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Mark J Ratain

Publications and source records attributed to Mark J Ratain.

At least 73 records · Page 4Linked to original sources
PubMed2003

Phase 1 dose escalation study of docetaxel with filgrastim support in patients with advanced solid tumors.

Docetaxel has demonstrated activity in a broad range of solid tumors. Phase I trials have shown 100 mg/m(2) every 21 d to be the recommended dose. This phase I trial was designed to define the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of docetaxel with granulocyte colony-stimulating factor (G-CSF) support in patients with advanced solid tumors. Eligible patients had advanced malignancies and up to two prior chemotherapy regimens, ECOG PS = 0 1, adequate organ function, and gave written, informed consent. Docetaxel was escalated in cohorts of patients starting at 100 mg/m(2) on a 21-d schedule. Prophylactic G-CSF was administered on d 3 10. The DLT was defined as grade IV neutropenia >4 d, febrile neutropenia, grade IV thrombocytopenia, any grade III nonhematologic toxicity, or the inability to receive cycle 2 because of ongoing toxicity. Twenty-three patients were enrolled at doses up to 145 mg/m(2). The median age was 59 yr and the median number of prior chemotherapy regimens was 1. No DLT was observed at 100 mg/m(2), and 2 of 11 patients at 120 mg/m(2) experienced DLT (neutropenic fever and stomatitis). At 145 mg/m(2), one of eight patients had DLT (fatigue). Two of eight patients at 145 mg/m(2) had brief grade IV neutropenia (without fever), and none had grade III-IV thrombocytopenia or anemia. The docetaxel dose can be safely escalated to 145 mg/m(2) every 21 d with GCSF support, a 45% increase above the standard recommended phase II dose. Further studies will clarify the role of dose-intensified docetaxel.

Adult↗
PubMed2003

Interethnic difference in the allelic distribution of human epidermal growth factor receptor intron 1 polymorphism.

PURPOSE: Epidermal growth factor receptor (EGFR) plays a critical role in signal transduction and is a target for a novel class of anticancer agents that aim to inhibit EGFR-mediated cancer cell growth. Previous studies have demonstrated a dinucleotide (CA)(n) repeat polymorphism in intron 1 of EGFR, ranging from 14 to 21 repeats, that has been suggested to regulate EGFR expression. The longer allele with 21 repeats showed an 80% reduction of gene expression compared with the shorter allele with 16 repeats. Therefore, the evaluation of the allelic distribution of this polymorphism in populations of various ethnic origins will be crucial to understand the interindividual variability in EGFR expression. EXPERIMENTAL DESIGN: We evaluated the influence of ethnicity on this polymorphism by genotyping individuals of Caucasian (n = 183), African-American (n = 84), and Asian (n = 66) background. RESULTS: The frequency of one of the longer alleles, allele 20 is significantly higher in Asian individuals (63% compared with 21% in Caucasians, P = 2 x 10(-18)). In confirmation of prior studies, the shorter allele 16 was the most common allele in Caucasians (43%) and African-Americans (42%), but its frequency was significantly lower in Asians (average 17%, P = 10(-7) compared with Caucasians). CONCLUSION: Major interethnic differences in the allelic frequencies of the EGFR intron 1 polymorphism exist. Our results may contribute to a better understanding of the molecular basis underlying ethnic differences in drug response and may be helpful for future strategies of individualized therapy with EGFR inhibitors.

Alleles↗
PubMed2003

Irinotecan treatment in cancer patients with UGT1A1 polymorphisms.

At the present time, pharmacogenetic investigation of irinotecan (CPT-11, Camptosar) therapy is mainly focused on the clinical relevance of genetic variation in the UDP-glucuronosyltransferase (UGT1A1) gene. The glucuronidation of the potent topoisomerase I inhibitor SN-38 is a major inactivation pathway of irinotecan metabolism. UGT1A1 genotypes associated with Gilbert's syndrome (a mild intermittent hyperbilirubinemia) are characterized by reduced glucuronidation of SN-38. Such UGT1A1 genetic variants have different distribution across individuals of different ethnicity. The (TA)n TAA polymorphism in the promoter is more frequent in Caucasians as compared to Asians, in whom missense polymorphisms in the exons are more common. Two recent pharmacogenetic trials (one performed in the United States and the other in Japan) investigated the clinical significance of UGT1A1 gene mutations for both the pharmacokinetics of irinotecan metabolites and the toxicity profile. The results of these association studies showed that preliminary genotyping of the (TA)n polymorphism might predict the occurrence of toxicity in genetically predisposed patients.

Animals↗
PubMed2002

Randomized discontinuation design: application to cytostatic antineoplastic agents.

PURPOSE: Propose a phase II study design to evaluate the activity of a putative cytostatic agent, acknowledging heterogeneity of tumor growth rates in the population of patients. METHODS: In the setting of renal cell carcinoma, some patients' tumors will grow slowly naturally. An appropriate design has to distinguish antiproliferative activity attributable to the novel agent from indolent disease. We propose a randomized discontinuation design that initially treats all patients with the study agent (stage 1) and then randomizes in a double-blind fashion to continuing therapy or placebo only those patients whose disease is stable (stage 2). This design allows the investigators to determine if apparent slow tumor growth is attributable to the drug or to selection of patients with naturally slow-growing tumors. RESULTS: By selecting a more homogeneous population, the randomized portion of the study requires fewer patients than would a study randomizing all patients at entry. The design also avoids potential confounding because of heterogeneous tumor growth. Because the two randomly assigned treatment groups each comprise patients with apparently slow growing tumors, any difference between the groups in disease progression after randomization is more likely a result of the study drug and less likely a result of imbalance with respect to tumor growth rates. Stopping rules during the initial open-label stage and the subsequent randomized trial stage allow one to reduce the overall sample size. Expected average tumor growth rate is an important consideration when deciding the duration of follow-up for the two stages. CONCLUSION: The randomized discontinuation design is a feasible alternative phase II study design for determining activity of possibly cytostatic anticancer agents.

Antineoplastic Agents↗
PubMed2002

Randomized study of three different doses of suramin administered with a fixed dosing schedule in patients with advanced prostate cancer: results of intergroup 0159, cancer and leukemia group B 9480.

PURPOSE: To test the hypothesis that the efficacy and toxicity of suramin in the treatment of patients with hormone-refractory prostate cancer was dose dependent. PATIENTS AND METHODS: Patients were randomized with equal probability to receive low-, intermediate-, or high-dose suramin (total doses 3.192, 5.320, and 7.661 g/m(2), respectively). Overall survival, time to progression, and response rate (prostate-specific antigen [PSA] and objective) for each treatment arm were compared. Relationships between plasma suramin concentrations and response, toxicity, and survival were also evaluated. RESULTS: Three hundred ninety patients were randomized. For the low-, intermediate-, and high-dose arms, the median survival time was 16, 14, and 13 months, respectively (P =.49). The objective response rate was 9%, 7%, and 15%, respectively (P =.10). PSA response rates were 24%, 28%, and 34%, respectively (P =.082). Landmark analyses of a 50% decline in PSA at 20 weeks showed a significant correlation with survival. There was a dose-response relationship between dose and toxicity. After adjusting for treatment arm, the measured suramin concentration was not associated with clinical response, PSA response, survival, or toxicity. CONCLUSION: Although high-dose suramin was associated with higher objective and PSA response rates, these were not statistically significant. Overall, no dose-response relationship was observed for survival or progression-free survival, but toxicity was increased with the higher dose. Patients treated with the low-dose level experienced modest toxicity, making it the preferred arm on this study. The lack of a dose-response relationship and the toxicity profile observed raise questions regarding the utility of suramin, particularly high-dose suramin, as administered on this schedule.

Aged↗
PubMed2002

Pentostatin pharmacokinetics and dosing recommendations in patients with mild renal impairment.

PURPOSE: The purpose of this study was to determine the pharmacokinetic parameters of pentostatin in renally impaired patients in order to establish dosing guidelines for this population. METHODS: Pentostatin doses were administered as 15-min intravenous infusions to patients based on their measured creatinine clearance (CLcr) as follows. Patients with normal renal function (NRF), defined as CLcr >60 ml/min, received 4 mg/m(2) repeated every14 days. Patients with impaired renal function (IRF) included those with CLcr 41-60 ml/min who received 3 mg/m(2) and those with CLcr 21-40 ml/min who received 2 mg/m(2), also repeated every 14 days. Heparinized plasma samples were collected during drug infusion and out through 96 h after dosing, except in two patients in whom sampling was extended to 144 h after dosing. Urine sampling extended to 96 h after dosing, and all samples were analyzed by a validated enzyme immunoassay for pentostatin concentrations. RESULTS: Enrolled in the study were 13 patients (7 IRF and 6 NRF), of whom 12 contributed samples for pharmacokinetic analysis. Median baseline CLcr values were 71.5 ml/min for NRF patients and 44 ml/min for IRF patients. Following the end of intravenous infusion, pentostatin plasma concentrations declined biexponentially with time. In some patients there was a transient increase in pentostatin equivalents 2 to 4 h after dosing. There was a good correlation between measured CLcr and pentostatin total plasma clearance. The AUC(0- infinity ) values seen in IRF patients, at lower doses, were within the range of the AUC(0- infinity ) values seen in patients with normal CLcr. Toxicities observed in the two groups of patients were similar. CONCLUSIONS: The pentostatin doses used in the study appear to be appropriate for administration to cancer patients with varying degrees of renal impairment.

Aged↗
PubMed2002

A phase I study of suramin with once- or twice-monthly dosing in patients with advanced cancer.

PURPOSE: The optimal schedule of administration of suramin has not been well defined. The purpose of this study was to determine the maximum tolerated dose and toxicities of suramin when administered using a fixed dosing scheme on a once- or twice-monthly schedule. METHODS: A total of 40 patients were treated on this phase I dose-escalation study employing a once-monthly (day 1 of each 28-day cycle) and a twice-monthly (days 1 and 8 of each 28-day cycle) schedule. RESULTS: The most common dose-limiting events included fatigue, neuropathy, and anorexia. We identified the 1440 mg/m(2) dose level to be the maximal tolerated dose for both schedules, with 83% of patients developing dose-limiting toxicity (DLT) on the twice-monthly schedule, and 67% developing DLT on the monthly schedule. At the 1200 mg/m(2) dose level, only 25% developed DLT on the twice-monthly schedule and 33% developed DLT on the monthly schedule. Trough suramin levels gradually increased with higher dose levels but fell well below the putative toxic concentration of 350 microg/ml. CONCLUSION: Suramin can be safely administered using a monthly schedule without using plasma concentrations to guide dosing.

Adult↗
PubMed2002

Estimation of the effect of food on the disposition of oral 5-fluorouracil in combination with eniluracil.

AIMS: To determine the effect of food on the pharmacokinetics of 5-fluoruracil (5-FU) taken orally with eniluracil and to compare the performance of different pharmacokinetic analysis methods in the detection a potential food-drug interaction. METHODS: In a randomized, open-label, two-way crossover study, 12 patients received eniluracil (50 mg, orally) on days 1 and 2 and 5-FU (20 mg/m(2), orally) on day 2 following either a 2-h fast or 20 min after a standard meal. Treatments were separated by 7 days. Timed blood samples were collected during the first two treatment periods and 5-FU concentrations determined by GC/MS. Data were analyzed and pharmacokinetic parameter estimates were obtained using a noncompartmental, two-stage and population analysis methods. RESULTS: In fasted individuals, the clearance/bioavailability of 5-FU was estimated to be 5.6 l/h. The mean absorption lag-time was 0.24 h and was followed by rapid absorption of 5-FU. Administration of 5-FU and eniluracil with food resulted in a decrease in the 5-FU absorption rate constant by 90%. As a result, the peak plasma concentration (C(max)) of 5-FU was decreased by 21% and the time to C(max) was increased 2.9-fold. Clearance of 5-FU, relative bioavailability, and area under the plasma concentration vs time curve (AUC) remained unchanged with coadministration of food. Similar results were obtained using all three data analysis methods. CONCLUSIONS: Administration of food with oral 5-FU and eniluracil slowed absorption of 5-FU and decreased 5-FU C(max), but did not effect AUC. Further investigation of the incorporation of population pharmacokinetic approaches in food effect studies is warranted.

Aged↗
PubMed2002

Biliary transport of irinotecan and metabolites in normal and P-glycoprotein-deficient mice.

PURPOSE: The extensive and unpredictable biliary excretion of CPT-11 and its metabolites, SN-38 and SN-38 glucuronide (SN-38G) may contribute to the wide interpatient variability reported in the disposition and gastrointestinal toxicity of CPT-11. We studied the role of P-glycoprotein (P-gp) in in vivo biliary excretion of CPT-11, SN-38 and SN-38G in mice lacking mdr1-type P-gp [ mdr1a/1b(-/-)] in the presence of the multidrug resistance (MDR) reversal agent, PSC833. METHODS: Wild-type (Wt) and mdr1a/1b(-/-) mice ( n=3 or 4) were treated intragastrically with PSC833 (50 mg/kg) or vehicle 2 h prior to i.v. CPT-11 dosing (10 mg/kg), and bile samples were collected. RESULTS AND CONCLUSIONS: P-gp was found to play an important role in CPT-11 biliary excretion, as there was a significant (40%, P<0.05) decrease in its biliary recovery in 90 min in mdr1a/1b(-/-) mice (6.6+/-0.6% dose) compared with Wt mice (11+/-1.2%). This also implied a major role of other undetermined non-P-gp-mediated mechanism(s) for hepatic transport of CPT-11, which was inhibited by PSC833 (1.8+/-0.8% with PSC833, 6.6+/-0.6% without PSC833) in mdr1a/1b(-/-) mice. SN-38 and SN-38G biliary transport was unchanged in mice lacking P-gp after vehicle treatment, indicating a lack of P-gp mediation in their transport. PSC833 significantly reduced (56-89%) SN-38 and SN-38G biliary transport in Wt and mdr1a/1b(-/-) mice, suggesting that PSC833 may be a candidate to modulate biliary excretion of SN-38 with potential use in reducing CPT-11 toxicity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Dose-escalating study of capecitabine plus gemcitabine combination therapy in patients with advanced cancer.

PURPOSE: The goals of this phase I study were to determine the maximum-tolerated doses of capecitabine and gemcitabine in patients with advanced cancer and to describe the dose-limiting toxicities (DLT) and safety profile of this combination. PATIENTS AND METHODS: Eligible patients had advanced solid tumors that had failed to respond to standard therapy or for which no standard therapy was available, measurable or assessable disease, Karnofsky performance status > or = 70%, and acceptable organ function. Capecitabine was administered twice daily by mouth each day for 21 consecutive days followed by a 1-week break. Gemcitabine was administered as a 30-minute intravenous infusion weekly for 3 weeks followed by a 1-week break. RESULTS: Forty patients were enrolled onto the study, and 33 are fully assessable for toxicity. The most common toxicities during the first cycle of chemotherapy were neutropenia and mucositis. Only one patient treated at gemcitabine and capecitabine doses of 800 and 2000 mg/m(2), respectively, met protocol-specified DLT criteria; however, at these doses 65% of successive cycles required dose reduction or delay for toxicity. No episodes of DLT were observed at gemcitabine and capecitabine doses of 1,000 and 1,660 mg/m(2), respectively, and 70% of cycles of therapy were delivered without dose reduction or delay. Therefore, these doses are recommended for further study. Tumor responses were observed in patients with metastatic colorectal and pancreatic cancer. CONCLUSION: Gemcitabine and capecitabine can be combined with acceptable toxicity at nearly full doses. Antitumor activity of the combination merits further investigation in phase II studies.

Administration, Oral↗
PubMed2002

In vitro characterization of hepatic flavopiridol metabolism using human liver microsomes and recombinant UGT enzymes.

PURPOSE: To assess the contribution of drug metabolism to the variability on flavopiridol glucuronidation observed in cancer patients, and to determine the ability of all known human UDP-glucuronosyltransferase (UGT) isoforms to glucuronidate flavopiridol. METHODS: Inter-individual variation in flavopiridol glucuronidation was determined by HPLC using hepatic microsomes from 62 normal liver donors. Identification of enzymes capable of glucuronidating flavopiridol was determined by LC/MS using human embryonic kidney 293 (HEK293) cells stably expressing all sixteen known human UGTs. RESULTS: The major product of the flavopiridol glucuronidation reaction in human liver microsomes was FLAVO-7-G. High variability (coefficient of variation = 49%) was observed in the glucuronidation of flavopiridol by human liver microsomes. In vitro formation of FLAVO-7-G and FLAVO-5-G was mainly catalyzed by UGT1A9 and UGT1A4, respectively. Similar catalytic efficiencies (Vmax/Km) were observed for human liver microsomes (1.6 microl/min/mg) and UGT1A9 (1.5 microl/min/mg). CONCLUSIONS: UGT1A9 is the major UGT involved in the hepatic glucuronidation of flavopiridol in humans. The data suggests that hepatic glucuronidation may be a major determinant of the variable systemic glucuronidation of flavopiridol in cancer patients. The large variability in flavopiridol glucuronidation may be due to differences in liver metabolism among individuals, as a result of genetic differences in UGT1A9.

Antineoplastic Agents↗
PubMed2002

Population pharmacokinetic model for irinotecan and two of its metabolites, SN-38 and SN-38 glucuronide.

OBJECTIVE: The objective of the study was to develop and validate a population pharmacokinetic model for irinotecan and 2 of its metabolites, SN-38 and SN-38 glucuronide (SN-38G). METHODS: Plasma concentrations were obtained during and up to 48 hours after a 90-minute continuous intravenous infusion of irinotecan (100-340 mg/m(2)) in 78 patients. Data splitting was used to create model-building and model-validation data sets. Pharmacokinetic parameter estimates were obtained by compartmental methods to describe the disposition of metabolites that are dependent on the disposition of the parent compound. Relationships between patient attributes and estimates of clearance (CL) and volume of the central compartment for irinotecan, as well as CL and volume of the central compartment adjusted for the fraction metabolized for SN-38 and SN-38G, were explored by use of generalized additive models and graphic analysis. Selected covariates were introduced into the final population model by stepwise additions or deletions with the likelihood ratio test. RESULTS: SN-38 and SN-38G were shown to be formation rate-limited and were characterized by first-order rate constants of formation and elimination. Two subpopulations of SN-38 disposition were identified, presumably because of differences in the fraction of metabolite formed from the parent compound. Estimated irinotecan CL (25.2 L/h) was similar to that determined in other studies. Age and performance status were found to be important predictors of irinotecan CL, whereas variability in systemic exposure to the active metabolite, SN-38, was predicted by sex and hepatic function. CONCLUSION: The validated population pharmacokinetic model describing the disposition of irinotecan and 2 of its metabolites should facilitate the design of future studies to elucidate the relative contributions of the parent compound and SN-38 to the pharmacologic and toxic effects of irinotecan therapy.

Adult↗
PubMed2002

Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups.

Genetic variation in UDP-glucuronosyltransferase 1A1 (UGT1A1)expression has several important clinical implications. UGT1A1 basal transcription is affected by a polymorphic (TA)n repeat, and another important regulatory element is the phenobarbital-responsive enhancer module (PBREM) which might contain variants affecting inducible gene expression. We assessed the extent of linkage disequilibrium between the (TA)n polymorphism and variants in the PBREM and UGT1A1 promoter. We also investigated the relationship between PBREM-(TA)n haplotypes and the glucuronidation rate of the UGT1A1 substrate SN-38. DNAs from 83 human livers were genotyped for the (TA)n polymorphism and microsomes from the same livers were phenotyped for SN-38 glucuronidation. The (TA)n polymorphism was genotyped in 24 additional African-Americans included in the Human Variation Panel (Coriell Institute). A 606-bp region spanning the PBREM was sequenced in 81 liver and a subset of 22 Human Variation Panel DNAs and six variants were found. The -3279G T and -3156G A variants are common (0.39 and 0.30, respectively). -3279G T is more common in Caucasians than African-Americans (P = 0.001). In Caucasians, linkage disequilibrium was highly significant between sites -3279, -3156, and the (TA)n polymorphism (P < 0.0001). In contrast, in African-Americans, only marginal levels of significance were observed between (TA)n and -3279 (P = 0.02) and between -3279 and -3156 (P = 0.04). Ten promoter haplotypes were identified. Haplotype I is the most common (0.39), from which haplotype II (0.15) differs at position -3279. SN-38G formation rates were correlated with (TA)n genotypes. This study showed that (i) common promoter variants are in linkage disequilibrium and (ii) the haplotype structure of promoter is probably different between Caucasians and African-Americans.

Black or African American↗
PubMed2002

Phase I clinical and pharmacokinetic study of protein kinase C-alpha antisense oligonucleotide ISIS 3521 administered in combination with 5-fluorouracil and leucovorin in patients with advanced cancer.

The present study was designed to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PKs), and antitumor activity of the protein kinase C-alpha antisense oligonucleotide ISIS 3521 (ISIS Pharmaceuticals, Inc., Carlsbad, CA) when administered in combination with 5-fluorouracil (5-FU) and leucovorin (LV). Patients with refractory solid tumors received ISIS 3521 as a 21-day continuous infusion administered simultaneously with 5-FU and LV given daily for 5 days repeated every 4-5 weeks (one cycle). 5-FU and ISIS 3521 PK analysis were performed on samples taken during the first cycle in all patients. Fifteen patients received ISIS 3521 at one of three dose levels: (a) 1.0 (n = 3 patients); (b) 1.5 (n = 3 patients); and (c) 2.0 (n = 9 patients) mg/kg/day. All patients simultaneously received 5-FU (425 mg/m(2)/day) and LV (20 mg/m(2)/day) for 5 consecutive days. Grade 1-2 toxicities included alopecia, fatigue, mucositis, diarrhea, anorexia, nausea/vomiting, and tumor pain. One patient had grade 3 chest pain considered to be related to 5-FU therapy, another patient had dose-limiting grade 3 mucositis resolving in <7 days, and one patient with a history of gastritis had an acute upper gastrointestinal bleed thought to be 5-FU-induced toxicity. Five patients developed cycle 1 grade 4 neutropenia, which resolved without colony-stimulating factors before the next treatment cycle. There were no effects on prothrombin time and activated partial thromboplastin time. A clinically defined MTD was not reached. The character and severity of these toxicities do not seem to be dose related, and, as such, there was no classical dose-limiting toxicity defining the MTD. ISIS 3521 PKs in the presence of 5-FU was consistent with those reported previously. 5-FU PK parameters were also similar in the presence or absence of ISIS 3521. Six of 14 patients ( approximately 43%) across all dose cohorts had an improvement in measurable tumor response ranging from minor reduction in tumor size (4 patients) to objective partial response (>50% reduction in tumor size, 2 patients). ISIS 3521 is tolerable at its recommended single-agent dose when given with 5-FU and LV. There is no apparent PK interaction between ISIS 3521 and 5-FU and LV. Antitumor activity was observed with the combination; however, it is uncertain whether clinical activity is a result of enhanced drug interaction. Our study warrants further exploration of efficacy in a Phase II and/or Phase III clinical trial setting.

Adult↗