Phase II trial of sequential gefitinib after minor response or partial response to chemotherapy in Chinese patients with advanced non-small-cell lung cancer

Background  

Basic research of gefitinib (Iressa, ZD1839) has demonstrated the combination effects of gefitinib and chemotherapy were sequence-dependent. To evaluate the efficacy of sequential administration of gefitinib following a minor response or partial response to two to three cycles of chemotherapy, a phase II clinical trial was done in Chinese patients with advanced non-small-cell lung cancer (NSCLC).     

Phase II trial of weekly paclitaxel in previously untreated advanced non-small-cell lung cancer

OBJECTIVE: New effective therapy is desirable for outpatients with advanced non-small-cell lung cancer (NSCLC). Fractionated administration of paclitaxel may be less toxic and more active against NSCLC. The aim of this study was to evaluate the activity and toxicity of weekly paclitaxel therapy for chemotherapy-naive NSCLC. METHODS: Patients with pathological or cytological diagnosis of NSCLC, measurable lesions, and no prior therapy were enrolled. We administered weekly infusions of 80 mg/m(2) paclitaxel 3 times in a 4-week cycle. In the absence of progressive disease or intolerable toxicity, we treated each patient for a minimum of four cycles. RESULTS: Of 35 patients enrolled, 17 patients achieved partial response, although no complete responses were observed (response rate 49%; 95% confidence interval 32-66%). The median survival time was 55 weeks (range 6-93 weeks). Grade 3 or 4 leukopenia occurred in only 1 patient (3%). Neurotoxicity was the most frequent adverse effect (grades 1 and 2, 26 and 3%, respectively). Serious toxicity, observed in 2 patients (6%), was interstitial pneumonia, and 1 patient died from sequela. CONCLUSION: Low-dose weekly paclitaxel is a promising therapy for advanced NSCLC with high effectiveness and low toxicity.     

Phase II trial of docetaxel and vinorelbine in patients with advanced non-small-cell lung cancer.

PURPOSE: Docetaxel and vinorelbine are active agents in advanced non-small-cell lung cancer (NSCLC) and demonstrate preclinical synergism perhaps, in part, through their inactivation of the proto-oncogene bcl-2. We show that docetaxel (60 mg/m(2)) and vinorelbine (45 mg/m(2)) can be safely combined when given on an every 2-week schedule with filgrastim, with encouraging antitumor activity observed. PATIENTS AND METHODS: Thirty-five chemotherapy na?ve patients with advanced NSCLC received vinorelbine as an intravenous push immediately followed by docetaxel as a 1-hour intravenous infusion once every 2 weeks. Prophylactic corticosteroids, ciprofloxacin, and filgrastim were used. RESULTS: We delivered median doses of 450 mg/m(2) of vinorelbine and 600 mg/m(2) of docetaxel. The major objective response rate was 51% (95% confidence interval [CI], 34% to 68%). With a median follow-up of 14 months, the predicted median survival time was 14 months, and the 1-year survival rate was 60% (95% CI, 44% to 80%). Febrile neutropenia occurred in five patients and five (1.3%) of 384 treatments. No dose-limiting neurotoxicity occurred. Symptomatic onycholysis and excessive lacrimation were observed after several months or more of therapy. CONCLUSION: Docetaxel 60 mg/m(2) and vinorelbine 45 mg/m(2), both given every 2 weeks, is a highly active combination for the treatment of advanced NSCLC. Filgrastim largely obviates neutropenic fever and allows for the single-agent dose-intensity of both drugs to be delivered. The occurrence of certain late toxicities can limit use in some cases and suggests that the combination could also be beneficial in settings requiring briefer, fixed periods of treatment, such as in induction or postoperative therapy.     

Efficacy and tolerability of gefitinib in pretreated elderly patients with advanced non-small-cell lung cancer (NSCLC)

The activity and toxicity profile of gefitinib in non-small cell lung cancer (NSCLC) patients aged 70 years or older has been only partially evaluated. The aim of this study was to evaluate the response rate and safety of gefitinib in elderly NSCLC patients. Elderly NSCLC patients pretreated with chemotherapy and with at least one measurable lesion received gefitinib at the daily dose of 250 mg until disease progression, unacceptable toxicity or refusal. From August 2001 to May 2003, 40 consecutive elderly patients have been enrolled onto the study in three Italian institutions. We observed one complete (2.5%) and one partial response (2.5%), 18 disease stabilisations (NC: 45%) lasting at least 2 months, including six patients (15%) who had disease stabilisation of 6 months or longer, for an overall disease control rate of 50% (95% CI: 34.5-65.5%). The median duration of response was 4.4 months (range 1.7-9.2). The side effects were generally mild and consisted of diarrhoea and skin toxicity. Grade 1-2 diarrhoea occurred in 23.6%, and one patient experienced grade 4 diarrhoea, requiring hospitalisation. Grade 1-2 skin toxicity, including rash, pruritus, dry skin, and acne, occurred in 20 patients (52.6%). Gefitinib is safe and well tolerated in elderly pretreated NSCLC patients. The disease-control rate achieved suggests that this drug could represent a valid option in the management of this unfavourable subgroup of patients.     

Erlotinib in advanced non-small-cell lung cancer after gefitinib failure

Purpose  To evaluate the efficacy and safety of erlotinib in advanced non-small-cell lung cancer after failure of gefitinib treatment. Patients and methods  Patients with advanced or metastatic NSCLC, who had progressed after gefitinib treatment, were included in this study; patients received erlotinib 150 mg/day until disease progression or intolerable toxicity. Results  Twenty-one patients were included in this study. Among them, 14 (66.7%) were male and 7 (33.3%) were female; median age was 63 years; 10 (47.6%) patients were smokers; 9 (42.9%)patients had squamous cell carcinoma subtype; 8 (38.1%) patients had adenocarcinoma subtype and 4 (19%) patients had the other NSCLC subtype. Out of 21 patients, 2 (9.5%) had PR and 4 (19.0%) had SD, giving an overall response rate of 9.5% and a disease control rate of 28.5%. The median TTP were 55 days, the median OS were 135 days. Two patients with PR to erlotinib treatment were female never smokers with adenocarcinoma histology and both had partial response to prior gefitinib treatment. Three of four patients with a SD to erlotinib treatment also had SD from prior gefitinib therapy. Smoking history, histology and response to erlotinib were significantly correlated with survival. The most common toxic effects were skin rash. Conclusions  Erlotinib may be an option for a more highly selected subset of patients, especially those who had already benefited from prior gefitinib treatment.     

Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer

BACKGROUND: Preclinical studies have demonstrated that the inhibition of the PI3K/Akt/mTOR pathway restores gefitinib sensitivity in resistant cancer cell lines. A phase 1 study was conducted of the combination of everolimus, an mTOR inhibitor, and gefitinib to determine a daily dose of everolimus with gefitinib in patients with advanced nonsmall-cell lung cancer (NSCLC). METHODS: Oral everolimus and gefitinib were both administered daily to patients with progressive NSCLC. Patients were enrolled in 3-patient cohorts at everolimus dose levels of 5 and 10 mg daily. All patients received gefitinib 250 mg daily. RESULTS: Ten patients were enrolled. The maximum tolerated dose of everolimus was 5 mg when administered daily with gefitinib 250 mg. Two patients who were treated at the 10 mg dose level of everolimus experienced dose-limiting toxicity, including grade 5 hypotension and grade 3 stomatitis. Pharmacokinetic studies demonstrated no consistent, significant interaction on the t(max), C(max), and AUC(0-8h) of either agent. Two partial radiographic responses were identified among the 8 response-evaluable patients. CONCLUSIONS: For further study, everolimus at a dose of 5 mg daily in combination with daily gefitinib 250 mg is recommended. The 2 radiographic responses identified are encouraging. A phase 2 trial in patients with NSCLC is under way.     

Phase II trial of S-1 and cisplatin with concurrent radiotherapy for locally advanced non-small-cell lung cancer

Background:

To assess the efficacy and safety of S-1 and cisplatin with concurrent thoracic radiation for unresectable stage III non-small-cell lung cancer (NSCLC).

Methods:

Eligible patients were 20–74 years old and had histologically or cytologically confirmed NSCLC, a performance status of 0–1, and no prior chemotherapy. Patients were treated with cisplatin (60 mg m⁻² on day 1) and S-1 (orally at 40 mg m⁻² per dose, b.i.d., on days 1–14), with the treatment repeated every 4 weeks for four cycles. Beginning on day 2, a 60-Gy thoracic radiation dose was delivered in 30 fractions.

Results:

Of 50 patients, 48 were eligible. Partial response was observed in 42 patients (87.5%; 95% CI: 79.1–96.9%). This regimen was well tolerated. Common toxicities included grade 3/4 neutropenia (32%), grade 3/4 leukopenia (32%), grade 3/4 thrombocytopenia (4%), grade 3 febrile neutropenia (6%), grade 3 oesophagitis (10%), and grade 3 pneumonitis (5%). Median progression-free survival was 12.0 months and median overall survival was 33.1 months. The 1- and 2-year survival rates were 89.5 and 56%, respectively.

Conclusion:

This chemotherapy regimen with concomitant radiotherapy is a promising treatment for locally advanced NSCLC because of its high response rates, good survival rates, and mild toxicities.     

Phase I/II trial of docetaxel and carboplatin in previously untreated patients with advanced non-small-cell lung cancer

Background. This trial was conducted to determine the maximum tolerated dose (MTD) and principal toxicities of combinations of docetaxel and carboplatin administered every 3 weeks to patients with advanced non-small-cell lung cancer (NSCLC) previously untreated with chemotherapy, and to find suitable doses for phase II studies in Japanese subjects. Methods. Japanese patients with advanced NSCLC and performance status 0 to 2 according to the World Health Organization classification, but previously untreated with chemotherapy received docetaxel followed by carboplatin, each infused over a 1-h period. The carboplatin dose was based on the target area under the curve (AUC), using Calvert's formula. Dose levels studied were: docetaxel (mg/m²)/carboplatin AUC (mg/ml·min), 50/4, 60/4, and 60/5, repeated every 3 weeks. Granulocyte-colony stimulating factor (G-CSF) support was first used when dose-limiting toxicities (DLTs) were encountered. Results. Of 14 patients entered, 12 were assessable for toxicity and response. The MTD schedule was: docetaxel, 60 mg/m², with carboplatin, AUC 5 mg/ml·min (DLTs in 3 of 3 patients). The recommended dosage was: docetaxel, 60 mg/m², with carboplatin, AUC 4 mg/ml·min (DLTs in 2 of 6 patients). The main toxic effect was neutropenia, and any nonhematologic toxic effects were mild. No thrombocytopenia occurred. Six of the 12 patients (50%) showed responses; 4 of the 6 at the recommended doses. Conclusion. Docetaxel 60 mg/m², given over a 1-h period, followed by carboplatin, AUC 4 mg/ml·min, given over a 1-h period, is recommended for phase II studies in Japan. This combined chemotherapy has mild toxicity, except for neutropenia, and is useful and easy to administer. We therefore believe that phase II and phase III studies of this therapy would be well justified. Received: October 4, 1999 / Accepted: June 28, 2000     

Phase II trial of paclitaxel plus gemcitabine in patients with locally advanced or metastatic non-small-cell lung cancer.

PURPOSE: Given the cisplatin-related myelotoxicity and nonhematologic toxicities, we were prompted to undertake a study of the noncisplatin combination of paclitaxel plus gemcitabine to evaluate the efficacy, tolerance, and survival of this combination in patients with locally advanced and metastatic non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients received gemcitabine 2,000 mg/m(2) and paclitaxel 150 mg/m(2) on days 1 and 15 of a 28-day cycle, for a maximum of eight cycles. RESULTS: Between December 1997 and June 1998, 89 untreated NSCLC patients were enrolled; 30 (34%) had stage IIIB disease (23 with malignant pleural effusion and seven without), and 59 (66%) had stage IV disease. Eighty-six percent of patients had a performance status of 0 or 1. The median number of cycles administered was four (range, one to eight cycles). The mean dose-intensity for both paclitaxel and gemcitabine was nearly 100%. Hematologic and nonhematologic toxicities were mild. Thirty-eight patients received second-line chemotherapy after completion of the study. The overall intent-to-treat response rate was 32.2%, with a higher response rate for stage IIIB patients (43.3%) than for stage IV patients (26.3%). Overall median survival was 9.9 months, and 1-year survival was 38.8% (14.2 months for stage IIIB and 7.7 months for stage IV; P =.007). Median survival was 10.2 months for patients with a performance status of 0 or 1 and 4.8 months for patients with a performance status of 2 (P =.007). CONCLUSION: A biweekly paclitaxel/gemcitabine regimen was well tolerated, with an acceptable response rate and a reasonable median survival time, especially in patients with good performance status. It merits further exploration in future studies.     

First-line single agent treatment with gefitinib in patients with advanced non-small-cell lung cancer

Background

Lung cancer is a malignant carcinoma which has the highest morbidity and mortality in Chinese population. Gefitinib, a tyrosine kinase (TK) inhibitor of epidermal growth factor receptor (EGFR), displays anti-tumor activity. The present data regarding first-line treatment with single agent gefitinib against non-small-cell lung cancer (NSCLC) in Chinese population are not sufficient.

Purpose

To assess the efficacy and toxicity of gefitinib in Chinese patients with advanced non-small-cell lung cancer (NSCLC), a study of single agent treatment with gefitinib in Chinese patients was conducted.

Methods

45 patients with advanced NSCLC were treated with gefitinib (250 mg daily) until the disease progression or intolerable toxicity.

Results

Among the 45 patients, 15 patients achieved partial response (PR), 17 patients experienced stable disease (SD), and 13 patients developed progression disease (PD). None of the patients achieved complete response (CR). The tumor response rate and disease control rate was 33% and 71.1%, respectively. Symptom remission rate was 72.5%, and median remission time was 8 days. Median overall survival and median progression-free survival was 15.3 months and 6.0 months, respectively. The main induced toxicities by gefitinib were skin rash and diarrhea (53.3% and 33.3%, respectively). The minor induced toxicities included dehydration and pruritus of skin (26.7% and 22.2%, respectively). In addition, hepatic toxicity and oral ulceration occurred in few patients (6.7% and 4.4%2, respectively).

Conclusions

Single agent treatment with gefitinib is effective and well tolerated in Chinese patients with advanced NSCLC.

     

A phase II study of single-agent oral vinorelbine in patients with pretreated advanced non-small-cell lung cancer

PURPOSE: Intravenous vinorelbine has demonstrated its efficacy and tolerability in advanced non-small-cell lung cancer (NSCLC). An oral formulation of vinorelbine has been developed, and a number of phase II studies have shown its activity in chemotherapy-naive NSCLC, even in elderly patients, but no study has been performed to test activity and toxicity of oral vinorelbine in pretreated patients. The aims of our study were to investigate the activity and toxicity of oral vinorelbine in patients with NSCLC as salvage treatment. PATIENTS AND METHODS: Twenty pretreated patients with locally advanced (n = 6) and metastatic (n = 14) NSCLC entered the study. The schedule was oral vinorelbine 60 mg/m(2) once a week until progression or development of unacceptable toxicity. Median age was 70 years (range, 49-84 years). RESULTS: Seventeen patients were evaluable for response and all for toxicity. A median of 9 cycles were administered (range, 2-21 cycles). No objective responses were reported, 5 patients experienced stable disease, and 12 patients had progressive disease. Median time to progression was 2 months (range, 1-6 months), and median survival was 4 months (range, 1-13 months). Treatment was well tolerated, with grade 4 neutropenia in 1 patient (heavily pretreated); grade 2 diarrhea in 2 patients; asthenia in 2 patients; and abdominal pain in 1 patient. CONCLUSION: Oral vinorelbine 60 mg/m(2) once a week is a very safe schedule in heavily pretreated locally advanced and metastatic NSCLC; however, at this dose, the drug is inactive. Other phase II studies with oral vinorelbine 80 mg/m(2) weekly are warranted.     

Phase I/II trial of gefitinib and oxaliplatin in patients with advanced colorectal cancer

Colorectal cancers frequently overexpress the epidermal growth factor receptor. Gefitinib (Iressa), an inhibitor of the epidermal growth factor receptor tyrosine kinase, is synergistic with oxaliplatin in preclinical colon cancer models. The authors conducted a phase I/II trial of gefitinib plus oxaliplatin in patients with previously treated metastatic colorectal cancer. In the phase I portion, 14 patients received oxaliplatin 130 mg/m2 intravenously every 21 days and gefitinib orally daily at 1 of 2 dose levels: 250 mg/day (8 patients), and 500 mg/day (6 patients). There were no objective responses. Three patients (38%) in the 250-mg cohort experienced disease stabilization for a median of 12 weeks, and 1 patient in the 500-mg cohort had stable disease for 18 weeks. Nausea/vomiting and rash were dose limiting. The randomized phase II part of the trial, in which patients were to receive oxaliplatin with or without gefitinib, was canceled due to the inactivity of single-agent gefitinib observed in the phase I portion, and emergent phase III data regarding the minimal activity of single-agent oxaliplatin. The authors conclude that the combination of gefitinib plus oxaliplatin is inactive in advanced colorectal cancer.     

Phase II trial of methylglyoxal-bis-(guanylhydrazone) in non-small-cell lung cancer

Fifty-two patients with metastatic or recurrent non-small-cell lung cancer (NSCLC) were treated, during a phase II trial, with methylglyoxal-bis-(guanylhydrazone) (MGBG). Of the 44 patients who had adequate trials, 4 had partial responses (PR), for an overall 9% PR rate. Response durations ranged from 3 to 5+ months. Prior treatment with chemotherapy may have adversely affected response rate; 15% of previously untreated patients responded, compared to only 4% of previously treated patients. A syndrome of weakness and fatigue was the most serious side effect. Anorexia and weight loss, stomatitis, nausea and vomiting, diarrhea, and peripheral neuropathy were the other toxic effects. We conclude that MGBG has activity in NSCLC, especially in previously untreated patients, and further studies are indicated in that population.     

Phase II study of gemcitabine and carboplatin in patients with advanced non-small-cell lung cancer

Purpose To evaluate the efficacy and safety of gemcitabine in combination with carboplatin at standard rate or fixed dose rate infusion in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods In this prospective study, patients with chemonaive advanced NSCLC were randomized to receive gemcitabine at a standard rate (gemcitabine 1,200 mg/m² over 30 min, the standard arm) or a fixed dose rate (gemcitabine 1,200 mg/m² over 120 min, the FDR arm) on days 1 and 8 every 3 week cycle. In both treatment arms, carboplatin at AUC of 5 was administered over 4 h following gemcitabine on day 1 of each cycle. Results From November 2003 to June 2005, a total of 42 patients, in which 7 (17%) patients had stage III_B disease and 35 (83%) had stage IV disease, were enrolled into this study. All patients were included in efficacy and toxicity assessment. No patient had a complete response. Seven (33%) patients in the standard arm and 10 (48%) in the FDR arm had a partial response. The median time to progression and median overall survival time in the standard arm was 5.4 months (95% CI, 3.8–7 months) and 11.5 months (95% CI, 8.2–14.8 months), respectively, while in the FDR arm was 6.5 (95% CI, 4.4–8.6 months) months, 12.0 months (95% CI, 11.3–12.7 months), respectively. The most frequently reported grade 3 or 4 hematological toxicities were thrombocytopenia (38% patients in the standard arm and 43% in the FDR arm) and neutropenia (24% in the standard arm and 33% in the FDR arm). Although hematological toxicity occurred in a little higher percent of patients in the FDR arm than in the standard arm, there were no discernible differences by statistical analysis in both treatment arms (P > 0.05). And significant nonhematologic toxicities were infrequent and tolerable in both arms. No significant difference existed also (P > 0.05). Conclusion In this phase II study, gemcitabine in combination with carboplatin either at standard rate or fixed dose rate infusion was clinically effective and well tolerated in patients with advanced NSCLC.     

A pilot trial of gefitinib in combination with docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer

Despite improvements in conventional treatment, patients with advanced non-small-cell lung cancer (NSCLC) have a poor prognosis, leaving a significant unmet need for novel treatments. One such novel, biologically targeted agent is the orally active epidermal growth factor receptor tyrosine kinase inhibitor gefitinib. This open-label pilot trial investigated the safety, pharmacokinetics, and efficacy of 2 doses of gefitinib (250 and 500 mg per day) combined with docetaxel (75 mg/m2) in patients with locally advanced or metastatic NSCLC as first- and second-line chemotherapy. Eighteen patients were recruited: 6 received gefitinib 250 mg per day plus docetaxel; 12 received gefitinib 500 mg per day plus docetaxel. Combination therapy was feasible with no overlapping toxicities. No patients experienced dose-limiting toxicities (DLTs) at 250 mg per day; 1 patient had 2 DLT events at 500 mg per day (grade 3 rash and diarrhea for >4 days). Adverse events were mild to moderate, including fatigue, mucositis, nausea, anorexia, rash, diarrhea, and fever. Docetaxel did not appear to alter steady-state exposure to gefitinib. The effect of gefitinib on exposure to docetaxel was equivocal; with the exception of 2 patients in the gefitinib 250 mg per day dose group, there appeared to be no trend toward a higher or lower exposure to docetaxel when given in the presence of gefitinib compared with that when given alone. Combination therapy was associated with antitumor activity and responses were seen with gefitinib in 2 of 6 patients at 250 mg per day and 4 of 12 patients at 500 mg per day. This combination is feasible and has an acceptable and predictable safety profile, as well as associated antitumor activity.     

Phase I trial of carboplatin and weekly paclitaxel in patients with advanced non-small-cell lung cancer

OBJECTIVE: This study was designed to determine the maximum tolerated dose of paclitaxel administered weekly in combination with carboplatin and to assess its dose limiting toxicity and preliminary activity in patients with previously untreated, advanced non-small-cell lung cancer. METHODS: Carboplatin was administered at a fixed dose that maintained an area under the curve of 6. Paclitaxel was given over 1 h once a week for 3 weeks starting at 60 mg/m(2) and escalated in 10 mg/m(2) increments. RESULTS: Twenty-one patients were treated with six dose levels (60, 70, 80, 90, 100, 110 mg/m(2)) of paclitaxel. The dose limiting toxicity was infection and the maximum tolerated dose was 110 mg/m(2). Nine of 21 (42.9%) patients demonstrated a therapeutic response. CONCLUSION: Weekly paclitaxel and carboplatin were well tolerated. Based on our results, 100 mg/m(2) of paclitaxel for 3 weeks of a 4-week cycle, in combination with carboplatin, was recommended for a phase II study.