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Annals of Oncology Advance Access originally published online on December 5, 2006
Annals of Oncology 2007 18(3):561-568; doi:10.1093/annonc/mdl418
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© 2006 European Society for Medical Oncology

phase I and pharmacokinetics

Concerted escalation of dose and dosing duration in a phase I study of the oral camptothecin gimatecan (ST1481) in patients with advanced solid tumors

C Sessa1, S Cresta2, T Cerny3, J Baselga4, E Rota Caremoli2, A Malossi1, D Hess3, J Trigo4, M Zucchetti6, M D'Incalci6, A Zaniboni7, G Capri2, B Gatti5, P Carminati8, C Zanna8, S Marsoni5 and L Gianni2,*

1 Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland
2 Istituto Nazionale Tumori, Milan, Italy
3 Kantonsspital, St.Gallen, Switzerland
4 Hospital General Vall d'Hebron, Barcelona, Spain
5 SENDO
6 Mario Negri, Milan
7 Casa di Cura Poliambulanza, Brescia
8 Sigma Tau SpA, Rome, Italy

* Correspondence to: Dr L. Gianni, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. E-mail: luca.gianni{at}istitutotumori.mi.it


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 Acknowledgements
 References
 
Background: Gimatecan is an orally bioavailable camptothecin analogue with preclinical findings of promising antitumor activity. A phase I design of concerted dose escalation and dosing duration was implemented to assess the potential schedule dependency of tolerability that emerged from animal studies.

Patients and methods: Gimatecan was given daily for five consecutive days per week for 1, 2 or 3 weeks every 28 days. Plasma levels of total gimatecan were measured on the first and the last day of treatment in each schedule.

Results: Overall, 108 patients were treated with 0.8–7.2 mg/m2 of gimatecan per cycle. The main toxicity was myelosuppression with dose-limiting thrombocytopenia. In the 1-, 2- and 3-week schedule, the maximum tolerated doses were 4.5, 5.6 and 6.4 mg/m2. Diarrhea and asthenia were of low grade and of minor clinical relevance, while the higher incidence of nausea and vomiting in the 1-week schedule required the use of antiemetic prophylaxis. Due to the prolonged half-life (~77 h), the plasma concentration of gimatecan increased from the first to the last day of dosing. Six partial responses were observed.

Conclusions: Tolerability of gimatecan was schedule dependent. Further testing with schedules taking into account its long persistence in human plasma is worthwhile.

Key words: concerted dose escalation, gimatecan, oral camptothecin, pharmacokinetics, phase I


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 Acknowledgements
 References
 
Gimatecan (ST1481; 7-[(E)-tert-butyloxyminomethyl]-camptothecin, Figure 1) is a new camptothecin characterized by persistent stabilization of the cleavable complex [1], and increased intracellular accumulation [2]. The clinical development of gimatecan was prompted by the availability of an oral formulation and the broad antitumor activity against several human tumor xenografts [3, 4]. Gimatecan also has a favorable plasmatic equilibrium between the lactone and its open ring form [5].


Figure 1
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  		Figure 1. Structure of gimatecan.

 
Bone marrow suppression, emesis and diarrhea were the main toxic effects after single and repeated administrations in rats and dogs. Gastrointestinal (GI) side effects were milder in rodents and dogs when gimatecan was administered for longer durations at low doses [6]. Pharmacokinetic studies showed that daily administrations in dogs resulted in negligible accumulation of the parent camptothecin [7].

Whether total dose or duration of treatment per cycle is more relevant for antitumor activity of camptothecins is still an open question [8–12]. The oral bioavailability of gimatecan made possible to mimic infusions of different duration and therefore address the question whether tolerability was schedule dependent. On the basis of the available preclinical data, we defined a trial design in which the increase of doses in different cohorts of patients could safely and concomitantly assess 3 schedules of different duration all given with a daily administration for five consecutive days per week repeated for 1, 2 or 3 weeks every four. The weekly block of 5 days of therapy followed by 2 days of rest was selected because of the consideration that five consecutive days were the longest duration of continuous dosing in animals [4]. In addition, treatment according to such schedule was associated with the optimal therapeutic window with respect to topotecan (Hycamtin; GlaxoSmithCline, Philadelphia, PA) in several solid tumors [7]. We called this design a ‘concerted’ escalation according to which the shortest and potentially more acutely toxic schedule was driving the escalation, so that the same total dose per level could be administered over a period of 2 or 3 weeks only after the same dose per cycle was proven safe and feasible when administered over 1 week (Figure 2).


Figure 2
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  		Figure 2. Concerted escalation design.

 

   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 Acknowledgements
 References
 
eligibility criteria
Patients with histological evidence of malignant solid tumor refractory or not amenable to conventional therapy were enrolled from four centers if they met the following criteria: age ≥18 years; Eastern Cooperative Oncology Group performance status of two or less; neutrophils ≥2.0 x 109/l; platelets ≥100 x 109/l; alkaline phosphatase ≤2.5 x UNL (upper normal limit); liver transaminases ≤1.5 x UNL (≤2.5 in case of liver metastases); bilirubin ≤UNL; serum creatinine ≤1.5 x UNL; life expectancy of at least 3 months and signed written informed consent. Patients with morbidity that could negatively affect drug absorption were excluded. The Institutional Ethical Boards approved the study.

treatment
Gimatecan, formulated in gel caps (gelucire 44/14 as diluent), was given orally 1 h before breakfast for five consecutive days for 1, 2 or 3 weeks long every four. In each week of therapy, 5 days of dosing were followed by 2 days of rest.

dose-escalation design
The different schedules were evaluated concomitantly (Figure 2). Eligible patients were enrolled consecutively according to slot availability in any of the three schedules. The longer schedules could be opened to accrual only after the safety of the same total dose was tested in the 1-week schedule. The entry level of the 1-week schedule was 0.8 mg/m2 (0.16 mg/m2/day x 5 days) corresponding to one-third of the toxic dose low in the dog. The dose was escalated in cohorts of at least three patients according to a modified Fibonacci scheme. Three patients in each dose level were followed for at least 3 weeks before entering patients at the next dose level. The 2-week schedule started when the second dose level of the 1-week schedule was completed. The 3-week schedule started when the second dose level of the 2-week schedule was completed.

Within each schedule, if one of three patients developed dose-limiting toxicity (DLT) during the first cycle, at least three additional patients were accrued into the same dose level. Whenever two or more patients out of three to six had a DLT at the first cycle, that dose was considered the maximum tolerated dose (MTD).

DLT was defined as follows: drug-related death; febrile neutropenia; grade 4 neutropenia for longer than 7 days; grade ≥3 thrombocytopenia; grade 2 cardiac, liver or renal toxicity; any other non-hematologic toxicity of grade ≥3; inability to receive full planned treatment and lack of full recovery from toxicity by day 35 of the cycle.

Patients could continue until progression or unacceptable toxicity.

treatment assessment
Patients' monitoring included physical examination, complete blood counts weekly and blood chemistry twice per cycle. Patients were assessable for response using RECIST [13] at any time if they progressed, or if they had at least one disease assessment repeated not earlier than 8 weeks after starting gimatecan. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 2.0 (http://ctep.cancer.gov).

sample collection and pharmacokinetic analysis
Pharmacokinetic studies were an integral part of the trial, but not mandatory. Overall 54 of the 108 patients were sampled for pharmacokinetic analysis. Blood samples were collected immediately before and at 30 min and 1, 1.5, 2, 4, 6, 8, 12 and 24 h after gimatecan on day 1 and at similar intervals on the last day of dosing until the 72nd hour after the last dose. Samples were kept on ice until centrifugation at 4°C, and stored at –20°C until analysis. Total and lactone concentration of gimatecan were measured in plasma by HPLC (lower limit of quantification of 5 ng/ml) [14].

Pharmacokinetic parameters were calculated by standard noncompartmental methods using the Win Nonlin software Pro Node 4.1 (Pharsight Co, Mountain View, CA): peak concentration (Cmax) on day 1 and on the last day of the cycle, time to Cmax (Tmax), area under the curve (AUC0–24 and AUC0–72) and terminal half-life (t1/2).


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 Acknowledgements
 References
 
patients characteristics
One hundred and eight patients entered the study and received 292 cycles of gimatecan including repeated administrations in stable/responding cases (Table 1). All patients but one had received at least one prior chemotherapy with/without localized radiotherapy. Most patients (68%) received prior drugs that induce thrombocytopenia, including carboplatin (16%), gemcitabine (15%), both drugs (12%) and other agents (25%).


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  		Table 1. Patients characteristics

 
DLTs, concerted dose escalation and conduct of the study
The MTD was defined at 4.5, 5.6 and 6.4 mg/m2 as total doses for the 1-, 2- and 3-week schedule, respectively. The most frequent and serious DLT was thrombocytopenia that was followed ~1 week later by neutropenia.

The concerted dose escalation was uneventful up to the dose of 4 mg/m2 per cycle (Table 2). At the subsequent dose (5.6 mg/m2), three of the four patients enrolled into the 1-week schedule had thrombocytopenia of grade 3 or worse. The sudden appearance of DLT was in contrast with the almost faultless tolerability of gimatecan up to the prior dose, and prompted to open an intermediate dose level at 5 mg/m2 for the 1-week schedule, and to extend to at least six patients any subsequent cohort at any dose level and for each schedule even in the absence of DLT in the first three patients. None of the first six patients administered 5 mg/m2 had a first cycle DLT. When the level was extended to eight additional cases to define the recommended dose, however, DLTs occurred in overall six cases, including episodes of late hematologic recovery from mild-moderate neutropenia or thrombocytopenia. A second intermediate dose level was therefore opened at 4.5 mg/m2, with hematologic DLTs in two of seven patients; 4.5 mg/m2 was defined as the MTD for the 1-week schedule.


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  		Table 2. First cycle DLTs by schedule and dose level

 
In the 2-week schedule, an expanded cohort of six patients was treated at 5.6 mg/m2 without DLTs. The subsequent planned dose of 7.2 mg/m2 was given to five patients; in the first four the dosing was uneventful, the fifth patient, a 57-year-old woman with a malignant mesothelioma pretreated with five cycles of cisplatin and gemcitabine, developed severe pancytopenia and infection and died of multiple organ failure 12 days after treatment. The prior dose level of 5.6 mg/m2 was reopened to nine additional patients to define the recommended dose. In contrast with the observation in the first six cases tested, four of the new patients developed hematologic DLT, thus defining 5.6 mg/m2 as the MTD for the 2-week schedule, and prompting the test of an intermediate dose level at 5 mg/m2. Two of seven patients enrolled at such dose had a DLT. The thrombocytopenia of one of the two (nadir 33 x 109/l), however, only lasted for 2 days, and all hematologic toxicity had fully resolved by day 29. The dose of 5 mg/m2 was therefore considered well tolerated.

The unexpectedness and unsystematic occurrence of toxic events observed with the 1- and 2-week schedules justified the expanded test of the 5.6-mg/m2 dose level in six patients for the 3-week schedule. After proving that dose safe, five patients were enrolled into the subsequent planned level of 7.2 mg/m2, and four had DLT. Again, the discrepancy between the pattern of tolerability at 5.6- and 7.2-mg/m2 doses justified the testing of an intermediate dose level at 6.4 mg/m2, which was defined as the MTD due to one late DLT and one case of early drug discontinuation because of worsening grade 1 thrombocytopenia requiring a cautionary approach. Three more patients were then accrued at 5.6 mg/m2.

hematologic toxicity
Tables 3 and 4 report the first cycle hematologic toxicity. Any grade thrombocytopenia occurred in 47% of cases, with a median platelet nadir of 151 x 109/l and a median time (range) to nadir of 19 (15–25), 24 (19–30) and 29 (21–31) days for the three schedules, respectively. Any grade neutropenia occurred in 45% of cases, with a median neutrophil nadir of 2.1 x 109/l and a median time (range) to nadir of 26 (15–36), 27 (9–40) and 33 (15–42) days. Hematologic re-treatment criteria were met by day 28 in ~75% of cases, with recovery delayed >1 week in 14% of cases.


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  		Table 3. First cycle neutropenia graded according to National Cancer Institute, Common Toxicity Criteria version 2.0

 

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  		Table 4. First cycle thrombocytopenia graded according to National Cancer Institute, Common Toxicity Criteria version 2.0

 
non-hematologic toxic effects
Asthenia was reported in 33%, 39% and 61% of patients at cycle 1 with the three schedules, respectively. Diarrhea appeared during treatment or shortly thereafter, worsened if gimatecan was continued, was controlled by loperamide and was not cumulative. Overall, the incidence of first cycle diarrhea was 12.5% in the 1-week, 18% in the 2-week and 20% in the 3-week schedule independently of dose, although minimal or no toxicity was observed up to 4 mg/m2. Nausea and vomiting in the first three patients receiving 4 mg/m2 with the 1-week schedule justified the use of prophylactic antiemetics for that schedule. With the described differences of antiemetic use, the incidence of nausea and vomiting at cycle 1 with the three schedules was similar (46%, 51% and 55%, respectively) and almost never of grade worse than 2. Loss of hair was rare (range 3%–10% across schedule), mostly mild (grade 1) and mainly observed with the 1-week administration at doses ≥5 mg/m2.

antitumor activity
Disease was measurable in 97 patients. Six had a partial response confirmed by an independent radiological review. The antitumor activity was observed with each of the three schedules even at doses lower than the recommended one. The six responses lasted from 3.5 to 8.2 months. Table 5 reports the relevant information on tumor type, prior chemotherapy and site of response for the responders.


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  		Table 5. Responses

 
pharmacokinetics
A full report of the pharmacokinetics is in preparation. Briefly, plasma disposition of gimatecan was assessed in 54 patients at different doses by each of the three schedules. Both total and lactone form were measured in plasma. The most remarkable characteristic was the high proportion of lactone in human plasma (>90%) (data not shown), which was stable over time.

The pharmacokinetics of gimatecan in humans was characterized by rapid absorption (Tmax ranged from 0.5 to 4 h) and very slow elimination [mean (±standard deviation) terminal t1/2 (N = 54): 77 (±29) h; range 31–147 h]. Gimatecan accumulated in plasma after multiple dosing, so that Cmax and AUCs increased by three to six times after repeated administrations. Table 6 reports the Cmax and AUC of gimatecan after the first and the last day of treatment on cycle 1 at the MTD for each schedule.


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  		Table 6. Mean ± SD pharmacokinetic parameters of gimatecan at the MTD by schedule (cycle 1)

 

   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
Acknowledgements
 References
 
The oral formulation and the broad spectrum of preclinical antitumor activity justified the clinical development of gimatecan. Pharmacological and therapeutic effects of camptothecins may be schedule dependent [9], and the possible schedule dependence of gimatecan had emerged from animal studies of antitumor activity and toxicology [7]. We devised a phase I study in which three schedules of different duration were tested in a concerted dose-escalation design. According to such design, the 1-week (acute) schedule, potentially more toxic but also more easily monitored, was driving the dose escalation for all schedules. Once proven safe, the dose tested in the acute schedule was released for trial with the 2- or 3-week schedule. In so doing, both dose and duration of treatment were increased in an interdependent fashion.

Overall, the concerted escalation design allowed for accruing 108 patients over a period of 2 years from four participating centers and together with the centralized triage of patients permitted a saving of one and two dose levels from those originally planned in the 2- and 3-week schedule. In addition, this design led to the application of homogeneous criteria of patient selection which lends weight to the observation that more total gimatecan could be delivered per cycle with increasing duration of administration.

The dose levels tested in the trial were seven, six and five in the three schedules, respectively, including intermediate step-down levels. In spite of the expectations, for gimatecan, the number of levels and patients was larger than originally planned because of the unexpected and unsystematic occurrence of dose-limiting bone marrow toxicity. Of note, we could not find any relationship between extent or type of prior chemotherapy and the occurrence of toxicity. Given the variability of the hematologic toxicity and particularly of thrombocytopenia, we consider more appropriate to suggest ranges within which to choose the optimal dose for phase II testing that can be defined as 4.0–4.5, 5.0–5.6 and 5.6–6.4 mg/m2 as total doses for the 1-, 2- and 3-week schedule, respectively.

When we designed the present trial, a protracted daily administration of gimatecan appeared reasonable on the basis of the better tolerability of chronic than acute administration in dogs, a species in which the drug was rapidly disposed of [7]. Pharmacokinetic studies were an integral part of the present trial. Quite unexpectedly, pharmacokinetics of gimatecan in humans had a long terminal t1/2, leading to accumulation after daily dosing. The 2-day rest period between blocks of five daily doses was originally introduced to mimic the longest continuous administration in animals, but it most likely contributed to limit the possible tolerability drawbacks of accumulating concentrations when gimatecan was given with the 2- or the 3-week schedules. On the basis of pharmacokinetic data now available, a weekly or twice weekly rather than a daily schedule would be theoretically more appropriate for the drug.

The main toxicity of gimatecan was myelosuppression, while asthenia and GI side effects were almost always of low grade and of minor clinical relevance. The 1-week schedule was associated with a higher incidence of nausea and vomiting that prompted the use of prophylactic antiemetics. Diarrhea was not increased by longer treatments or repeated administrations, and was well controlled by loperamide. Alopecia was partial and occurred only at the higher doses with the 1-week schedule.

The pharmacokinetics of gimatecan in humans were characterized by a large interpatient variability, also typical of almost all camptothecins [15]. What is interesting to note is that the proportion of the lactone form, which is the active species, was ~90% of total gimatecan levels, thus much higher than that previously described for other camptothecins that were developed in the clinic. Studies on protein binding and on other sources of variability are ongoing to further explore if a relationship exists between the drug disposition and its effects.

We observed six objective tumor responses that occurred with all schedules and also at low and nontoxic doses in patients with histological types in which recently a clinical benefit of camptothecins has been shown, such as endometrial cancer [16, 17] or breast carcinoma [18].

An overall appraisal of the results of the present study leads to consider the 3-week-long administration as suboptimal because it was more often associated with thrombocytopenia that limited the administration of subsequent cycles in time. In the absence of elements of antitumor activity guiding a different decision, the 1- and the 2-week-long schedules are now both being tested in phase II.

In conclusion, gimatecan is a new camptothecin derivative which showed antitumor activity in this phase I trial with thrombocytopenia as main DLT across all schedules. Gimatecan deserves further testing with schedules that take into account its pharmacokinetics in humans. The present study has, however, defined safe doses of daily schedules currently evaluated in phase II trials.


   Acknowledgements
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 Acknowledgements
References
 
We thank Irene Corradino, Graziella Pratesi and Mercedes Lassus. We also acknowledge the support of the Swiss League Against Cancer to the SENDO Foundation.

Received for publication June 13, 2006. Revision received September 4, 2006. Accepted for publication September 22, 2006.


   References
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 Acknowledgements
 References
 
1. Dallavalle S, Ferrari A, Merlini L, et al. (2001) Novel cytotoxic 7-iminomethyl and 7-aminomethyl derivatives of camptothecin. Bioorg Med Chem Lett 11:291–294.[CrossRef][Medline]

2. Pratesi G, De Cesare M, Zunino F. (2000) Improvement of therapeutic index of low-dose topotecan delivered per os. Ann NY Acad Sci 922:330–333.[Free Full Text]

3. Pratesi G, De Cesare M, Carenini N, et al. (2002) Pattern of antitumor activity of a novel camptothecin, ST1481, in a large panel of human tumor xenografts. Clin Cancer Res 8:3904–3909.[Abstract/Free Full Text]

4. De Cesare M, Pratesi G, Veneroni S, et al. (2004) Efficacy of the novel camptothecin gimatecan against orthotopic and metastatic human tumor xenograft models. Clin Cancer Res 10:7357–7364.[Abstract/Free Full Text]

5. Pratesi G, Beretta GL, Zunino F. (2004) Gimatecan, a novel camptothecin with a promising preclinical profile. Anticancer Drugs 15:545–552.[CrossRef][Medline]

6. Lucreziotti MR, De Angelis C, Ferretti R, et al. (2001) Toxicology profile of the novel oral camptothecin analog ST1481. Toxicol Lett 123:102.

7. Sigma-Tau. Investigator's Brochure Edition No 6. (2004) (Pomezia, Italy).

8. Houghton PJ, Cheshire PJ, Hallman JD II, et al. (1995) Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol 36:393–403.[ISI][Medline]

9. Houghton PJ, Stewart CF, Zamboni WC, et al. (1996) Schedule-dependent efficacy of camptothecins in models of human cancer. Ann NY Acad Sci 803:188–201.[ISI][Medline]

10. Houghton PJ and Santana VM. (2002) Clinical trials using irinotecan. J Pediatr Hematol Oncol 24:84–85.[CrossRef][ISI][Medline]

11. Furman WL, Stewart CF, Kirstein M, et al. (2002) Protracted intermittent schedule of topotecan in children with refractory acute leukemia: a pediatric oncology group study. J Clin Oncol 20:1617–1624.[Abstract/Free Full Text]

12. Santana VM, Zamboni WC, Kirstein MN, et al. (2003) A pilot study of protracted topotecan dosing using a pharmacokinetically guided dosing approach in children with solid tumors. Clin Cancer Res 9:633–640.[Abstract/Free Full Text]

13. Therasse P, Arbuck SG, Eisenhauer EA, et al. (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216.[Abstract/Free Full Text]

14. Zucchetti M, Pace S, Frapolli R, et al. (2002) Clinical pharmacokinetic profile of gimatecan (ST 1481), a new oral campthotecin derivative. Am Soc Clin Oncol(Annual Meeting, Orlando) pp. 476.

15. Garcia-Carbonero R and Supko JG. (2002) Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins. Clin Cancer Res 8:641–661.[Abstract/Free Full Text]

16. Miller DS, Blessing JA, Lentz SS, et al. (2002) A phase II trial of topotecan in patients with advanced, persistent, or recurrent endometrial carcinoma: a gynecologic oncology group study. Gynecol Oncol 87:247–251.[CrossRef][ISI][Medline]

17. Traina TA, Sabbatini P, Aghajanian C, et al. (2004) Weekly topotecan for recurrent endometrial cancer: a case series and review of the literature. Gynecol Oncol 95:235–241.[CrossRef][ISI][Medline]

18. Perez EA, Hillman DW, Mailliard JA, et al. (2004) Randomized phase II study of two irinotecan schedules for patients with metastatic breast cancer refractory to an anthracycline, a taxane, or both. J Clin Oncol 22:2849–2855.[Abstract/Free Full Text]


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