Biomedical subjects

Hedy L Kindler

Publications and source records attributed to Hedy L Kindler.

At least 19 recordsLinked to original sources

PubMed2006

The cancer and leukemia group B respiratory committee.

The Cancer and Leukemia Group B Respiratory Committee has a 30-year track record of clinical investigation in patients with small-cell lung cancer and non-small-cell lung cancer (NSCLC) and mesothelioma. The most widely recognized contributions of the Committee include the early confirmation of the role of concurrent chemoradiotherapy in LD-SCLC, the effect of combination chemotherapy followed by radiation in stage III NSCLC, the introduction of third-generation agents into concurrent chemoradiation for stage III disease, the prospective demonstration of the benefit of treating older (70 years old) and poorer performance status (performance status = 2) patients with first-line combinations for stage IV disease, and the development of the "Herndon prognostic index" to normalize patient characteristics and outcomes in sequential phase II trials of new agents in patients with mesothelioma. Many other contributions have also emerged from the Committee's clinical trials and correlative science programs. We look forward to making additional critical contributions during future decades of Cancer and Leukemia Group B Respiratory Committee research.

Antineoplastic Agents↗

PubMed2006

Modeling of mesothelioma growth demonstrates weaknesses of current response criteria.

Applicability of the Response Evaluation Criteria in Solid Tumors (RECIST) to the geometry of mesothelioma has been recently investigated. A "modified RECIST" measurement technique developed for mesothelioma proposes measurement of tumor thickness rather than maximum diameter. This study evaluated the volumetric consistency of the RECIST response criteria as applied to the modified RECIST measurement technique. Geometric models were developed to simulate mesothelioma growth, and measurements of these models were calculated. Relationships between change in model measurements and corresponding change in model volume were derived and evaluated. Application of the RECIST response criteria to the typical spherical tumor model results in partial response (PR) classification based on a 66% volume decrease and progressive disease (PD) based on a 73% volume increase; for mesothelioma model thickness measurements, the RECIST criteria result in PR classification based on a 30% volume decrease and PD based on a 20% volume increase. Alternative response criteria for mesothelioma thickness measurement (-66% for PR, +74% for PD) achieve volumetric equivalence with the RECIST criteria for spherical tumor measurement. Application of the RECIST response criteria to mesothelioma thickness measurements yields PR and PD classifications based on smaller volume changes than for spherical tumors.

Adult↗

PubMed2006

Functional analysis of c-Met/hepatocyte growth factor pathway in malignant pleural mesothelioma.

c-Met receptor tyrosine kinase (RTK) has not been extensively studied in malignant pleural mesothelioma (MPM). In this study, c-Met was overexpressed and activated in most of the mesothelioma cell lines tested. Expression in MPM tissues by immunohistochemistry was increased (82%) in MPM in general compared with normal. c-Met was internalized with its ligand hepatocyte growth factor (HGF) in H28 MPM cells, with robust expression of c-Met. Serum circulating HGF was twice as high in mesothelioma patients as in healthy controls. There was a differential growth response and activation of AKT and extracellular signal-regulated kinase 1/2 in response to HGF for the various cell lines. Dose-dependent inhibition (IC50 < 2.5 micromol/L) of cell growth in mesothelioma cell lines, but not in H2052, H2452, and nonmalignant MeT-5A (IC50 > 10 micromol/L), was observed with the small-molecule c-Met inhibitor SU11274. Furthermore, migration of H28 cells was blocked with both SU11274 and c-Met small interfering RNA. Abrogation of HGF-induced c-Met and downstream signaling was seen in mesothelioma cells. Of the 43 MPM tissues and 7 cell lines, we have identified mutations within the semaphorin domain (N375S, M431V, and N454I), the juxtamembrane domain (T1010I and G1085X), and an alternative spliced product with deletion of the exon 10 of c-Met in some of the samples. Interestingly, we observed that the cell lines H513 and H2596 harboring the T1010I mutation exhibited the most dramatic reduction of cell growth with SU11274 when compared with wild-type H28 and nonmalignant MeT-5A cells. Ultimately, c-Met would be an important target for therapy against MPM.

Aged↗

PubMed2006

Variability in mesothelioma tumor response classification.

OBJECTIVE: The objective of our study was to evaluate observer variability in the measurement of temporal change in mesothelioma tumor thickness and in the resulting tumor response classification from CT scans. In addition, the performance of a semiautomated measurement method was evaluated. MATERIALS AND METHODS: Four observers individually used an interface that displayed two serial CT scans from the same patient to measure mesothelioma tumor thickness on the follow-up CT scans of 22 patients based on baseline scan measurements. During one session, observers acquired measurements on the follow-up scans based on written reports of baseline scan measurements; in another session, baseline scan measurements were superimposed on the baseline scan for direct visual comparison. Follow-up scan measurements also were obtained from a semiautomated method. Measurement variability and tumor response classification concordance were evaluated for manual measurements acquired in both modes and for semiautomated measurements. RESULTS: Although only a small increase in tumor response classification concordance rate was obtained with the visual approach (84.8%) relative to the more standard written-report approach (82.6%), the actual measurements acquired by observers were statistically significantly different between the two approaches (p = 0.03). Both the semiautomated measurements and the resulting tumor response classifications were consistent with manual measurements. CONCLUSION: The presentation of baseline scan tumor measurements affects measurements acquired on follow-up scans and could influence tumor response classification. The potential utility of semiautomated tumor thickness measurements was shown in the context of measuring tumor response.

Adult↗

PubMed2005

Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer.

PURPOSE: Vascular endothelial growth factor (VEGF) plays a key role in the biology and prognosis of pancreatic cancer. Inhibitors of VEGF suppress the growth of pancreatic cancer in preclinical models. The objectives of this phase II study were to assess the response rate and overall survival of pancreatic cancer patients who received gemcitabine with the recombinant humanized anti-VEGF monoclonal antibody bevacizumab. PATIENTS AND METHODS: Patients with previously untreated advanced pancreatic cancer received gemcitabine 1,000 mg/m(2) intravenously over 30 minutes on days 1, 8, and 15 every 28 days. Bevacizumab, 10 mg/kg, was administered after gemcitabine on days 1 and 15. Tumor measurements were assessed every two cycles. Plasma VEGF levels were obtained pretreatment. RESULTS: Fifty-two patients were enrolled at seven centers between November 2001 and March 2004. All patients had metastatic disease, and 83% had liver metastases. Eleven patients (21%) had confirmed partial responses, and 24 (46%) had stable disease. The 6-month survival rate was 77%. Median survival was 8.8 months; median progression-free survival was 5.4 months. Pretreatment plasma VEGF levels did not correlate with outcome. Grade 3 and 4 toxicities included hypertension in 19% of the patients, thrombosis in 13%, visceral perforation in 8%, and bleeding in 2%. CONCLUSION: The combination of bevacizumab plus gemcitabine is active in advanced pancreatic cancer patients. Additional study is warranted. A randomized phase III trial of gemcitabine plus bevacizumab versus gemcitabine plus placebo is ongoing in the Cancer and Leukemia Group B.

Adenocarcinoma↗

PubMed2005

Modulation of irinotecan with cyclosporine: a phase II trial in advanced colorectal cancer.

INTRODUCTION: Despite the extensive clinical experience with irinotecan, significant concerns remain regarding its toxicity. In a phase I trial, we modulated irinotecan pharmacokinetics by inhibiting biliary excretion of SN-38, the active metabolite of irinotecan, using cyclosporine. The modulation appeared to decrease the gastrointestinal toxicity of irinotecan and suggested that irinotecan activity might also be retained. Hence, we conducted this phase II trial in patients with colorectal cancer (CRC) to further evaluate the toxicity and activity of irinotecan modulated with cyclosporine. PATIENTS AND METHODS: Sixteen patients with 5-fluorouracil refractory CRC were treated. Cyclosporine (5 mg/kg) was administered as a 6-h infusion and irinotecan (60 mg/m2/day, 90-min infusion) was started 3 h after initiation of the Cyclosporine. Both agents were given weekly for 4 weeks, every 6 weeks. Responses were assessed every 12 weeks, and toxicity was monitored weekly. RESULTS: Sixteen patients were evaluable for toxicity and 11 for response. There was 1 partial response (6%). Five patients had SD lasting a median of 12 weeks. Grade 3/4 diarrhea was observed in only 13% of the patients. CONCLUSION: Pharmacokinetic modulation of irinotecan using parenteral cyclosporine appears to decrease the incidence of diarrhea in CRC patients. Given the modest activity of irinotecan monotherapy, a larger study would be required to assess if the modulation improves the toxicity without compromising this activity. The available clinical data suggest that pharmacokinetic modulation of irinotecan should be evaluated further to define its optimal clinical utility.

Adult↗

PubMed2005

Gefitinib in patients with malignant mesothelioma: a phase II study by the Cancer and Leukemia Group B.

PURPOSE: The Cancer and Leukemia Group B conducted a phase II study of gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, in patients with previously untreated malignant mesothelioma. EXPERIMENTAL DESIGN: Eligible patients had unresectable pleural or peritoneal mesothelioma, measurable disease, no prior therapy, and performance status 0-1 by Cancer and Leukemia Group B criteria. Gefitinib (500 mg p.o.) was administered once a day for 21 days. Patients underwent restaging after every two cycles. Therapy was continued until disease progression or unacceptable toxicity. RESULTS: The most common grade 3 toxicities were diarrhea (16%) and nausea (12%). Of 43 patients enrolled, 1 patient (2%) had a complete response, 1 patient (2%) had a partial response, 21 (49%) had stable disease lasting two to eight cycles, 15 (35%) had progressive disease, and 5 (12%) had early deaths. One-year survival was 32% [95% confidence interval (CI), 21-50%]. Median survival and failure-free survival were 6.8% (95% CI, 3.5-10.3) and 2.6 months (95% CI, 1.5-4.0), respectively. The 3-month failure-free survival was 40% (95% CI, 25-56%). EGFR expression score by immunohistochemistry done in 28 patients was categorized as low (EGFR 1+ or 2+) or high (EGFR 3+) expression: 97% had EGFR overexpression (2+ or 3+). The median and 3-month failure-free survival were 3.6 months and 40% for those patients with low EGFR expression compared with 8.1 and 40% for those with high EGFR expression. CONCLUSIONS: Although 97% of patients with mesothelioma had EGFR overexpression, gefitinib was not active in malignant mesothelioma. EGFR expression does not correlate with failure-free survival.

Adult↗

PubMed2005

Irinotecan for malignant mesothelioma A phase II trial by the Cancer and Leukemia Group B.

PURPOSE: The Cancer and Leukemia Group B (CALGB) conducted a multi-center phase II trial to evaluate the activity of irinotecan in malignant mesothelioma (CALGB protocol 9733). PATIENTS AND METHODS: Twenty-eight patients accrued between January 1998 and January 1999 received irinotecan 125 mg/m2 by intravenous infusion over 90 min weekly for 4 weeks, every 6 weeks. Eligibility included a performance status of 0-2 by CALGB criteria, and no prior chemotherapy. Twenty-five patients had pleural mesothelioma; two patients had peritoneal mesothelioma, and one patient had pericardial mesothelioma. Sixty-one percent of patients had epithelial histology. RESULTS: There were no complete or partial responders. Thirty-three percent of patients had stable disease and 52% were shown to have progressive disease at the first reassessment. One patient was not evaluable for response. Median survival from study entry was 9.3 months (95% CI 4.5-13.2 months); 1-year survival was estimated at 46% (95% CI 28-65%). Toxicity was moderately severe. Grade 3 or 4 toxicities included neutropenia in 28% of patients, lymphopenia in 43%, and diarrhea in 18%. Three patients died of treatment-related toxicities. All three experienced grade 4 diarrhea, two also had neutropenic sepsis. CONCLUSION: Single-agent irinotecan in this dose and schedule has considerable toxicity in patients with malignant mesothelioma and has no anti-tumor activity. The relatively long median survival seen in this study principally reflects the prognostic features of the accrued patients.

Adult↗

PubMed2005

Phase II trials of dolastatin-10 in advanced pancreaticobiliary cancers.

BACKGROUND: Pancreaticobiliary malignancies respond poorly to conventional chemotherapy, and novel agents are needed. Dolatstatin-10 is a potent antimitotic pentapeptide isolated from the marine mollusk Dolabella auricularia that inhibits microtubule assembly. We conducted 2 parallel phase II trials of dolastatin-10 in patients with advanced hepatobiliary cancers and pancreatic adenocarcinoma. PATIENTS AND METHODS: Eligible patients had histologically-confirmed metastatic pancreatic adenocarcinoma or metastatic, locally advanced or recurrent cancer of the liver, bile duct or gallbladder, and had received no prior chemotherapy for advanced disease. Dolastatin-10 400 microg/m(2) was administered intravenously by bolus every 21 days. Restaging CT scans were obtained every 2 cycles. RESULTS: Twenty-eight patients (16 hepatobiliary, including 7 hepatomas, 6 cholangiocarcinomas, 2 gallbladder carcinomas, and 12 pancreatic carcinomas) enrolled; 27 were evaluable for response. There were no objective responses. Grade 3/4 neutropenia occurred in 59% of patients and neutropenic fever in 18%. Median and 1-year survival were 5.0 months and 17% for the pancreatic cancer patients, and 3.0 months and 29% for the hepatobiliary patients. Median time to progression was 1.3 months for the pancreatic cancer patients and 1.6 months for the hepatobiliary patients. CONCLUSIONS: Dolastatin-10 is inactive against hepatobiliary and pancreatic carcinomas.

Adult↗

PubMed2005

Evaluation of semiautomated measurements of mesothelioma tumor thickness on CT scans.

RATIONALE AND OBJECTIVES: To evaluate the clinical acceptability of semiautomated methods for the measurement of mesothelioma tumor thickness in computed tomography (CT) scans. MATERIALS AND METHODS: A computer interface was developed to allow the acquisition of semiautomated mesothelioma tumor thickness measurements, which require the manual selection of a point along the outer margin of the tumor in a CT section. After application of an automated lung segmentation method, the computer automatically identifies a corresponding point along the inner margin of the tumor (as represented by the lung boundary), constructs a line segment between the manually selected outer tumor margin point and the computer-determined inner tumor margin point, and computes tumor thickness as the length of this line segment. Three radiologists and oncologists independently reviewed line segments representing the semiautomated measurements generated by three different algorithms at 134 measurement sites in the CT scans of 22 mesothelioma patients. The observers either accepted a measurement line segment or modified it through the interface. Differences between the initial semiautomated measurements and the measurements as modified by the observers were analyzed. RESULTS: The frequency with which observers accepted the semiautomated measurements without modification was as high as 86%. Of all measurements across all observers and methods (1,206 measurements), 89% were changed by 2 mm or less. CONCLUSION: We have developed semiautomated methods to measure mesothelioma tumor thickness. The potential of these methods has been demonstrated through an observer study. We expect these methods to become important tools for the efficient quantification of tumor extent.

Adult↗

PubMed2004

Delivery of a liposomal c-raf-1 antisense oligonucleotide by weekly bolus dosing in patients with advanced solid tumors: a phase I study.

PURPOSE: Rapid cleavage in vivo and inefficient cellular uptake limit the clinical utility of antisense oligonucleotides (AON). Liposomal formulation may promote better intratumoral AON delivery and inhibit degradation in vivo. We conducted the first clinical evaluation of this concept using a liposomal AON complementary to the c-raf-1 proto-oncogene (LErafAON). EXPERIMENTAL DESIGN: A dose escalation study was done to determine the maximum tolerated dose and to characterize the toxicities of LErafAON given as weekly intravenous infusion for 8 weeks to adults with advanced solid tumors. Pharmacokinetic analysis and evaluation of c-raf-1 target suppression in peripheral blood mononuclear cells were included. RESULTS: Twenty-two patients received LErafAON (median 7 infusions; range 1-27) at doses of 1, 2, 4, and 6 mg/kg/week. Across all dose cohorts patients experienced infusion-related hypersensitivity reactions including flushing, dyspnea, hypoxia, rigors, back pain, and hypotension. Prolonged infusion duration and pretreatment with acetaminophen, H1- and H2-antagonists, and corticosteroids reduced the frequency and severity of these reactions. Progressive thrombocytopenia was dose-limiting at 6 mg/kg/week. No objective responses were observed. Two patients treated at the maximum tolerated dose of 4 mg/kg/week had evidence of stable disease, with dosing extended beyond 8 weeks. Pharmacokinetic analysis revealed persistence of detectable circulating rafAON at 24 hours in 7 of 10 patients in the highest 2 dose cohorts. Suppression of c-raf-1 mRNA was noted in two of five patients analyzed. CONCLUSIONS: Dose-independent hypersensitivity reactions and dose-dependent thrombocytopenia limited tolerance of LErafAON. Future clinical evaluation of this approach will depend on modification of the liposome composition.

Adult↗

PubMed2004

Phase II study of the proteasome inhibitor bortezomib (PS-341) in patients with metastatic neuroendocrine tumors.

PURPOSE: This phase II study was undertaken to assess objective response, toxicity, tumor marker response, and pharmacodynamics of bortezomib in patients with metastatic neuroendocrine (carcinoid and islet cell) tumors. EXPERIMENTAL DESIGN: A total of 16 patients with measurable metastatic carcinoid (n=12) or islet cell (n=4) tumors received i.v. bolus of single agent bortezomib at a dose of 1.5 mg/m2 on days 1, 4, 8, and 11 every 21 days. Tumor response was assessed at 12-week intervals using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. All patients were chemotherapy naïve and had Eastern Cooperative Oncology Group performance status of 0 to 1. RESULTS: No patient achieved a partial or a complete remission. The patients received total of 264 doses of therapy with a median of 15 doses per patient. Grade 4 toxicities were not observed. The most common grade 3 adverse events included peripheral sensory neuropathy (37%), diarrhea (25%), vomiting (18%), and ileus (18%). Six of 10 patients who experienced grade 2 to 3 peripheral sensory neuropathy also had grade 2 to 3 dizziness (n=2), orthostatic hypotension (n=2), syncope (n=1), ileus (n=2), or abdominal cramps (n=1). Changes in tumor marker levels did not correlate with tumor response. The mean percentage of 20S proteasome inhibition achieved in whole blood at 1 and 24 hours after bortezomib administration was 68 and 30%, respectively. CONCLUSIONS: Despite achieving the surrogate biologic end point, single-agent bortezomib did not induce any objective responses in patients with metastatic carcinoid or islet cell tumors. Additional investigation is warranted to clarify the possible association of autonomic neuropathy with bortezomib.

Adult↗

PubMed2004

Dose-ranging study of the safety and pharmacokinetics of atrasentan in patients with refractory malignancies.

PURPOSE: Atrasentan is an orally bioavailable selective antagonist of the endothelin receptor ET(A). Due to the potential activity of this agent against prostate cancer, the majority of subjects enrolled in prior studies had been male. This Phase I study sought to determine the toxicity and pharmacokinetics of daily atrasentan in a population of both female and male subjects with advanced malignancies. EXPERIMENTAL DESIGN: Patients with refractory malignancies received atrasentan once daily at doses ranging from 5 mg to 75 mg. At least 3 subjects were treated at each dose level before enrollment began at the next higher dose level. Enrollment for specific dose levels was expanded if any subject experienced serious drug-related toxicity. Plasma concentration profiles for atrasentan were determined after dosing on days 1 and 28. RESULTS: Thirty-five patients received atrasentan at doses from 5 mg to 75 mg. The most frequent drug-related adverse events were headache (60%), rhinitis (49%), and peripheral edema (31%). These toxicities were mild to moderate in severity and reversible on cessation of treatment. Dose escalation was stopped at the 75-mg dose level due to the occurrence of three severe adverse events (2 hyponatremia and 1 hypotension). Atrasentan was rapidly absorbed after oral administration; mean time to maximum observed concentration ranged from 0.3 to 1.7 h. Terminal elimination half-life averaged 26 h. No significant difference between sexes was found in any atrasentan pharmacokinetic parameter tested, including maximum observed plasma concentration, time to maximum observed concentration, minimum observed plasma concentration, area under the plasma concentration-time curve, and elimination rate constant. CONCLUSIONS: Atrasentan is well tolerated in both female and male cancer patients at doses of up to 60 mg/day with dose-limiting toxicity observed at 75 mg/day. The most frequently observed toxicities were headache, rhinitis, and edema. There was no statistically significant difference in atrasentan pharmacokinetics between sexes.

Administration, Oral↗

PubMed2004

A phase I study of cantuzumab mertansine administered as a single intravenous infusion once weekly in patients with advanced solid tumors.

PURPOSE: The purpose is to determine the maximum-tolerated dose, assess the toxicities, characterize the pharmacokinetic behavior, and seek preliminary evidence of biological activity of cantuzumab mertansine when administered as a weekly i.v. infusion without interruption. EXPERIMENTAL DESIGN: Patients with incurable solid tumors that expressed the target antigen for cantuzumab mertansine, CanAg, were treated with doses of cantuzumab mertansine ranging from 40 to 138 mg/m(2). The maximum-tolerated dose was defined as the highest dose at which no more than 1 of 6 patients experienced dose-limiting toxicity. Plasma concentrations of cantuzumab mertansine and total humanized antibody were determined, and area under the plasma concentration-time curve (to the last measured concentration) was calculated. RESULTS: Thirty-nine patients received a total of 280 weekly doses of cantuzumab mertansine. Acute, transient elevation of the hepatic transaminases and reversible fatigue were identified as the dose-limiting toxicities at the highest dose level. The maximum-tolerated dose was determined to be 115 mg/m(2)/week. Evidence of clinical activity was noted in 3 patients. Pharmacokinetic analyses revealed that the pharmacokinetic variability was moderate, without evidence of dose dependency. Furthermore, the drug had a long terminal half-life ( approximately 40 h). CONCLUSIONS: This study identified a safe and tolerable dose of the novel immunoconjugate prodrug cantuzumab mertansine. The evidence of antitumor activity suggests that additional clinical development is warranted, with a focus on tumors that express high levels of CanAg and which are known to be sensitive to antimicrotubule agents.

Adult↗

PubMed2004

Capecitabine in malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B (39807).

PURPOSE: The CALGB performed a phase II multicenter study to evaluate the activity of oral capecitabine in patients with malignant mesothelioma (CALGB 39807). PATIENTS AND METHODS: Between November 15, 2000 and August 31, 2001, 27 patients with mesothelioma were enrolled in this study. Capecitabine was administered at 2500 mg/m(2) per day divided in two doses for 14 days followed by a seven-day break. Cycles were repeated every 21 days with restaging performed every two cycles and therapy continuing for up to six cycles. One patient withdrew from the study prior to receiving therapy and is removed from further analysis. Eligibility criteria included no prior treatment, PS 0-1 by CALGB criteria and histologically documented mesothelioma. PATIENT CHARACTERISTICS: gender; male 19 (73%), female seven; median age 70 (range 40-81); histology: epithelial 15 (58%), mixed eight (31%), unclassified three; site of origin pleura, 25 (96%); weight loss in previous six months of more than 10% in seven (27%), symptoms longer than six months in five (19%). RESULTS: One patient (4%) had a confirmed PR while 10 (38%) achieved SD for 2-6 cycles. Ten patients (38%) had PD as their best response. There were three patients unevaluable for response and two early deaths. Median survival and failure free survival were 4.9 (95% CI 4-10.8) and 2.4 (95% CI 1.5-4.2) months respectively with a one-year survival of 23% (95% CI 11-49%). Grade three or greater toxicities encountered by at least 10% of patients included lymphopenia (12%), fatigue (12%), dehydration (12%) and diarrhea (15%). Three patients (12%) had grade three skin toxicity or hand-foot syndrome. One patient died of treatment related toxicity during cycle one. CONCLUSION: The antitumor activity of capecitabine is insufficient to warrant further exploration in patients with malignant mesothelioma.

Administration, Oral↗

PubMed2004

Moving beyond chemotherapy: novel cytostatic agents for malignant mesothelioma.

It is now known that vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are autocrine growth factors in malignant mesothelioma; epidermal growth factor receptor (EGFR) is also highly overexpressed. Cytotoxic drugs that target these growth factors offer fresh potential for the treatment of mesothelioma. Clinical trials have recently been initiated to evaluate the anti-tumour activity of the VEGF inhibitors SU5416, bevacizumab and thalidomide. ZD1839 (Iressa, AstraZeneca), an inhibitor of EGFR tyrosine kinase, is also being evaluated. Two clinical trials are planned to evaluate the two PDGF inhibitors Gleevec (Imatinib mesylate, STI-571, Novartis Pharmaceuticals) and PTK787 (Novartis Pharmaceuticals).

Antineoplastic Agents↗

PubMed2004

9-Aminocamptothecin (9-AC) given as a 120-hour continuous infusion in patients with advanced adenocarcinomas of the stomach and gastroesophageal junction: A phase II trial of the University of Chicago phase II consortium.

9-Aminocamptothecin (9-AC) is a water-insoluble camptothecin derivative that demonstrated broad activity in pre-clinical studies. In vitro, greater anti-tumor efficacy can be achieved with prolonged administration. A minor response was observed in gastric cancer in a phase I study. We conducted a phase II study of 9-AC in 15 patients with previously untreated metastatic gastric cancer and adenocarcinoma of the gastroesophageal junction. 9-AC was administered at a dose of 25 microg/m(2)/h over 120 hours (3000 microg/m(2) over 5 days) on two consecutive weeks every 21 days. Fourteen patients were evaluable for response. There were no objective responses. Three patients had stable disease lasting a median of 3.4 months (range 1.6-4.3 months). Median time to progression was 1.4 months; median survival was 5.2 months. Grade 3 neutropenia developed in 20% of patients, and anemia in 7%. Grade 3 nausea and fatigue each developed in 7% of patients. We conclude that 9-AC given by 120-hour continuous infusion demonstrates no clinical activity in patients with metastatic gastric cancer.

Adenocarcinoma↗

PubMed2004

A Phase II trial of fixed dose rate gemcitabine in patients with advanced biliary tree carcinoma.

Gemcitabine is a commonly used chemotherapy for biliary tree carcinomas, achieving response rates of 10% to 60%. Preclinical studies indicate that fixed dose rate infusion optimizes accumulation of gemcitabine triphosphate and may enhance the clinical activity of gemcitabine. We conducted a phase II study of fixed dose rate gemcitabine in 15 chemotherapy-naive patients with advanced cholangiocarcinoma and gallbladder carcinoma. Gemcitabine was administered at a dose of 1500 mg/m2 over 150 minutes weekly for 3 weeks every 28 days. Fourteen patients were evaluable for response. No complete or partial responses were observed. Two patients (13%) had stable disease lasting a median of 9 weeks. The median time to progression was 9 weeks; median survival was 20 weeks. There was considerable grade 3/4 hematologic toxicity, including neutropenia in 49% of patients, leukopenia in 40%, anemia in 27%, and thrombocytopenia in 27%. Grade 3/4 nonhematologic toxicities were minimal. We conclude that fixed dose rate gemcitabine results in significant myelosuppression and has minimal activity in patients with biliary tree carcinoma.

Adult↗