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Phase I/II Study of Vinorelbine, Mitomycin, and Cisplatin for Stage IIIB or IV Non–Small-Cell Lung Cancer

From the Department of Internal Medicine, National Kinki Central Hospital for Chest Diseases; Division of Respiratory Oncology, National Cancer Center Hospital East, Chiba; Department of Respiratory Medicine, Osaka General Hospital, Osaka; Department of Internal Medicine, Prefectural Habikino Hospital, Osaka; and Department of Adult Health and Nursing, Faculty, Faculty of Medicine, University of Tokyo, Tokyo, Japan.

Address reprint requests to Kiyoyuki Furuse, MD, Division of Respiratory Diseases, Health Insurance Union Osaka Central Hospital, 3-3-17, Niwashirodai, Sakai, Osaka 590-0133 Japan; email ha7k-frs{at}asahi-net.or.jp

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine the maximum-tolerated doses (MTDs) of vinorelbine (VRB), mitomycin (MMC), and cisplatin (P), given in two courses every 28 days to previously untreated patients with stage IIIB or IV non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: At least three or four patients were entered at each dose level. The starting dose was 20 mg/m² for VRB on days 1 and 8 and 4 mg/m² for MMC on day 1, with a fixed dose of P 80 mg/m² on day 1 every 4 weeks. MMC was increased to 6 mg/m² at dose level 2 and subsequently to 8 mg/m² at dose level 4. At dose level 3, VRB was increased to 25 mg/m². Twenty-five patients were entered onto the phase I study and 19 patients were entered onto phase II study.

RESULTS: Nadir leukocyte and platelet counts decreased at each dose level. At dose levels 1 and 2, the dose-limiting toxicity (DLT) was not seen, but at dose levels 3 and 4, DLT was encountered in two patients. Nearly half the patients at dose level 4 had dose reduction due to grade 4 leukopenia. A mathematic model of all toxicity suggested that dose level 4 (VRB 25 mg/m² on days 1 and 8 and MMC 8 mg/m² and P 80 mg/m² on day 1, every 4 weeks) would be the recommended dose for phase II study at which grade 4 toxicity is expected in 25% of patients over two courses. Of the 25 assessable patients in the phase I study, 13 achieved a partial response and one had a complete response for a response rate of 56.0%. Of the 19 assessable patients in the phase II study, 12 had a partial response (63.2%; 95% confidence interval, 38.4% to 83.7%). Grade 3 and 4 leukopenia was observed in 19 (100%), and grade 3 thrombocytopenia was seen in seven (36.8%). Median survival time was 10.7 months and the 1-year survival rate was 43.2% in the 44 assessable patients.

CONCLUSION: The VRB/MMC/P regimen is effective against NSCLC, and its efficacy should be confirmed through a randomized study.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
VINORELBINE (VRB; nor-5'-anhydrovinblastine) is a new, semisynthetic vinca alkaloid that was selected for development during the evolution of vindolin derivatives for binding to tubulin.¹ However, the effect of this drug on microtubule polymerization is different from the effect of vincristine and may be selective on certain isoforms of tubulin.² VRB was more active than vinblastine, vincristine, and vindesine (VDS) against a bronchial epidermoid carcinoma cell line (NSCLC N6).³

VRB produced a response rate of approximately 30% in previously untreated non–small-cell lung cancer (NSCLC) in our (25 mg/m²)⁴ and Depierre et al's (30 mg/m²)⁵ phase II trials. Our randomized trial of VRB versus VDS in previously untreated NSCLC demonstrated that VRB yields a significantly higher response rate than VDS, and VRB plus cisplatin (P) produced a notable response rate compared with VDS plus P in stage IIIB and IV NSCLC.⁶ The peripheral neurotoxicities that occurred with VRB were milder than those with VDS. A recent randomized European trial showed a significant improvement in response rate and survival duration with P-VRB compared with P-VDS or VRB alone.⁷

In our other randomized study of VDS and P versus mitomycin (MMC), VDS, and P (MVP) versus etoposide and P alternating with VDS and MMC (EP/VM), the response rate was the highest (43%) with MVP and the lowest (19%) with EP/VM; the difference was statistically significant (P < .01), although the difference in response rates for the VDS/P and MVP regimens was not significant.⁸ A multivariate analysis of response, using the multiregression method, showed that treatment with MVP was one of the independent prognostic factors significant in the attainment of a major response.

To determine the efficacy of VRB, MMC, and P in stage IIIB or IV NSCLC, we undertook a phase I study; the objective of the subsequent phase II study was to determine the activity of the combination of these drugs in NSCLC.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Phase I Study
The purpose of this trial was to determine the maximum-tolerated dose (MTD) of MMC/P/VRB in previously untreated stage IIIB or IV NSCLC. Patients had to fulfill the following criteria to be eligible for the phase I study: age more than 15 years and less than 75 years; histologically or cytologically proven diagnosis of NSCLC; measurable lesions; Eastern Cooperative Oncology Group performance status of 0, 1, or 2; stage IIIB or IV disease; no prior treatment; no symptoms of brain metastasis; no pregnant/nursing women; no active concomitant malignancy; no disseminated bone metastasis requiring radiotherapy; massive pleural effusion requiring tube drainage; adequate blood cell counts (hemoglobin level 9.5 g/dL, WBC count 4,000 to 12,000/µL, and platelet [PLT] count 100,000 µL); adequate renal and liver functions (serum creatinine level less than the upper limit of normal, blood urea nitrogen level 25 mg/dL, bilirubin level 1.5 mg/dL); and no severe heart or pulmonary diseases. Written informed consent was obtained. The study was approved by the institutional review boards of participating institutions.

Treatment Schedule
Five dose levels were chosen (Table 1). Administration of P was fixed at a dose of 80 mg/m² on day 1. MMC was administered on day 1 and VRB was administered on days 1 and 8. This chemotherapy regimen was repeated every 4 weeks and given in two courses. Prophylactic antiemetic medications were administered to all patients. If the WBC or neutrophil count decreased to more than grade 3 after chemotherapy and the need to recover normal range was necessary, granulocyte colony-stimulating factor was administered until the normal range was achieved. MMC and VRB were administered first, followed by P. Dose escalation for each cohort was undertaken based on the toxicity encountered during two courses of chemotherapy, and there was no dose escalation for individual patients. Dose reductions or omissions were permitted based on toxicity. Blood counts and chemistry analyses were repeated weekly before each treatment as well as during the rest week. Full doses of VRB were given unless the WBC count was less than 2,000/µL or the PLT count was less than 50,000/µL on day 8 or 36 of treatment. If either the WBC or PLT count was below its respective level, VRB administration was withheld until the count recovered, at which time it was reinstituted at the full dosage. If the WBC count was less than 3,000/µL or the PLT count was less than 75,000/µL on day 29, VRB and MMC were withheld until the count recovered. If grade 4 hematologic toxicity occurred during the first course, doses of VRB and MMC in the second course were reduced to levels below the initial dose. P was permanently discontinued at any time when the serum creatinine level was greater than 2 mg/dL. If the serum creatinine level was 1.5 to 2.0 mg/dL, P administration was withheld for 2 weeks; if the serum creatinine level did recover, P was discontinued.

The dose-limiting toxicity (DLT) was defined as follows: (1) a WBC count less than 1,000/µL that lasted for more than 4 days, (2) a PLT count of less than 25,000/µL, (3) grade 4 febrile neutropenia that lasted for more than 3 days, and (4) any grade 3 nonhematologic toxicities that met World Health Organization (WHO) criteria,⁹ except for hair loss and nausea/vomiting. Three patients were entered at dose level 1. To increase the accuracy of the DLT, four patients were entered at each dose level starting at dose level 2. The dose was escalated if three or more of the first four patients did not exhibit the DLT. If the DLT was exhibited in four patients, the study was withdrawn. If the DLT was seen in two or three of the first four patients, five patients were entered at this cohort level. If the DLT was seen in three of nine patients, the dose was escalated. If the DLT was seen in six of nine patients, the study was withdrawn. If the DLT was seen in four or five of these nine patients, six patients were entered at this cohort. If the DLT was seen in seven or fewer of 15 patients, the dose was escalated. If DLT was seen in eight or more of 15 patients, the study was withdrawn. The study was initially designed to accrue until the DLT was encountered in six or more of nine patients, or seven or more of 15 patients in two treatment courses; the previous dose level would then be defined as the MTD for the subsequent phase II trial.

The MTD was also calculated retrospectively using a Bayesian parameter estimation method. This parameter estimation procedure was selected because it forms the foundation of the continual reassessment method reported by O'Quigley et al.^10,11 The continual reassessment method, which was developed by O'Quigley et al for use in a prospective fashion in phase I cancer trials, combines Bayesian statistics (parameter estimation) with decision making by estimating the dose-response curve based on prior and all current information available at any given stage of a study. As a result, the estimation of the MTD is updated by the toxicity data from every patient over time.

In this study, we set a clinically acceptable rate of WHO grade 4 toxicity at 25%, which roughly reflects the one-in-four rule in phase I trials, except for step 1. The MTD estimations were made for treatment courses 1 and 2 and was chosen to determine the phase II dose for MMC and VRB at which a minimum of two treatment courses could be given without risk of more than 25% of patients experiencing WHO grade 4 toxicity.

Evaluation
Pretreatment evaluation included a complete history and physical examination, ECG, bronchoscopy, chest x-ray, computed tomography scan of the brain, chest, and abdomen, and a bone scan. The laboratory examination included a complete blood cell count with WBC differential and PLT counts, a full chemistry analysis, and a urinalysis.

For response and toxicity, a history, physical examination, routine blood chemistry analysis, complete blood cell count, and chest x-ray, including conventional tomography or computed tomography, if necessary, were repeated every week.

Response and toxicity were evaluated in accordance with WHO criteria.⁹ Extramural reviewers assessed the eligibility, assessability, and response of each patient.

Phase II Study
Once the MTD was determined, the previous dose level was then chosen to treat patients with the same eligibility requirements as in the phase I portion of the study. The criteria of response and toxicity were used to assess efficacy according to the same criteria as in the phase I portion of the study.

The expected response rate for this regimen is fixed at 40% or higher, and a response rate of less than 20% is considered to show the lack of efficacy according to the previously reported data for MVP. By using the Fleming method, 25 patients are treated at the recommended dose, divided into two steps according to the following procedures: If seven or more responders are obtained in the first 15 patients, the response rate is judged to exceed the expected one; but if three or fewer patients respond to the treatment, the response rate is judged not to reach 20%, and the study is terminated early. If four or six responders are obtained in the first 15 patients, additional patients are collected up to a total of 25 patients, the final target number of patients. If nine or more responders are obtained in the evaluation of the 25 patients, the response rate is judged to exceed the expected one; if there are eight or fewer responders, the response rate is judged not to reach 20%, and the study is terminated. In the phase II study, response was evaluated using response data obtained at the same dose level in the phase I study.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Phase I Study
Twenty-six patients were entered onto the phase I portion, but one patient withdrew informed consent after enrollment. Thus, 25 patients were assessable for response, toxicity, and survival. The baseline characteristics of these patients are listed in Table 1. All patients received two or more courses. Toxicity analysis and response were evaluated during two courses of treatment at dose levels 1 through 4.

The hematologic toxicity after two treatment courses is listed in Table 2. At dose levels 1 through 4, the frequency of grade 3 or worse leukopenia increased progressively: one (16.7%) of six courses at dose level 1; four (50.0%) of eight courses at dose level 2; 13 (72.2%) of 18 courses at dose level 3; and 15 (83.3%) of 18 courses at dose level 4. Because one patient (11.1%) had grade 4 neutropenia at dose level 3 and four patients (44.4%) had grade 4 leukopenia at dose level 4 after receiving the first course of chemotherapy, chemotherapy in the second course was given by dose reduction. At dose level 4, grade 4 leukopenia occurred in four patients, but only two patients experienced grade 4 leukopenia for more than 4 days. The leukocyte count nadir was usually reached at around day 14, with recovery in most patients by day 28. Thrombocytopenia occurred much less frequently than leukopenia and was milder in severity. The PLT count nadir was also recorded around day 12 and resolved by day 28 in most patients. Grade 4 thrombocytopenia occurred in one patient at dose level 3. Also, grade 3 constipation occurred in another patient at dose level 3 (Table 3). These results did not meet our criteria for MTD, but almost half of patients at dose level 4 underwent dose reduction because of grade 4 leukopenia. On the basis of these results, we did not conduct a dose escalation study.

The recommended dose was estimated retrospectively using the Bayesian parameter estimation method. For toxicity, the estimated probability (average) of the DLT at dose level 4 was 30.1% (90% Bayesian posterior percentile, 14.4% to 46.4%), and at dose level 5 (MMC 8 mg/m², VRB 30 mg/m²), 44.7% (90% Bayesian posterior percentile, 27.6% to 59.7%), which would be considered nearly equal to the acceptable upper limit (Fig 1). With regard to efficacy, the estimated probability (average) of a complete/partial response for dose level 4 was 66.6% (90% Bayesian posterior percentile, 54.6% to 79.3%), and for dose level 5, it was 74.7% (90% Bayesian posterior percentile, 66.1% to 83.5%) (Fig 2). According to the results of the Bayesian parameter estimation, the MTD was estimated at dose level 5.

View larger version (17K): [in this window] [in a new window]   Fig 1. Estimated toxicity of dose-response curve (——) and 90% Bayesian posterior percentile (– – –). Observed toxicity probabilities (•) are shown for each dose, and estimated toxicity probabilities for dose levels 4 and 5 are indicated by the dotted line.

View larger version (18K): [in this window] [in a new window]   Fig 2. Estimated effectiveness of dose-response curve (——) and 90% Bayesian posterior percentile (– – –). Observed effectiveness probabilities (•) are shown for each dose, and estimated effectiveness probabilities for dose levels 4 and 5 are indicated by the dotted line.

Nonhematologic toxicities are listed in Table 3. Grade 2 to 3 nausea/vomiting was observed in 22 (44%) of 50 courses, but it was transient. Grade 2 to 3 alopecia was seen in 11 courses (22%), and grade 2 to 3 constipation in three (6%). Grade 2 protenuria was seen in one course (2%). Grade 2 AST (n = 1), ALT (n = 1), and infection (n = 4) toxicities were also seen.

Of 25 patients with assessable lesions, 13 had a partial response (PR) and one had a complete response (CR), for a response rate of 56% (95% confidence interval, 34.9% to 75.6%).

Phase II Study
Using the results obtained in the phase I study for our phase II study, we choose a schedule of VRB 25 mg/m² on days 1 and 8, MMC 8 mg/m² on day 1, and P 80 mg/m² on day 1 for 28 days repeated in two courses. Dose reduction criteria for toxicity were based on previously defined criteria. After 20 patients were enrolled onto the study, extramural reviewers concluded that there was a response rate of more than 60%. If the response rate (eight = CR + PR/nine) for nine patients treated at the same dose level (VRB 25 mg/m² and MMC 8 mg/m²) in the phase I study were added to this result, the phase II study would have been terminated using criteria for the Fleming method. However, results in the phase II study were limited to only those patients enrolled onto that portion of the study. A total of 20 patients were entered onto the phase II study, but because one patient who received VRB 25 mg/m² on days 1 and 8 and MMC 6 mg/m² and P 80 mg/m² on day 1 for 28 days repeated in two courses was considered ineligible, 19 patients were eligible and assessable for response, toxicity, and survival. Patient characteristics are listed in Table 4.

Of the assessable 19 patients, 12 had a PR (63.2%; 95% confidence interval, 38.4% to 83.7%), with a median response duration of 77.5+ days (29 days to 339+ days) (Table 5). Of the 28 assessable patients in the phase I and II studies, 19 had a PR and one had a CR, for a response rate of 71.4% (95% confidence interval, 51.3% to 86.8%).

View this table: [in this window] [in a new window]   Table 5. Phase II: Toxicity (grade 3) in 19 Eligible Patients

Survival
At the median follow-up time of 30 months, the median survival time of the 44 assessable patients in the phase I and II studies was 10.7 months. The median survival time according to stage was 10.9 months for stage IIIB (n = 19) and 11.0 months for stage IV (n = 25). The median survival time for the 19 assessable patients who participated in the phase II study was 13.0 months. The 1-year survival rate was 43.2% for all assessable patients (n = 44) and 52.6% for patients in the phase II study (n = 19).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
A number of more recently discovered agents, such as paclitaxel, docetaxel, gemcitabine, and irinotecan, show promise in the treatment of NSCLC. However, of the new generation of agents, VRB has undergone the most thorough evaluation.

In previously untreated patients with stage III and IV NSCLC, the objective response rate for the combination of P and VRB^7,11,12 was at least double that for VRB monotherapy^5,12,13 in comparative trials. Overall, response rates for VRB plus P ranged from 32% to 49% in noncomparative trials.¹³ The trial by Le Chevalier et al⁷ demonstrated a survival advantage with the combination over VRB monotherapy (median survival duration, 40 v 31 weeks). The survival duration has ranged from 22 to 52 weeks with VRB plus P in comparative trials.¹² The trial by Pérol et al¹⁴ reported a significantly greater 1-year survival in stage III patients treated with VRB plus P and MMC (44.6%) than in those treated with VDS plus P and MMC (26.2%), although response rates, median survival duration, and 1-year survival rates did not differ between the groups.

In our randomized trial of VRB versus VDS in advanced NSCLC, VRB produced a significantly superior response rate than VDS, and VRB plus P showed a notable response rate compared with VDS plus P. Also, in our previously mentioned randomized study of chemotherapy for advanced NSCLC, MVP demonstrated the highest response rate among regimens.⁸ I think that this regimen seems to be more effective on cancers with relatively small tumor burdens, as in the neoadjuvant setting. On the basis of these results, we have conducted phase I and II studies of VRB in combination with P and MMC in previously untreated patients with advanced NSCLC.

In this study, the main toxicity was myelosuppression, especially leukopenia. From dose level 2 on, increasing the dose of VRB and MMC increased the rate of WHO grade 3 and 4 toxicity. However, because four patients (44.4%) at dose level 4 had grade 4 leukopenia in the first course, chemotherapy in the second course was given by dose reduction. Because we believed that it was important to determine a dose of VRB that could be safely administered over multiple courses, we decided to stop dose escalation at dose level 5 in this study. From the results of the Bayesian parameter estimation, the estimated toxicity probability of dose level 5 was 44.4%, which is nearly equal to the acceptable upper limit. Moreover, the estimated response probability was 66.6% for dose level 4. This response rate was superior to that previously reported for chemotherapy regimens that used MMC, VDS, and cisplatin.⁸ We considered the target response probability to be 40% before the trial.⁸ This result suggests that the recommended dose for our phase II study has a sufficient efficacy with a moderate toxicity. We believe the results of the Bayesian parameter estimation, even retrospectively, support our decision, which avoided somewhat dangerous dose escalation. The Bayesian method seems to provide a rational and ethical basis for the dose escalation in the phase I/II studies.

In the phase I portion, 14 (56%) of the 25 assessable patients had CR/PR, and in the phase II portion, 12 (63.2%) of 19 assessable patients had a PR. Of the 44 eligible patients in both phase I and II, 26 (59%) responded to VRB, MMC, and P. This response rate was significantly higher compared with the previously reported results (32% to 49%) in nonrandomized trials using VRB-containing regimens for advanced NSCLC.¹³ Also, this regimen produced a median survival time of 10.7 months and a 1-year survival rate of 43.2%; furthermore, these results were promising when reviewed against survival data (6.0 to 13 months) in the randomized trials.¹³

We have demonstrated that we have the ability to safely administer chemotherapy to patients with stage IIIB or IV NSCLC and also obtain an excellent response rate and median survival time. To evaluate the true benefit and utility, including quality of life and toxicity, in August 1996, we initiated a randomized study to compare this regimen with an MVP regimen for stage IIIB or IV NSCLC.

	ACKNOWLEDGMENTS

 
Supported by Kyowa Hakko Company

We thank Katunori Miyoshi for data collection and statistical analysis.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Potier P: The synthesis of Navelbine prototype of a new series of vinblastine derivatives. Semin Oncol16:2-4, 1989 (suppl)

2. Fellous A, Ohayon R, Vacasin T, et al: Biochemical effect of Navelbine on tubulin and associated proteins. Semin Oncol16:9-14, 1989 (suppl)

3. Cros S, Wright M, Morimoto M, et al: Experimental antitumor activity of Navelbine. Semin Oncol16:15-20, 1989 (suppl)[Medline]

4. Furuse K, Kubota K, Kawahara M, et al: A phase II study of vinorelbine, a new derivative of vinca alkaloid, for previously untreated advanced non-small cell lung cancer. Lung Cancer11:385-391, 1994[Medline]

5. Depierre A, Lemarie E, Dabouis G, et al: A phase II study of Navelbine (vinorelbine) in the treatment of non-small cell lung cancer. Am J Clin Oncol14:115-119, 1991[Medline]

6. Furuse K, Fukuoka M, Kuba M, et al: Randomized study of vinorelbine (VRB) versus vindesine (VDS) in previously untreated stage IIIB or IV non-small cell lung cancer (NSCLC). Ann Oncol7:815-820, 1996[Abstract/Free Full Text]

7. Le Chevalier T, Brisgand D, Douillard JY, et al: Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: Results of a European multicenter trial including 612 patients. J Clin Oncol12:360-367, 1994[Abstract]

8. Fukuoka M, Masuda N, Furuse K, et al: A randomized trial in inoperable non-small-cell lung cancer: Vindesine and cisplatin versusmitomycin, vindesine, and cisplatin versus etopside and cisplatin alternating with vindesine and mitomycin. J Clin Oncol9:606-613, 1991[Abstract]

9. World Health Organization: WHO Hand Book for Reporting Results of Cancer Treatment: WHO Offset publication no. 48. Geneva, Switzerland, World Health Organization, 1979

10. O'Quigley J, Pepe M, Fisher L: Continual reassessment method: A practical design for phase I clinical studies in cancer. Biometrics46:33-48, 1990[Medline]

11. O'Quigley J: Estimating the probability of toxicity at the recommended dose following a phase I clinical trial in cancer. Biometrics48:853-862, 1992[Medline]

12. Crowford J, O'Rouke M, Schiller JH, et al: Randomized trial of vinorelbine compared with fluorouracil plus leucovorin in patients with stage IV non-small-cell lung cancer. J Clin Oncol14:2774-2784, 1996[Abstract/Free Full Text]

13. Goa KL, Faulds D: Vinorelbine: A review of its pharmacological properties and clinical use in cancer chemotherapy. Drugs Aging5:200-234, 1994[Medline]

14. Pérol M, Guérin JC, Thomas P, et al: Multicenter randomized trial comparing cisplatin-mitomycin-vinorelbine versus cisplatin-mitomycin-vindesine in advanced non-small cell lung cancer. Lung Cancer14:119-134, 1996[Medline]

Submitted March 11, 1999; accepted June 10, 1999.

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