Uridine diphosphate glucuronosyltransferase (UGT) 1A1 and irinotecan: practical pharmacogenomics arrives in cancer therapy.
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Alleles↗
Biomedical subjects
Peter J O'Dwyer
Publications and source records attributed to Peter J O'Dwyer.
Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma.
PURPOSE: This phase II randomized discontinuation trial evaluated the effects of sorafenib (BAY 43-9006), an oral multikinase inhibitor targeting the tumor and vasculature, on tumor growth in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Patients initially received oral sorafenib 400 mg twice daily during the initial run-in period. After 12 weeks, patients with changes in bidimensional tumor measurements that were less than 25% from baseline were randomly assigned to sorafenib or placebo for an additional 12 weeks; patients with > or = 25% tumor shrinkage continued open-label sorafenib; patients with > or = 25% tumor growth discontinued treatment. The primary end point was the percentage of randomly assigned patients remaining progression free at 24 weeks after the initiation of sorafenib. RESULTS: Of 202 patients treated during the run-in period, 73 patients had tumor shrinkage of > or = 25%. Sixty-five patients with stable disease at 12 weeks were randomly assigned to sorafenib (n = 32) or placebo (n = 33). At 24 weeks, 50% of the sorafenib-treated patients were progression free versus 18% of the placebo-treated patients (P = .0077). Median progression-free survival (PFS) from randomization was significantly longer with sorafenib (24 weeks) than placebo (6 weeks; P = .0087). Median overall PFS was 29 weeks for the entire renal cell carcinoma population (n = 202). Sorafenib was readministered in 28 patients whose disease progressed on placebo; these patients continued on sorafenib until further progression, for a median of 24 weeks. Common adverse events were skin rash/desquamation, hand-foot skin reaction, and fatigue; 9% of patients discontinued therapy, and no patients died from toxicity. CONCLUSION: Sorafenib has significant disease-stabilizing activity in metastatic renal cell carcinoma and is tolerable with chronic daily therapy.
Administration, Oral↗
Mechanisms of hypertension associated with BAY 43-9006.
PURPOSE: BAY 43-9006 (sorafenib) is an inhibitor of Raf kinase, the vascular endothelial growth factor (VEGF) receptor-2, and angiogenesis in tumor xenografts. The current study investigated the incidence, severity, and mechanism of blood pressure (BP) elevation in patients treated with BAY 43-9006. PATIENTS AND METHODS: Twenty patients received BAY 43-9006 400 mg orally twice daily. BP and heart rate were measured at baseline and then every 3 weeks for 18 weeks. VEGF, catecholamines, endothelin I, urotensin II, renin, and aldosterone were measured at baseline and after 3 weeks of therapy. We assessed vascular stiffness at baseline, after 3 to 6 weeks of therapy, and again after 9 to 10 months of therapy. RESULTS: Fifteen (75%) of 20 patients experienced an increase of > or = 10 mmHg in systolic BP (SBP), and 12 (60%) of 20 patients experienced an increase of > or = 20 mmHg in SBP compared with their baseline value, with a mean change of 20.6 mmHg (P < .0001) after 3 weeks of therapy. There were no statistically significant changes in humoral factors, although there was a statistically significant inverse relationship between decreases in catecholamines and increases in SBP, suggesting a secondary response to BP elevation. Measures of vascular stiffness increased significantly during the period of observation. CONCLUSION: Treatment with BAY 43-9006 is associated with a significant and sustained increase in BP. The lack of significant change in circulating factors suggests that these humoral factors had little role in the increase in BP.
Administration, Oral↗
The present and future of angiogenesis-directed treatments of colorectal cancer.
The level of angiogenic activity in colorectal tumors has been shown to be a determinant of survival. Recent trials established that, in both the first- and second-line treatment of metastatic colorectal cancer, the addition of the vascular endothelial growth factor (VEGF)-directed antibody bevacizumab to chemotherapy significantly prolongs survival compared to chemotherapy alone. Those trials provided proof of principle that inhibition of angiogenesis has the potential to enhance the effectiveness of treatment of this disease. Oral agents directed toward VEGF receptor signaling are in advanced development, but none to date has proven beneficial in phase III trials in advanced colorectal cancer. Additional trials are needed to determine if improved pharmacological characteristics of the small molecules can be modified to replicate the activity of the antibody or if mechanistic differences require a more specific approach. Since bevacizumab has minimal activity as a single agent, a key question for future therapeutic development relates to the interaction between antiangiogenic strategies and cytotoxic therapies. We hypothesize that bevacizumab may potentiate the efficacy of cytotoxics not solely by alterations of tumor interstitial pressure but also by promoting sensitivity to proapoptotic signals consequent upon nutrient and oxygen withdrawal.
Angiogenesis Inhibitors↗
Macrophage migration inhibitory factor is a determinant of hypoxia-induced apoptosis in colon cancer cell lines.
Hypoxia contributes to cytotoxic chemotherapy and radiation resistance and may play a role in the efficacy of antiangiogenesis cancer therapy. We have generated a series of cell lines derived from the colon adenocarcinoma models HT29 and HCT116 by exposing cells in vitro to repeated sublethal periods of profound hypoxia. These cell lines have altered sensitivity to hypoxia-induced apoptosis: those derived from HT29 are resistant, whereas those from HCT116 are more susceptible. We used cDNA selected subtractive hybridization to identify novel genes mediating sensitivity to hypoxia-induced apoptosis and isolated macrophage migration inhibitory factor (MIF) from the hypoxia-conditioned cell lines. MIF expression correlates with susceptibility of the cell lines to apoptosis. In hypoxia-resistant cells, the induction of apoptosis by hypoxia can be restored by the addition of exogenous recombinant MIF protein, suggesting that resistance may result in part from down-regulation of MIF production possibly through an autocrine loop. Inhibition of MIF using small interfering RNA in the susceptible lines conferred resistance to hypoxia-induced cell death. The relative expression of MIF in the hypoxia-conditioned cells implanted s.c. in severe combined immunodeficient mice in vivo was similar to that observed in vitro. In an analysis of 12 unrelated colon tumor cell lines, MIF expression and response to hypoxia varied widely. Cell lines in which MIF was inducible by hypoxia were more sensitive to oxaliplatin. In human colon tumor specimens analyzed by immunohistochemistry, MIF expression was similarly variable. There was no detectable expression of MIF in normal colon mucosa or adenoma but positive staining in all carcinomas tested. Taken together, these data indicate that MIF may be a determinant of hypoxia-induced apoptosis in vitro and that its variable expression in human colon cancers may indicate a functional role in vivo. We suggest that MIF expression in colorectal cancer may be a marker of susceptibility to therapies that may depend on induction of hypoxia, possibly including antiangiogenic therapy.
Apoptosis↗
17-Allylamino-17-demethoxygeldanamycin overcomes TRAIL resistance in colon cancer cell lines.
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a promising candidate for treatment of cancer, but displays variable cytotoxicity in cell lines. The mechanisms of sensitivity and resistance have not been fully elucidated; both AKT and NF-kappaB pathways may modulate cytotoxic responses. We have shown that the Hsp90 inhibitor 17-AAG enhances the cytotoxicity of oxaliplatin in colon cancer cell lines through inhibition of NF-kappaB. We analyzed the effects of TRAIL and 17-AAG in combination in a series of nine colon cancer cell lines and characterized activation of the pathways to apoptosis. IC(50) values for a 72 h exposure to TRAIL ranged from 30 to 4000 ng/ml. Cytotoxicity assays demonstrated additivity or synergism of the TRAIL/17-AAG combination in all cell lines, with combination indices at IC(50) ranging from 0.53 to 1. The sensitizing effect of 17-AAG was greater in the TRAIL-resistant cell lines. In TRAIL-resistant cell lines, the combination of 17-AAG and TRAIL resulted in activation of both extrinsic and intrinsic apoptotic pathways, though with quantitative differences between HT29 and RKO cells: differential effects of 17-AAG on AKT and NF-kappaB characterized these cell lines. In both cell lines, the combination also led to down-regulation of X-linked inhibitor of apoptosis protein (XIAP) and enhanced activation of caspase-3. We conclude that either AKT or NF-kappaB may promote resistance to TRAIL in colon cancer cells, and that the ability of 17-AAG to target multiple putative determinants of TRAIL sensitivity warrants their further investigation in combination.
Apoptosis Regulatory Proteins↗
Phase I trial of combretastatin a-4 phosphate with carboplatin.
PURPOSE: Preclinical evidence of synergy led to a phase I trial employing combretastatin A-4 phosphate (CA4P), a novel tubulin-binding antivascular drug, in combination with carboplatin. EXPERIMENTAL DESIGN: Based on preclinical scheduling studies, patients were treated on day 1 of a 21-day cycle. Carboplatin was given as a 30-minute i.v. infusion and CA4P was given 60 minutes later as a 10-minute infusion. RESULTS: Sixteen patients with solid tumors received 40 cycles of therapy at CA4P doses of 27 and 36 mg/m(2) together with carboplatin at area under the concentration-time curve (AUC) values of 4 and 5 mg min/mL. The dose-limiting toxicity of thrombocytopenia halted the dose escalation phase of the study. Four patients were treated at an amended dose level of CA4P of 36 mg/m(2) and carboplatin AUC of 4 mg min/mL although grade 3 neutropenia and thrombocytopenia were still observed. Three lines of evidence are adduced to suggest that a pharmacokinetic interaction between the drugs results in greater thrombocytopenia than anticipated: the carboplatin exposure (as AUC) was greater than predicted; the platelet nadirs were lower than predicted; and the deviation of the carboplatin exposure from predicted was proportional to the AUC of CA4, the active metabolite of CA4P. Patient benefit included six patients with stable disease lasting at least four cycles. CONCLUSION: This study of CA4P and carboplatin given in combination showed dose-limiting thrombocytopenia. Pharmacokinetic/pharmacodynamic modeling permitted the inference that altered carboplatin pharmacokinetics caused the increment in platelet toxicity.
Adult↗
Phase I study of the novel taxane CT-2103 in patients with advanced solid tumors.
BACKGROUND: CT-2103 (Cell Therapeutics, Seattle, Wash.) is a water-soluble macromolecular conjugate of paclitaxel to a polyglutamate backbone, designed to enhance tumor permeability and to improve intratumoral delivery of paclitaxel. Preclinical studies indicate that CT-2103 has substantial antitumor efficacy in xenograft tumor models. METHODS: We performed a phase I trial in patients with advanced solid tumors to determine the maximum tolerated doses (MTD) of CT-2103 when administered as short intravenous infusion every 3 weeks. RESULTS: Seven patients received a total of 16 cycles (range 1-3) of CT-2103 at doses of 235 and 270 mg/m(2). Two of five patients treated at 235 mg/m(2) and one of two patients treated at 270 mg/m(2) experienced grade 3/4 neutropenia. Four patients experienced a marked increase in PTT within 30 min of the start of infusion. Neuropathy was more severe than expected. Two patients developed grade 3 neuropathy that prompted a 50% dose reduction of CT-2103 and persisted for 8 months in one, and over a year in the other. Three patients experienced grade 1 or 2 neuropathy. Neurotoxicity was cumulative and prevented patients from receiving prolonged administration of CT-2103. CONCLUSIONS: The unexpectedly high rate of cumulative toxicity observed in our study needs to be taken into consideration in future trials of CT-2103. Prior taxane use may not be a predictor of severe neurotoxicity.
Dose-Response Relationship, Drug↗
Genetic linkage of prostate cancer risk to the chromosome 3 region bearing FHIT.
We conducted linkage analysis of 80 candidate genes in 201 brother pairs affected with prostatic adenocarcinoma. Markers representing two adjacent candidate genes on chromosome 3p, CDC25A and FHIT, showed suggestive evidence for linkage with single-point identity-by-descent allele-sharing statistics. Fine-structure multipoint linkage analysis yielded a maximum LOD score of 3.17 (P = 0.00007) at D3S1234 within FHIT intron 5. For a subgroup of 38 families in which three or more affected brothers were reported, the LOD score was 3.83 (P = 0.00001). Further analysis reported herein suggested a recessive mode of inheritance. Association testing of 16 single nucleotide polymorphisms (SNP) spanning a 381-kb interval surrounding D3S1234 in 202 cases of European descent with 143 matched, unrelated controls revealed significant evidence for association between case status and the A allele of single nucleotide polymorphism rs760317, located within intron 5 of FHIT (Pearson's chi(2) = 8.54, df = 1, P = 0.0035). Our results strongly suggest involvement of germline variations of FHIT in prostate cancer risk.
Acid Anhydride Hydrolases↗
NF-kappaB activation by the chemopreventive dithiolethione oltipraz is exerted through stimulation of MEKK3 signaling.
Chemoprevention by the dithiolethione analogue oltipraz (4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione) may occur through several mechanisms, among them stimulation of detoxication activity. The phase II detoxication enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1; EC 1.6.99.2) also known as quinone reductase (QR) is well established to undergo transcriptional activation following oltipraz treatment of colon cancer cells in culture. Promoter analysis of the QR gene in oltipraztreated cells reveals the involvement of both the AP-1 and NF-kappaB elements in the response. The emerging role of NF-kappaB in cell survival prompted a fuller analysis of effects of oltipraz on this pathway. Oltipraz treatment of both HCT116 and HT29 cells results in the induction of proteins involved in both pathways of NF-kappaB activation, including p65, IkappaB kinase alpha (IKKalpha), IkappaB kinase beta (IKKbeta), and NF-kappaB-inducing kinase (NIK). IkappaBalpha total protein levels were unchanged, but phosphorylation of the inhibitor was also induced in both lines. Electrophoretic mobility shift assay (EMSA) analysis confirmed induction of protein binding to a consensus NF-kappaB element, and transcriptional activation was further confirmed using a reporter construct. Transcriptional activation of QR was decreased in a dose-dependent manner by dominant-negative NF-kappaB in both cell lines. The molecular mechanism that triggers IKK activation in response to oltipraz was also examined using inhibitory constructs of NIK and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3 (MEKK3). We found that both MEKK3 and NIK exert effects on IKKalpha/beta activation, but through different pathways. Furthermore, the receptor-interacting protein (RIP) was found to interact strongly with MEKK3 during oltipraz-induced NF-kappaB signaling, implying a role for tumor necrosis factor receptor signaling in the action of oltipraz. These results implicate a novel signaling pathway for the action of oltipraz in QR gene regulation.
Anticarcinogenic Agents↗
Phase I and pharmacokinetic study of the cytotoxic ether lipid ilmofosine administered by weekly two-hour infusion in patients with advanced solid tumors.
PURPOSE: A Phase I trial was performed to determine the dose-limiting toxicity and maximum tolerated dose, and to describe the pharmacokinetics of the alkyl-lysophospholipid, ilmofosine, when administered as a weekly 2-h infusion in patients with solid tumors. EXPERIMENTAL DESIGN: Thirty-nine patients were entered into a trial of ilmofosine administered weekly for 4 weeks followed by a 2-week rest period. Dose escalation occurred in 10 levels from 12 to 650 mg/m(2). RESULTS: Thirty-six patients were evaluable for toxicity. The median number of cycles per patient was 1 (range, 1-4). Dose-limiting gastrointestinal toxicity occurred at 650 mg/m(2) with grade 3 nausea in two patients and grade 3 vomiting and diarrhea in one patient. Grade 2 diarrhea was observed in four of six patients treated at 550 mg/m(2). In addition, two patients treated at 550 mg/m(2) and two patients treated at 650 mg/m(2) experienced a decline in performance status of two or more levels that was determined to be due to treatment. There were no tumor responses. Stabilization of disease for at least 8 weeks occurred in six patients. Plasma concentrations of ilmofosine and its sulfoxide metabolite were evaluated by high-pressure liquid chromatography. The elimination of both compounds was biexponential with terminal half-lives of approximately 40 h for ilmofosine and 48 h for the sulfoxide. The area under the concentration-time curve was dose-proportional for each compound, and there was no evidence of saturable kinetics. CONCLUSIONS: The dose-limiting toxicity of ilmofosine is gastrointestinal and the recommended dose for Phase II trials is 450 mg/m(2) as a 2-h weekly infusion. The relatively long half-life of ilmofosine and its active metabolite support the use of this intermittent schedule.
Adult↗
Phase I trial of the antifolate ZD9331 in combination with cisplatin in patients with refractory solid malignancies.
PURPOSE: To determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of ZD9331 in combination with cisplatin in patients with refractory solid tumors and to describe any preliminary antitumor activity associated with this regimen. MATERIALS AND METHODS: Patients received combination therapy with ZD9331 as a 30-min infusion on days 1 and 8 of a 21-day cycle at doses of 100 or 130 mg/m(2), followed by cisplatin at 50 or 75 mg/m(2) as a 30- to 60-min infusion on day 1 only. RESULTS: A total of 16 patients received 59 cycles of ZD9331 and cisplatin. Patients were enrolled at three dose levels: ZD9331/cisplatin 100/50 ( n=3), 130/50 ( n=9), 130/75 ( n=4). DLTs at 130/75 included thrombocytopenia, neutropenia, fatigue, nausea, vomiting and stomatitis. Among 15 evaluable patients, 2 showed a partial response (patients with mesothelioma and head and neck cancer) and 6 showed stable disease (for a median of 5.5 cycles). CONCLUSIONS: ZD9331 in combination with cisplatin was well tolerated at a dose of 130/50 mg/m(2) after establishing the principal DLTs of neutropenia and thrombocytopenia. The combination shows evidence of antitumor activity in a pretreated population.
Adult↗
A phase I, dose escalation trial of ZD0473, a novel platinum analogue, in combination with gemcitabine.
PURPOSE: To develop a combination regimen for clinical testing, we performed a dose escalation study of ZD0473 in combination with gemcitabine. ZD0473 is a novel platinum analogue with an aliphatic cyclic carrier ligand. In vitro and in vivo studies suggest that it possesses a different spectrum of antitumor activity from cisplatin and carboplatin. In single-agent studies of ZD0473, myelosuppression was the predominant toxicity and responses wer observed. METHODS: In this combination phase I trial, 36 patients with advanced cancer were accrued to four dose levels, with doses of ZD0473 and gemcitabine ranging from 60 to 120 mg/m2 and 600 to 750 mg/m2, respectively ZD0473 was administered on day 1 and gemcitabine was given on days 1 and 8 of a 21-day cycle. RESULTS: Hematologic toxicity was dose-limiting. Grade 3 and 4 thrombocytopenia and neutropenia occurred during 60% and 41% of all cycles. Nonhematologic toxicities were mild and reversible. Two partial responses and 19 patients with stable disease were observed. CONCLUSIONS: The recommended phase II doses are 90 mg/m2 of ZD0473 and 750 mg/m2 of gemcitabine for lightly pretreated patients and 600 mg/m2 for heavily pretreated patients. The combination of ZD0473 and gemcitabine is associated with dose-dependent thrombocytopenia and neutropenia as well as having promising clinical activity.
Adolescent↗
Monoclonal antibodies in the treatment of colorectal cancer.
Monoclonal antibodies have been developed to target specific proteins involved in the development and progression of cancer. These reagents have the advantage of exquiste specificity, and as currently engineered, low toxicity. The impact monoclonal antibody therapy has recently been demonstrated in colorectal cancer, in which two pathways critical to carcinogenesis have been targeted. The targets are the epidermal growth factor receptor signaling pathway and angiogenesis. Antibodies directed to proteins in both pathways have shown significant activity especially in combination with chemotherapy, and studies in the adjuvant setting are in progress. We review the use of monoclonal antibodies in the treatment of colorectal cancer with particular attention to edrecolomab (Mab 17-1A), bevacizumab (Avastin), cetuximab (IMC-C225), ABX-EGF and EMD 72000. Additional compounds are in earlier stages of development, and the future of this approach in solid tumours is promising.
Antibodies, Monoclonal↗
Quantitative effects on c-Jun N-terminal protein kinase signaling determine synergistic interaction of cisplatin and 17-allylamino-17-demethoxygeldanamycin in colon cancer cell lines.
We investigated the effects of cisplatin and the hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in combination in a panel of human colon adenocarcinoma cell lines that differ in their p53 and mismatch repair status. Analysis of cytotoxicity after combined treatment revealed additive effects of cisplatin and 17-AAG in the HCT 116, DLD1, and SW480 cell lines and antagonism in HT-29 cells. Clonogenic assays demonstrated antagonism in HT-29, an additive effect in SW480, and synergism in HCT 116 and DLD1 cell lines. Analysis of signaling pathways revealed that cisplatin-induced activation of c-Jun N-terminal kinase (JNK) was fully blocked by 17-AAG in HT-29 and SW480 cells, whereas in HCT 116 and DLD1 cells it was inhibited only partially. The activation of caspases was also more pronounced in DLD1 and HCT 116 cell lines. These data suggested that a minimal level of apoptotic signaling through JNK was required for synergism with this combination. To test this hypothesis, we used the specific JNK inhibitor SP600125; when JNK was inhibited pharmacologically in HCT 116 and DLD1 cells, they demonstrated increased survival in clonogenic assays. Alternatively, sustained activation of JNK pathway led to an increase of the cytotoxicity of the cisplatin/17-AAG combination in HT-29 cells. Taken together, these data suggest that the synergistic interaction of this combination in colon cancer cell lines depends on the effect exerted by 17-AAG on cisplatin-induced signaling through JNK and associated pathways leading to cell death. An implication of that finding is that quantitative effects of signaling inhibitors may be critical for their ability to reverse cisplatin resistance.
Antineoplastic Agents↗
Additive interaction of oxaliplatin and 17-allylamino-17-demethoxygeldanamycin in colon cancer cell lines results from inhibition of nuclear factor kappaB signaling.
Elucidation of the mechanism by which oxaliplatin induces cell death is essential to enhancing its action. We investigated the effects of oxaliplatin and 17-allylamino-17-demethoxygeldanamycin (17-AAG) in a panel of four colon adenocarcinoma cell lines. Cytotoxicity assays demonstrated at least additivity in three of the cell lines. Activation of the c-Jun NH(2)-terminal kinase pathway by oxaliplatin does not determine cytotoxicity. Activation of p38 was shown to be a key proapoptotic mediator of oxaliplatin-induced cell death. Modulation of extracellular signal-regulated kinase and AKT signaling had no impact on oxaliplatin toxicity in these cells. Nuclear factor (NF)-kappaB was constitutively active in all of the cell lines and was inhibited by 17-AAG. Down-regulation of NF-kappaB transactivation by pharmacological inhibitors enhanced oxaliplatin cytotoxicity. These data support an interaction between 17-AAG and components of the NF-kappaB pathway in the modulation of oxaliplatin sensitivity in colon cancer cells.
Adenocarcinoma↗
Phase I trial of the antivascular agent combretastatin A4 phosphate on a 5-day schedule to patients with cancer: magnetic resonance imaging evidence for altered tumor blood flow.
PURPOSE: Combretastatin A4 (CA4) phosphate (CA4P) inhibits microtubule polymerization and is toxic to proliferating endothelial cells in vitro. It causes reversible vascular shutdown in established tumors in vivo, consistent with an antivascular mechanism of action. The present study investigated escalating doses of CA4P administered intravenously to patients with advanced cancer. PATIENTS AND METHODS: Patients with solid malignancies and good performance status received CA4P as a 10-minute infusion daily for 5 days repeated every 3 weeks. Pharmacokinetic sampling was performed during cycle 1. Patients receiving >/= 52 mg/m2/d had serial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies to measure changes in tumor perfusion with CA4P treatment. RESULTS: Thirty-seven patients received 133 treatment cycles. CA4P dose levels ranged from 6 mg/m2 to 75 mg/m2 daily. Severe pain at sites of known tumor was dose limiting at 75 mg/m2. Dose-limiting cardiopulmonary toxicity (syncope and dyspnea or hypoxia) was noted as well in two patients treated at 75 mg/m2. Other toxicities included hypotension, ataxia, dyspnea, nausea or vomiting, headache, and transient sensory neuropathy. Plasma CA4P and CA4 area under the concentration-time curve and maximal concentration values increased linearly with dose. Tumor perfusion, as measured by the first-order rate constant of gadolinium plasma to tissue transfer during DCE-MRI studies, was found to decrease in eight of 10 patients. Relationships were also demonstrated between perfusion changes and pharmacokinetic indices. A partial response was observed in a patient with metastatic soft tissue sarcoma, and 14 patients exhibited disease stability for a minimum of two cycles. CONCLUSION: Doses of CA4P on a daily times five schedule of 52 to 65 mg/m2 were reasonably well-tolerated. The 52 mg/m2 dose is recommended for further study based on cumulative phase I experience with CA4P. Antitumor efficacy was observed, and the use of DCE-MRI provided a valuable noninvasive measure of the vascular effects of CA4P treatment.
Adult↗
Phase I and pharmacokinetic trial of the novel taxane BMS-184476 administered as a 1-hour intravenous infusion in combination with cisplatin every 21 days.
BMS-184476 is a 7-methylthiomethyl ether derivative of paclitaxel that displays potency superior to paclitaxel against tumor cells in culture and human tumor xenografts. It also inhibits the growth of paclitaxel-resistant human tumor cell lines with multidrug resistance mediated by either P-glycoprotein or mutated tubulin. Given the known synergy between taxanes and cisplatin in vitro and their clinical activity in combination, we performed a Phase I trial of BMS-184476 as a 1-h i.v. infusion followed by cisplatin every 21 days. Twenty-seven patients with a variety of solid tumors and good performance status received 116 cycles of therapy at BMS-184476 doses of 40-60 mg/m(2) together with cisplatin at 75 mg/m(2). The early observation of hypersensitivity reactions required prophylactic premedication in all patients. At the planned highest dose of BMS-184476 (60 mg/m(2)) and cisplatin (75 mg/m(2)), we observed dose-limiting toxicity in the form of neutropenia and diarrhea. Also at this level, five patients experienced grade 3 or worse nausea and vomiting. Aggressive prophylactic treatment eliminated the gastrointestinal toxicity. Mild to moderate peripheral neuropathy was infrequent, as was alopecia. Patient benefits included three partial responses in patients with mesothelioma, esophageal cancer, and head and neck cancer, and two additional minor responses. Plasma pharmacokinetic data are available for 23 patients treated at 40-60 mg/m(2). The mean maximum plasma concentrations and areas under the curves increased in a dose-related manner. The pharmacokinetics of BMS-184476 appeared independent of dose. The mean (+/- SE) values for clearance, volume of distribution at steady state, and the apparent terminal half-lives of the three dose groups during cycle 1 were 243 +/- 5 ml/min/m(2), 423 +/- 58 l/m(2), and 32.2 +/- 4.5 h, respectively. BMS-184476 60 at mg/m(2) with cisplatin at 75 mg/m(2) with appropriate supportive therapy is the dose recommended for further evaluation.
Adult↗