Phase I pharmacokinetic-pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin (17AAG, NSC 330507), a novel inhibitor of heat shock protein 90, in patients with refractory advanced cancers.

PURPOSE: 17-(Allylamino)-17-demethoxygeldanamycin (17AAG), a benzoquinone antibiotic, down-regulates oncoproteins by binding specifically to heat shock protein 90 (HSP90). We did a phase I study of 17AAG to establish the dose-limiting toxicity and maximum tolerated dose and to characterize 17AAG pharmacokinetics and pharmacodynamics. EXPERIMENTAL DESIGN: Escalating doses of 17AAG were given i.v. over 1 or 2 hours on a weekly x 3 schedule every 4 weeks to cohorts of three to six patients. Plasma pharmacokinetics of 17AAG and 17-(amino)-17-demethoxygeldanamycin (17AG) were assessed by high-performance liquid chromatography. Expression of HSP70 and HSP90 in peripheral blood mononuclear cells was measured by Western blot. RESULTS: Forty-five patients were enrolled to 11 dose levels between 10 and 395 mg/m2. The maximum tolerated dose was 295 mg/m2. Dose-limiting toxicity occurred in both patients (grade 3 pancreatitis and grade 3 fatigue) treated with 395 mg/m2. Common drug-related toxicities (grade 1 and 2) were fatigue, anorexia, diarrhea, nausea, and vomiting. Reversible elevations of liver enzymes occurred in 29.5% of patients. Hematologic toxicity was minimal. No objective responses were observed. 17AAG pharmacokinetics was linear. Peak plasma concentration and area under the curve of 17AG, the active major metabolite of 17AAG, increased with 17AAG dose, but the relationships were more variable than with 17AAG. 17AAG and 17AG in plasma were >90% protein bound. There were no consistent changes in peripheral blood mononuclear cell HSP90 or HSP70 content. CONCLUSIONS: 17AAG doses between 10 and 295 mg/m2 are well tolerated. 17AAG pharmacokinetics is linear. Peripheral blood mononuclear cell HSP90 and HSP70 are uninformative pharmacodynamic markers. The dose recommended for future studies is 295 mg/m2 weekly x 3, repeated every 4 weeks.

Intravesical gemcitabine therapy for superficial transitional cell carcinoma of the bladder: a phase I and pharmacokinetic study.

PURPOSE: To determine maximum-tolerated dose, toxicities, and pharmacokinetics associated with weekly intravesical gemcitabine therapy in patients with superficial bladder cancer. PATIENTS AND METHODS: Fifteen patients with recurrent superficial transitional cell bladder carcinoma who experienced prior intravesical therapy failure were studied. Two to 4 weeks after complete transurethral resection, gemcitabine was administered intravesically, once weekly for 6 consecutive weeks. Dwell time was 2 hours. Pharmacokinetics of gemcitabine and its metabolite, 2'2'-difluorodeoxyuridine (dFdU), were studied in plasma and urine. Cystoscopy was repeated 6 weeks after therapy. RESULTS: Three-patient cohorts were enrolled sequentially at doses of 500, 1,000, and 1,500 mg in 100 mL 0.9% NaCl. Two patients received 2,000 mg in 100 mL. An additional four patients received 2,000 mg in 50 mL. No grade 4 toxicity or clinically relevant myelosuppression was noted. Nine of 13 evaluable patients were recurrence-free at 12 weeks. Low concentrations of gemcitabine (< or = 1 microg/mL) were present transiently in plasma of all patients receiving 2,000 mg in 50 mL. Gemcitabine was undetectable in plasma of other patients. dFdU was undetectable in plasma of patients receiving less than 1,500 mg. At doses > or = 1,500 mg, dFdU concentrations increased until 90 to 120 minutes and then declined little, if any. Plasma dFdU concentrations implied absorption of 0.5% to 5.5% of instilled dose. Between 61% and 100% of the gemcitabine dose was accounted for in voided urine. No dFdU was measured in voided urine. CONCLUSION: Intravesical gemcitabine, at doses up to 2 g/wk, is well tolerated, is associated with minimal systemic absorption, and has promising efficacy in treatment of superficial bladder cancer.

Phase I study of weekly (day 1 and 8) docetaxel in combination with capecitabine in patients with advanced solid malignancies.

PURPOSE: Capecitabine in combination with docetaxel given every 3 weeks has shown a high degree of activity in a number of tumor types, but at the expense of significant toxicity. To improve the therapeutic index, we evaluated a weekly regimen of docetaxel in combination with capecitabine, and determined the maximum tolerated dose, toxicities and pharmacokinetics of this combination. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with docetaxel on days 1 and 8, and capecitabine, twice daily on days 1-14, of an every-21-day cycle. Pharmacokinetics of docetaxel were assessed on days 1 and 8 of the first cycle of chemotherapy. RESULTS: Enrolled in the study were 25 patients. The most frequent toxicities were asthenia, hand-foot syndrome and mucositis. Inability to deliver at least 75% of the planned doses of both drugs during the first two cycles of chemotherapy was noted at dose levels 2, 3 and 4. Dose level 1 (docetaxel 30 mg/m2 and capecitabine 825 mg/m2 twice daily) is the recommended dose for phase II studies. Five patients experienced a partial response, and eight patients had stabilization of disease. Coadministration of capecitabine did not alter the pharmacokinetics of docetaxel. CONCLUSION: The regimen consisting of docetaxel 30 mg/m2 (days 1, 8) and capecitabine 825 mg/m2 twice daily (days 1-14) was well tolerated. Capecitabine did not alter pharmacokinetics of docetaxel. Further testing of this regimen in tumor-specific trials, especially gastric, lung and breast cancer, is warranted.

State-of-the-art chemotherapy for advanced non-small cell lung cancer.

The treatment of advanced non-small cell lung cancer (NSCLC) has continued to evolve over recent years. We have moved from an era of therapeutic nihilism to optimism, largely because of the advent of the newer cytotoxic agents developed in the 1990s that have complemented the platinum compounds for treatment of advanced NSCLC. Doublet chemotherapy combinations have become the current standard of care for patients with advanced NSCLC who have a good performance status. For patients with poor performance status and the elderly, single-agent chemotherapy results in modest improvements in survival. Prolongation of survival and improved quality of life have also been shown with second-line chemotherapy for patients who are either refractory to or relapse following first-line chemotherapy. Noncytotoxic, molecularly targeted agents currently under various phases of development for the treatment of lung cancer will serve as the cornerstones for further innovations in the treatment of NSCLC.

Meaningful survival in lung cancer patients.

Lung cancer is diagnosed at an advanced stage in a majority of patients. Recent advances made in the treatment of lung cancer have resulted in a prolongation in survival and an improvement in quality of life. The majority of lung cancer patients experience multiple symptoms, which result from both the cancer and its treatment. Fatigue and anemia cause significant morbidity and impaired quality of life among patients with lung cancer. They also contribute to a suboptimal response to treatment modalities such as radiation, decreased performance status, and poor patient compliance with treatment. The impact of anemia is frequently under-recognized. Improvements in survival made with multimodality therapy can only be meaningful when combined with interventions to improve symptoms and overall quality of life. Prompt recognition of these problems and early intervention are an integral part of cancer therapy. In this review, we discuss the impact of anemia and the treatment options that could contribute to a truly meaningful survival in lung cancer patients.

Carboplatin and docetaxel in advanced non-small-cell lung cancer: results of a multicenter phase II study.

BACKGROUND: To evaluate the efficacy of carboplatin and docetaxel combination in patients with advanced non-small-cell lung cancer. METHODS: In a phase II study, patients with inoperable stage IIIB or stage IV non-small-cell lung cancer (ECOG performance status of 0 or 1) were treated with the combination of carboplatin AUC 5 mg/ml.min and docetaxel 80 mg/m2 administered once every 3 weeks. RESULTS: A total of 45 patients were accrued to the study. The median age was 62 years and adenocarcinoma was the most common histology. Patients received a median of four cycles of chemotherapy. The objective response rate was 29% with a median survival of 11.9 months among evaluable patients. The 1-year survival rate was 47%. Febrile neutropenia (17%) was the most common hematological toxicity associated with the regimen whereas grade 3 fatigue (4%) was the major nonhematological toxicity. CONCLUSIONS: The combination of carboplatin plus docetaxel is well tolerated and is effective for the treatment of patients with previously untreated advanced or metastatic non-small-cell lung cancer.

Basic treatment considerations: chemotherapy.

Lung cancer represents a major global health problem, with more than a million deaths reported each year. Because there are no effective screening tools to date, diagnosis of the disease at an advanced stage is a common feature. Over the past 20 years, elegant strides have been made in the treatment of patients with advanced NSCLC. Several novel chemotherapy agents that are efficacious and possess favorable toxicity profiles have been developed recently. In addition to evaluating novel combinations, alternative schedules to improve toxicity profiles are subjects of clinical trials. Much work needs to be done, however, to improve the outcome for patients with lung cancer. Chemotherapy extends life and improves quality of life for patients with stage IIIB/IV NSCLC. Combined modality therapy with radiation and chemotherapy improves the outcome for patients with locally advanced NSCLC and is associated with a curative potential. Molecularly targeted therapies are under rigorous evaluation, although the initial results have been disappointing. In the upcoming years, we will learn effective means to incorporate molecularly targeted therapies to existing treatment paradigms in lung cancer.

Cyclooxygenase-2 inhibitors in lung cancer.

Prostanoids produced by the arachidonic acid pathway play an important role in multiple stages of carcinogenesis and progression of cancer. Cyclooxygenase (COX), which exists in 2 isoforms, is the rate-limiting enzyme in the COX pathway. Cyclooxygenase-1 is constitutively expressed in normal tissues and is essential for several important physiologic functions. Cyclooxygenase-2 is selectively overexpressed in neoplastic and inflammatory tissues. Non-small-cell lung cancer (NSCLC), especially adenocarcinomas, overexpress COX-2, which contributes to the progression of malignancy by several mechanisms. This represents the basis of therapy with COX-2 inhibitors. Cyclooxygenase-2 inhibitors, which are currently in clinical use for the management of inflammatory arthritis, are well tolerated by patients. They exhibit anticancer activity by several mechanisms including induction of apoptosis, inhibition of angiogenesis, and decreased invasiveness and metastatic potential. These effects have been documented in several preclinical studies. Clinical efficacy of COX-2 inhibitors in the treatment of NSCLC is presently undergoing evaluation.

Biliary excretion of imatinib mesylate and its metabolite CGP 74588 in humans.

Imatinib mesylate, licensed to treat chronic myelogenous leukemia and gastrointestinal stromal tumors, is metabolized by cytochrome P450 3A and undergoes little renal excretion, but its biliary excretion by humans is uncharacterized. Liquid chromatography-mass spectrometry was used to quantitate imatinib and its metabolite CGP 74588 in the bile of two patients with biliary stents; the ratio of imatinib:CGP 74588 in each was approximately 9:1. In the first patient, who was receiving long-term therapy with imatinib 400 mg/day and had normal liver function tests, biliary imatinib accounted for 17.7% of the daily dose and CGP 74588 accounted for 2.1%. In the second patient, who had elevated liver function tests and was studied after his first dose of imatinib 300 mg, biliary imatinib accounted for only 1.8% of the daily dose and CGP 74588 accounted for 0.2%. These data show both the qualitative similarities and the quantitative variability in biliary excretion of imatinib and its principal metabolite.

Carboplatin/gemcitabine combination in advanced NSCLC.

The treatment of advanced non-small-cell lung cancer (NSCLC) has evolved rapidly over the past few years. Systemic chemotherapy is associated with both quality of life and modest survival benefit for patients with advanced NSCLC. Platinum-based doublet combinations are the "standard of care." The US Food and Drug Administration (FDA) has approved gemcitabine (Gemzar), a pyrimidine analog, to be used in combination with cisplatin for the treatment of advanced NSCLC in the first-line setting. Randomized clinical trials have established comparable efficacy with improved therapeutic index for the carboplatin/gemcitabine regimen when compared with cisplatin/gemcitabine and other platinum doublets. Nonhematologic toxicities occur at a lower frequency with carboplatin/gemcitabine combinations compared with other "standard" platinum-based doublets, whereas dose-limiting thrombocytopenia, the most common toxicity, rarely requires therapeutic intervention. Both the 3- and 4-week schedules of carboplatin/gemcitabine result in similar efficacy and toxicity profiles, but the 3-week regimen is preferred. The combination of carboplatin and gemcitabine is an effective regimen with an acceptable toxicity profile for the treatment of advanced NSCLC. This regimen can also be used as a foundation for the development of innovative combinations with molecularly targeted agents.

Results of clinical trials for locally advanced and metastatic nonsmall-cell lung cancer.

Chemotherapy in nonsmall-cell lung cancer (NSCLC) is not just a reality but has resulted in important improvements in quality of life and survival for patients with locally advanced and metastatic NSCLC. For patients with stage IV NSCLC, platinum-based 2-drug combinations are superior to single-agent therapy and have a superior therapeutic index than 3-drug combinations. Concurrent chemoradiation has become the standard of care for patients with locally advanced NSCLC. The addition of consolidation chemotherapy following definitive chemoradiation appears to improve median survival. The era of molecularly targeted therapies for NSCLC is here. Early results with some of the targeted agents studied for the treatment of NSCLC have generated a great deal of excitement. In this article, we review the results of recent clinical trials in locally advanced and metastatic NSCLC.

Taxanes for advanced non-small cell lung cancer.

The emergence of novel chemotherapeutic agents with promising anticancer activity in non-small cell lung cancer (NSCLC) during the 1990s has led to an expanded role for chemotherapy in the management of this disease. The taxanes (paclitaxel and docetaxel) are novel microtubule stabilising agents, and have become an integral part of several commonly-used chemotherapy regimens in NSCLC. Taxanes inhibit the growth of lung cancer cell lines, exhibit synergistic interaction with other chemotherapy agents and enhance the efficacy of radiation in vitro. When used in low doses (metronomic dosing), they have important antiangiogenic properties. Several Phase II and III clinical trials have established the efficacy of the taxanes, as single agents and when used in combination with a platinum compound, in the treatment of advanced NSCLC. The use of a taxane in combination with a platinum compound has become an acceptable standard for patients with advanced or metastatic NSCLC. In addition to its efficacy in the first-line therapy of NSCLC, docetaxel is also the FDA-approved second-line agent for recurrent or relapsed NSCLC in the US. Several ongoing trials are comparing the efficacy of combining molecularly targeted agents with taxane-based regimens for the treatment of advanced NSCLC.

Docetaxel in advanced non-small cell lung cancer.

Based on the survival benefit demonstrated in large randomized clinical trials, docetaxel is approved for the treatment of advanced non-small cell lung cancer (NSCLC) in both the first- and second-line settings. The efficacy of docetaxel in combination with cisplatin is equivalent to some, and superior to other, platinum-based doublets for first-line management of NSCLC, and has a manageable toxicity profile. Carboplatin-based regimens and nonplatinum combinations with docetaxel also have proven efficacy in first-line therapy of patients with advanced NSCLC. Combinations of docetaxel with various novel targeted agents have produced encouraging data in Phase II studies. This article reviews recent studies of docetaxel as a single agent and in combination regimens with cytotoxic and more recent targeted agents in the management of advanced NSCLC.

Paclitaxel for non-small cell lung cancer.

Paclitaxel, a tubulin-binding agent, is widely used for the treatment of non-small cell lung cancer (NSCLC). The combination of paclitaxel and a platinum compound is an approved regimen for the treatment of advanced NSCLC. The dose-limiting toxicity of paclitaxel is myelosuppression when administered on a prolonged infusion schedule, whereas neuropathy is more common with short infusions. Although the 3-weekly schedule of paclitaxel is the commonly utilised regimen for the treatment of advanced NSCLC, the weekly regimens appear to be associated with lesser myelosuppression and neuropathy. A randomised clinical trial is currently underway to compare the efficacy of the weekly versus 3-weekly regimen of paclitaxel, in combination with carboplatin for the treatment of advanced NSCLC. The radiosensitising effect of paclitaxel has led to its incorporation into multi-modality treatment of NSCLC patients in combination with thoracic radiation. Paclitaxel has also demonstrated synergistic interaction with several molecularly-targeted agents and is at present being evaluated in the neoadjuvant and adjuvant treatment settings for early stage NSCLC.