15 results on '"Hudes G"'
Search Results
2. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma.
- Author
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Rini BI, Wilding G, Hudes G, Stadler WM, Kim S, Tarazi J, Rosbrook B, Trask PC, Wood L, and Dutcher JP
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- 2009
- Full Text
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3. Nomograms to predict serious adverse events in phase II clinical trials of molecularly targeted agents.
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Pond GR, Siu LL, Moore M, Oza A, Hirte HW, Winquist E, Goss G, Hudes G, and Townsley CA
- Published
- 2008
4. Drug-related pneumonitis in patients with advanced renal cell carcinoma treated with temsirolimus.
- Author
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Maroto JP, Hudes G, Dutcher JP, Logan TF, White CS, Krygowski M, Cincotta M, Shapiro M, Duran I, and Berkenblit A
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- Carcinoma, Renal Cell complications, Carcinoma, Renal Cell mortality, Humans, Incidence, Interferon-alpha therapeutic use, Kidney Neoplasms complications, Kidney Neoplasms mortality, Pneumonia diagnostic imaging, Randomized Controlled Trials as Topic, Sirolimus adverse effects, TOR Serine-Threonine Kinases antagonists & inhibitors, Tomography, X-Ray Computed, Antineoplastic Agents adverse effects, Carcinoma, Renal Cell drug therapy, Kidney Neoplasms drug therapy, Pneumonia epidemiology, Sirolimus analogs & derivatives
- Abstract
Purpose: Pneumonitis has occurred in patients treated with inhibitors of the mammalian target of rapamycin (mTOR). In a phase III study of patients with previously untreated, poor-prognosis, advanced renal cell carcinoma (ARCC), the mTOR inhibitor temsirolimus improved survival compared with interferon. We performed a retrospective, independent, blinded radiographic review of chest computed tomography (CT) images of patients in this study to characterize temsirolimus-related pneumonitis., Patients and Methods: Patients were treated with intravenous temsirolimus 25 mg once weekly or subcutaneous interferon alfa 3 million units, with an increase to 18 million units, thrice weekly. Drug-related pneumonitis was identified based on sequential chest CT images, required every 8 weeks, showing changes consistent with pneumonitis and not pneumonia (infection) or disease progression as correlated with clinical data. Cumulative probability of drug-related pneumonitis was estimated using the Kaplan-Meier method., Results: Eight (6%) of 138 and 52 (29%) of 178 evaluable patients on interferon and temsirolimus treatment, respectively, developed radiographically identified drug-related pneumonitis. Time to onset of pneumonitis was significantly shorter on the temsirolimus arm than on the interferon arm (log-rank P < .001). Estimated cumulative probability of pneumonitis at 8 and 16 weeks from first dose was 21% and 31%, respectively, on the temsirolimus arm and 6% and 8%, respectively, on the interferon arm. Respiratory symptoms were observed around time of onset of radiographically diagnosed temsirolimus-related pneumonitis in 16 (31%) of 52 patients., Conclusion: Patients with ARCC receiving temsirolimus should be monitored closely for development of pneumonitis, and their management should be altered if clinical symptoms appear.
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- 2011
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5. Role of androgen deprivation therapy for node-positive prostate cancer.
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Wong YN, Freedland S, Egleston B, Hudes G, Schwartz JS, and Armstrong K
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- Aged, Aged, 80 and over, Humans, Lymphatic Metastasis, Male, Prostatic Neoplasms mortality, Prostatic Neoplasms pathology, SEER Program, Androgen Antagonists therapeutic use, Prostatic Neoplasms drug therapy
- Abstract
Purpose: To determine the impact of adjuvant androgen deprivation therapy (ADT) for patients who have node-positive prostate cancer in the prostate-specific antigen (PSA) era., Patients and Methods: We used linked Surveillance, Epidemiology and End Results-Medicare data to construct a cohort of men who underwent radical prostatectomy (RP) between 1991 and 1999 and who had positive regional lymph nodes. We classified men as receiving adjuvant ADT if they received ADT within 120 days of RP, and we compared them to the men who had not received adjuvant ADT. We used propensity scores to balance potential confounders of receiving adjuvant ADT (ie, tumor characteristics, extent of nodal disease, demographics, receipt of radiation therapy) and Cox proportional hazard methods to measure the impact of adjuvant ADT on overall survival (OS), stratified by propensity score quintile. We conducted a sensitivity analysis that used 90, 150, 180, and 365 days as the definition for adjuvant ADT., Results: A total of 731 men were identified, 209 of whom received ADT within 120 days of RP. There was no statistically significant difference in OS between the adjuvant ADT and non-ADT group (HR, 0.97; 95% CI, 0.71 to 1.27). There was no statistically significant survival difference with 90, 150, 180, and 365 days as the adjuvant ADT definition., Conclusion: Deferring immediate ADT in men with positive lymph nodes after RP may not significantly compromise survival. Because observational studies should be considered hypothesis-generating studies, these results should be validated in a prospective fashion in a similar patient population.
- Published
- 2009
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6. Boosting bioavailability of topotecan: what do we gain?
- Author
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Hudes G
- Subjects
- ATP Binding Cassette Transporter, Subfamily G, Member 2, Administration, Oral, Antineoplastic Agents administration & dosage, Biological Availability, Breast Neoplasms drug therapy, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Enzyme Inhibitors administration & dosage, Female, Humans, Intestinal Absorption drug effects, Neoplasm Proteins antagonists & inhibitors, Topotecan administration & dosage, ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, ATP-Binding Cassette Transporters antagonists & inhibitors, Acridines pharmacology, Antineoplastic Agents pharmacokinetics, Breast Neoplasms metabolism, Enzyme Inhibitors pharmacokinetics, Isoquinolines pharmacology, Tetrahydroisoquinolines, Topoisomerase I Inhibitors, Topotecan pharmacokinetics
- Published
- 2002
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7. Phase I clinical and pharmacologic trial of intravenous estramustine phosphate.
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Hudes G, Haas N, Yeslow G, Gillon T, Gunnarsson PO, Ellman M, Nordle O, Eriksson B, Miller L, Cisar L, Kopreski M, Viaro D, and Hartley-Asp B
- Subjects
- Aged, Aged, 80 and over, Antineoplastic Agents, Hormonal administration & dosage, Antineoplastic Agents, Hormonal pharmacokinetics, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Estramustine administration & dosage, Estramustine pharmacokinetics, Fatigue chemically induced, Humans, Hypotension chemically induced, Infusions, Intravenous, Liver drug effects, Liver pathology, Male, Middle Aged, Nausea chemically induced, Pain chemically induced, Prostatic Neoplasms pathology, Thrombosis chemically induced, Vomiting chemically induced, Antineoplastic Agents, Hormonal adverse effects, Estramustine adverse effects, Prostatic Neoplasms drug therapy
- Abstract
Purpose: To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of intravenous estramustine phosphate (IV EMP)., Patients and Methods: A total of 31 patients with hormone-refractory prostate cancer received IV EMP as a 30- to 90-minute infusion weekly (n = 28) or for 3 consecutive days followed by a single weekly dose (n = 3). IV EMP dose was escalated from 500 to 3,000 mg/m(2). Pharmacokinetics of EMP and the metabolites estramustine (EaM), estromustine (EoM), estradiol, and estrone were assessed after weeks 1 and 4 of treatment., Results: The initial IV EMP infusion caused perineal discomfort that was ameliorated by lengthening the infusion time. Other common toxicities were grade 1 to 2 hepatotoxicity, nausea or vomiting, and fatigue or malaise. Lower-extremity thrombosis occurred in one patient, and two others developed upper-extremity thrombosis associated with venous infusion catheters. Dose-limiting fatigue and hypotension occurred at 3,000 mg/m(2), and cumulative fatigue developed after multiple cycles at 2,500 mg/m(2). Mean EMP clearance, estimated steady-state volume of distribution, and elimination half-life were 3.7 L/h, 10.6 L, and 3.7 hours, respectively. Variability of EMP clearance was 21%, and variation in area under the curve per dose for the metabolites was 28% to 36%. Elimination half-lives of EoM and EaM were 110 hours and 64 hours, and peak plasma concentrations of these active metabolites exceeded 10 micromol/L after IV EMP doses greater-than-or-equal 2,000 mg/m(2)., Conclusion: High-dose IV EMP can be administered safely as a weekly short infusion to patients with HRPC. High peak concentrations of active metabolites after IV EMP may provide an advantage over oral EMP in antimicrotubule drug combinations.
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- 2002
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8. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group.
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Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, Figg WD, Freidlin B, Halabi S, Hudes G, Hussain M, Kaplan R, Myers C, Oh W, Petrylak DP, Reed E, Roth B, Sartor O, Scher H, Simons J, Sinibaldi V, Small EJ, Smith MR, Trump DL, and Wilding G
- Subjects
- Androgens metabolism, Guidelines as Topic, Humans, Male, Prostatic Neoplasms therapy, Reference Values, United States, Clinical Trials, Phase II as Topic standards, Consensus Development Conferences, NIH as Topic, Patient Selection, Prostate-Specific Antigen blood, Prostatic Neoplasms pathology
- Abstract
Purpose: Prostate-specific antigen (PSA) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells. For patients with metastatic disease, changes in PSA will often antedate changes in bone scan. Furthermore, many but not all investigators have observed an association between a decline in PSA levels of 50% or greater and survival. Since the majority of phase II clinical trials for patients with androgen-independent prostate cancer (AIPC) have used PSA as a marker, we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting. We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters., Result: We defined four patient groups: (1) progressive measurable disease, (2) progressive bone metastasis, (3) stable metastases and a rising PSA, and (4) rising PSA and no other evidence of metastatic disease. The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials. We propose that investigators report at a minimum a PSA decline of at least 50% and this must be confirmed by a second PSA value 4 or more weeks later. Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period. Some investigators may want to report additional measures of PSA changes (ie, 75% decline, 90% decline). Response duration and the time to PSA progression may also be important clinical end point., Conclusion: Through this consensus conference, we believe we have developed practical guidelines for using PSA as a measurement of outcome. Furthermore, the use of common standards is important as we determine which agents should progress to randomized trials which will use survival as an end point.
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- 1999
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9. Vinblastine versus vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: A Hoosier Oncology Group and Fox Chase Network phase III trial.
- Author
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Hudes G, Einhorn L, Ross E, Balsham A, Loehrer P, Ramsey H, Sprandio J, Entmacher M, Dugan W, Ansari R, Monaco F, Hanna M, and Roth B
- Subjects
- Administration, Oral, Adult, Aged, Aged, 80 and over, Disease Progression, Drug Administration Schedule, Humans, Injections, Intravenous, Male, Middle Aged, Neoplasm Recurrence, Local pathology, Prostate-Specific Antigen analysis, Prostatic Neoplasms pathology, Survival Analysis, Treatment Outcome, Antineoplastic Agents, Phytogenic administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Estramustine administration & dosage, Neoplasm Recurrence, Local drug therapy, Prostatic Neoplasms drug therapy, Vinblastine administration & dosage
- Abstract
Purpose: To compare vinblastine versus the combination of vinblastine plus estramustine as treatment for patients with hormone-refractory prostate cancer (HRPC)., Patients and Methods: A total of 201 patients with metastatic prostate cancer, progressive after hormonal therapy and antiandrogen withdrawal (if prior antiandrogen treatment), were randomized to receive vinblastine (V) 4 mg/m(2) by intravenous bolus weekly for 6 weeks followed by 2 weeks off, either alone or together with estramustine phosphate (EM-V) 600 mg/m(2) PO days 1 through 42, repeated every 8 weeks. Of 193 eligible patients, 98 received V, and 95 received EM-V., Results: Overall survival trended in favor of EM-V but was not significantly different as determined by Kaplan-Meier analysis (P =.08). Median survival was 11.9 months for EM-V and 9.2 months for V. EM-V was superior to V for secondary end points of time to progression (P <. 001, stratified log rank test; median 3.7 v 2.2 months, respectively) and for proportion of patients with >/= 50% prostate-specific antigen (PSA) decline sustained for at least 3 monthly measurements (25.2% v 3.2%, respectively; P <.0001). Granulocytopenia was significantly less for EM-V compared with V (grade 2, 3, and 4 = 7%, 7%, and 1% v 27%, 18% and 9%, respectively; P <.0001); however, grade 2 or worse nausea (26% v 7%, respectively; P =.0002) and extremity edema (22% v 8%, respectively; P =.005) were more frequent for EM-V., Conclusion: Although overall survival was not significantly greater for the combination, EM-V was superior to V for time to progression and PSA improvement. These results encourage further study of estramustine-based antimicrotubule drug combinations in HRPC.
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- 1999
- Full Text
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10. Signaling inhibitors in the clinic: new agents and new challenges.
- Author
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Hudes G
- Subjects
- Clinical Trials, Phase I as Topic, Growth Inhibitors metabolism, Humans, Isoxazoles metabolism, Leflunomide, Neoplasms metabolism, Phosphorylation, Growth Inhibitors pharmacology, Isoxazoles pharmacology, Neoplasms drug therapy, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Signal Transduction drug effects
- Published
- 1999
- Full Text
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11. Phase II trial of 96-hour paclitaxel plus oral estramustine phosphate in metastatic hormone-refractory prostate cancer.
- Author
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Hudes GR, Nathan F, Khater C, Haas N, Cornfield M, Giantonio B, Greenberg R, Gomella L, Litwin S, Ross E, Roethke S, and McAleer C
- Subjects
- Administration, Oral, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Alkylating administration & dosage, Antineoplastic Agents, Hormonal administration & dosage, Antineoplastic Agents, Phytogenic administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Disease-Free Survival, Drug Administration Schedule, Estramustine administration & dosage, Humans, Infusions, Intravenous, Male, Middle Aged, Paclitaxel administration & dosage, Survival Analysis, Treatment Outcome, Adenocarcinoma drug therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Prostatic Neoplasms drug therapy
- Abstract
Purpose: To evaluate the antitumor activity of 96-hour paclitaxel and daily oral estramustine phosphate (EMP) in patients with metastatic hormone-refractory prostate cancer (HRPC)., Patients and Methods: Thirty-four patients with adenocarcinoma of the prostate that progressed after one or more hormonal therapies and a trial of antiandrogen withdrawal were enrolled onto this phase II trial. Patients received paclitaxel 120 mg/m2 by 96-hour intravenous (i.v.) infusion on days 1 through 4 of each 21-day cycle, together with daily oral EMP 600 mg/m2/d, continuously., Results: Four of nine patients with measurable disease had objective responses (one complete response [CR] and three partial responses [PRs]) in liver (two patients) or nodes (two patients) of 2, 6, 8, and 20 months' duration. Of 25 assessable patients with metastases limited to bone, 14 had a > or = 50% decline in pretreatment prostate-specific antigen (PSA) level sustained for at least 6 weeks and seven had a > or = 80% decline. Overall, 17 of 32 patients (53.1%) with elevated pretreatment PSA levels had a > or = 50% decline of PSA and nine (28.1%) had a > or = 80% decrease. The main toxicities (> or = grade 2) were nausea, fluid retention, and fatigue, which occurred in 33%, 33%, and 24.2% of patients. Median time to progression, based on increasing PSA level and other clinical criteria, was 22.5 weeks. The estimated median overall survival time is 69 weeks., Conclusion: The combination of EMP and 96-hour paclitaxel is an active regimen for patients with HRPC. These results further support the therapeutic strategy of combining agents that impair microtubule function by complementary mechanisms.
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- 1997
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12. Patterns-of-failure analysis of patients with high pretreatment prostate-specific antigen levels treated by radiation therapy: the need for improved systemic and locoregional treatment.
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Hanks GE, Hanlon AL, Hudes G, Lee WR, Suasin W, and Schultheiss TE
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- Analysis of Variance, Humans, Male, Treatment Failure, Prostate-Specific Antigen blood, Prostatic Neoplasms immunology, Prostatic Neoplasms radiotherapy
- Abstract
Purpose: The patterns of failure (local and/or regional v metastatic) have been determined for patients with prostate cancer and pretreatment prostate-specific antigen (PSA) levels > or = 20 ng/mL treated with radiation alone with the purpose to design appropriate multimodal treatments., Materials and Methods: One hundred twenty patients with pretreatment PSA levels > or = 20 ng/mL were treated with external-beam radiation alone between February 1988 and October 1993. They were arbitrarily divided by PSA levels, 20 to 29.9 ng/mL, 30 to 49.9 ng/mL, and > or = 50 ng/mL, and analyzed in terms of freedom from any failure (no evidence of biochemical disease [bNED], and PSA level < 1.5 ngm/mL and not increasing), as well as freedom from imaging evidence of distant metastasis (fdm)., Results: There was no significant difference in short-term outcome by pretreatment PSA level, and thus all patients were pooled for analysis. At 4 years, 81% were fdm and 28% were free of any failure. This suggests that approximately 50% have recurred with local and/or regional disease or undetectable metastatic disease. Multivariate analysis indicated that low palpation stage and higher center of prostate dose were associated with better bNED survival. Multivariate analysis indicated that increasing stage and younger age are significantly associated with increasing distant metastasis., Conclusion: Patients with pretreatment PSA levels > or = 20 ng/mL are not optimally treated by irradiation alone. The pattern of failure suggests improvement may come from systemic treatment of metastatic disease and high-dose radiation to improve locoregional disease. To evaluate this, we have begun a multimodal trial of chemohormonal therapy followed by extended-field irradiation.
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- 1996
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13. Significant activity of paclitaxel in advanced transitional-cell carcinoma of the urothelium: a phase II trial of the Eastern Cooperative Oncology Group.
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Roth BJ, Dreicer R, Einhorn LH, Neuberg D, Johnson DH, Smith JL, Hudes GR, Schultz SM, and Loehrer PJ
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- Adult, Aged, Aged, 80 and over, Agranulocytosis chemically induced, Anemia chemically induced, Carcinoma, Transitional Cell mortality, Carcinoma, Transitional Cell secondary, Female, Filgrastim, Granulocyte Colony-Stimulating Factor therapeutic use, Humans, Infusions, Intravenous, Male, Middle Aged, Paclitaxel administration & dosage, Paclitaxel adverse effects, Recombinant Proteins therapeutic use, Thrombocytopenia chemically induced, Urinary Bladder Neoplasms mortality, Urinary Bladder Neoplasms pathology, Carcinoma, Transitional Cell drug therapy, Paclitaxel therapeutic use, Urinary Bladder Neoplasms drug therapy
- Abstract
Purpose: To assess the efficacy and toxicity of single-agent paclitaxel as first-line chemotherapy in patients with locally advanced or metastatic transitional-cell carcinoma of the urothelium., Patients and Methods: Twenty-six eligible patients were enrolled onto this cooperative group study and treated with paclitaxel at a dosage of 250 mg/m2 by 24-hour continuous infusion every 21 days until progression or patient intolerance. All patients received recombinant human granulocyte colony-stimulating factor (rhG-CSF) at 5 micrograms/kg/d for at least 10 days during each cycle., Results: Eleven of 26 patients (42%; 95% confidence interval [CI], 23% to 63%) demonstrated an objective response, with seven achieving a complete clinical response (CR) (27%; 95% CI, 12% to 48%) and four (15%) a partial response (PR). The median duration of response in the 11 responders is 7+ months (range, 4 to 17), with five responders (four CRs, one PR) remaining progression-free at 5, 6, 10, 12, and 16 months from the start of therapy. The estimated median survival duration for all patients is 8.4 months. Hematologic toxicity consisted of anemia (12% grade 3) and granulocytopenia (4% grade 3, 19% grade 4), with two patients developing granulocytopenic fevers. Nonhematologic toxicity included grade 3 mucositis in 11%, grade 3 neuropathy in 11%, and grade 4 diarrhea in 4%., Conclusion: Single-agent paclitaxel at this dosage and schedule is one of the most active single agents in previously untreated patients with advanced urothelial carcinoma, and is well tolerated by this patient population when given with hematopoetic growth factor support.
- Published
- 1994
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14. Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer.
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Hudes GR, Greenberg R, Krigel RL, Fox S, Scher R, Litwin S, Watts P, Speicher L, Tew K, and Comis R
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- Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols pharmacology, Drug Resistance, Estramustine administration & dosage, Gonadal Steroid Hormones therapeutic use, Humans, Male, Middle Aged, Pain Measurement, Prostate-Specific Antigen blood, Prostate-Specific Antigen drug effects, Prostatic Neoplasms blood, Survival Analysis, Vinblastine administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Microtubules drug effects, Prostatic Neoplasms drug therapy
- Abstract
Purpose: Estramustine phosphate (EMP) and vinblastine are two microtubule inhibitors with distinct molecular targets and at least additive antimicrotubule effects in vitro. Their modest single-agent activities in hormone-refractory prostate cancer, nonoverlapping toxicities, and lack of cross-resistance prompted a phase II trial in hormone-refractory prostate cancer., Patients and Methods: Thirty-six assessable patients at the Fox Chase Cancer Center and seven Fox Chase Cancer Center Network institutions were treated with oral EMP 600 mg/m2 on days 1 to 42 and vinblastine 4 mg/m2 intravenously (IV) once a week for 6 weeks. Courses were repeated every 8 weeks. Response assessment was based on a change in serum prostate-specific antigen (PSA) levels and was correlated with change in pain scores., Results: PSA decreased from baseline by at least 50% in 22 patients (61.1%) and by > or = 75% in eight patients (22.2%). A 50% or more decrease in PSA on three successive 2-week measurements together with an improved or stable pain score, performance status, and measurable soft tissue disease (if present) was required for a partial response (PR), which occurred in 11 patients for an overall response rate of 30.5% (95% confidence interval, 15.6% to 45.6%). In seven patients with measurable nonosseous disease, there was one PR (14%) and one minor response (MR). In 28 patients with assessable pain, major pain responses occurred in 12 (42.9%). PSA response (> or = 50% decrease times three measurements) was predictive of major pain response with a 93.7% specificity, a 50% sensitivity, and a positive predictive value of 85.7%., Conclusion: We conclude that EMP and vinblastine is an active combination in hormone-refractory prostate cancer.
- Published
- 1992
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15. Phase I trial of thiotepa in combination with recombinant human granulocyte-macrophage colony-stimulating factor.
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O'Dwyer PJ, LaCreta FP, Schilder R, Nash S, McAleer C, Miller LL, Hudes GR, and Ozols RF
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- Aged, Drug Administration Schedule, Drug Evaluation, Female, Humans, Male, Middle Aged, Neutropenia etiology, Recombinant Proteins therapeutic use, Thiotepa pharmacokinetics, Thiotepa therapeutic use, Granulocyte-Macrophage Colony-Stimulating Factor therapeutic use, Neoplasms drug therapy, Neutropenia prevention & control, Thiotepa adverse effects
- Abstract
Purpose: The ability of growth factors to stimulate marrow recovery suggests their potential for use in dose intensification of cytotoxic drugs. We performed a phase I study of the alkylating agent thiotepa in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), with the goal of dose-escalation of thiotepa. Thiotepa was selected based on its capacity for dose escalation to more than 1 g/m2 in the marrow transplantation setting., Patients and Methods: The starting dose of thiotepa (75 mg/m2) was the highest dose evaluated in our previous phase I trial. Thirteen patients received 22 courses of thiotepa and GM-CSF. The dose of GM-CSF was 10 micrograms/kg subcutaneously daily in six patients and 5 micrograms/kg in seven patients., Results: Three patients (23%) developed grade 3 to 4 neutropenia on the first course, with a recovery to more than 1000/mm3 in 4.7 days (mean). Recovery was as rapid with the 5 micrograms/kg as it was with the 10 micrograms/kg GM-CSF dose. Thrombocytopenia grade 3 to 4 affected seven of 13 (54%) patients in the first course; counts recovered to more than 50,000/mm3 in a median of 15 days. GM-CSF at either dose did not influence markedly the severity or duration of thrombocytopenia, and did not permit dose escalation of thiotepa. Among the seven patients who received a second cycle of treatment, six of seven experienced grade 3 or 4 thrombocytopenia that lasted a median of 15.5 days. Five had thrombocytopenia that lasted more than 35 days after one to three cycles of treatment. Plasma concentrations of thiotepa and tepa were measured by gas chromatography in eight patients. The plasma elimination of thiotepa fit a two-compartment open model with a harmonic mean terminal half-life of 2.44 hours. The mean total body clearance was 217.9 mL/min/m2, and the mean steady-state volume of distribution (Vdss) was 36.8 L/m2. The half-life of tepa was 7.98 hours, and the ratio of the area under the plasma concentration versus time curve (AUC) of tepa to that of thiotepa was 0.79., Conclusions: These data were consistent with our previous observations at this dose, and indicated that the severity of toxicity in these patients was not explained by aberrant pharmacokinetic indices. We conclude that, independent of effects on neutropenia, severe and cumulative platelet toxicity precludes further escalation of thiotepa dose despite the use of GM-CSF.
- Published
- 1992
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