicities, including nausea, vomiting, anorexia, and fatigue, were mild to moderate in severity. The MTD of SAM486A was 102.4 mg/m(2)/day. Pharmacokinetic analyses demonstrated a rapid initial decrease in plasma drug concentrations at the end of infusion, followed by a long terminal elimination phase with a mean (+/- SD) terminal elimination half-life of 65.4 +/- 55.6 h. Dose and area under the concentration-time curve correlated with the appearance of grade 4 neutropenia with correlation coefficients of 0.70 and 0.69, respectively. Analysis of paired tumor biopsy specimens taken before and after SAM486A treatment in 1 patient with metastatic melanoma revealed decreased SAMDC activity, increased ornithine decarboxylase activity, increased levels of putrescine, and depleted levels of decarboxylated S-adenosylmethionine and spermine, all of which are consistent with the proposed mode of action of SAM486A. CONCLUSIONS: SAM486A was well tolerated on this schedule of administration with the MTD established at 102.4 mg/m(2)/day. Neutropenia was dose-limiting and correlated with dose and area under the concentration-time curve. Pharmacodynamic assessment of tumoral tissues in 1 study patient demonstrated changes in the levels of polyamines and their biosynthetic enzymes consistent with SAMDC inhibition.


Subject(s)
Adenosylmethionine Decarboxylase/antagonists & inhibitors , Antineoplastic Agents/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Neoplasms/drug therapy , Polyamines/antagonists & inhibitors , Adenosylmethionine Decarboxylase/metabolism , Adult , Aged , Amidines/adverse effects , Amidines/pharmacokinetics , Amidines/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Area Under Curve , Dose-Response Relationship, Drug , Drug Administration Schedule , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/therapeutic use , Female , Gastrointestinal Diseases/chemically induced , Hematologic Diseases/chemically induced , Humans , Indans/adverse effects , Indans/pharmacokinetics , Indans/therapeutic use , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/enzymology , Polyamines/metabolism
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