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Clinical Trials |
Department of Medical Oncology, Christie Hospital National Health Service Trust, Manchester [S. C. W., S. C., N. T., H. A., B. C., M. R.], and SmithKline Beecham, Harlow [S. H., G. R.], United Kingdom
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ABSTRACT |
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Three patients had radiological responses with a reduction in tumor size of 30–40%. No patients achieved complete or partial responses to treatment. Thirteen patients had a stable disease (43.3%), and the median survival was 39.9 weeks with a 1-year survival of 33.3%. At the time of analysis, 27 patients had died. Median time to progression was 12.3 weeks.
Treatment was well tolerated. A total of 125 cycles of treatment were completed. Twelve patients (40%) experienced grade III/IV neutropenia. Five patients (16.6%) had grade III/IV anemia. There were two episodes of grade III/IV thrombocytopenia. The main nonhematological toxicities consisted of grade III nausea (13%) and grade III vomiting (13%).
The most frequently reported disease-related symptoms at baseline were dyspnea, cough, and fatigue. There was a subsequent improvement in patient scores of dyspnea in 17% of patients, 31% showed improvement in cough, and 32% showed improvement in fatigue.
The mean area under the curve of TPT following 2.3 mg/m2 p.o. was 51.6 ng.h/ml (%SD, 25%). The area under the curve of TPT on day 1 of the first cycle was correlated with the percentage fall in leukocytes.
Although oral TPT at the applied dose and schedule showed modest activity as a single agent, almost one-half of the patients had a stable disease, and median time to progression was 12.3 weeks. The overall median survival was a promising 39.9 weeks, and useful palliation of symptoms was seen.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The development of new drugs has raised an expectation of improved activity and reduced toxicity. The camptothecin family of compounds has demonstrated activity in preclinical models and clinical studies of NSCLC (4) . Camptothecin and its derivatives interfere with the function of topoisomerase I, forming a stable complex with the enzyme and DNA. In the S phase, advancing replication forks convert these complexes into cytotoxic double-stranded breaks (5) .
TPT (9-dimethylaminomethyl-10-hydroxy-camptothecin) is a semisynthetic
analogue of the plant alkaloid camptothecin. Initial Phase I studies of
the i.v. formulation demonstrated the tolerability of the drug, with
myelosuppression being the major toxicity (6)
. When given
on a schedule daily for 5 days every 3 weeks, TPT was
efficacious in relapsed ovarian cancer and small cell lung cancer
(7
, 8)
. Phase II studies of the i.v. formulation in
non-small cell lung cancer have reported varying response rates of 0%,
4%, 15%, and 18.4% (9, 10, 11, 12)
. The median survival of 
8
months in each of these studies was encouraging despite the low
response rates. The feasibility of administering TPT p.o. has been
tested (13)
. Such a formulation could have implications
for patient convenience, schedule manipulation, and use in combined
therapy protocols. Oral TPT was shown to have 32–44% bioavailability
(14)
. Phase I studies demonstrated differing toxicities
depending on the schedule. A protocol of twice daily for 21 days
demonstrated an MTD of 0.5 mg/m2 with the DLT
being diarrhea (15)
. The schedule of 5 days every 3 weeks
showed an MTD of 2.3 mg/m2/day, with DLT being
grade IV neutropenia (12)
. The i.v. MTD for the same
schedule was 1.5 mg/m2/day (16)
.
In this study, we report the results of a Phase II study of oral TPT in chemotherapy-naïve patients with advanced NSCLC. The primary efficacy variables assessed were response rate, duration of response, and time to disease progression. Secondary variables were survival, time to response, symptom changes, and pharmacokinetics.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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60
ml/min, adequate bone marrow reserve (hemoglobin 9.0 g/dl,
neutrophils 1500/mm3, platelets
100,000/mm3), and hepatic function (serum
bilirubin 
34 µmol/liter, transaminases and alkaline
phosphatase two times the upper limit of normal) were required.
Patients with known brain metastases were excluded from the study.
Specific exclusion criteria were conditions affecting gastrointestinal
motility or absorption, or patients on maintenance
H2 antagonists or proton pump inhibitors. All patients gave informed, written consent, and the trial was approved by the local research ethics committee and conducted in accordance with good clinical practice obligations.
Treatment Schedule.
Patients commenced treatment at a baseline TPT dose of 2.3
mg/m2/day p.o. daily for 5 days every 3 weeks.
Patients received up to six cycles of treatment providing there was no
unacceptable toxicity or evidence of disease progression.
Dose Modification.
The treatment dose could be increased in subsequent cycles in steps of
0.4 mg/m2, providing there was no grade III/IV
toxicity. The maximum dose allowed was 3.1
mg/m2/day. The dose was reduced by 0.4
mg/m2 if substantial toxicity was experienced
with each course, e.g., grade IV thrombocytopenia or grade
IV neutropenia associated with fever.
Pharmacokinetics.
Blood samples for the determination of the pharmacokinetics were
collected up to 12 h after dosing on day 1 of the first cycle.
Samples were taken in all patients at the initial dose level and
subsequently in four patients who received the maximum dose of 3.1
mg/m2. Whole blood samples (3.0 ml) were
collected into cold heparinized tubes before dosing at the nominal
times of 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 h. Samples were placed
in ice and centrifuged within 10 min at 4°C at 1500 rpm. The sample
was transferred to appropriately labeled polypropylene tubes and frozen
on dry ice.
Plasma samples were stored at -30°C until analysis. Plasma samples were collected from patients at the Christie Hospital (Manchester, United Kingdom) and analyzed at the Netherlands Cancer Institute (Amsterdam, the Netherlands). Determination of plasma concentrations of total TPT were performed using high performance liquid chromatography with fluorescence detection (17) . The lower limit of quantitation was 0.10 ng/ml based on a 100-µl aliquot of plasma. The average within run and between run precision was <15% for all quality control samples. The average accuracies were within 85% and 115%.
Pharmacokinetic analysis of the plasma concentration time point
data for total TPT in each patients was analyzed separately by
noncompartmental methods using WinNonlin Professional (version 1.5).
Pharmacokinetic parameters determined for the total TPT concentration
time data included maximum observed plasma concentration
(Cmax) and time to which
Cmax occurred
(Tmax). Area under the concentration
time curve from zero to the time of the last quantifiable concentration
(AUC 0-t) was determined using the linear
trapezoidal rule for each incremental trapezoid up to the time of
Cmax and the log trapezoidal rule for
each trapezoid thereafter. AUC extrapolated to infinity (AUC
0-
) was calculated as the sum of AUC (0-t) and
Cpred/
z where
Cpred is the predicted concentration
at time t. The apparent terminal elimination rate constant
(z) was derived from the log-linear disposition phase of
the concentration time curve using least squares regression analysis.
With visual inspection of the data to determine the appropriate number
of data points to include in the calculation of z. The
apparent terminal elimination half-life
(T1/2) was calculated as ln
2/z.
Mean plasma concentrations were determined for each time point for each
dose regimen and displayed graphically. Pharmacokinetic parameters were
summarized descriptively (mean, median, SD, minimum, and maximum) for
each regimen. Spearman rank correlations were calculated between
AUC (t-) day 1 and the percentage decrease of
WBCs.
Treatment Assessment.
Patients were followed with weekly full blood examinations, and
history, physical examination, urinalysis, and biochemistry at the
commencement of each cycle. The objective response was evaluated
according to WHO criteria with a more stringent definition of stable
disease requiring a duration of at least 56 days. All claimed responses
were subject to independent radiological review. Radiological
assessment was performed at the baseline and following cycles 2, 4, and
6. Patients also completed a lung cancer-based symptom questionnaire
before assessment on the day of treatment. Toxicities were graded
according to National Cancer Institute common toxicity criteria.
Statistical Analysis.
The primary aim of the study was the assessment of the response rate
with oral TPT. The sample size of 30 patients allowed the true rate to
be predicted with a SE of no more than 9.13%.
Time to progression was taken from the date of the first treatment to the date of the progression. Survival was calculated from the date of the first treatment to death, and a survival curve was formed using Kaplan-Meier estimation.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Two-thirds of the patients were
male, and the median age was 61.5 years. All except 2 patients had
performance status 1 or 2, and 18 patients (60%) had evidence of
metastatic disease.
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The thirty patients received a total of 125 cycles, 41 of these at the starting dose. Twenty-six patients (86.7%) had an increase in dose to 2.7 mg/m2. A further 15 of the latter patients received a further dose increase to 3.1 mg/m2/day. Only one patient required a dose reduction to 1.9 mg/m2/day.
Response and Survival.
There were no patients who achieved either a complete or partial
response to treatment, although three patients had objective tumor
shrinkage of <50%. Response to treatment is summarized in Table 2
. Three patients were not
assessable for tumor response. One patient was withdrawn after cycle 1
because of toxicity. Another patient was not assessable for tumor
response due to the absence of measurable disease, and a further
patient had stable disease that was not confirmed at 56 days. All
patients with stable disease received six cycles of TPT. Patients who
developed progressive disease received a median of three cycles. Median
time to progression was 12.3 weeks. Median overall survival was 39.9
weeks (range, 4–59.1 weeks), and the 1-year survival was 33.3%.
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Symptom Benefit.
Nine symptoms were evaluated on a four-point scale based on the Lung
Cancer Symptom Score. A symptom improvement was defined as an
amelioration of the symptom by one or more points, which were sustained
for at least two treatment cycles, as described by von Pawel et
al. (8)
. The results are summarized in Table 3
. There was improvement in both
respiratory symptoms and general symptoms, with dyspnea improving in
17% of patients, cough in 31%, chest pain in 20%, and hemoptysis in
33%.
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. Grade 3 or 4 neutropenia occurred in
22.6% of courses, and grade 3 or 4 leukopenia occurred in 16.9%.
Grade 3 or 4 thrombocytopenia was uncommon, occurring in 1.6% of
courses. Fever or infection of at least grade 2 was experienced by
seven patients (23.3%), but only one patient experienced fever in the
context of grade 4 neutropenia. Grade 3 or 4 anemia occurred in five
patients. Sixteen patients received a blood transfusion at some stage
during treatment, usually to ameliorate symptoms of fatigue or dyspnea.
The mechanism of anemia was considered to be myelosuppression because
none of the transfused patients demonstrated clinical signs of blood
loss or had an abnormal blood film.
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Pharmacokinetics.
A total of 30 patients were enrolled and provided complete
pharmacokinetic data on day 1 of cycle 1 after oral dosing of 2.3
mg/m2. The pharmacokinetics following escalation
to 3.1 mg/m2 was studied in four patients who
provided additional pharmacokinetic data on their first day of the new
dose regimen.
After oral administration of 2.3 mg/m2, total TPT
plasma concentrations were quantifiable over the 12-h sampling
interval. Peak plasma concentrations generally occurred within 2 h
after dosing. The mean AUC (0–12h) was 51.6 ng.h/ml.
Because the terminal phase was not well described in four patients, no
extrapolation of the AUC could be performed. Therefore, AUC
(0-) and T1/2 were not calculated
for these patients. In the remaining 26 patients, mean AUC
(0-) and T1/2 were 61.8 ng.h/ml and
3.96 h, respectively (See Table 5
).
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) were 76.6 and 85.0 ng.h/ml,
respectively. The mean T1/2 following
the 3.1-mg/m2 dose was 3.56 h.
Spearman rank correlations were performed in the 26 patients who
had an estimated AUC (0-). A statistically significant
correlation between AUC (0-) and percentage fall in white
cells (P = .002) was found, with a correlation
coefficient of .575.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Forty-three percent of patients had stabilization of disease, with a median time to progression of 12.3 weeks. The median survival of 39.9 weeks and a 1-year survival of 33.3% appeared promising. Such results are in excess of typical survival figures in advanced lung cancer (18 , 19) . Although this may reflect a selection bias, it may also be possible that TPT has had an impact on the course of the disease. Similar survival results have been observed in Phase II studies of i.v. TPT in NSCLC (9, 10, 11, 12) . One of the latter studies had no responses and another study of infusional topotecan had a response rate of 4%.
Have objective radiological response rates been shown to correlate with survival? Many randomized studies in NSCLC failed to demonstrate that superior response rates translate into improved survival (20, 21, 22) . Conversely, an ECOG study comparing carboplatin to combination therapy showed superior 1-year survival results in the carboplatin arm despite a modest response rate of 8% (23) . The results of a neoadjuvant study also demonstrated the poor correlation between radiological and pathological response (24) .
Accordingly, response rates are not necessarily good predictors of outcome, and the emphasis on response ignores the potential impact of disease stabilization on survival in NSCLC. Stabilization of disease has been associated with prolonged survival in NSCLC (25 , 26) .
It is possible that second line therapy has impacted on overall survival. Eighteen patients (60%) received palliative radiotherapy resulting in stable disease in nine patients. Ten patients (33.3%) received chemotherapy, with one patient responding and another four patients having stable disease. The progression-free survival of 12.3 weeks is still, however, suggestive of some benefit from TPT.
The symptomatic improvement in some patients would be consistent with some cytotoxic effect. About one-third of patients had some improvement in one or more disease-related symptoms. Similar data have been obtained from quality of life questionnaires used in other recent studies in NSCLC. A Phase II study using single-agent gemcitabine achieved a 20% objective RR, but symptom improvement occurred in a greater proportion of patients. In response to gemcitabine, 46% of patients reported improvement in cough, dyspnea improved in 26%, and pain in 32% (27) . In the latter study, the median survival was 8.1 months.
Is it possible to explain the absence of objective responses in this study? Phase II studies in advanced NSCLC using the i.v. formulation have demonstrated varying levels of activity. Although one study showed no responses, another demonstrated a 4% RR, a third study 15% RR, and a final study comparing the 5-day schedule with a monthly 3-day infusion found an RR of 18.4% in the 5-day arm. (9, 10, 11, 12) .
It has been suggested that topotecan may be more active against SCC than other NSCLC histological subtypes. This was hypothesized to explain the lack of response in the Lynch study where only 3 of 20 patients had SCC histology. Perez-Soler et al. (28) proceeded to the Phase II study of TPT treating only SCC of the lung, achieving a 24% RR. In our study where 10 of 30 patients had SCC histology, there were no objective responses in the subgroup, and indeed the three minor responses occurred in patients with non-SCC histology.
Could our results reflect a difference in the intensity of therapy between oral and IV TPT on a 5-day schedule? A bioavailability study demonstrated that the mean AUC of 2.3 mg/m2 of oral TPT (57.9 h.ng/ml) was considerably lower than the mean AUC of i.v. TPT at the MTD for the 5-day schedule (91.2 h.ng/ml; Ref. 29 ). Our results also yielded a similar mean AUC for oral TPT. It is therefore possible that the lack of objective responses reflect a difference in intensity compared with i.v. TPT. Such a hypothesis would not be supported by the results of a randomized study of small cell lung cancer patients; oral TPT given at the same dose and schedule as our study yielded similar response rates to IV TPT (30) . Furthermore, no definite data from TPT studies has correlated cytotoxic activity with pharmacokinetic end points or dosage. Some in vitro data have suggested that time above a critical threshold is more important than actual AUC in the inhibition of topoisomerase I (31 , 32) .
It is unlikely that the lack of activity reflected an alteration in the ratio of the active lactone moiety:hydroxy acid form. Although this was not assessed in our study, the bioavailability study by Schellens et al. (14) reported no difference in this ratio between i.v. and oral administration of TPT.
It was evident that most of our patients could have tolerated a higher starting dose because 26 patients (87%) were dose-escalated after cycle 1 to 2.7 mg/m2. A further 15 patients (50%) received the maximum protocol dose of 3.1 mg/m2. The low dose intensity may have implications for achieving tumor cell kill, and conversely, an inadequate dose may theoretically promote the growth of resistant clones. Phase II studies with alternative schedules await examination in NSCLC. There is preclinical evidence that a prolonged exposure time to TPT may have greater efficacy (33) . At a pharmacodynamic level, Hochster demonstrated that a 21-day infusion of TPT induced a progressive depletion of lymphocyte topoisomerase I levels until day 15, and this extended schedule may be worthy of assessment.
Oral TPT was well tolerated by patients, with a qualitative toxicity profile similar to the 5-day i.v. schedule, except that the incidence of grade 4 neutropenia was lower for oral topotecan (10%) compared to i.v. topotecan (47%; Ref. 9 ). Myelosuppression was the most prevalent toxicity, with 12 patients experiencing grade 3/4 neutropenia. Only one patient in our study experienced neutropenic fever. Mild anemia was common with over one-half of the patients requiring some transfusion support.
Mild to moderate nausea was seen in over one-third of patients but was easily controlled with antiemetic therapy. Diarrhea was uncommon and self-limiting. This is in contrast to the Phase I study of oral TPT using a schedule of twice daily for 21 days where diarrhea was the DLT. It occurred in the third week of drug administration, and the authors speculated that it may have resulted from an enhanced local effect of oral TPT on the gut mucosa with this schedule (15) .
Interestingly, a correlation was found with total TPT AUC and the percentage fall in leukocytes. Similar findings were noted in three other i.v. TPT studies. Two of the studies observed that the total TPT AUC rather than the lactone AUC correlated better with neutrophil fall (34 , 35) . Reasons for this may have included intracellular conversion of the carboxylate to the lactone form or variability in the kinetics of the carboxylate form among patients treated with the same TPT dosage. A recent study comparing different schedules of oral TPT also found correlations between day 1 lactone AUC and myelosuppression. The authors concluded that the TPT plasma level rather than length of exposure to TPT was responsible for myelosuppression (36) . These observations may have implications for combination therapy where additive myelosuppression may be lessened by a protracted schedule of oral TPT (37) . The unpredictable and sometimes severe diarrhea seen with such schedules, however, may limit this application.
The minimal toxicity exhibited in cycle one implied that the initial 2.3-mg/m2 dosage was conservative in a chemotherapy-naive population. Eighty-seven percent of patients were dose-escalated, and only two of the remaining four patients had grade 3/4 myelosuppression. Accordingly, we would conclude that 2.7 mg/m2 is a more appropriate commencement dose in untreated patients. The broad scatter of AUCs obtained in the pharmacokinetic analysis do not permit the development of a predictive model of individual dosing. Pharmacokinetic studies examining a much larger study population may, however, lead to a more refined dose.
Despite the modest activity demonstrated in this study, the oral formulation of TPT is convenient and has effects on stabilization that might translate to survival benefit in advanced lung cancer. Because oral TPT is well tolerated and provides symptom benefit, it may be useful in combination with platinum or taxane-based compounds. Some preclinical data suggests possible synergism between TPT and radiation (38) , and topotecan and cisplatin (39) . Combination Phase II studies are in progress.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 To whom requests for reprints should be
addressed, at Department of Medical Oncology, Christie Hospital NHS
Trust, Manchester M20 4BX, United Kingdom. Phone: 44-161-446-3000; Fax:
44-161-446-3299; E-mail: malcolm.ranson{at}man.ac.uk 
2 The abbreviations used are: NSCLC,
non-small cell lung cancer; TPT, topotecan; MTD, maximum-tolerated
dose; DLT, dose-limiting toxicity; ECOG, Eastern Cooperative Oncology
Group; SCC, squamous cell carcinoma; AUC, area under the curve.
Received 10/ 6/99; revised 12/ 8/99; accepted 12/ 9/99.
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REFERENCES |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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