Gefitinib: The Ranson Study
Ranson et al. conducted a phase I, escalating, multiple-dose trial to investigate the tolerability, pharmacokinetics, and antitumor activity of gefitinib in patients with solid malignant tumors. The study was designed to evaluate dose levels of 50, 100, 150, 225, 300, 400, 525, 700, and 925 mg/day. Additional patients could be recruited for the study if they had not completed the first 14-day daily dosing period for any reason other than the occurrence of DLT. DLT was defined as any NCI-CTC grade 3 or 4 drug-related toxicity, significant corneal epithelial change in two patients at a specific dose, or a PR interval of more than 217 milliseconds. Escalation of the dose was to continue up to 925 mg/day unless DLT was observed in two or more patients at a specific dose in the first 28 days.
Sixty-four patients received gefitinib treatment, with seven to 10 patients receiving each dosage. The dosage levels were 50, 100, 150, 225, 300, 500, 525, and 700 mg/day. As a result of a grade 3 or 4 drug-related DLT of diarrhea in three patients, the dose was not escalated above 700 mg/day.
Overall, patients had a variety of tumors, but the most common tumor was NSCLC (n = 16). All 16 patients had received at least one earlier chemotherapy regimen. There were 14 platinum-based regimens, 11 with gemcitabine, and five with vinorelbine tartrate (Navel-bine®, GlaxoSmithKline) in addition to other chemotherapy agents.
Exposure to gefitinib increased after administration of doses greater than 50 mg/day. The Cmaxand AUC concentration increased from 41 to 756 ng/ml and from 529 to 8,683 ng/hour per ml, respectively, after daily oral doses of 100 to 700 mg. When the plasma concentrations were elevated because of higher doses, skin and gastrointestinal ADEs occurred more often.
Four patients with NSCLC had a partial response with doses of 300, 400, 525, and 700 mg/day. Three other NSCLC patients had stabilized disease with doses of 225, 400, and 525 mg/day. Six NSCLC patients continued to take the study drug regimen for three or more months.
The authors concluded that gefitinib, when administered for 14 consecutive days every 28 days, was well tolerated. DLT occurred at a dose well beyond that at which antitumor activity was observed. The pharmacokinetic analysis demonstrated that oral gefitinib could be administered once daily.
The Uejima Study
Uejima et al. examined the tolerability, pharmacokinetics, and efficacy of intermittent daily oral dosing of gefitinib in Japanese patients with solid tumors (n = 31, 23 with NSCLC). Initially, patients were given a single oral dose of gefitinib and were then observed for 10 to 14 days. Thereafter, escalating oral doses of gefi-tinib (50-900 mg/day) were to be given for 14 days, followed by 14 days of observation.
The most frequent ADEs were skin reactions, gastrointestinal symptoms, and elevated transaminase levels. Grade 3 elevations in aspartate and alanine transaminases (SGOT and SGPT) were observed in two patients, one who received 225 mg and one who received 525 mg. After multiple dosing for 14 days, gefitinib exhibited dose-related increases in mean Cmax and AUC concentration (73.8-384 ng/ml and 1,236-5,875 ng/hour per ml, respectively); the half-life was 45 hours.
Five patients with NSCLC (22%) showed a confirmed partial response at the following doses: 225 (one patient), 400 (one patient), 525 (two patients), and 700 mg (one patient); these responses persisted for four months, six or more months, one month, three or more months, and two or more months, respectively.
IDEAL-1 and IDEAL-2 were two randomized, double-blind phase II trials that investigated tumor response and safety of oral gefitinib in patients with locally advanced or metastatic NSCLC. In IDEAL-1, patients had not responded to one or two chemotherapy regimens, of which one had to be platinum-based therapy. IDEAL-2 patients had not responded to two or more chemotherapy regimens containing platinum and doce-taxel, given simultaneously or sepa-rately. Patients in both studies were given 250 or 500 mg/day of gefitinib continuously until their disease progressed or the doses reached unacceptable levels of toxicity.
The Functional Assessment of Cancer Therapy-Lung (FACT-L) and its disease-specific, seven-item Lung Cancer Sub-scale were also used in the IDEAL-1 and IDEAL-2 studies to assess disease-related symptoms and quality of life. Over a four-week time frame, increases in the FACT-L by six or more points and in the Lung Cancer Subscale by two or more points, respectively, were defined as an improvement in disease-related symptoms and quality of life.
In the IDEAL-1 study (n = 210), patients were unresponsive to one (56%) or two (44%) previous chemotherapy regimens. In the 250- and 500-mg/day groups, tumor response rates were 18.4% versus 19%, and progression-free survival was 2.7 versus 2.8 months, respectively. In general, tumor response rates were also similar when gefitinib was used as a second-line or third-line treatment (17.9% vs. 19.8%). More patients taking 500 mg/day experienced drug-related grade 3 or 4 ADEs (30.2%) and withdrawals (9.4%); patients taking 250 mg/day experienced all grade 3 ADEs (8.7%) and fewer withdrawals (1.9%).
The authors evaluated symptom improvement and compliance in 140 IDEAL-1 patients. Overall, quality of life improved within 29 days in 24% of patients receiving gefitinib 250 mg/day and in 22% of patients receiving 500 mg/day. The authors concluded that gefitinib provided clinically significant antitumor activity, symptom relief, and improved quality of life in patients with advanced NSCLC who had previously undergone a platinum-based regimen.
Outcomes in IDEAL-2 were similar to those of IDEAL-1. IDEAL-2 included 216 patients who had not responded to two previous chemotherapy regimens (41%), three regimens (33%), or four or more regimens (25%). In the groups receiving 250 and 500 mg/day, tumor response rates were 11.8% (95% confidence interval [CI], 6.2-19.7) and 8.8°% (95°% CI, 4.3-15.5). Median survival was 6.1 (95% CI, 4.8-7.7) and 6.0 (95% CI, 4.3-7.2) months, respectively. Grade 3 or 4 drug-related ADEs occurred in 6.9% of the patients taking gefitinib 250 mg/day and in 17.5% of the patients taking 500 mg/day. Apcalis Oral Jelly
The symptom response rate was a primary endpoint of IDEAL-2; therefore, patients with disease-related symptoms, as assessed by a score of 24 or higher on the Lung Cancer Subscale, were included in the study. Symptom response was seen in 43% of patients taking 250 mg/day and in 34% of patients taking 500 mg/day. Improved quality of life occurred in 34% of patients taking 250 mg/day and in 23% of patients taking 500 mg/day. Longer survival was observed in patients with symptom response (8.1 months) than in patients who did not show symptom response (3.7 months).
The authors concluded that in patients who had had an earlier platinum or doce-taxel chemotherapy regimen, both doses of gefitinib demonstrated clinically significant antitumor activity and had an acceptable tolerability profile. As in IDEAL-1, symptom improvement was correlated with tumor response.
The Iressa NSCLC Trials Assessing Combination Treatment (INTACT-1 and INTACT-2) were two randomized, double-blind, placebo-controlled studies of chemotherapy plus gefitinib in patients with NSCLC. Study participants were chemotherapy-naive patients with stage III or IV disease, age 18 years or older, and a performance status of 0 to 2. The patients were randomly selected to receive chemotherapy plus placebo, chemotherapy plus 250 mg/day of gefi-tinib, or chemotherapy plus 500 mg/day of gefitinib. Treatment with gefitinib or placebo was continued until disease progressed.
In both studies, the primary endpoint was overall survival. Secondary end-points included progression-free survival and time to worsening of disease-related symptoms. Symptom improvement, objective tumor response rate, disease control rate, quality of life, and ADEs were also evaluated.
The chemotherapy regimen consisted of six cycles of gemcitabine 1,250 mg/m2 on days one and eight, plus cisplatin (Platinol®, Bristol-Myers Squibb) 80 mg/m2 on day one. Across all three arms (placebo, 250 mg, and 500 mg), there were no statistically significant differences in overall survival. The median for overall survival was 11.1 (CI, 10.1-11.9) for the placebo group, 9.9 (CI, 8.7-10.8) for the 250-mg group, and 9.9 (CI, 8.8-11.4) for the 500-mg group. In addition, progression-free survival and time to worsening of symptoms were not statistically significant.
The toxicity profile was similar across all three groups, except for additive dose-dependent diarrhea and skin rash. generic cialis tadalafil
The authors concluded that combination therapy with gefitinib plus two other chemotherapy agents did not improve outcomes (overall survival, time to progression, or tumor response rates) in patients with advanced NSCLC.
The chemotherapy regimen consisted of carboplatin (AUC = 6) plus paclitaxcel (225 mg/m2) every three weeks for at least six cycles. In the placebo arms (250 and 500 mg), there were no statistically significant differences in overall survival. The median for overall survival was 9.9 (CI, 8.9-11.1) for the placebo group, 9.8 (CI, 8.4-10.6) for the 250-mg group, and 8.7 (CI, 8.0-10.3) for the 500-mg group. Moreover, progression-free survival and time to worsening of symptoms were not statistically significant.
As in INTACT-1, combination therapy with gefitinib did not improve survival in patients with stage III or IV NSCLC, and the dose-dependent ADEs of diarrhea and skin rash occurred at a higher rate in the patients receiving gefitinib.