Sakkaraiappan Ramalingam

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 × 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 × 3, repeated every 4 weeks.

Pharmacokinetic study of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced malignancies

S‐CKD602 is a pegylated liposomal formulation of CKD‐602. This study is the first to evaluate the factors affecting the high interpatient variability in the pharmacokinetic disposition of S‐CKD602. S‐CKD602 was administered intravenously (i.v.) every 3 weeks as part of a phase I study. Pharmacokinetics studies of the liposomal encapsulated and released CKD‐602 in plasma were performed. The pharmacokinetic variability of S‐CKD602 is associated with both linear and nonlinear clearances. Patients ≥60 years of age have a 2.7‐fold higher exposure of S‐CKD602 as compared with patients <60 years of age (P = 0.02). Patients with a lean body composition have a higher plasma exposure of S‐CKD602 (P = 0.02). Patients who have received prior therapy with pegylated liposomal doxorubicin (PLD) have a 2.2‐fold higher exposure of S‐CKD602 as compared with patients who have not received PLD (P = 0.045). Prolonged exposure of the encapsulated drug in plasma over 1–2 weeks provides significant pharmacologic advantages. The high interpatient variability in the pharmacokinetic disposition of S‐CKD602 was associated with age, body composition, saturable clearance, and prior PLD therapy.

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.

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.

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.

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.

Phase I pharmacokinetic (PK) study of daily imatinib in combination with docetaxel for patients with advanced solid tumors

2047 Background: Imatinib (Gleevec) is an oral tyrosine kinase inhibitor with established clinical activity in chronic myeloid leukemia & gastrointestinal stromal tumors. Imatinib also targets Kit and the platelet derived growth factor receptor (PDGFR). PDGFR inhibition may result in activity against malignancies of the breast, head & neck, prostate, and lung. Docetaxel, a cytotoxic agent, has known activity in a broad range of solid tumors. Hence, the combination of imatinib with docetaxel may be advantageous. Imatinib and docetaxel are both dependent on cytochrome P450 (CYP3A4) for clearance, hence there is a possibility of pharmacokinetic (PK) interactions. METHODS We conducted a phase I study to establish the recommended phase II dose, and evaluate PK interactions for the above combination. The treatment consisted of daily oral imatinib in combination with docetaxel administered intravenously every 3 weeks. A total of 18 patients with refractory solid tumors with normal organ function were enrolled. Cohort 1: imatinib 400 mg + docetaxel 50 mg/m2 (3 pts); cohort 2: imatinib 600 mg + docetaxel 50 mg/m2 (6 pts); cohort 3: imatinib 400 mg + docetaxel 60 mg/m2 (3 pts); cohort 4: imatinib 400 mg + docetaxel 75 mg/m2 (6pts) . RESULTS The primary toxicity was a grade 3 skin rash (2 of 3 in cohort 2), necessitating treatment with steroids and discontinuation of the imatinib. One pt in cohort 2 experienced an intratumoral retroperitoneal bleed. The dosages in cohort 3 were well tolerated. However 2 of 6 pts in cohort 4, experienced DLT (febrile neutropenia). PK analysis of imatinib was performed on d1 & d7; and PK analysis of docetaxel on d7 by LC/MS assays developed by us. In all the 18 pts analyzed, there was no interaction between the imatinib and docetaxel. Six of eight patients with advanced prostate cancer, who enrolled on the study, experienced a ≥50% reduction in PSA. CONCLUSIONS Thus, the recommended phase II dose of the above combination is: imatinib 400 mg po qd + docetaxel 60 mg/m2 q 3 weeks. At these dosages, the regimen is well tolerated. 12 additional patients are being currently accrued at this dose. (Supported by Novartis & NIH #5M01 RR 00056). [Table: see text].

Weekly docetaxel and irinotecan for patients with advanced non-small cell lung cancer (NSCLC): Results of a multi-center, phase II study

7298 Background: The toxicity profiles of non-platinum regimens compare favorably to platinum-based combinations when used for the treatment of advanced NSCLC. Docetaxel and irinotecan, exhibit synergistic interaction in vitro and in vivo. Both agents also have documented single agent activity in NSCLC. We conducted a phase II study to evaluate the safety and efficacy of a weekly schedule of docetaxel in combination with irinotecan for patients with advanced NSCLC. METHODS Patients (N=45) with previously untreated stage IIIB (pleural or pericardial effusion)/IV NSCLC, ECOG PS < 2, normal hepatic, renal and bone marrow function were eligible. Docetaxel (35 mg/m2) and irinotecan (50 mg/m2) were administered on a weekly schedule for 4 consecutive weeks followed by a 2-week rest period (4 out of 6 weeks). RESULTS Baseline patient characteristics were: median age 60 years (range 38-76), males - 24, stage IIIB/IV - 11/34, adenocarcinoma - 20, squamous cell carcinoma - 12, large cell carcinoma - 4, undifferentiated carcinoma - 7. A total of 105 cycles of chemotherapy were administered. All patients were evaluable for toxicity and 36 patients were evaluable for efficacy. The results are summarized below: [Figure: see text] Conclusions: The combination of docetaxel and irinotecan administered on a weekly schedule is active for first-line treatment of patients with advanced NSCLC. The regimen was associated with the principal toxicity of grade 3/4 diarrhea, but the incidence of myelosuppression was low. [Table: see text].

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.

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.