Oral Topotecan Given Once Or Twice Daily for Ten Days: a Phase I Pharmacology Study in Adult Patients with Solid Tumors

Vol. 4, 1153-1158, May /998 Clinical Cancer Research 1153

Oral Topotecan Given Once or Twice Daily for Ten Days: A Phase I Pharmacology Study in Adult Patients with Solid Tumors

Cees J. H. Gerrits, Howard Burns, grade HI diarrhea. The maximum tolerated dose was 1.4 mg/ Jan H. M. Schellens, John R. Eckardt, m2/day. In the 10-day b.i.d. administration ofTPT, a total of 64 courses were studied in 20 patients. DLT was reached at a dose Andre S. T. Planting, Maria E. L. van der Burg, of 0.8 mg/m2 b.i.d. and consisted of CTC grade IV myelosup- Gayle I. Rodriguez, Walter J. Loos, pression and CTC grade IV diarrhea. The maximum tolerated Vera van Beurden, Ian Hudson, Scott Fields, dose was 0.7 mgfm2 b.i.d. Nonhematological toxicities with both Dan D. Von Hoff, and Jaap’ schedules included mild nausea and vomiting, fatigue, and Department of Medical Oncology, Rotterdam Cancer Institute (Daniel anorexia. Pharmacokinetics revealed a substantial variation of den Hoed Kliniek) and University Hospital. 3075 EA Rotterdam, the the area under the plasma concentration-lime curve of TN’ Netherlands [C. J. H. G., J. H. M. S., A. S. T. P., M. E. L. v. d. B.. lactone in both schedules. Significant correlations were ob- W. J. L., V. v. B., J. V.]; Cancer Therapy and Research Center, the served between the myelotoxicity parameters and the area University of Texas at San Antonio and Brooke Arms Medical Center, San Antonio, Texas 78245 [H. B., J. R. E., G. I. R.. under the plasma concentration-time curve at day 1 of TN’ D. D. V. H.]: and SmithKline Beecham Pharmaceuticals, United lactone o.d. and b.i.d. Kingdom [I. H]. and U.S.A. [S. F.] The DLT of 10 daily administrations of oral topotecan every 3 weeks consisted of a combination of myelosuppression and diarrhea for both schedules studied. The recom- ABSTRACT mended doses for Phase II studies are 1.4 mg/m2/day for 10 Prolonged exposure to topotecan (TPT) in in vitro ex- days for the o.d. administration and 0.7 mg/m2 for the b.i.d. periments and in vivo studies in animals yielded the highest schedule. antitumor efficacy. An oral bioavailability of TPT of 32.- 44% enables convenient prolonged administration. Because INTRODUCTION of unpredictable diarrhea in the third week of the twice TPT2 (9-dimethylaminomethyl-lO-hydroxycamptothecin) daily (b.i.d.) 21-day schedule of p.o. administered TN’ and is a specific topoisomerase I inhibitor ( I - 8). Studies with a the finding of optimal down-regulation of topoisomerase I 5-day daily iv. administration every 3 weeks showed brief level after 10-14 days in mononuclear peripheral blood myelosuppression as the most important side effect, and prom- cells, a shorter period of administration (10 days) was cho- ising antitumor effects were reported in patients with small cell sen for Phase I and pharmacological studies of oral admin- lung cancer and in pretreated patients with ovarian cancer (9- istration of TPT. 19). Cytotoxicity of topoisomerase I inhibitors is more specific Adult patients with malignant solid tumors that were to the S-phase of the cell cycle, and preclinical in vitro and in refractory to standard forms of chemotherapy were entered. vivo studies indicate that prolonged exposure to low-dose topoi- Two dose schedules were studied: once daily (o.d.) and b.i.d. sornerase I inhibitors yields higher antitumor efficacy (20-25). administration for 10 days every 3 weeks. TPT o.d. for 10 The clinical feasibility of using prolonged exposure to TPT days was studied at dose levels 1.0, 1.4, and 1.6 mg/m2/day, was initially reported by Hochstcr et a!. (26) in a Phase I study and dose levels were 0.5, 0.6, 0.7, and 0.8 mg/rn2 with the using a 21-day continuous infusion every 28 days. Recent stud- 10-day b.i.d. schedule. Pharmacokinetics were performed on ies in humans reported a 32-44% bioavailability of TPT when days 1 and 8 of the first course using a validated high- it was given p.o. (27, 28). We have previously reported a Phase performance liquid chromatographic assay and noncom- I study with oral TPT given b.i.d. for 21 days in a 28-day cycle. partmental pharmacokinetic methods. Side effects were CTC grade III-IV diarrhea occurring during Nineteen patients were entered in the 10-day o.d. schedule, the third week of drug administration (29). In addition, it was with a total of 48 courses given. Dose-limiting toxicity (DLT) reported that topoisomerase down-regulation in peripheral blood was reached at 1.6 mglm2/day and consisted of common tox- mononuclear cells was optimal after 2 weeks in the Phase I icity criteria (CTC) grade IV thrombocytopeula and CTC study on 21-day continuous infusion of TPT (30). In view of these observations, it was considered of interest to also study shorter schedules of oral administration of TPT than the 21 -day schedule. In this Phase I study, we investigated o.d. and bid.

Received 7/29/97; revised 1/23/98: accepted 2/3/98. oral TPT given for 10 days every 3 weeks. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with I 8 U.S.C. Section 1 734 solely to indicate this fact. 2 The abbreviations used are: TPT, topotecan; bid., twice daily: CTC, I To whom requests for reprints should be addressed, at Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital common toxicity criteria; o.d., once daily; MTD, maximum tolerated Rotterdam, Groene Hillcdijk 301, 3075 EA Rottcrdam, the Netherlands. dose: DLT. dose-limiting toxicity: AUC, area under the plasma concen- Phone: 31-10-4391754; Fax: 31-10-485 1618. tration-time curve: civ., continuous iv.

PATIENTS AND METHODS

Patient Selection. Patients with a histologically con- Drug administration firmed diagnosis of a malignant solid tumor that was refractory o.d. bid. to standard forms of therapy were eligible. Other eligibility No. of patients entered 19 20 criteria included: age of 18 years; WHO performance score of No. of patients evaluable 19 18 2; an estimated life expectancy of 12 weeks; no anticancer Age therapy in the preceding 4 weeks (6 weeks for nitrosoureas or Median 53 55 mitomycin C); adequate hematopoetic (WBC, 4 X lO9fliter; Range 19-85 41-69 Sex platelets, 100 x l09/liter), hepatic (bilirubin within normal Female 8 7 limits; aspartate aminotransferase, alanine aminotransferase, Male 11 13 and/or alkaline phosphatase, 2 X upper limit of normal), and WHO performance renal [serum creatinine, l33 i.molflitcr (2.0 mg/dl)1 function. 0 12 12 I 7 7 Specific exclusion criteria included: active peptic ulcer or any 2 0 1 gastrointestinal condition that could alter absorption or motility Tumor types or patients taking H, antagonists or proton pump inhibitors. All Colorecta! 4 1 1 patients gave written informed consent. Ovarian 4 3 Treatment and Dose Escalation. On the basis of the SCLC” 3 1 NSCLC 2 1 data of Creemers et a!. (29), who demonstrated a MID of 0.5 Miscellaneous 6 4 mg/rn2 bid. for oral TPT in a 21-day schedule, the starting Prior treatment doses for the 10-day administrations were set at 0.5 mg/m2 b.i.d. Chemotherapy II 14 Radiotherapy I and I .0 mg/m2/day o.d. Courses were to be repeated every 21 I Both S I days, as tolerated. Immunotherapy 0 I TPT was supplied as capsules containing TPT-HC1, equiv- None 2 3 alent to 0.25, 0.50, or I .0 mg of the anhydrous free base. “ SCLC, small cell lung cancer . NSCLC, non-sm all cell lung can- Capsules had to be stored between 2#{176}Cand8#{176}C.Capsules were cer. taken with a glass of water in the morning on an empty stomach with a 2-h period of fasting. With bid. administration of TN’, the second dose was taken with an interval of I 2 h with a glass an indwelling i.v. cannula, prior to dosing, 15, 30, and 45 mm

of water at least 10 mm before meals, preferably on an empty and I , 1 .5, 2.5, 3.5, 4.5, 8.5, and 12 h after administration of the stomach. Patients were treated as outpatients. Dose escalations drug on days I and 8 of the first course. For the b.i.d. schedule, were based on the prior dose level toxicity. this was done after the morning dose. The samples were imme- The MTD was defined as one dose level below the dose diately prepared and analyzed according to the method de- that induced DLTs, which were defined as CTC grade IV scribed previously (33). The lower limit of quantitation was 0.1 hematological toxicities and/or CTC grade III or higher nonhe- ng/ml for TN’ lactone, as well as for the hydroxy-acid. The matological toxicities during the first course in more than two of AUCs of TN’ lactone and hydroxy-acid were calculated by six patients. If grade IV neutropenia, grade III thrombocytope- noncompartmental analysis (linear-logarithmic trapezoideal nia or higher, and/or grade III or higher nonhematological method). The AUC(t) was calculated up to the last measured toxicity occurred during treatment days, TN’ administration was time point “t” because, in half of the cases with b.i.d. adminis- stopped immediately. Intrapatient dose escalation was not a!- tration, the extrapolated part was 20% of the total AUC. The lowed. terminal half-life was calculated as ln(2/k), where k is the Treatment Assessment. Prior to therapy, a complete elimination rate constant (in h ‘). The AUC(t) was fitted to the medical history was taken, and a physical examination was observed percentage decrease in WBC using the sigmoidal Emax performed. A complete blood count, including WBC differential mode! (34). For all calculations, the Siphar software package and serum chemistry (sodium, potassium, chloride, bicarbonate, release 4.0 (Siphar SIMED, Cedex, Creteil, France) was used. calcium, phosphorus, magnesium, creatinine, urea, uric acid, For statistical analysis, linear regression analysis was used to bilirubin, aspartate aminotransferase, alanine aminotransferase, evaluate relationships between dose and dose/m2 and AUC(t), alkaline phosphatase, total protein, and albumin), was per- and Pearson correlation coefficients were calculated. formed, as were urinalysis, electrocardiogram, and chest X-ray. Spearman rank correlation coefficients were calculated be- Weekly evaluations included history, physical examination, tox- tween AUC(t) and the percentages of decrease of leukocytes, icity assessment according to the CTC criteria (31), and serum granulocytes, and platelets. chemistries. Complete blood counts were determined twice weekly. RESULTS Tumor measurements were performed after every two A total of 39 patients were entered in the study (Table 1). All courses and evaluated according to the WHO criteria for re- patients were eligible, and 37 were fully evaluable for toxicity sponse (32). Patients were taken off protocol in case of disease and response. Two patients with b.i.d. administration withdrew progression. from the study during the first course, one after 3 days because Pharmacokinetics. For pharmacokinetic analysis, whole of nausea and the second patient after 9 days because of ab- blood samples (2.8 ml) in heparinized tubes were collected from dominal cramping and weakness.

Table 2 Major toxicities of 10-day administration of oral topotecan (CTC grades: worst per course)

Granulocytes Platelets Diarrhea No. of No. of Dose level (mg/m2) patients courses III IV III IV III IV o.d. administration 1.0 7(3)” 17(9)” 0 0 1 0 0 0 1.4 9(1)” 18(1)” 0 2 0 2 3 0 1.6 7 13 0 0 0 1 2 0 Total 19 48 bid. administration 0.5 3 26 0 0 0 0 0 0 0.6 7 21 0 0 0 0 1 1 0.7 6 15 0 1 0 1 1 1 0.8 2 2 0 2 1 0 0 2 Total 18 64

a Numbers in parentheses are the numbers of patients also studied at this dose level but previously treated at a higher do se level.

Most patients had prior chemotherapy. Dose levels studied Treatment never had to be delayed due to slow recovery were 0.5, 0.6, 0.7, and 0.8 mg/m2 bid. and 1.0, 1.4, and 1.6 from myelosuppression. mg/m2/day o.d. The total numbers of evaluable courses were 48 CTC grade II or higher anemia occurred in I I (17.2%) and 64 for o.d. and bid. administration, respectively. The courses, and 24 units of RBC transfusions were required in 7 median number of courses per patient was 2 (range, 1-I 7). (38.8%) patients.

Hematological Toxicity Nonhematological Toxicity o.d. Schedule. Overall, hematological toxicity was mild o.d. Schedule. DLT was reached in patients treated at 1.6 and mostly occurred in subsequent courses. CTC grade III-IV mg/m2/day o.d. Two patients developed CTC grade III diarrhea leukopenia and gramulocytopenia was observed in 3 (6.2%) and in the first course, with onset on days 8 and 9 and durations of 2 (4.2%) of 48 courses, respectively (Table 2), with days of 5 and 3 days, respectively (Table 2). Another patient at this dose onset for both on days 12, 14, and 19 and durations of 8, 10, and level had CTC grade IV thrombocytopenia as a DLT. Further 12 days. One patient had neutropenic fever lasting for 2 days. dose escalation was not considered possible. CTC grade II or Treatment delay was necessary in 2 patients because of slow higher diarrhea was observed in a total of in 7 patients, with a recovery from grade II and grade III leukopenia, respectively. median day of onset on day 9 (range, 7-1 3 days) and a median One patient treated at 1.6 mg/m2/day had CTC grade IV duration of 4 days (range, 1-7 days). Two patients treated at I .4 thrombocytopenia as a DLT. In 4 courses (8.3%), CTC grade mg/m2/day had CTC grade III diarrhea lasting 1-4 days. Diar- III-IV thrombocytopenia was noted, twice in conjunction with rhea appeared to respond poorly to administration of loperam- leukopenia. The onset of CTC grade III-IV thrombocytopenia ide. Other nonhematological toxicities were mild. Mild nausea was on day 12 in three patients and on day 14 in one patient. The and vomiting could easily be circumvented with standard do- durations of thrombocytopenia were 8 and 12 days in the two pamine antagonists. CTC grade III nausea and CTC grade III patients with complete hematological follow-up. Five platelet vomiting each only occurred in one (2. 1 %) course. Anorexia transfusions were given in two (10.5%) patients. CTC grade II and fatigue was reported in 16 (33%) and 24 (50%) courses, or higher anemia occurred in 15 of 48 courses (31.2%), and 23 respectively. Fatigue was mainly experienced during TN’ intake units of RBCs were given to 7 (36.8%) patients to keep their and subsided after a few days. It occurred in six (32%) patients. hemoglobin at 6.0 mmollliter. One patient withdrew from the study after seven courses be- b.i.d. Schedule. CTC grade III-IV leukocytopenia and cause of progressive fatigue and malaise. Other nonhematologi- granulocytopenia were both observed in 3 of 64 (4.7%) courses cal toxicities reported were: abdominal discomfort (16.7%), (Table 2). The days of onset of grade III-IV leukopenia and headache (4.2% of courses), and CTC grade I alopecia in four granulocytopenia were similar: days 8, 10, and 14. Durations of patients (21%). granulocytopenia were 8 and 14 days in the two patients with b.i.d. Schedule. CTC grade IV diarrhea in combination complete follow-up. Granulocytopenia was complicated by fe- with CTC grade IV granulocytopenia occurred in both patients ver in 3 patients, all were treated with empiric broad spectrum treated at 0.8 mg/m2 bid. Thus, DLT also consisted of a antibiotics. Both patients treated at the DLT (0.8 mg/m2 b.i.d.) combination of diarrhea and granulocytopenia. Diarrhea CTC had granulopenic fever, and one patient died from pneumonia grade II or higher occurred in a total of nine patients, was always with sepsis. The third patient with granulopenic fever was self-limiting, had a median day of onset on day 10 (range, 6-17 treated at 0.7 mg/m2 b.i.d. days), and had a median duration of 3 days (range, 1-I 2 days). CTC grade III-IV thrombocytopenia was noted in two Other nonhematological toxicities were usually mild. CTC courses (3.3%), with nadirs on days 12 and 14, both events grade I-I! nausea and vomiting were observed in 25 (39. 1 %) occurring in conjunction with granulocytopenia requiring plate- and 14 (21.9%) courses, respectively (Table 3). CTC grade III let transfusion (5 units in total). nausea and CTC grade IV vomiting occurred in three (4.7%) and

Tab le 3 Pharmacokinetics in lO-d ay administration of oral admin istration of oral topotecan (me dian ± SD)”

Topotecan lactone, Topotecan hydroxy-acid, Topotecan hydroxy-acid, day 1 day I Topotecan lactone, day 8 day 8

AUC(t) AUC(t) AUC(t) AUC(t)

Dose level (mg/m2) (ng . h/mI) I/2 (h) (ng . h/mI) t112 (h) (ng - h/rn!) t,,2 (h) (ng . h/m!) t112 (h)

o.d. administration

1.0 (a = 3) 6.87 ± 1.61 3.13 ± 0.10 16.79 ± 2.97 4.25 ± 0.44 9.46 ± 3.70 4.63 ± 2.39 18.09 ± 6.35 4.21 ± 1.18

1.4 (a = 3) 13.17 ± 2.38 3.46 ± 0.14 28.15 ± 6.73 3.91 ± 0.48 21.02 ± 7.56 2.34 ± 0.74 32.92 ± 5.63 3.71 ± 0.64

1.6 (n - 4) 14.58 ± 5.68 3.37 ± I 1.64 21.19 ± 10.00 3.36 ± 1.04 12.88 ± 3.82 2.93 ± 0.74 19.82 ± 6.74 3.33 ± 0.57 bid. administration

0.5 (a = I) 2.62 1.20 5.74 3.22 5.55 6.91 9.27 2.93

0.6 (to = 4) 5.13 ± 2.48 2.09 ± 2.07 8.38 ± 4.34 3.22 ± 0.47 7.64 ± 3.06 2.03 ± 1.00 15.04 ± 7.76 2.81 ± 0.81

0.7 (,z = 4) 5.64 ± 2.39 3.55 ± 0.79 10.57 ± 6.18 5.48 ± 1.02 7.34 ± 3.50 3.24 ± 0.77 12.85 ± 10.00 3.18 ± 1.16

0.8 (n = 1) 16.73 3.17 31.56

(I ‘1/2’ half-life (h): n, number of patients per dose level.

two (3. 1 %) courses. Other toxicities reported were abdominal 40 discomfort (I 8.7%) and headache (7.8%). Two patients developed CTC grade I alopecia, and one patient had grade II alopecia. Skin rash, hematuria, cardiac, pulmonary, renal, hepatic, or neurological toxicities were not observed in both dose schedules 30 studied.

E Pharmacokinetics and Dynamics .c 20 Pharmacokinetics were performed in 10 patients in each C i: EiiiF schedule of administration (Table 3). The AUC(t) of TN’ lac-

tone was consistently higher on day 8 than on day 1 , but for the o.d. administration, this did not reach statistical significance, whereas for the 10-day bid. administration, it was significant (P < 0.05; Table 3). The mean AUC(t) on day 8 ofTN’ lactone 10-day o.d. administration was 14.0 ± 7.1 ng . h/ml and was hJJhdl.6I 2 1 .0% higher than the AUC(t) day 1 , which was 1 1 .6 ± 4.7 0.5 0.6 0.7 0.8 ng . h/m!. In the 10-day bid. schedule, the mean AUC(t) on day b.i.d. x 10 o.d. x 10 8 was 8.0 ± 3.0 ng . h/m!, which was 37.0% higher than the mg/rn2

AUC(t) on day I , which was of 5.9 ± 4.3 ng . h/m!. Fig. I Interpatient variation of AUC on day I versus AUC on day 8 of The interpatient variabilities in AUC(t) of TN’ lactone on day TPT lactone. #{149},AUC on day I: 0, AUC on day 8. 1 were 40.1 and 73.4% for the 10-day o.d. and bid. administrations, respectively (Fig. 1). For both schedules of administration, no significant correlation was found between the dose (mg), dose level (mg/m2), and AUC(t) on day 1 of TN’ lactone. dose level of 0.5 mg/m2, and two patients with colorectal cancer For both 10-day schedules, the relationship between had stable disease for 18 and 24 weeks. With the o.d. adminis- AUC(t) on day 1 versus percentage decrease of leukocytes was tration, one patient with small cell lung cancer and one patient sigmoidal. The correlation coefficients of the AUC(t) on day 1 with carcinoma of unknown primary origin had stable disease of TN’ lactone and the percentages of decrease of leukocytes for 18 and 21 weeks, respectively.

were r = 0.61 (P 0.06) for 10-day o.d. and r 0.69 (P 0.03) for b.i.d. administration. The correlation between the DISCUSSION AUC(t) on day I of TN’ lactone and the percentage decrease of in vitro experiments and in vivo studies with human xc-

granulocytes was r = 0.64 (P 0.08) for o.d. and r - 0.70 (P = nografts revealed a better antitumor effect with prolonged cx- 0.03) for bid. administration. A significant correlation between posure to topoisomerase I inhibitors (20-25, 35, 36); this dose the AUC(t) of TN’ lactone and the percentage decrease in scheduling of topoisomerase I inhibitors might be of importance

platelets was observed in both dose schedules with r = 0.83 in humans as well.

(P = 0.008) for 10-day o.d. and r = 0.78 (P = 0.03) for 10-day In Phase I and Phase II studies of 21 days of c.i.v. infusion b.i.d., respectively. of TN’, tolerability was confirmed, and in patients with ovarian cancer, remarkable response rates were observed (26, 37, 38). Responses Continuous infusion is inconvenient for patients and sometimes No complete or partial responses were noted. At the I 0-day leads to complications of the central venous catheters (26, 37). b.i.d dose schedule, one patient with ovarian carcinoma had Oral TN’ with a bioavailability of 32-44% and a moderate stable disease and was treated for 17 courses (5 1 weeks) at the intrapatient variation may be more convenient for prolonged

administration in patients. In a previous study with oral TN’ between creatinine levels or the occurrence of diarrhea with the b.i.d. for 2 1 days every 28 days, diarrhea appeared to be dose observed increase in AUC, changes in TN’ excretion could not limiting (29). Diarrhea occurred in the third week of the admin- account for the increase. The clinical significance of the increase istration. Because of this and in view of the fact that topoisomer- remains unknown. ase I down-regulation appeared to be optimal after 10-14 days There were no objective responses in this study despite the (26), we studied the presently reported 10-day dosing schedules. fact that several patients had ovarian or small cell lung cancer, DLT consisted of diarrhea and myelosuppression, and oc- diseases known to be sensitive to iv. TN’. The reason why these curred at 1.6 mg/m2 o.d. and at 0.8 mg/m2 b.i.d. In the previ- patients did not respond here could be due to the fact that all of ously reported 21 days of b.i.d. oral TN’, diarrhea was the only them had previously received two or more multidrug regimens. DLT. Through all studies, diarrhea was always self-limiting. Compared to the 21-day b.i.d. schedule, the 10-day schcd- Diarrhea is a well known side effect of camptothecin and ule again resulted unpredictable diarrhea but was also dose its derivatives, but the types of diarrhea appear to differ. CPT-1 1 limited by myclosuppression. Diarrhea tended to be less pro- administered i.v. induced delayed-onset diarrhea with a median longed in the 10-day schedules than in the 21-day schedule. day of onset on day 5 and had a median duration of 5 days (38). Therefore, at MTD levels, p.o. administered TN’ given for 10 This diarrhea can be treated by vigorous administration of days is feasible. The recommended Phase II doses for 10-day loperamide to prevent hospitalization. CPT-1 1 also induced schedules are 0.7 mg/m2 bid. and I .0 mg/m2 o.d., courses acute-onset early diarrhea on day 1 that can be treated by repeated every 3 weeks. We will perform a pharmacokinetic- atropinc (39). Oral 20-S-camptothecin for 21 days every 28 days pharmacodynamic analysis on all of our Phase I studies with and oral 9-nitro-camptothecin S days a week induced severe oral TN’ to try to identify a schedule of preference. diarrhea in 40 and 33% of patients, respectively (40, 41). With 2 1 days of civ. infusion of TN’, diarrhea occurred in 13.6% of REFERENCES patients, but CTC grade III-IV diarrhea was not observed (26). 1. Kingsburry, W. D., Boehm, J. C., Jakas, D. R.. Holden, K. G., Hecht, 20-S-Camptothecin and CPT-I 1 were shown to induce intestinal S. M., Gallagher, G., Caranfa, M. J., McCabe, F. L., and Johnson, R. K. mucosal destruction in animal models (40, 42). 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