Phase II trial of irinotecan plus celecoxib in adults with recurrent malignant glioma

BACKGROUND: In the current study, the authors report a Phase II trial of irinotecan (CPT-11), a topoisomerase I inhibitor active against malignant glioma (MG), with celecoxib, a selective COX-2 inhibitor, among MG patients with recurrent disease. METHODS: Patients with MG at any type of recurrence received CPT-11, administered as a 90-minute intravenous infusion on Weeks 1, 2, 4, and 5 of each 6-week cycle plus celecoxib, which was administered continuously at a dose of 400 mg twice a day. CPT-11 was given at a dose of 350 mg/m(2) for patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and at a dose of 125 mg/m(2) for those patients not receiving EIAEDs. Assessments were performed after every cycle. The primary endpoint was radiographic response and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and therapeutic safety. RESULTS: Thirty-four of the 37 patients enrolled in the current study (92%) were diagnosed with recurrent GBM and 3 patients (8%) were diagnosed with recurrent anaplastic astrocytoma (AA). Twenty-one patients were receiving EIAEDs and 16 patients were not. The median follow-up time was 76.9 weeks. Concomitant CPT-11 plus celecoxib was found to be well tolerated and safe. Hematologic toxicities of >/= Grade 3 (according the second version of the Common Toxicity Criteria of the National Cancer Institute) reportedly complicated 8.6% of treatment courses. Grade 3 diarrhea, the most commonly reported nonhematologic toxicity, occurred with equal frequency (8%), regardless of whether the patient was receiving EIAED. Six patients (16%), all whom were diagnosed with recurrent GBM, achieved an objective radiographic response whereas an additional 13 patients (35%) achieved stable disease. The median PFS was 11.0 weeks and the 6-month PFS was reported to be 25.1%. The median OS was 31.5 weeks. CONCLUSIONS: The results of the current study confirm that CPT-11 plus celecoxib can be safely administered concurrently at full dose levels, and that this regimen has encouraging activity among heavily pretreated patients with recurrent MG.     

Phase I dose-finding and pharmacokinetic trial of irinotecan hydrochloride (CPT-11) using a once-every-three-week dosing schedule for patients with advanced solid tumor malignancy.

A Phase I study was performed to determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic profile of irinotecan (CPT-11) and its active metabolites when given on a once-every-3-week schedule. Thirty-four patients with advanced refractory solid malignancies were treated with CPT-11 (240-340 mg/m2) administered as a 90-min i.v. infusion every 3 weeks. Patients were divided into two groups: those with and those without prior abdominal/pelvic (AP) radiotherapy. Gastrointestinal toxicity (nausea, vomiting, and diarrhea) and hematological toxicity (leukopenia and neutropenia) were dose-limiting side effects. Other common toxicities included anorexia, asthenia, and acute cholinergic symptoms (abdominal cramps, diaphoresis, and lacrimation). For patients with no prior AP radiation therapy, the MTD was determined to be 320 mg/m2, whereas those with prior AP radiation therapy had a MTD of 290 mg/m2. Dose-proportional increases in the mean area under the concentration-time curves for CPT-11, SN-38, and SN-38G were not observed over the narrow dose range studied. Mean values of terminal phase half-life, clearance, terminal phase volume of distribution, and steady-state volume of distribution for CPT-11 were 12.4 +/- 1.8 h, 13.0 +/- 3.8 liters/h/m2, 234 +/- 83 liters/m2, and 123 +/- 38 liters/m2, respectively. The pharmacodynamic analyses indicated the strongest correlation to be between SN-38 area under the concentration-time curves and neutropenia (p = 0.60; P = 0.001). A total of five responses (one complete response and four partial responses) were observed in the cohort of 32 patients with previously treated metastatic colorectal carcinoma. In conclusion, gastrointestinal toxicity and hematological toxicity were the dose-limiting toxicities of CPT-11 when administered as a 90-min infusion every 3 weeks. In this trial, the recommended Phase II starting dose for patients with no prior AP radiation therapy was found to be 320 mg/m2; for patients with prior AP radiation, the recommended Phase II starting dose was 290 mg/m2. This once-every-3-week schedule has been incorporated into a Phase I trial of CPT-11 combined with 5-fluorouracil and leucovorin.     

Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis

Epidemiological observations and laboratory research have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colon cancer and that the inhibition of colon carcinogenesis by NSAIDs is mediated through the modulation of prostaglandin production by rate-limiting enzymes known as cyclooxygenases (COXs). Because traditional NSAIDs inhibit both COX-1 and COX-2, these drugs induce side effects, such as gastrointestinal ulceration and renal toxicity, through the inhibition of the constitutive COX-1. Overexpression of COX-2 has been observed in colon tumors; therefore, specific inhibitors of COX-2 could serve as chemopreventive agents. Our previous study has shown that celecoxib, an inhibitor of COX-2, while sparing COX-1, inhibited azoxymethane (AOM)-induced colon tumorigenesis when administered during both initiation and postinitiation stages, ie., celecoxib administered continuously before, during, and after carcinogen treatment. This study examined the dose-response effect of celecoxib when administered during the initiation and postinitiation stages. In addition, the chemopreventive effects of high-dose celecoxib administered during the promotion/progression stage of colon carcinogenesis, ie., continuous celecoxib administration beginning 14 weeks after the carcinogen treatment, was determined in male F344 rats. We also measured the steady-state levels of celecoxib in the plasma of animals given this inhibitor. Groups of 5-week-old male F344 rats were fed either a control diet or experimental diets containing 500, 1000, or 1500 ppm celecoxib. At 7 and 8 weeks of age, rats scheduled for carcinogen treatment were injected s.c. with AOM at a dose rate of 15 mg/kg body weight/week. Groups of animals destined for the promotion/ progression study and initially receiving the control diet were switched to a diet containing 1500 ppm celecoxib beginning 14 weeks after the second AOM treatment. All rats remained on their respective dietary regimens until the termination of the study, ie., 52 weeks, and were then sacrificed. Colon tumors were evaluated histopathologically. Administration of 500, 1000, or 1500 ppm celecoxib during the initiation and postinitiation stages significantly inhibited the incidence (P < 0.01 to P < 0.0001) as well as the multiplicity (P < 0.01 to P < 0.0001) of adenocarcinomas of the colon in a dose-dependent manner. Importantly, administration of 1500 ppm celecoxib during the promotion/progression stage also significantly suppressed the incidence and multiplicity of adenocarcinomas of the colon (P < 0.01). Also, administration of celecoxib to the rats during the initiation and postinitiation periods and throughout the promotion/progression stage strongly suppressed colon tumor volume (P < 0.0002 to P < 0.001). The steady-state plasma concentration of celecoxib increases somewhat with the dose. Thus, in this model system, the chemopreventive efficacy of celecoxib is dose-dependent when this COX-2 inhibitor is administered during the initiation and postinitiation periods. This study provides the first evidence that celecoxib is also very effective when it is given during the promotion/progression stage of colon carcinogenesis, indicating that the chemopreventive efficacy is achieved during the later stages of colon tumor development. This suggests that celecoxib may potentially be an effective chemopreventive agent for the secondary prevention of colon cancer in patients with familial adenomatous polyposis and sporadic polyps.     

Pilot randomized phase II study of celecoxib in oral premalignant lesions

PURPOSE: Cyclooxygenase-2 (COX-2)-specific inhibition suppresses carcinogenesis in preclinical models and is a promising strategy for preventing oral cancer. In this pilot randomized phase II study, we evaluated the efficacy and safety of the COX-2 inhibitor celecoxib in patients with oral premalignant lesions (OPL). EXPERIMENTAL DESIGN: Patients were randomly assigned to placebo (n=18), celecoxib 100 mg twice daily (n=17), or celecoxib 200 mg twice daily (n=15) for 12 weeks. Six additional patients received celecoxib (400 mg twice daily) in an unblinded extension of the study. Biopsies were obtained at baseline and week 12. All patients entering the study were required to have at least one histologically confirmed early (atypical hyperplasia, atypical hyperkeratosis, or mild dysplasia) or advanced (moderate to severe dysplasia) OPL. RESULTS: Forty-nine patients (46 of 50 randomized and 3 of 6 open label) were evaluable for efficacy analyses. There were no statistically significant differences between the response rates of the randomly assigned arms: placebo, 33.3% (6 of 18); celecoxib 100 mg twice daily, 41.2% (7 of 17); and celecoxib 200 mg twice daily, 20.0% (3 of 15). Two patients responded on celecoxib 400 mg twice daily. Celecoxib was generally well tolerated. Patients with higher baseline COX-2 mRNA levels had an increased risk of disease progression within 3 months. CONCLUSIONS: Celecoxib at 100 or 200 mg twice daily was ineffective in controlling OPLs in this randomized controlled trial. This result and cardiovascular toxicity results of other (large scale) randomized controlled trials of selective COX-2 inhibitors have discouraged the continued investigation of these agents in oral cancer chemoprevention. Better methods for identifying high-risk patients and more active interventions are needed for future oral cancer chemoprevention trials.     

A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies.

PURPOSE: The purpose of this study was to evaluate the toxicity and pharmacodynamic behavior of the novel proteasome inhibitor PS341 administered as a twice weekly i.v. bolus for 2 weeks, followed by a 1-week recovery period in patients with advanced solid tumor malignancies. EXPERIMENTAL DESIGN: In this Phase I trial, 43 patients were treated with PS341 in doses ranging from 0.13 to 1.56 mg/m2/dose. A standard Phase I design was used. Pharmacodynamic studies were performed to access 20S proteasome activity. RESULTS: Forty-three patients were treated with 89 cycles of PS341. Patients were heavily pretreated. Dose-limiting toxicities on this schedule were diarrhea and sensory neurotoxicity. Other side effects seen were fatigue, fever, anorexia, nausea, vomiting, rash, pruritus, and headache. There was no dose-limiting hematological toxicity. A dose-related inhibition of 20S proteasome activity with increasing dose of PS341 was seen. There was one major response in a patient with refractory non-small cell lung carcinoma. CONCLUSIONS: Given the results of this trial, it is safe and reasonable to recommend treatment with PS341 on the schedule used in this trial at 1.56 mg/m2/dose in Phase II trials. Particular care should be taken with patients with preexisting neuropathy. Further testing in Phase II trials is warranted.     

A Phase II study of acute toxicity for Celebrex (celecoxib) and chemoradiation in patients with locally advanced cervical cancer: primary endpoint analysis of RTOG 0128

PURPOSE: To determine treatment-related acute toxicity rates in patients with locally advanced cervical cancer treated by oral celecoxib, i.v. cisplatin and 5-FU, and concurrent pelvic radiation therapy. METHODS AND MATERIALS: Eligible patients on this RTOG Phase I-II study for advanced cervix cancer included FIGO Stage IIB-IVA or patients with FIGO Stage IB through IIA with biopsy proven pelvic node metastases or tumor size > or =5 cm. Patients were treated with pelvic radiotherapy and brachytherapy. Celecoxib was prescribed at 400 mg twice daily beginning on day 1 for 1 year. Cisplatin (75 mg/m2) and 5-FU (1g/m2 for 4 days) were administered every 3 weeks times 3. The primary end point of the study was treatment related toxicity. RESULTS: Between August 2001 and March 2004, 84 patients were accrued to the study and 77 patients were evaluable for toxicity. Regarding the primary end point, toxicities were observed in the following areas: blood/bone marrow (16), gastrointestinal (14), pain (7), renal/genitourinary (6), cardiovascular (3), hemorrhage (1), and neurologic (1). For the first 75 evaluable patients, a toxicity failure was identified in 36 patients for a rate of 48%. CONCLUSIONS: Celecoxib at 400 mg twice daily together with concurrent cisplatin and 5-FU and pelvic radiotherapy has a high incidence of acute toxicities. The most frequent toxicities were hematologic. Albeit, the toxicity was deemed excessive in this trial, the rate of toxicities was not too different compared to other recent experiences with concurrent chemoradiation for advanced cervix cancer.     

Phase I and pharmacokinetic study of 10-propargyl-10-deazaaminopterin, a new antifolate.

The 10-deazaaminopterins are a new class of rationally designed antifolates demonstrating greater antitumor effects than methotrexate in murine tumor models and human tumor xenografts. Their design was aimed at improving membrane transport and polyglutamylation in tumor cells, resulting in increased intracellular accumulation and enhanced cytotoxicity. Compared with other 4-aminofolate analogues, 10-propargyl-10-deazaaminopterin (PDX) is the most efficient permeant for the RFC-1-mediated internalization and substrate for folylpolyglutamate synthetase. PDX demonstrates greater in vitro and in vivo antitumor efficacy than methotrexate or edatrexate. We undertook a Phase I study with PDX to identify the potential toxicities and define an optimal dose and schedule. Thirty-three patients were enrolled, all of whom had non-small cell lung cancer (NSCLC) and were treated previously with a median of two prior chemotherapy regimens. Initially, PDX was administered weekly for 3 weeks in a 4-week cycle. Mucositis requiring dose reduction and/or delay in the first cycle occurred in four of six patients treated at the initial dose level (30 mg/m2), making this the maximal tolerated dose for PDX given on this schedule. The treatment schedule was then modified to every 2 weeks. Twenty-seven patients were treated twice weekly with a total of 102 four-week cycles (median, 2 cycles/patient). Mucositis was the dose-limiting toxicity, with grade 3 and 4 mucositis occurring in the first two patients treated at the 170 mg/m2 dose level. Other toxicities were mild and reversible. No neutropenia was observed. The recommended Phase II dose is 150 mg/m2 biweekly. At that dose level, the mean area under the curve was 20.6 micromol x h, and the mean terminal half-life was 8 h. Two patients with stage IV NSCLC had major objective responses, and five patients had stable disease for 7 (two patients), 9 (one patient), 10 (one patient), and 13 months (one patient). PDX is a new antifolate with manageable toxicity and evidence of antitumor activity in NSCLC. A Phase II trial in NSCLC and a Phase I trial with paclitaxel are under way. These studies will also quantitate the expression of genes controlling internalization (RFC-1) and polyglutamylation of PDX in tumor cells as correlates of response.     

Post-study aspirin intake and factors motivating participation in a colorectal cancer chemoprevention trial.

We conducted an exploratory, cross-sectional study examining motivators for study participation and post-study aspirin intake in a chemoprevention trial. The parent clinical trial aimed to determine the optimal aspirin dose for colorectal cancer chemoprevention using prostaglandin E(2) as a mucosal biomarker. This trial was randomized and double-blinded in 60 subjects with prior sporadic colorectal adenoma(s) and evaluated three aspirin doses or placebo taken once daily for 4 weeks. A cross-section of 55 evaluable participants who completed the chemoprevention trial were mailed a 16-item, self-administered questionnaire evaluating subject demographics, motivational factors, and health-related behaviors within the framework of Pender's Health Promotion Model (HPM). Forty-three (78%) of 55 participants returned the questionnaire. The most important motivators for study participation were altruistic, i.e., a desire to help future generations at risk of colorectal cancer and personal factors including a desire to reduce one's own risk. Nineteen (44%) of 43 respondents reported that they chose to take daily aspirin post-study without knowledge of study results. At a mean follow-up of 17.3 months, 18 of these 19 subjects continued to take aspirin regularly. Regular use of vitamin supplements pre-study was found to correlate with post-study aspirin use (Mann-Whitney U test, U = 154.0; P = 0.04). We demonstrate, for the first time, that participation in a chemoprevention study can influence the decision to continue the study drug, if available, to reduce perceived cancer risk. Continued post-study aspirin intake indicates an impact of study participation on a health-related behavior and underscores the importance of patient education to guide such decision-making.     

Phase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme: interim analysis of safety and tolerability

PURPOSE: To assess interim safety and tolerability of a 10-patient, Phase II pilot study using bevacizumab (BV) in combination with temozolomide (TMZ) and regional radiation therapy (RT) in the up-front treatment of patients with newly diagnosed glioblastoma. METHODS AND MATERIALS: All patients received standard external beam regional RT of 60.0 Gy in 30 fractions started within 3 to 5 weeks after surgery. Concurrently TMZ was given daily at 75 mg/m(2) for 42 days during RT, and BV was given every 2 weeks at 10 mg/kg starting with the first day of RT/TMZ. After a 2-week interval upon completion of RT, the post-RT phase commenced with resumption of TMZ at 150 to 200 mg/m(2) for 5 days every 4 weeks and continuation of BV every 2 weeks. RESULTS: For these 10 patients, toxicities were compiled until study discontinuation or up to approximately 40 weeks from initial study treatment for those remaining on-study. In terms of serious immediate or delayed neurotoxicity, 1 patient developed presumed radiation-induced optic neuropathy. Among the toxicities that could be potentially treatment related, relatively high incidences of fatigue, myelotoxicity, wound breakdown, and deep venous thrombosis/pulmonary embolism were observed. CONCLUSION: The observed toxicities were acceptable to continue enrollment toward the overall target group of 70 patients. Preliminary efficacy analysis shows encouraging mean progression-free survival. At this time data are not sufficient to encourage routine off-label use of BV combined with TMZ/RT in the setting of newly diagnosed glioblastoma without longer follow-up, enrollment of additional patients, and thorough efficacy assessment.     

Phase I clinical investigation of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate (NSC 312887), a new purine antimetabolite

9-beta-D-Arabinofuranosyl-2-fluoroadenine 5'-monophosphate (NSC 312887) is a new purine antimetabolite that has been evaluated in a Phase I clinical trial. The schedule of administration consisted of a single i.v. infusion over a period of 30 min once each day for 5 consecutive days, repeated at 4-week intervals. Thirteen patients received 30 courses of the drug in a dose range of 18 to 40 mg/sq m/day. Granulocytopenia and thrombocytopenia were dose limiting. Repeated courses produced similar degrees of granulocytopenia, but in 7 of 7 patients receiving 2 or more courses, the degree of thrombocytopenia was less severe during the first than during subsequent courses. Myelosuppression in humans was more severe than predicted from the mouse model. Lymphopenia was profound at all dose levels, but reversed within 3 weeks. Somnolence occurred during infusion in 8 of 13 patients, but quickly cleared after the infusion was completed. The infused drug was rapidly dephosphorylated in plasma and then cleared so there was no cumulation of drug in plasma when it was rapidly infused once each day in these doses. Phase II studies of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate are planned at a starting dose of 18 mg/ sq m/day for patients with prior chemotherapy or radiotherapy and 25 mg/sq m/day for those without prior therapy, as a single dose on each of 5 consecutive days repeated at 21- to 28-day intervals.     

Phase II trial of gefitinib in recurrent glioblastoma.

PURPOSE: To evaluate the efficacy and tolerability of gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. PATIENTS AND METHODS: This was an open-label, single-center phase II trial. Fifty-seven patients with first recurrence of a glioblastoma who were previously treated with surgical resection, radiation, and usually chemotherapy underwent an open biopsy or resection at evaluation for confirmation of tumor recurrence. Each patient initially received 500 mg of gefitinib orally once daily; dose escalation to 750 mg then 1,000 mg, if a patient received enzyme-inducing antiepileptic drugs or dexamethasone, was allowed within each patient. RESULTS: Although no objective tumor responses were seen among the 53 assessable patients, only 21% of patients (11 of 53 patients) had measurable disease at treatment initiation. Seventeen percent of patients (nine of 53 patients) underwent at least six 4-week cycles, and the 6-month event-free survival (EFS) was 13% (seven of 53 patients). The median EFS time was 8.1 weeks, and the median overall survival (OS) time from treatment initiation was 39.4 weeks. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent at higher doses. Withdrawal caused by drug-related adverse events occurred in 6% of patients (three of 53 patients). Although the presence of diarrhea positively predicted favorable OS from treatment initiation, epidermal growth factor receptor expression did not correlate with either EFS or OS. CONCLUSION: Gefitinib is well tolerated and has activity in patients with recurrent glioblastoma. Further study of this agent at higher doses is warranted.     

Phase I and pharmacokinetic study of prinomastat, a matrix metalloprotease inhibitor.

PURPOSE: Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these MMPs has been postulated to block tumor invasion and metastasis. This Phase I, dose-escalation study was designed to evaluate the acute and chronic toxicities of various doses of prinomastat and to determine prinomastat pharmacokinetics. Experimental Design: Seventy-five patients with advanced cancer were given 1, 2, 5, 10, 25, 50, or 100 mg prinomastat orally twice daily until tumor progression or development of significant toxicities. Prinomastat pharmacokinetics were measured on day 29 of therapy. RESULTS: The primary toxicities identified were joint and muscle-related pain, which were generally reversible with treatment rest and/or dose reduction. No dose-limiting toxicities were noted within the first 4 weeks of treatment, but grade 2-3 arthralgias and myalgias were noted 2-3 months after initiation of therapy in >25% of patients at doses >25 mg twice a day. The frequency and severity of symptoms were dose related. Plasma prinomastat concentrations greater than the K(i) for MMPs 2 and 9 were achieved at all of the dose levels. CONCLUSIONS: Doses of 5-10 mg bid were recommended for additional trials, because this dose range was well tolerated for a treatment duration of at least 3 months and achieves trough plasma concentrations 10-100-fold greater than the K(i) (in vitro inhibition constant) for the targeted MMPs (2 and 9).     

Weekly docetaxel therapy is useful for gastric carcinoma as a second-line chemotherapy

In the present study, we demonstrate the results of weekly administered docetaxel treatments as a second-line chemotherapy after TS-1 treatment in 4 gastric cancer patients. Twenty-five mg/m2 of docetaxel was administered once a week for 3 weeks followed by a 1-week rest period as one cycle. The treatment was continued for 2 to 16 weeks. In case 1, a 60% reduction of the primary tumor was observed for 20 weeks. In cases 2 and 3, the decrease of tumor marker was observed. In one case, progression of the tumor was observed and the treatment was not performed. As for adverse effects, no hematological toxicity was observed; however, in one case, grade 2 hair loss, pleural effusion and grade 2 nail changes were observed. These results indicate that the weekly docetaxel therapy is useful for gastric carcinoma patients, as it reduces the hematologic toxicities and improves the quality of life of the patients in the outpatient setting.     

A phase II trial of the cyclin-dependent kinase inhibitor flavopiridol in patients with previously untreated stage IV non-small cell lung cancer.

PURPOSE: Flavopiridol is a potent cyclin-dependent kinase inhibitor with preclinical activity against non-small cell lung cancer (NSCLC), inhibiting tumor growth in vitro and in vivo by cytostatic and cytotoxic mechanisms. A Phase II trial was conducted to determine the activity and toxicity of flavopiridol in untreated patients with metastatic NSCLC. EXPERIMENTAL DESIGN: A total of 20 patients were treated with a 72-h continuous infusion of flavopiridol every 14 days at a dose of 50 mg/m(2)/day and a concentration of 0.1-0.2 mg/ml. Dose escalation to 60 mg/m(2)/day was permitted if no significant toxicity occurred. Response was initially assessed after every two infusions; patients treated longer than 8 weeks were then assessed after every four infusions. Plasma levels of flavopiridol were measured daily during the first two infusions to determine steady-state concentrations. RESULTS: This study was designed to evaluate a total of 45 patients in two stages. However, because no objective responses were seen in the first 20 patients, the early-stopping rule was invoked, and patient accrual was halted. In four patients who received eight infusions, progression was documented at 15, 20, 40, and 65 weeks, respectively. The most common toxicities included grade 1 or 2 diarrhea in 11 patients, asthenia in 10 patients, and venous thromboses in 7 patients. The mean +/- SD steady-state concentration of drug during the first infusion was 200 +/- 89.9 nM, sufficient for cytostatic effects in in vitro models. CONCLUSIONS: At the current doses and schedule, flavopiridol does not have cytotoxic activity in NSCLC, although protracted periods of disease stability were observed with an acceptable degree of toxicity.     

A multicenter phase II trial of thalidomide and celecoxib for patients with relapsed and refractory multiple myeloma.

Preclinical data indicates that cyclooxygenase-2 (COX-2) inhibition impairs plasma cell growth and potentially synergizes with thalidomide. We performed a trial in previously treated patients with myeloma using thalidomide up to a maximum dose of 800 mg/d with celecoxib (400 mg bid). Outcomes were compared with a prior trial of thalidomide. Sixty-six patients with median age of 67 (range, 43-85) received a median dose of thalidomide and celecoxib of 400 and 800 mg/d, respectively, with median durations of treatment of 27 and 13 weeks, respectively. The most common toxicities associated with premature discontinuation of celecoxib (n = 30 of 53, 57%) were fluid retention and deterioration of renal function. Overall response rate (RR) was 42% and with 20 months median follow-up; the actuarial median progression-free survival and overall survival were 6.8 and 21.4 months, respectively. Unlike our prior study, age >65 years was not predictive of inferior RR due to improvement in RR in older patients with the combination (37% versus 15%, P = 0.08). The RR was superior in patients who received a total dose of celecoxib exceeding 40 g in the first 8 weeks of therapy (62% versus 30%, P = 0.021). Progression-free survival and overall survival were also improved. Other predictors for inferior progression-free survival were age >65 years (P = 0.016) and elevated beta(2)-microglobulin (P = 0.017). This study provides evidence that the addition of high-dose celecoxib adds to the antimyeloma activity of thalidomide but this comes with unacceptable toxicity. Future studies should use newer COX-2 inhibitors with thalidomide, or their respective derivatives.     

Effects of chemical form of selenium on plasma biomarkers in a high-dose human supplementation trial.

Intervention trials with different forms of selenium are under way to assess the effects of selenium supplements on the incidence of cancer and other diseases. Plasma selenium biomarkers respond to selenium administration and might be useful for assessing compliance and safety in these trials. The present study characterized the effects of selenium supplementation on plasma selenium biomarkers and urinary selenium excretion in selenium-replete subjects. Moderate (approximately 200 microg/d) to large (approximately 600 microg/d) selenium supplements in the forms sodium selenite, high-selenium yeast (yeast), and l-selenomethionine (selenomethionine) were administered. Subjects were randomized into 10 groups (placebo and three dose levels of each form of selenium). Plasma biomarkers (selenium concentration, selenoprotein P concentration, and glutathione peroxidase activity) were determined before supplementation and every 4 weeks for 16 weeks. Urinary selenium excretion was determined at 16 weeks. Supplementation with selenomethionine and yeast raised the plasma selenium concentration in a dose-dependent manner. Selenite did not. The increased selenium concentration correlated with the amount of selenomethionine administered. Neither glutathione peroxidase activity nor selenoprotein P concentration responded to selenium supplementation. Urinary selenium excretion was greater after selenomethionine than after selenite, with excretion after yeast being intermediate and not significantly different from either of the other two. We conclude that plasma selenium concentration is useful in monitoring compliance and safety of selenium supplementation as selenomethionine but not as selenite. Plasma selenium seems to reflect the selenomethionine content of yeast but not the other yeast selenium forms. As judged by urinary selenium excretion, selenium in the form of selenomethionine is better absorbed than selenite.     

A phase I clinical trial of thoracic radiotherapy and concurrent celecoxib for patients with unfavorable performance status inoperable/unresectable non-small cell lung cancer.

OBJECTIVES: Preclinical observations that selective cyclooxygenase-2 inhibitors enhance in vitro cell radiosensitivity and in vivo tumor radioresponse led to clinical trials testing therapeutic efficacy of these agents. Our study was designed to determine whether the COX-2 inhibitor celecoxib could be safely administered in doses within those approved by the Food and Drug Administration when used concurrently with thoracic radiotherapy in patients with poor prognosis non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: The trial consisted of three cohorts of patients: (a) locally advanced NSCLC with obstructive pneumonia, hemoptysis, and/or minimal metastatic disease treated with 45 Gy in 15 fractions; (b) medically inoperable early-stage NSCLC treated with definitive radiation of 66 Gy in 33 fractions; and (c) patients who received induction chemotherapy but who were not eligible for concurrent chemoradiotherapy trials. These patients received 63 Gy in 35 fractions. Celecoxib was administered p.o. on a daily basis 5 days before and throughout the course of radiotherapy. Celecoxib doses were escalated from 200, 400, 600, to 800 mg/d given in two equally divided doses. Two to eight patients of each cohort were assigned to each dose level of celecoxib. RESULTS: Forty-seven patients were enrolled in this protocol (19 in cohort I, 22 in cohort II, and 6 in cohort III). The main toxicities were grades 1 and 2 nausea and esophagitis, and they were independent of the dose of celecoxib or radiotherapy schedule. Only two patients in group II developed grade 3 pneumonitis 1 month after treatment, one on 200 mg, and the other on 400 mg celecoxib. Celecoxib-related toxicity developed in 3 of 47 patients: an uncontrolled hypertension in one patient on 800 mg celecoxib and hemorrhagic episodes in 2 patients (shoulder hematoma in one and hemoptysis in the other) on 200 mg celecoxib who were on warfarin for other medical reasons. Of 37 patients evaluable for tumor response, 14 had complete response, 13 partial responses, and 10 stable or progressive disease. The actuarial local progression-free survival was 66.0% at 1 year and 42.2% at 2 years following initiation of radiotherapy. CONCLUSIONS: These results show that celecoxib can be safely administered concurrently with thoracic radiotherapy when given up to the highest Food and Drug Administration-approved dose of 800 mg/d, which we used. A maximal tolerated dose was not reached in this study. The treatment resulted in actuarial local progression-free survival of 66.0% at 1 year and 42.2% at 2 years, an encouraging outcome that warrants further assessment in a phase II/III trial.     

Antitumor enhancement of celecoxib,a selective Cyclooxygenase-2 inhibitor,in a Lewis lung carcinoma expressing Cyclooxygenase-2

Background

The goal of this study was to determine the effects of a selective Cyclooxygenase (COX)-2 inhibitor on the inhibition of tumor growth and pulmonary metastasis in a Lewis Lung Carcinoma (LLC) animal model.

Methods

For immunoblot analysis of COX-2 and PGE2, cells were treated with irradiation in the presence or absence of celecoxib. The right thighs of male, 6-week old C57/BL mice were subcutaneously injected with 1 × 10⁶ LLC cells. The animals were randomized into one of six groups: (1) no treatment, (2) 25 mg/kg celecoxib daily, (3) 75 mg/kg celecoxib daily, (4) 10 Gy irradiation, (5) 10 Gy irradiation plus 25 mg/kg celecoxib daily, and (6) 10 Gy irradiation plus 75 mg/kg celecoxib daily. Mice were irradiated only once, and celecoxib was administered orally. Mice were irradiated with 4-MV photons once the tumor volume of the control group reached 500 mm³. All mice were sacrificed when the mean tumor volume of control animals grew to 4000 mm³. The left lobes of the lungs were extracted for the measurement of metastatic nodules.

Results

Irradiation resulted in a dose-dependent increase in PGE2 production. PGE2 synthesis decreased markedly after treatment with celecoxib alone or in combination with irradiation. Compared to mice treated with low dose celecoxib, mean tumor volume decreased significantly in mice treated with a high dose of celecoxib with or without irradiation. Mice treated with a high dose celecoxib alone, with irradiation alone, or with irradiation plus celecoxib had markedly fewer metastatic lung nodules than controls. The mean metastatic area was the smallest for mice treated with irradiation plus a high dose celecoxib.

Conclusion

Oral administration of high dose celecoxib significantly inhibited tumor growth, as compared to a low dose treatment. Radiotherapy in combination with high dose celecoxib delayed tumor growth and reduced the number of pulmonary metastases to a greater extent than celecoxib or radiotherapy alone.     

Final results of a phase II clinical trial of weekly docetaxel in combination with capecitabine in anthracycline-pretreated metastatic breast cancer

The addition of capecitabine to docetaxel on a 3-week schedule resulted in superior response rate, increased time to progression (TTP), and improved overall survival in patients with anthracycline-pretreated metastatic breast cancer (MBC). Because the toxicity profile of weekly docetaxel differs from the standard 21-day docetaxel schedule, we performed a phase I/II trial to test the efficacy and safety of weekly docetaxel in combination with capecitabine given for 14 days every 21 days. The phase I study identified the doses of docetaxel (30 mg/m2 weekly) and capecitabine (900 mg/m2 twice daily on days 1-14 every 21 days) used in phase II. Twenty female patients with measurable or assessable MBC were enrolled. Eighteen patients had previously received anthracyclines; 2 had contraindications to anthracyclines. Patients remained on study for a maximum of eight 3-week cycles or until tumor progression or unacceptable toxicity occurred; response assessments were scheduled after cycle 2, 5, and 8. Seventeen patients were assessed after cycle 2; 3 subjects (18%) had a partial response (PR), 9 had stable disease (53%; SD), and 5 patients (29%) had progressive disease (PD). Ten patients were assessable after cycle 5. Two patients (20%) had a PR, 5 patients (50%) had SD, and 3 patients (30%) had PD. The most common grade 3 toxicities were nail loss (45%), asthenia (30%), and hand-foot syndrome (30%), and toxicities led to study discontinuation in 10 patients. The median time to treatment failure was 10 weeks and median TTP was 26 weeks. The median duration of response was 9 weeks and the median duration of SD was 16 weeks. The median overall survival was 82 weeks. This schedule of weekly docetaxel in combination with day 1-14 capecitabine has activity; however, toxicity discourages the use of this schedule in lieu of the standard docetaxel/capecitabine regimen.     

A phase I study of intravenous iododeoxyuridine as a clinical radiosensitizer

Twenty-four patients with locally advanced (19 patients) or metastatic (5 patients) tumors were treated in a Phase I study combining constant intravenous infusions of iododeoxyuridine (IUdR) and hyperfractionated radiation therapy. IUdR was given as a constant infusion for 12 hours/day for two separate 14-day infusion periods in most patients. The dose of IUdR was escalated from 250 to 1200 mg/m2/12-hour infusion in this study. The initial tumor volume was treated to 45 Gy/1.5 Gy BID/3 weeks followed by a cone-down boost to 20-25 Gy/1.25 Gy BID/2 weeks after a planned 2-week break. THe IUdR infusion preceded the initial and cone-down irradiation by 1 week. Local acute toxicity (within the radiation volume) was uncommon and few patients required an alteration of the planned treatment schedule. Two patients developed late local toxicity with one patient showing clinical signs of radiation hepatitis and another patient developing a large bowel obstruction that required surgical bypass. Dose-limiting systemic toxicity was confined to the bone marrow with moderate to severe thrombocytopenia developing on Day 10-14 of infusions at 1200 mg/m2/12 hours. Mild stomatitis and partial alopecia occurred in some patients at this dose level. No systemic skin toxicity was seen. Pharmacology studies revealed steady-state arterial plasma levels of IUdR of 1 to 8 X 10(-6) M over the dose range used. In vivo IUdR incorporation into tumors was studied in three patients with high-grade sarcomas using an anti-IUdR monoclonal antibody and immunohistochemistry and demonstrated incorporation in up to 50-70% of tumor cells. The preliminary treatment results, particularly in patients with unresectable sarcomas, are encouraging. In comparison to our previous experience with intravenous bromodeoxyuridine, this Phase I study of IUdR shows less systemic toxicity (especially to skin), higher (2-3X) steady-state arterial levels, and comparable in vivo tumor cell incorporation.