Results of randomised phase II studies comparing S16020 with methotrexate in patients with recurrent head and neck cancer

X. Pivot1,+, A. Awada2, D. Gedouin3, J. Kerger4, F. Rolland5, D. Cupissol6, F. Caponigro7, G. Comella7, J. J. Lopez-Pousa8, E. Guardiola1, B. Giroux9, B. Gérard9 and M. Schneider10

1 CHU J. Minjoz, Besançon, France; 2 Institut Jules Bordet, Brussels, Belgium; 3 Centre Eugène Marquis, Rennes, France; 4 Cliniques Universitaires de Mont-Godinne, Yvoir, Belgium; 5 Centre René Gauducheau, Saint Herblain, France; 6 Centre Val d’Aurelle, Montpellier, France; 7 National Tumour Institute, Naples, Italy; 8 Hopital San Pau, Barcelona, Spain; 9 Institut de Recherches Internationales Servier, Courbevoie; 10 Centre Antoine Lacassagne, Nice, France

Received 12 August 2002; revised 24 September 2002; accepted 22 October 2002


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

The purpose of this study was to carry out two randomised phase II trials of S16020, a new olivacine derivative, tested as a single agent in patients with recurrent head and neck cancer, using methotrexate as the control arm to validate the results.

Patients and methods:

S16020 at either 80 or 100 mg/m2 was administered as a 3-h infusion every 3 weeks. Methotrexate, 40 or 50 mg/m2, was given by bolus injection, weekly for a minimum of 6 weeks. In total, 36 patients were entered in the randomised studies (25 in an initial study, 11 in a confirmatory study) of whom 24 received S16020 and 12 received methotrexate.

Results:

A scheduled interim analysis showed one patient having a non-confirmed objective response with S16020 and three patients having a confirmed objective response with methotrexate. In the methotrexate group, there were no patients with severe non-haematological toxicity. With S16020, there was a high incidence of severe non-haematological toxicities, including asthenia, oedema of the face, oedema and pain at the tumour sites and erythematous rash; consequently, both studies were stopped.

Conclusions:

Both studies were stopped due to the poor anticipated benefit/risk ratio for S16020, although time to progression and overall survival time were similar in both treatment arms.

Key words: head and neck squamous cell carcinoma, methotrexate, randomised trial, recurrence, S16020


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer worldwide. In the European Union, in 1998, >70 000 new cases of SCCHN were diagnosed. The prognosis for patients with recurrent or metastatic disease remains dismal, with a median survival time of ~6 months [1]. Chemotherapy in locally recurrent or metastatic disease is usually only palliative, the main objective being to improve quality of life by reducing symptoms. Methotrexate monotherapy is still considered to be the standard chemotherapy in this situation. Indeed, despite the fact that better response rates are obtained with combination chemotherapy, no survival advantage has so far been demonstrated over single-agent chemotherapy with methotrexate [24]. Further investigation of new agents is therefore needed to try to improve survival in this patient population.

S16020 (9-hydroxy-5,6-dimethyl-N-[2-(dimethylamino)ethyl]-6H-pyrido[4,3-b]carbazole-1-carboxamide) is a new cytotoxic agent belonging to the olivacine family developed by IRIS (Institut de Recherches Internationales Servier). A phase I study determined a recommended phase II dose of 100 mg/m2 given by a 3-h intravenous infusion every 21 days [5]. During this phase I trial, two patients among nine with head and neck cancer had a partial response. These observations justified that activity of S16020 should first be assessed in patients with recurrent or metastatic SCCHN. Two phase II randomised studies comparing methotrexate with S16020 were undertaken. The initial randomisation plan was designed to take into account all the patients included in the two phase II trials in case they were prolonged as a phase III study to allow time and patient sparing. Thus, the second European trial using the same design and starting a few months after the French trial was aimed at confirming the results of the first one, and eventually pooling the patients’ results in case a phase III trial was launched.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Both studies were open-label multicentre randomised trials of S16020 versus methotrexate as first-line chemotherapy for patients with locally or metastatic recurrent SCCHN. The main inclusion criteria were: measurable disease, normal blood cell count, normal renal and hepatic function, Eastern Cooperative Oncology Group performance status of two or less, and signed informed consent. The main exclusion criteria included: adenocarcinoma or undifferentiated carcinoma of the nasopharynx, known brain metastases and uncontrolled infection. The approval of the local regulatory committees was obtained.

Patients were randomly assigned to the treatment arms in a ratio of 2:1 to receive S16020 or methotrexate, respectively. The S16020 was provided by IRIS. The randomisation was stratified according to the duration of the disease-free interval (>6 or <6 months) and initial exposure or not to chemotherapy during the treatment of the primary tumour. It was planned that S16020 was to be administered at a dose of 100 mg/m2 as a 3-h infusion repeated every 3 weeks. The seventh included patient developed a life-threatening sub-acute laryngeal oedema. Then a bolus of 120 mg of methylprednisolone was added before chemotherapy, and the dose of S16020 was reduced to 80 mg/m2. Methotrexate 40 mg/m2 was administered weekly as a bolus intravenous injection. For patients who did not show haematological toxicity or mucositis after the first three courses, the dose could be increased to 50 mg/m2. Patients continued to receive treatment as assigned at randomisation until disease progression or excessive toxicity occurred (severe acne or mucositis). The extent of the disease was evaluated by cervical computed tomography (CT) scans, chest X-rays and liver ultrasound or CT scan in the 4 weeks before starting the treatment, and assessments were repeated at 6-week intervals by physical examination and the same procedures according to WHO criteria. Toxicities were assessed at 1-week intervals according to the National Cancer Institute common toxicity criteria or International Union against Cancer criteria.

Statistical analysis
The planned analyses were intended to evaluate S16020 activity, and to validate the S16020 results using the results in the methotrexate group as a reference activity rate. The main criterion was the objective response rate (ORR). Secondary criteria were the percentage of patients alive at 6 months, the duration of the response and the toxicity assessment. The study was designed to reject S16020 if it was inactive, i.e. with an ORR <10% and to accept the drug if the ORR was between 10% and 25% [6]. In case of outstanding activity, i.e. with an ORR >25%, the study was to be closed. The {alpha} and ß risks were chosen at 10% because of the poor prognosis of the selected population. Accepting {alpha} and ß errors at 10% and a randomisation ratio of 2:1, a total of 50 patients had to enter the trial in the S16020 investigational arm and 25 patients in the methotrexate control arm. The number of patients was calculated according to the optimal three-stage design of Ensign et al. [6], which implied that the ORR would be calculated three times during the trial to allow early cessation in case of insufficient activity, i.e. if no response was observed out of the first 11 patients or if less than three patients had a response among the first 29 patients. Then, if more than five patients had a response among the 50 included patients, S16020 could be considered as a potentially active drug and the trial could be continued as a phase III study. The French study and the confirmatory European study both had the same plan, in order for them to be possibly pursued in a single phase III study. The decision to pool the data of both studies was made at the design stage.

Pharmacokinetic sampling
All patients were asked to participate in a population pharmacokinetic and pharmacodynamic study with blood sampling procedures on days 1, 22 and 43.

The sampling times were: before the infusion start on day 1 only, once during the infusion (between 0 and 3 h), once just before the end of the infusion, once between 3 and 7 h after the infusion start and once between 7 and 24 h on day 1 only. The exact times of sampling were provided at the time of inclusion to allow an analysis using the non-linear mixed-effect model. At each sampling time, 5 ml of blood were taken in the opposite arm to the infusion in a plastic tube with heparin, then gently shaken and kept frozen at –20°C. The blood concentrations of S16020 and its N-demethylated metabolite (S16018) were determined in the same laboratory by a high pressure liquid chromatography method with a previously validated UV detection.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Between February 1998 and March 1999, 37 patients were selected for the two studies (26 patients in the French and 11 in the European study). One patient, randomised to receive S16020, died suddenly before receiving the first treatment and was not included. Of the 36 included patients, 24 were randomised to receive S16020 and 12 to receive methotrexate. The patient characteristics were well balanced between both arms except for the median disease-free interval (Table 1).


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Table 1. Patient characteristics
 
Toxicity
Table 2 shows the incidence of haematological and non-haematological toxic effects in the 36 assessable patients.


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Table 2. Worst grade of toxicity (NCIC-CTC) in the patients (%) in the two treatment arms
 
In the S16020 arm, seven patients received the planned dose of 100 mg/m2 of whom three received one or two more courses at this dose and the other patients were included after an amendment reducing the S16020 dose to 80 mg/m2 in association with 120 mg methylprednisolone. A total of 56 courses of S16020 were administered. All the patients received the first course, 14 received two courses and five received three or more courses (range one to six). Four patients died of progressive disease after the first course. In six patients, the second course had to be delayed by >=7 days. The reason was related to the test drug in one case only. Haematological toxicity was mild. Frequent and severe non-haematological toxicities reaching grade 3/4 in ~25% of the patients treated with S16020 led to a poor overall tolerance with asthenia, oedema of the face, oedema and pain at the tumour site, and erythematous rash as main adverse events. Six patients were withdrawn from the study because of an adverse event: sub-acute laryngeal oedema resulting in death (one patient) (justifying the amendment about dose reduction and corticoids administration); severe pain at the tumour site (two patients); arrhythmia (two patients); and asthenia (one patient) related to the test drug. Two cases of pericarditis and pneumonia not related to the study drug were observed.

In the methotrexate arm, all 12 patients received a total of 101 courses at full dose (40 or 50 mg/m2). The median number of courses was six (range 2–18). One patient had an administration delayed by 7 days, related to grade 3 neutropenia, and another due to hepatic toxicity. Twelve cycles were delayed by 7 days for patient’s personal reasons. Mucositis (42%) and asthenia (33%) were the most frequent adverse events but no grade 3/4 non-haematological toxicities occurred.

Pharmacokinetic analysis
In 18 patients, blood samples were collected on day 1. In 14 patients, S16020 clearance could be calculated after two consecutive drug administrations at the same dose (80 mg/m2 in 12 patients and 100 mg/m2 in two patients) on day 1 and 3 weeks later, allowing comparisons of values over time. The comparison of S16020 clearance between two consecutive administrations at the same dose for each patient was performed in 14 patients (12 at 80 mg/m2 and two at 100 mg/m2). As S16020 pharmacokinetics are linear with the dose, clearances can be compared independently of the dose received [5]; furthermore, a similar result is obtained when considering the 80 mg/m2 group only. S16020 clearance mean value on day 1 was 888 ml/min (range 417–1433) and 1133 ml/min (range 767–1783) on day 22. The mean area under the curve (AUC) value of the metabolite S16018 was 144 ng·h/ml (range 47–299) on day 1 and 230 ng·h/ml (range 83–510) 3 weeks later. The increased clearance of S16020 (ratio 1.41) could be due to the induction of P450 cytochromes in the liver. The increased AUC of the quantitatively important metabolite S16018 in a similar ratio (1.64) seems to confirm this hypothesis.

Response and survival results
At the time of data collection, nine of the 36 patients enrolled were alive (seven in the S16020 group and two in the methotrexate group). Since most of the patients had died by 6 months (survival rate 22%), we calculated the median survival time: it was 3 months (range <1–16.5) for the S16020 group and 2 months (range <1–11) for the methotrexate group. Since the duration of response was not applicable, we calculated the median time to progression: it was 1.5 months (range 0.2–4.8) after S16020 and 1.5 months (range 0.4–5.7) after methotrexate.

Three patients were not assessable for the response in the S16020 arm due to early death not related to early disease progression. Out of the 21 evaluated patients, only one patient had an objective response at the site of liver metastases after the first two courses but the response was not confirmed 2 months later. Because one response was observed among the first 11 assessable patients included in the French study, the recruitment was pursued and the confirmatory European study started. Because this response was unconfirmed 2 months later and no other response was evidenced, both studies were closed due to anticipated lack of efficacy when considering that actually no activity was observed in a total of 24 enrolled patients. Three of the 12 patients treated with methotrexate had an objective response lasting for 4 months, giving a 25% response rate (95% confidence interval 0.5% to 49.5%). Stable disease was observed in four patients (17%) after the first two courses of S16020 but later confirmed in only one patient after six courses. Sixteen patients (67%) had progressive disease in the S16020 group versus nine patients (75%) in the methotrexate group.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This report presents the results of two phase II trials, since these two studies had exactly the same design and patient selection criteria. The first one started in France a few months before the second one, which was supposed to be a confirmatory European study. In case of useful activity, both studies were planned to be prolonged as a common phase III trial. Unfortunately, both studies had to be stopped after the second evaluation according to the planned early stopping rules. The data were pooled to allow presentation of the results in this restricted number of patients.

These studies were undertaken to evaluate the activity of the promising new agent S16020 using a control group treated with methotrexate to validate the results. Since one patient out of the first 11 treated with S16020 in the French trial responded at the first evaluation time, the next step—accrual up to 29 patients according to Ensign design [6]—was undertaken and the confirmatory European study launched. The next interim analysis failed to confirm this response and no useful activity could be shown for S16020 used as a single agent with an every 3-week schedule, although the overall survival time and time to progression were similar for the two treatment groups. Indeed, the non-haematological toxicities of S16020 were severe in 25% of the patients, while there was none in the control group, thus not encouraging anticipation of a favourable benefit/risk ratio compared with that of methotrexate.

Weekly doses of 40–50 mg/m2 methotrexate provide response rates ranging between 8 and 16% in randomised studies [24], but despite this low efficacy rate, methotrexate being well tolerated, it is still considered as a major option for second- and even first-line chemotherapy by the oncological community. All the recent investigational agents that have been compared with methotrexate failed to demonstrate any benefit in terms of response rate, time to progression and overall survival—edatrexate [7], paclitaxel [8] and nolatrexed [9]. These results stress the urgent need for new active agents in the treatment of recurrent SCCHN.


    Acknowledgements
 
We thank the following for their participation in the study: F. Chomy, Bordeaux, France; H. Cortes-Funes, Madrid, Spain; C. Dugast and B. Laguerre, Rennes, France; R. Messia, Barcelona, Spain; C. Lucas, Courbevoie, France.


    Footnotes
 
+ Correspondence to: Dr X. Pivot, Service d’Oncologie, CHU J. Minjoz, 25030 Besançon Cedex, France. Tel: +33-3-81-66-93-86; Fax: +33-3-81-66-88-59; E-mail: xpivot{at}chu-besancon.fr Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Pivot X, Poissonnet G, Dassonville O et al. An analysis of overall survival clinical prognostic factors for patients with locally recurrent or metastatic head and neck squamous cell carcinoma. Oncology 2001; 61: 197–204.[CrossRef][ISI][Medline]

2. Liverpool Head and Neck Oncology Group. A phase III randomised trial of cisplatinum, methotrextate, cisplatinum + methotrexate and cisplatinum + 5-FU in end stage squamous carcinoma of the head and neck. Br J Cancer 1990; 61: 311–315.[ISI][Medline]

3. Forastiere AA, Metch B, Schuller DE et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 1992; 10: 1245–1251.[Abstract]

4. Vogl SE, Schoenfeld DA, Kaplan BH et al. A randomized prospective comparison of methotrexate with a combination of methotrexate, bleomycin, and cisplatin in head and neck cancer. Cancer 1985; 56: 432–442.[ISI][Medline]

5. Awada A, Giacchetti S, Gerard B et al. Clinical phase I and pharmacokinetic study of S16020, a new olivacine derivative: report on three infusion schedules. Ann Oncol 2002; 13: 1925–1934.[Abstract/Free Full Text]

6. Ensign L, Gehan E, Kamen D, Thall P. An optimal 3-stage design for phase II clinical trials. Stat Med 1994; 13: 1727–1736.[ISI][Medline]

7. Schornagel JH, Verweij J, de Mulder PH et al. Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: a European Organization for Research and Treatment of Cancer Head and Neck Cancer Cooperative Group study. J Clin Oncol 1995; 13: 1649–1655.[Abstract]

8. Vermoken J, Catimel G, De Mulder P et al. Randomized phase II trial of weekly methotrexate versus two schedules of triweekly paclitaxel in patients with metastatic or recurrent squamous cell carcinoma of the head and neck. Proc Am Soc Clin Oncol 1999; 18: 395a.

9. Pivot X, Wadler S, Kelly C et al. Result of two randomized trials comparing nolatrexed (ThymitaqTM) versus methotrexate in patients with recurrent head and neck cancer. Ann Oncol 2001; 12: 1595–1599.[Abstract]





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