A Phase I and Pharmacokinetic Study of Pegylated Camptothecin as a 1-Hour Infusion Every 3 Weeks in Patients With Advanced Solid Malignancies

2003 ◽  
Vol 21 (1) ◽  
pp. 148-157 ◽  
Author(s):  
Eric K. Rowinsky ◽  
Jinee Rizzo ◽  
Leonel Ochoa ◽  
Chris H. Takimoto ◽  
Bahram Forouzesh ◽  
...  
Keyword(s):  
Dose Level ◽  
Topoisomerase I ◽  
Small Cell Lung Carcinoma ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Unknown Primary ◽  
Pharmacokinetic Parameters ◽  
Cell Lung Carcinoma ◽  
Phase Ii Studies ◽  
Solid Malignancies

Purpose: To assess the feasibility of administering camptothecin (CPT), the prototypic topoisomerase I inhibitor, as polyethylene glycol (PEG)-CPT, a macromolecule consisting of CPT conjugated to chemically modified PEG. The study also sought to determine the maximum-tolerated dose (MTD) of PEG-CPT, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity. Patients and Methods: Patients with advanced solid malignancies were treated with escalating doses of PEG-CPT as a 1-hour intravenous (IV) infusion every 3 weeks. A modified continual reassessment method was used for dose-level assignment to determine the MTD, which was defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%. Results: Thirty-seven patients were treated with 144 courses of PEG-CPT at seven dose levels ranging from 600 to 8,750 mg/m2. Severe myelosuppression was consistently experienced by heavily pretreated (HP) and minimally pretreated (MP) patients at the highest dose level evaluated, 8,750 mg/m2, whereas both HP and MP patients tolerated repetitive treatment at 7,000 mg/m2. Cystitis, nausea, vomiting, and diarrhea were also observed but were rarely severe. A partial response was noted in a patient with platinum- and etoposide-resistant small-cell lung carcinoma, and minor responses were noted in one patient each with adenocarcinoma of unknown primary type and osteosarcoma. The pharmacokinetics of free CPT were dose proportional. Free CPT accumulated slowly in plasma, with maximal plasma concentrations achieved at 23 ± 12.3 hours; the harmonic mean half-life (t1/2) of free CPT was long (t1/2, 77.46 ± 36.77 hours). Conclusion: Clinically relevant doses of CPT can be delivered by administering PEG-CPT. The recommended dose for phase II studies in both MP and HP patients is 7,000 mg/m2 as 1-hour IV every 3 weeks. The characteristics of the myelosuppressive effects of PEG-CPT, the paucity of severe nonhematologic toxicities with repetitive treatment, the preliminary antitumor activity noted, and the slow clearance of CPT enabling simulation of desirable pharmacokinetic parameters with a convenient single-dosing regimen warrant further disease-directed evaluations.

Phase I and Pharmacokinetic Study of the Camptothecin Analog DX-8951f Administered as a 30-Minute Infusion Every 3 Weeks in Patients With Advanced Cancer

2000 ◽  
Vol 18 (23) ◽  
pp. 3986-3992 ◽  
Author(s):  
Valérie Boige ◽  
Eric Raymond ◽  
Sandrine Faivre ◽  
Michel Gatineau ◽  
Kathleen Meely ◽  
...  
Keyword(s):  
Phase I ◽  
Intravenous Infusion ◽  
Topoisomerase I ◽  
High Performance ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Analysis ◽  
Phase Ii Studies ◽  
Heavily Pretreated ◽  
Dose Limiting Toxicity

PURPOSE: DX-8951f is a totally synthetic derivative of camptothecin with greater cytotoxicity and more potent topoisomerase I inhibition than SN-38, topotecan, and camptothecin in preclinical studies. This phase I study aimed to describe the toxicity and to determine the maximum-tolerated dose (MTD) and pharmacokinetics of DX-8951f given as a 30-minute intravenous infusion every 3 weeks. PATIENTS AND METHODS: Twelve patients with refractory solid malignancies were treated with DX-8951f at dose levels ranging from 4 to 7.1 mg/m2. All but one patient had received previous chemotherapy, and eight patients were considered heavily pretreated. Total DX-8951f plasma concentrations were assayed using high-performance liquid chromatography. RESULTS: Thirty-six cycles of DX-8951f were administered. Neutropenia was the dose-limiting toxicity, and it was dose-related, reversible, and noncumulative. Other toxicities included nausea and vomiting, alopecia, asthenia, fever, and anemia. Grade 1 or 2 diarrhea was observed in seven patients but was transient and resolved without requiring treatment. Pharmacokinetic analysis showed that DX-8951f had a half-life of 7.15 hours and a clearance rate of 1.65 L/h·m2. The DX-8951f area under the plasma-concentration curve increased linearly with the dose. We defined the MTD of DX-8951f administered as a 30-minute intravenous infusion every 3 weeks as 7.1 mg/m2. CONCLUSION: The dose-limiting toxicity of DX-8951f is neutropenia. The recommended dose for phase II studies is 5.33 mg/m2 every 3 weeks in patients previously treated with chemotherapy.

DX-8951f, a Hexacyclic Camptothecin Analog, on a Daily-Times-Five Schedule: A Phase I and Pharmacokinetic Study in Patients With Advanced Solid Malignancies

2000 ◽  
Vol 18 (17) ◽  
pp. 3151-3163 ◽  
Author(s):  
Eric K. Rowinsky ◽  
Thomas R. Johnson ◽  
Charles E. Geyer ◽  
Lisa A. Hammond ◽  
S. Gail Eckhardt ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Dose Level ◽  
Compartment Model ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Water Soluble ◽  
Severe Thrombocytopenia ◽  
Phase Ii Studies ◽  
Solid Malignancies ◽  
Wide Range

PURPOSE: To assess the feasibility of administering DX-8951f (exatecan mesylate), a water-soluble, camptothecin analog, as a 30-minute intravenous infusion daily for 5 days every 3 weeks, determine the maximum-tolerated dose (MTD) and pharmacokinetic (PK) behavior of DX-8951f, and seek preliminary evidence of anticancer activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of DX-8951f. After three patients were treated at the first dose level, doses were to be escalated in increments of 100%, using a single patient at each dose level unless moderate toxicity was observed. The MTD, defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%, was calculated separately for minimally pretreated (MP) and heavily pretreated (HP) patients. The PK and excretory profiles of DX-8951, the anhydrous form of DX-8951f, were also characterized. RESULTS: Thirty-six patients were treated with 130 courses of DX-8951f at six dose levels ranging from 0.1 to 0.6 mg/m2/d. Brief, noncumulative neutropenia was the most common toxicity observed. Severe myelosuppression (neutropenia that was protracted and/or associated with fever and/or severe thrombocytopenia) was consistently experienced by HP and MP patients at doses exceeding 0.3 and 0.5 mg/m2/d, respectively. Nonhematologic toxicities (nausea, vomiting, and diarrhea) were also observed, but these effects were rarely severe. Objective antitumor activity included partial responses in one patient each with platinum-resistant extrapulmonary small-cell and fluoropyrimidine- and irinotecan-resistant colorectal carcinoma, and minor responses in patients with prostate, hepatocellular, thymic, primary peritoneal, and irinotecan-resistant colorectal carcinomas. The PKs of total DX-8951 were linear and well fit by a three-compartment model. CONCLUSION: The recommended doses for phase II studies of DX-8951f as a 30-minute infusion daily for 5 days every 3 weeks are 0.5 and 0.3 mg/m2/d for MP and HP patients, respectively. The characteristics of the myelosuppressive effects of DX-8951f, paucity of severe nonhematologic toxicities, and antitumor activity against a wide range of malignancies warrant broad disease-directed evaluations of DX-8951f on this schedule.

Phase I and Pharmacokinetic Study of the Differentiating Agent Vesnarinone in Combination With Gemcitabine in Patients With Advanced Cancer

2000 ◽  
Vol 18 (23) ◽  
pp. 3974-3985 ◽  
Author(s):  
Amita Patnaik ◽  
Eric K. Rowinsky ◽  
Brinda K. Tammara ◽  
Manuel Hidalgo ◽  
Ronald L. Drengler ◽  
...  
Keyword(s):  
Dose Level ◽  
Small Cell Lung Carcinoma ◽  
Single Agent ◽  
Pharmacokinetic Interaction ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
Cell Lung Carcinoma ◽  
Once Daily ◽  
Biologically Relevant

PURPOSE: To evaluate the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetic profile of vesnarinone given once daily in combination with gemcitabine. PATIENTS AND METHODS: Twenty-six patients were treated with oral vesnarinone once daily on a continuous schedule at doses of 60, 90, 120, 150, and 180 mg in combination with intravenous (IV) gemcitabine at a dose of 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks. To determine whether biologically relevant concentrations were being achieved, predose concentrations (Cmin) of vesnarinone were obtained weekly. Plasma gemcitabine and 2′,2′-difluorodeoxyuridine concentrations were obtained during courses 1 and 2. RESULTS: Twenty-six patients were treated with 92 courses of vesnarinone/gemcitabine. The principal toxicities of the regimen consisted of neutropenia and thrombocytopenia, which were dose-limiting in two of eight heavily pretreated new patients treated at the 90 mg/1,000 mg/m2 dose level and one of 10 minimally pretreated new patients at the 120 mg/1,000 mg/m2 dose level. None of three patients treated with 15 courses at the vesnarinone/gemcitabine dose levels of 60 mg/1,000 mg/m2 experienced DLT. Pharmacokinetic studies of vesnarinone revealed significant interpatient variability at any given dose level. There was evidence of a linear relationship between vesnarinone dose and mean Cmin at dosages of vesnarinone less than 150 mg, with plateauing of mean Cmin values at higher dosages. There was no impact of vesnarinone on gemcitabine concentrations, and the vesnarinone pharmacokinetics did not change with gemcitabine between weeks 1 and 2. Two partial responses occurred in patients with refractory breast and non–small-cell lung carcinoma. CONCLUSION: When combined with gemcitabine, the recommended dose of vesnarinone for phase II evaluations is 90 mg orally once daily with gemcitabine 1,000 mg/m2 IV on days 1, 8, and 15 every 4 weeks. There is no evidence of pharmacokinetic interaction between vesnarinone and gemcitabine. Further studies of vesnarinone as a single agent or in combination with gemcitabine and other antineoplastic agents are warranted.

Phase I and Pharmacokinetic Study of Docetaxel and Irinotecan in Patients With Advanced Solid Tumors

2000 ◽  
Vol 18 (20) ◽  
pp. 3545-3552 ◽  
Author(s):  
Corinne Couteau ◽  
Marie-Laure Risse ◽  
Michel Ducreux ◽  
Florence Lefresne-Soulas ◽  
Alessandro Riva ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Pharmacokinetic Study ◽  
Topoisomerase I ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies ◽  
Grade 3

PURPOSE: We conducted a phase I and pharmacokinetic study of docetaxel in combination with irinotecan to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the dose at which at least 50% of the patients experienced a DLT during the first cycle, and to evaluate the safety and pharmacokinetic profiles in patients with advanced solid tumors. PATIENTS AND METHODS: Patients with only one prior chemotherapy treatment (without taxanes or topoisomerase I inhibitors) for advanced disease were included in the study. Docetaxel was administered as a 1-hour IV infusion after premedication with corticosteroids followed immediately by irinotecan as a 90-minute IV infusion, every 3 weeks. No hematologic growth factors were allowed. RESULTS: Forty patients were entered through the following seven dose levels (docetaxel/irinotecan): 40/140 mg/m2, 50/175 mg/m2, 60/210 mg/m2, 60/250 mg/m2, 60/275 mg/m2, 60/300 mg/m2, and 70/250 mg/m2. Two hundred cycles were administered. Two MTDs were determined, 70/250 mg/m2 and 60/300 mg/m2; the DLTs were febrile neutropenia and diarrhea. Neutropenia was the main hematologic toxicity, with 85% of patients experiencing grade 4 neutropenia. Grade 3/4 nonhematologic toxicities in patients included late diarrhea (7.5%), asthenia (15.0%), febrile neutropenia (22.5%), infection (7.5%), and nausea (5.0%). Pharmacokinetics of both docetaxel and irinotecan were not modified with the administration schedule of this study. CONCLUSION: The recommended dose of docetaxel in combination with irinotecan is 60/275 mg/m2, respectively. At this dose level, the safety profile is manageable. The activity of this combination should be evaluated in phase II studies in different tumor types.

Phase I and pharmacokinetic study of the water-soluble dolastatin 15 analog LU103793 in patients with advanced solid malignancies.

1998 ◽  
Vol 16 (8) ◽  
pp. 2770-2779 ◽  
Author(s):  
M A Villalona-Calero ◽  
S D Baker ◽  
L Hammond ◽  
C Aylesworth ◽  
S G Eckhardt ◽  
...  
Keyword(s):  
Cardiovascular Effects ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Water Soluble ◽  
Maximum Effect ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Emax Model ◽  
Solid Malignancies

PURPOSE To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic profile of the dolastatin 15 analog LU103793 when administered daily for 5 days every 3 weeks. PATIENTS AND METHODS Fifty-six courses of LU103793 at doses of 0.5 to 3.0 mg/m2 were administered to 26 patients with advanced solid malignancies. Pharmacokinetic studies were performed on days 1 and 5 of course one. Pharmacokinetic variables were related to the principal toxicities. RESULTS Neutropenia, peripheral edema, and liver function test abnormalities were dose-limiting at doses greater than 2.5 mg/m2 per day. Four of six patients developed DLT at 3.0 mg/m2 per day, whereas two of 12 patients treated at 2.5 mg/m2 per day developed DLT. Pharmacokinetic parameters were independent of dose and similar on days 1 and 5. Volume of distribution at steady-state (Vss) was 7.6 +/- 2.0 L/m2, clearance 0.49 +/- 0.18 L/h/m2, and elimination half-life (t1/2) 12.3 +/- 3.8 hours. Peak concentrations (Cmax) on day 1 related to mean percentage decrement in neutrophils (sigmoid maximum effect (Emax) model). Patients who experienced dose-limiting neutropenia had significantly higher Cmax values than patients who did not, whereas nonhematologic DLTs were more related to dose. CONCLUSION The recommended dose for phase II evaluations of LU103793 daily for 5 days every 3 weeks is 2.5 mg/m2 per day. The lack of prohibitive cardiovascular effects and the generally acceptable toxicity profile support the rationale for performing disease-directed evaluations of LU103793 on the schedule evaluated in this study.

Phase I and Pharmacokinetic Study of Novel l-Nucleoside Analog Troxacitabine Given as a 30-Minute Infusion Every 21 Days

2002 ◽  
Vol 20 (10) ◽  
pp. 2567-2574 ◽  
Author(s):  
Karl Belanger ◽  
Malcolm Moore ◽  
Sharyn D. Baker ◽  
Jeanne Dionne ◽  
Martha Maclean ◽  
...  
Keyword(s):  
Phase I ◽  
Skin Rash ◽  
Maximum Tolerated Dose ◽  
Nucleoside Analog ◽  
Unknown Primary ◽  
Bone Lesions ◽  
Phase Ii Studies ◽  
Best Response ◽  
Metastatic Lung ◽  
Hand Foot Syndrome

PURPOSE: Troxacitabine (Troxatyl, BCH-4556; BioChem Pharma Inc, Basingstoke, United Kingdom) is a novel synthetic l-nucleoside analog with activity against a broad range of human tumors in preclinical models. Preclinical toxicity suggested a predictable toxicity profile consistent with an agent of this class, with evidence of interspecies differences. We conducted a phase I study of troxacitabine given as a 30-minute infusion once every 21 days. PATIENTS AND METHODS: The starting dose of troxacitabine was 0.025 mg/m2, based on toxicology data from the most sensitive species studied (cynomolgus monkey). Doses were doubled until grade 1 skin or mucosal or grade 2 other toxicity was encountered. A modified Fibonacci scale was used. RESULTS: A total of 45 patients were enrolled at 13 dose levels. Most common nonhematologic side effects were skin rash (44%), lethargy (29%), nausea (24%), alopecia, dry skin (18%), anorexia (13%), neurosensory symptoms (13%), and hand-foot syndrome (13%). In patients treated with prednisone 25 mg/d orally for 5 days, starting on day 1, skin rash was less problematic. Two patients at 12.5 mg/m2 experienced dose-limiting (grade 4) granulocytopenia. Confirmed partial responses were documented in one patient with previously untreated renal cell carcinoma with metastatic lung and bone lesions and in one patient with an unknown primary tumor. Eighteen patients had a best response of stable disease with a median duration of 5.1 months (range, 2.1 to 18.7 months). CONCLUSION: When given in this schedule, the maximum-tolerated dose of troxacitabine is 12.5 mg/m2, and the recommended dose for additional phase II studies is 10 mg/m2 once every 21 days with steroid premedication.

Phase I/II trial of sorafenib combined with FOLFOX4 in untreated patients with advanced gastric adenocarcinoma: Phase I results.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14606-e14606
Author(s):  
Yihebali Chi ◽  
Jianliang Yang ◽  
Feng Du ◽  
Sheng Yang ◽  
Yongkun Sun ◽  
...  
Keyword(s):  
Phase I ◽  
Gastric Adenocarcinoma ◽  
Dose Level ◽  
Standard Dose ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Combination Regimen ◽  
Phase Ii Studies ◽  
Best Response ◽  
Advanced Gastric Adenocarcinoma

e14606 Background: Sorafenib (Sor) is a potent inhibitor of multiple intracellular and cell surface kinases. FOLFOX4 was demonstrated to be an active and well-tolerated chemotherapy for advanced gastric adenocarcinoma (AGA). The phase I portion of the phase I/II study is designed to assess the maximum tolerated dose (MTD) of Sor combined with standard dose FOLFOX4, as well as safety, tolerance, and activity of the combination in patients (pts) with AGA. Methods: Pts with AGA with ECOG 0-1 and without prior chemotherapy or radiotherapy were eligible. Three patients per cohort were treated with FOLFOX4 [Oxaliplatin (85 mg/m2), LV (200mg/m2) and 5-FU (400 mg/m2), followed by 5-FU continuously infusion (1200mg/ m2) for 44h every 2 weeks, up to 8 cycles, along with escalating doses of Sor (200, 400, 600mg) PO BID, continuously. If one patient experienced DLT, three additional patients were entered at the same dose level. Dose escalation continued until DLTs were experienced in two or more out of six patients, which was then defined as the MTD. Radiographic responses were assessed every 6 weeks per RECIST v1.0. Results: Nine pts were enrolled. Median age was 59.3 yr (range 42.6-71.6). M/F: 6/3; ECOG PS 0/1: 2/7. One out of 6 pts experienced DLT (G3 HFSR) in dose level 1 (200 mg BID), and 2 out of 3pts experienced DLT in dose level 2 (400 mg BID). The Sor 200mg BID was therefore identified as the MTD when combined with FOLFOX4. Major toxicity of this combination include neutropenia (G3/4: 7/3), leucopenia (G3/4: 2/0), HFSR (G3/4: 2/0) and incomplete bowel obstruction (G3/4: 1/0). One patient experienced G4 ALT/AST elevation accompanied with G3 GGT/bilirubin elevation, which led to treatment discontinuation. Preliminary efficacy data in 9 evaluable pts included 1 complete response (CR), 6 partial responses (PR) and 1 stable disease (SD) as best response. Median time to progression was 6.6 months. Median overall survival was 12.2 months. Conclusions: The MTD of Sor when used in combination of FOLFOX4 in AGA is 200mg PO BID, and this combination regimen has a manageable toxicity profile and promising activity in AGA. This efficacy and safety profiles need to be confirmed in further phase II studies.

scholarly journals Phase I and Pharmacokinetic Study of YM155, a Small-Molecule Inhibitor of Survivin

2008 ◽  
Vol 26 (32) ◽  
pp. 5198-5203 ◽  
Author(s):  
Anthony W. Tolcher ◽  
Alain Mita ◽  
Lionel D. Lewis ◽  
Christopher R. Garrett ◽  
Elizabeth Till ◽  
...  
Keyword(s):  
Steady State ◽  
Antitumor Activity ◽  
Small Molecule ◽  
Plasma Concentrations ◽  
Specific Antigen ◽  
Maximum Tolerated Dose ◽  
Small Molecule Inhibitor ◽  
Pharmacokinetic Parameters ◽  
Minor Response ◽  
Molecule Inhibitor

Purpose To determine the maximum-tolerated dose (MTD) and assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of YM155, a small-molecule inhibitor of survivin. Patients and Methods Patients with advanced solid malignancies or lymphoma were treated with escalating doses of YM155 administered by 168-hour continuous intravenous infusion (CIVI). Plasma and urine samples were assayed to determine pharmacokinetic parameters and excretion. Results Forty-one patients received 127 cycles of YM155 at doses ranging from 1.8 to 6.0 mg/m2/d by 168-hour CIVI every 3 weeks. Overall, the most common grade 1 to 2 toxicities were stomatitis, pyrexia, and nausea, whereas grade 3 and 4 toxicities were rare. Reversible elevation in serum creatinine in two patients, with one developing acute tubular necrosis, was dose-limiting at 6.0 mg/m2. The MTD was 4.8 mg/m2. At the MTD, the mean steady-state concentration, clearance, volume of distribution at steady-state, and terminal elimination half-life were 7.7 ng/mL, 47.7 L/h, 1,763 L, and 26 hours, respectively. One complete and two partial responses lasting 8, 24+ and 48+ months occurred in three patients with non-Hodgkin's lymphoma, two patients with hormone- and docetaxel-refractory prostate cancer had prostate-specific antigen responses, and one patient with non–small-cell lung cancer had a minor response. Conclusion YM155 can be administered safely at 4.8 mg/m2/d 168 hours CIVI every 3 weeks. The absence of severe toxicities, attainment of plasma concentrations active in preclinical models, and compelling antitumor activity warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors.

1-123-Iodo-α-methyl tyrosine SPECT in non-parenchymal brain tumours

2002 ◽  
Vol 41 (04) ◽  
pp. 191-196 ◽  
Author(s):  
P. Matheja ◽  
M. Weckesser ◽  
Ch. Rickert ◽  
St. Palkovic ◽  
B. Riemann ◽  
...  
Keyword(s):  
Lung Carcinoma ◽  
Renal Cell ◽  
Brain Tumours ◽  
Small Cell Lung Carcinoma ◽  
Systematic Evaluation ◽  
Unknown Primary ◽  
Contralateral Hemisphere ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma

Summary Purpose: Scintigraphy using I-123-iodo-α-methyl tyrosine (IMT) is useful in the preoperative characterization of gliomas, in detecting recurrent glioma and in the biological re-evaluation of residual or recurrent tumours. A systematic evaluation of non-parenchymal brain tumours has not yet been performed. The aim of the present study was to evaluate IMT SPECT in the management of intracerebral metastases and lymphomas. Patients and methods: IMT uptake was analyzed in 31 patients with 28 metastases of extracerebral solid tumours and 7 cerebral lymphomas. Histology revealed high grade lymphomas, melanomas, and carcinomas of the following origin: lung, unknown primary, breast, colon, renal cell, ovary, vagina, frontal sinus. IMT uptake was quantified as ratio between maximal tumour accumulation and average uptake in the contralateral hemisphere. Results: All tumours except two renal cell and one small cell lung carcinoma metastases accumulated IMT (91%). The highest IMT uptake was found in a metastasis of lung carcinoma. IMT uptake was highly variable and was similar in primary and in recurrent tumours. Conclusion: Significant accumulation of IMT is seen in the majority of tumours, so that this technique might be helpful for the management of cerebral metastases and lymphomas.

Phase I and Pharmacologic Study of Oral (PEG-1000) 9-Aminocamptothecin in Adult Patients With Solid Tumors

1999 ◽  
Vol 17 (7) ◽  
pp. 2219-2219 ◽  
Author(s):  
Maja J.A. de Jonge ◽  
Cornelis J.A. Punt ◽  
A. Hans Gelderblom ◽  
Walter J. Loos ◽  
Vera van Beurden ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Topoisomerase I ◽  
High Performance ◽  
Specific Inhibitor ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Analysis ◽  
Time Curve ◽  
Phase Ii Studies

PURPOSE: 9-Amino-20(S)-camptothecin (9-AC) is a specific inhibitor of topoisomerase-I. Recently, a bioavailability of approximately 48% for the oral PEG-1000 formulation was reported. We conducted a phase I and pharmacokinetic study of the oral PEG-1000 formulation of 9-AC to define the maximum-tolerated dose, toxicity profiles, pharmacokinetic-dynamic relationships, and preliminary antitumor activity in patients with solid tumors. PATIENTS AND METHODS: Patients were treated with oral (PEG-1000) 9-AC given once a day for 7 or 14 days at doses ranging from 0.25 to 1.1 mg/m2/d; cycles were repeated every 21 days. For pharmacokinetic analysis, plasma sampling was performed on days 1 and 6 or 8 of the first course using a validated high-performance liquid chromatographic assay. RESULTS: Thirty patients were entered onto the study; three patients were not assessable for toxicity and response. Twenty-seven patients received a total of 89 courses. The dose-limiting toxicities (DLTs) were myelosuppression and diarrhea at a dose of 1.1 mg/m2/d for 14 days. Pharmacokinetics showed a substantial interpatient variation of the area under the plasma concentration-time curve (AUC) of 9-AC. The intrapatient variability was extremely small. A significant correlation was observed between the percentage decrease in WBC count and the AUC of 9-AC lactone (r2 = 0.86). One partial response was noted in a patient with metastatic colorectal cancer. CONCLUSION: DLTs in this phase I study of oral 9-AC daily for 14 days every 21 days were myelosuppression and diarrhea. The recommended dose for phase II studies is 0.84 mg/m2/d. In view of the substantial interpatient variability in AUC and the availability of a limited sampling model, a pharmacokinetic guided phase II study should be considered.

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