Biweekly vinorelbine and gemcitabine: a phase I dose-finding study in patients with advanced solid tumors

D. Castellano+, R. Hitt, E. Ciruelos, H. Cortés-Funes and R. Colomer

Division of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain

Received 3 June 2002; revised 18 November 2002; accepted 3 December 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

The purpose of this study was to determine the dose-limiting toxicity (DLT) and maximum tolerated dose of a combination of vinorelbine plus gemcitabine administered on a biweekly schedule in patients with advanced solid tumors.

Patients and methods:

Patients with advanced or refractory solid tumors included in this phase I study were treated with vinorelbine followed by gemcitabine. Vinorelbine was given intravenously over 10 min, and gemcitabine was given intravenously at an fixed-dose infusion rate of 10 mg/m2/min. Six dose levels of vinorelbine/gemcitabine were explored: 20/2000, 25/2500, 25/3000, 30/3000, 30/3500 and 30/2500 mg/m2.

Results:

Nineteen patients were included in the study. Fourteen patients were pretreated with chemotherapy and/or radiotherapy. A total of 123 cycles of chemotherapy were administered. DLTs were neutropenic fever and grade 3 asthenia at dose level 5 (30/3500 mg/m2); at dose level 4 (30/3000 mg/m2) they were grade 3 asthenia, and a radiation-recall reaction and pneumonitis. Sixteen patients were evaluable for efficacy. Five patients had an objective response (one complete response and four partial responses), for an overall response rate of 31%.

Conclusions:

The recommended dose for phase II study is vinorelbine 30 mg/m2 and gemcitabine 2500 mg/m2 administered once every 2 weeks. This regimen is feasible and well-tolerated at this dose, and shows a good clinical activity in all levels explored.

Key words: advanced solid tumors, biweekly schedule, gemcitabine, metastatic carcinoma, phase I trial, vinorelbine


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Vinorelbine is a semisynthetic vinca alkaloid with clinical activity against different solid tumors. It is approved for the treatment of advanced non-small-cell lung cancer (NSCLC) and breast cancer. Vinorelbine interferes with the polymerization of tubulin, a protein responsible for building the microtubule system that appears during cell division. The dose-limiting toxicities of vinorelbine are leucopenia and neurotoxicity. In phase II studies, this drug was administered on a weekly schedule with doses ranging from 25 to 30 mg/m2, and a 29–44% response rate was reported in chemotherapy-naïve patients [1, 2].

Gemcitabine (2'-2'difluorodeoxycytidine) is a nucleoside antimetabolite analog of deoxycitidine with biological activity based on its ability to inhibit DNA synthesis and repair. The phosphorylation of gemcitabine to the monophosphate by deoxicytidine kinase is the rate-limiting step in the formation of the triphosphate, the active form. This agent inhibits the synthesis of DNA by incorporation of its triphosphorylated metabolite defluorodeoxycitidine triphosphate (dFdCTP) into DNA [3]. Gemcitabine has broad activity in a variety of solid tumors, and it is approved for the treatment of advanced pancreatic cancer, NSCLC and bladder cancer [4, 5]. The concentration of dFdCTP in mononuclear cells is stable at infusions between 250 and 1000 mg/m2 over 30 min. It results in plasma dFdCyd concentrations of ~20 mmol/l, suggesting saturation of dFdCyd51-phosphate accumulation. Prolonged exposure results in a higher concentration of dFdCTP, which may be associated with a better therapeutic index [6].

The combination of vinorelbine and gemcitabine has been developed in the past using the single agent schedules of weekly doses for 3 or 4 weeks. It has been described that vinorelbine and gemcitabine can be combined with other antineoplastic agents given every 2 weeks with a good clinical and toxicity profile [79]. Based on these data, we decided to undertake a phase I trial of the biweekly combination.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient selection
Patients were eligible if they had an advanced or refractory histologically or cytologically confirmed malignant solid tumor, for which no standard therapy was available. This included, but was not limited to, metastatic cancer of unknown primary origin. Other eligibility criteria included the following: age 18–70 years; Eastern Cooperative Oncology Group (ECOG) performance status <=2; no previous anticancer therapy for at least 4 weeks (6 weeks for nitrosoureas or mitomycin); no previous radiotherapy for at least 4 weeks; no treatment with more than two prior chemotherapy combination regimens; and adequate hematopoietic (absolute neutrophil count >=2 x 109/l and platelet count >=100 x 109/l), renal (serum creatinine concentration <=135 µmol/l or creatinine clearance >=60 ml/min) and hepatic [total serum bilirubin level <=1.25x upper normal limit (UNL) and serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels <=3x UNL; in case of liver metastasis, total serum bilirubin level <=1.5x UNL and serum AST and ALT levels <=5x UNL] function. Other eligibility criteria included measurable or assessable disease. All patients gave written informed consent before they were entered into the study.

Treatment and dose escalation
This was an open-label, single center, non-randomized, dose-escalating phase I study. All laboratory tests required had to be completed within 7 days before start of treatment.

The starting dose level of gemcitabine and vinorelbine was based on the dose intensity of both agents achieved in weekly schedules. Vinorelbine and gemcitabine were escalated according to a planned schedule in five different dose levels.

Vinorelbine was diluted in 100 ml of dextrose 5% or normal saline. Gemcitabine was supplied as a lyophilized powder in sterile vials containing 200 mg, and the hydrochloride salt, mannitol and sodium acetate as 1000 mg. Gemcitabine was reconstituted with normal saline to make a solution containing gemcitabine 10 mg/ml. Dose level 6 was added after the observation of early and severe non-hematological toxicity at dose level 4. Cycles were administered every 2 weeks to a maximum of 12 cycles for the patients that achieved an objective response or stable disease. Cohorts of at least three patients, each receiving escalating doses of vinorelbine and gemcitabine, were included. Before entry of patients onto a new dose level, all patients at the previous dose level must have been observed for at least 2 weeks. No intrapatient dose escalation was permitted.

Dose-limiting toxicity and maximum tolerated dose
Severe or life-threatening non-hematological toxicity (grades 3 or 4), with the exception of nausea and vomiting, was considered as dose limiting. An ANC of <0.5 x 109 cells/l lasting >5 days, or associated with fever or infection, as well as a platelet count of <25 x 109 cells/l of any duration, were also considered dose limiting. If one or more patients at a dose level experienced dose-limiting toxicity (DLT), three additional patients were treated at that dose level. The maximum tolerated dose (MTD) was defined as one dose level below the dose that induced DLT in one-third or more of patients (at least two of a maximum of six new patients).

Treatment assessment
Before therapy started, a complete medical history was taken and a physical examination was performed for each patient. A complete blood count including white blood cell differential was performed, as was a complete serum biochemistry analysis. The following evaluations were carried out weekly: clinical history, physical examination, toxicity assessment according to National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0 [10] and serum chemistry analysis. Tumors were evaluated every two courses, according to the World Health Organization (WHO) criteria for response. Laboratory studies were performed weekly while patients were on study. All objective responses [partial response/complete response (PR/CR)] were required to last for at least 4 weeks.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Nineteen patients with advanced or refractory solid tumors were included in this phase I study between February 1998 and May 1999. Patient characteristics are listed in Table 1. The majority of patients were either asymptomatic or had only mild symptoms. There were five female patients and 14 male patients. Fourteen patients had received prior chemotherapy and/or radiotherapy. The most common tumor types were cancer of unknown primary site and NSCLC. At the highest dose levels studied, most patients were not pretreated. The total number of assessable cycles was 123. The median number of cycles delivered by dose levels are listed in Table 2.


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Table 1.  Patient characteristics
 

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Table 2.  Drug delivery
 
Dose-limiting toxicity
DLTs were observed at the first cycle of dose levels 4 and 5 (Table 3). The DLTs reported were: grade 4 neutropenia and fever in one patient at dose level 5 and, grade 3 asthenia and grade 3 neutropenia in one patient. Both patients continued treatment with dose reductions. At dose level 4, two patients developed grade 3 asthenia at the third cycle and sixth cycle, respectively, and one patient experienced a radiation-recall reaction, with dermatitis and pneumonitis, induced by gemcitabine after the first cycle (Figures 1 and 2). This reaction resolved after the patient was withdrawn from the study. This case was included in the toxicity analysis. After the observation of an early non-hematological toxicity at dose level 4, one more dose level was explored (dose level 6: vinorelbine 30 mg/m2 and gemcitabine 2500 mg/m2). Three patients were included at this dose level. No DLT was observed at these doses.


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Table 3.  Hematological and non-hematological toxicitya
 


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Figure 1. Radiation-recall dermatitis over the radiation field.

 


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Figure 2. Pneumonitis associated with the radiation field at the right lung upper lobe.

 
Hematological toxicity
The most important hematological side effect was neutropenia. Grade 3 or 4 neutropenia was reported in two patients at dose level 4, and two patients at dose level 5. Neutropenic fever occurred in two patients. One of these patients required admission to hospital for treatment with intravenous antibiotics. Grade 1 or 2 neutropenia was observed in 30 cycles (25%). Thrombocytopenia was infrequent, with grade 1 or 2 ocurring in 16 cycles (13%), and grade 3 or 4 in four cycles (3%). Although five patients required dose reductions after experiencing DLT, no cumulative hematological toxicity was observed. Grade 1 or 2 anemia was observed in 23 cycles (19%) (listed in Table 3).

Non-hematological toxicity
There was no evidence of severe non-hematological toxicity in our study. The major non-hematological adverse effect observed was grade 3 asthenia in three patients: two cases at dose level 4, and one at dose level 5. Grade 1 or 2 asthenia was observed in 41 cycles (33%). Grade 1 or 2 nausea and vomiting was observed in 19 cycles (15%), but no grade 3 or 4 was observed. There were no other gastrointestinal toxicities. Two patients showed transient grade 1 or 2 elevation of hepatic transaminases (listed in Table 3).

Other clinical toxicities included grade 2 rash in two patients (at dose levels 4 and 5, respectively), and moderate flu-like syndrome in two patients (at dose levels 3 and 4, respectively). One patient developed grade 2 phlebitis related to the vinorelbine injection, which resolved after 10 days. This patient subsequently continued therapy after the placement of an implantable venous access device.

Recommended dose
Two dose levels were considered feasible for subsequent phase II trials: vinorelbine 25 mg/m2 plus gemcitabine 3000 mg/m2 (dose level 3) and vinorelbine 30 mg/m2 plus gemcitabine 2500 mg/m2 (dose level 6). At dose level 6, fewer overall toxicities of any grade (asthenia, thrombopenia and anemia) were observed compared with dose level 3. Therefore dose level 6 was chosen as the recommendation for further study.

Antitumor activity
Sixteen patients were evaluable for tumor response. One patient experienced a CR and four a PR, for an overall response rate of 31% (five of 16 patients). One chemonaïve patient with adenocarcinoma of unknown primary origin showed a CR after 12 courses at dose level 2. One patient with synchronous NSCLC and pancreatic adenocarcinoma and one patient with a NSCLC refractory to paclitaxel/carboplatin showed PRs at dose level 2 and dose level 3, respectively. One patient with peritoneal carcinomatosis, who progressed to a platinum-based regimen, had a PR at dose level 4. One patient with NSCLC refractory to concurrent chemotherapy and radiotherapy had a PR at dose level 6 and is presently alive at >20 months after initiation of therapy. In addition, one patient showed a minor response, and five experienced stable disease.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Various phase II studies have shown that either vinorelbine or gemcitabine as single agents have activity in a broad spectrum of tumor types [11, 12]. The different toxicity profiles of vinorelbine and gemcitabine, and the lack of cross-resistance, further supports the use of these agents in combination. Previous phase I or phase II studies have used different schemes of administration with emphasis on weekly dosing (repeated every 3 or 4 weeks). These schedules have reported moderate myelosuppression, with frequent dose delays and dose reductions [1322]. How-ever, preclinical and clinical data support the better therapeutic index of gemcitabine when it is given a constant infusion rate of 10 mg/m2/min [46].

The DLT in our study was neutropenic fever and asthenia in two patients at dose level 5, and asthenia in two patients and one patient with radiation-recall reaction at dose level 4. The latter patient developed radiation-recall dermatitis and pneumonitis on the second cycle, over the mediastinal radiation field. This suggests that gemcitabine is a potent radiosensitizer and confirms the preclinical data showing that gemcitabine causes radiosensitization [23].

In our study, little significant hematological and non-hematological toxicities were observed, despite the 2 week schedule and gemcitabine dose intensity administered. Repetitive cycles could be given without dose reduction or delay in >85% of cycles. This is better than observed in other studies that used 3 or 4 week schedules. Identical results were previously published in two different clinical trials using the same biweekly gemcitabine schedule [2426]. In a phase II study in patients with advanced NSCLC, Isokangas et al. [27] administered vinorelbine 30 mg/m2 on days 1, 8, 15 and 22, and gemcitabine 1000 mg/m2 on days 1, 8 and 15 of a 28 day cycle with significant myelotoxicity (75% of grade 3–4 neutropenia) and low dose intensity. Subsequently, the regimen was changed to vinorelbine 35 mg/m2 and gemcitabine 1250 mg/m2 on days 1 and 15 of a 28 day cycle, with good hematological tolerance and favourable clinical activity (45% response rate).

In our study, five patients experienced objective responses (response rate 31%), including two patients with NSCLC previously treated with chemotherapy and/or radiotherapy. Pharmacokinetic studies were not undertaken as part of this clinical trial, but it is unlikely that a pharmacokinetic interaction would occur between vinorelbine and gemcitabine.

In this study, at the recommended dose level 6 (vinorelbine 30 mg/m2 and gemcitabine 2500 mg/m2), the delivered median doses of vinorelbine and gemcitabine given during all cycles were 28.5 and 1215 mg/m2/week, respectively. These data indicate that gemcitabine can be safely administered prolonging the time infusion rate (at a constant rate of 10 mg/m2/min), and can also be combined with vinorelbine without substantially changing the single-agent toxicity profile of both drugs.


    Acknowledgements
 
This study was presented in part at the 9th World Conference on Lung Cancer, Tokyo, Japan, September 2000.


    Footnotes
 
+ Correspondence to: Dr D. Castellano, Servicio de Oncología Médica, Hospital Universitario ‘12 de Octubre’, Av Córdoba Km 5,4, Madrid 28041, Spain. Tel: +34-1-913908349; Fax: +34-1-914603310; E-mail: danicas{at}ene.es Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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