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pharmacokinetic study of the topoisomerase I inhibitor GG211 administered as a 21-day continuous infusion
Annals of Oncology 10: 339-344, 1999. © 1999 Khmer Academic Publishers. Primed in the Netherlands.
Original article Phase I/pharmacokinetic study of the topoisomerase I inhibitor GG211 administered as a 21-day continuous infusion J. P. Stevenson,1 D. DeMaria, 2 J. Sludden,3 S. B. Kaye,3 L. Paz-Ares,3 L. B. Grochow,4 A. McDonald, 3 K. Selinger,5 P.Wissel,5 P. J. O'Dwyer 1 ' 2 & C. Twelves3
cytopenia was dose-limiting with 0.5 mg/rrr/day dosing but was not cumulative. Other grade 3-4 toxicities included neuBackground: Preclinical results support a prolonged schedule tropenia, nausea, vomiting, diarrhea, and fatigue. Partial reof administration for topoisomerase I inhibitors, and we have sponses occurred with 21-day infusion in two patients with previously demonstrated the safety and activity of the novel breast and ovarian cancer at the 0.3 and 0.4 mg/m2/day dose water-soluble topoisomerase I inhibitor GG211 when given as levels, respectively. Mean GG211 lactone Css ranged from 0.17 to 0.64 ng/ml. a 72-hour continuous infusion to cancer patients. Conclusion: The maximum tolerated dose of GG211 adminPatients and methods: In a three-center international phase I trial, 38 patients received GG211 doses from 0.3 to 0.5 istered as a 21-day continuous infusion is 0.4 mg/m2/day with mg/m2/day by continuous intravenous infusions for seven, 14, antitumor activity noted at tolerable doses. and 21 days. Patients' median performance status was 1; nearly half had colorectal cancer, and 35 patients had prior chemo- Key words: camptothecin analogues, GG211, continuous infusion, phase I trial, topoisomerase I inhibitors therapy. Results: The first patient cohort received 0.3 mg/rrr/day for seven days with no significant toxicities. Subsequent cohorts Abbreviations: Css - blood steady-state concentration; IC50 received continuous infusions for 14 and 21 days at this dose half-maximal inhibitory concentration; ECOG - Eastern level with only mild myelosuppression noted. Dose-escalation Cooperative Oncology Group; DLT - dose-limiting toxicity; on the 21-day schedule was then performed. No dose-limiting AUC - area under the concentration-time curve; HPLC toxicity occurred at the 0.4 mg/m2/day dose level. Thrombo- high-performance liquid chromatography Summary
Introduction
The camptothecins are novel cytotoxic agents which are the only well-characterized compounds to target the nuclear enzyme topoisomerase I [1]. The principal function of topoisomerase I is believed to be the relief of torsional strain produced in supercoiled DNA during processes which alter DNA topology such as replication and gene transcription [2]. Topoisomerase I binds covalently to double-stranded DNA and forms what is termed the 'cleavable complex' through the introduction of a single-strand break, allowing free rotation of DNA about the remaining phosphodiester bond. The camptothecins bind and stabilize the cleavable complex; double-strand breaks then result when the advancing replication fork encounters the persistent single-strand break [3]. The subsequent mechanism of cell death is not well understood, but double-strand breaks are major correlates of camptothecin cytotoxicity [4]. Topoisomerase I expression is greater than that of normal tissue in a range of cancer cell lines and surgical tumor specimens. Progres-
sive alterations in expression have also been described in tissues during malignant transformation, making topoisomerase I an attractive target for antineoplastic therapy [5, 6]. The development of camptothecin in the 1970s was limited by its insolubility in aqueous solutions and the occurrence of unpredictable bone marrow and bladder toxicity in early clinical trials [7]. Recently, the semisynthetic camptothecin analogues irinotecan (CPT-11) and topotecan have proven to be valuable in the clinic, given their solubility and tolerablility, as well as meaningful antitumor activity. GG211 (7-(4-methyl piperazinomethylene)-10,l 1 -ethylenedioxy-20-(S)-camptothecin) is a novel water-soluble synthetic camptothecin which displays potent topoisomerase I inhibition (Figure 1). Preclinical studies of GG211 in a range of tumor cell lines and xenografts revealed an antitumor profile similar to, but with two to five times the potency of, topotecan [8-10]. Interestingly, in two human colon xenografts, GG211 displayed a superior therapeutic index to topotecan [8], and this stimulated further preclinical and
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'University of Pennsylvania Cancer Center; 2Fox Chase Cancer Center, Philadelphia, PA, USA; 3CRC Department of Medical Oncology, University of Glasgow, Western Infirmary Hospital, Glasgow, UK; "Johns Hopkins Oncology Center, Baltimore, MD; 5Gla.\o Wellcome Research Inc., Research Triangle Park, NC, USA
340
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clinical evaluation of the compound. GG211 had in vitro activity against HT-29 (colon), T47D (breast), LOX (melanoma), and SKOV3 (ovarian) cell lines, and against HT-29 and SW480 (colon), MX1 (breast), SKOV3, PC3 (prostate), and H460 (lung) xenografts in vivo. Hematologic and gastrointestinal toxicities predominated in animal studies, and were dose-dependent. Prolonged administration of topoisomerase I inhibitors in preclinical models produced superior activity over intermittent bolus dosing, suggesting schedule dependency [11, 18]. Hochster et al. have investigated 21-day continuous infusions of topotecan and demonstrated this to be a tolerable and active regimen. In their phase I study, responses occurred in breast, ovarian, renal, and non-small-cell lung cancers; bone marrow suppression (predominantly thrombocytopenia) was dose-limiting [12]. They reported a 43% response rate (one CR) in their phase II trial of 21-day topotecan infusion in platinum-pretreated ovarian cancer patients, and no grade 4 hematologic toxicity [13]. Continuous infusion schedules of GG211 are therefore warranted, especially as we have observed antitumor activity in our previous phase I study of 72-hour administration of GG211 as a continuous infusion [14]. Pharmacokinetic analyses from the 72-hour infusion trial indicated that mean GG211 lactone concentrations at steady-state increased with dose (range 0.24-1.24 ng/ml) with a mean terminal half-life of 7.5 hours. Based upon these promising results, we initiated this phase I trial to determine the toxicity, efficacy, and an appropriate phase II dose of GG211 when given to patients as a 21-day continuous intravenous infusion.
Patients and methods
Drug administration GG211 is stable as a concentrate or as a more dilute solution in 5% dextrose A uniform solution of 5% dextrose USP was the standard diluent in this study. GG21I was mixed with diluent to a total volume of 100 ml and administered as a seven-day continuous infusion using a calibrated ambulatory infusion pump. Drug containers and extension tubing were protected from light at all times. Aliquots of the administered solution were used to confirm the stability of GG211. GG2I1 infusions were administered for seven. 14, or 21 days according to the study design. Patients who received 14 or 21-day infusions had 50% and 33%, respectively, of the total GG211 dose administered in 100 ml over seven-day periods.
Study design In order to evaluate the safety and tolerability of GG211 when administered as a prolonged continuous infusion, length of infusion was extended in stepwise fashion. Cohorts of three to nine patients were entered into each treatment group. The starting dose of GG211 was 0.3 mg/m 2 /day administered for seven days, followed in the absence of DLT by infusions for 14 and then 21 days at the same daily dose. All subsequent patients received 21-day infusions and dose levels were escalated by 15% to 50% as tolerated. There was no dose escalation in individual patients. If at any time during treatment the neutrophil count fell to <750/mm 3 or platelet count $ 50,000/mm 3 the infusion was discontinued. Courses were repeated 14 days following the end of the previous infusion if laboratory values were adequate on day one of each cycle. If DLT was observed in any patient, an additional three patients were treated at that dose level. The maximum tolerated dose was denned as one dose level below that which produced DLT in a minimum of two of six patients. DLT was defined as the occurrence of any of the following: 1) an absolute neutrophil count <500/mm 3 or platelet count < 50,000/mm 3 for > 5 days; 2) an absolute neutrophil count < 500/mm 3 with fever requiring parenteral antibiotics or platelet count < 50,000/mm 3 requiring transfusion; 3) any non-hematologic toxicity > grade 3 excluding alopecia or emesis.
Patient population Pharmacokinetic sampling and analysis Patients were treated on this study between April 1995 and May 1996 as part of an international collaborative effort between Fox Chase Cancer Center, Johns Hopkins University Cancer Center, and the Cancer Research Campaign (CRC) Department of Medical Oncology at the University of Glasgow. Eligible patients were at least 18 years of age with histologically confirmed solid tumors that were refractory to standard therapy or for which no effective therapy was available. An
Blood and urine samples for the determination of GG211 pharmacokinetics were obtained from all patients during the first cycle. Blood samples (7 ml) were collected in heparinized tubes prior to infusion and on days 4 and 8 (seven-day infusion), days 4, 8, 11, and 15 (14-day infusion), or days 4,8.11,15.18, and 22 (21-day infusion). Blood samples were immediately placed on ice and stored at -20 C until analysis.
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Figure I. Structure of GG211 [7-(4-methyl piperazinomethylene)10,ll-ethylenedioxy-20-(S)-camptothecin].
ECOG performance status < 2 and a life expectancy > 3 months were required. All patients had recovered from prior treatment and had received no cytotoxic chemotherapy in the previous three weeks (six weeks for nitrosoureas or mitomycin C). Patients had adequate bone marrow function (neutrophils ^2000/mm 3 and platelets ^ 100,000/mm3), creatinine ^ 1.5 mg/dl, serum bilirubin < 1.5 mg/dl, and AST/ALT $ 4 times the upper limit of normal. All patients received information on the purpose and conduct of this study, and signed written informed consent. Pretreatment evaluation consisted of a history and physical examination, full blood count, serum electrolytes, creatinine and liver biochemistries, urinalysis, electrocardiogram, chest X-ray, and assessment of ECOG performance status. All patients had a central venous catheter placed prior to treatment. Blood counts were performed twice weekly, biochemical profiles were performed weekly, and patients were examined prior to every course. Toxicity during each treatment cycle was assigned according to the NCI Common Toxicity Criteria (Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, 1988). Lesions noted at baseline that were measured or evaluated by radiographic scan or x-ray were reviewed before each alternate course and evaluated for response according to standard criteria [15],
341 Table I. Patient characteristics. 38/37 Toxicity 23 15 53 27-72 0-2 18 6 4 4 3 2 1
Granulocytopenia 0.3 mg/m 2 x 7d 0.3 mg/m 2 x 14d 0.3 mg/m 2 x21d 0.4 mg/m 2 x 21d 0.5 mg/m 2 x21d Thrombocytopenia 0.3 mg/m 2 x 7d 0.3 mg/m 2 x 14d 0.3 mg/m 2 x21d 0.4 mg/m 2 x 21d 0.5 mg/m 2 x21d
n
Grade 1
Grade 2
Grade 3
Grade 4
3 8 5 14 7
0 1 0 1 1
0 1 0 0 3
0 0 0 1 1
0 0 0 0 0
3 8 5 14 7
0 1 0 1 0
0 0 0 2 0
0 0
0 0 0 0 2
0 1 2
27
GG211 lactone measurements were performed using a GLP validated HPLC assay [16]. GG211 was extracted from cold blood by a mixture of 1 :4 (v/v) acetonitrile and butylchloride. Samples were kept in an ice slurry bath prior to extraction to slow conversion of GG211 lactone to carboxylate. The organic phase was collected and evaporated down under a stream of nitrogen. The residue was reconstituted with a 1:4 (v/v) solution of acetonitrile and sodium phosphate buffer with a pH of 4. The solution was then injected onto an HPLC system equipped with a Cis extraction column and fluorescence detector. The range of the assay is 0.15 ng/ml to 100 ng/ml with sufficient precision and accuracy (CV < 10%). The mobile phase consisted of 25% acetonitrile and 10% ammonium acetate buffer pumped at 1.7 ml/min. The internal standard used the assay was 6,7-dimethoxy-4-methylcoumarin. Blood GG211 concentration versus time curves were evaluated using model independent methods [17]. AUC0-t was determined by WinNonlin (Scientific Consulting Inc., North Carolina, USA). The average steady-state concentration (Css) was determined by calculating the average GG211 concentration after steady-state was attained. Systemic blood clearance (CL) was estimated with the equation: CL = infusionrate/Css Pharmacokinetic and pharmacodynamic relationships were investigated using the sigmoid E max (Hill) equation of the following form: % decrease in neutrophils or platelets = 100 x (parameter) y/(parameter50) y + (parameter) y where the estimated parameters are the Hill constant (•/) and the pharmacokinetic parameters that produce the half-maximal Css. The data were fit to the above relationship using WinNonlin.
all had a good performance status. Nearly half of the patients had colorectal cancer and received 5-fluorouracil based chemotherapy. Most were not extensively pretreated; three patients were previously untreated, and 27 patients received ^ 2 chemotherapy regimens. Hematologic toxicity There were no significant toxicities noted in the first three patients treated with seven-day infusion of GG211 at 0.3 mg/m2/day (Table 2). Eight patients subsequently received 14-day infusions at this same dose level. As only grade 1-2 granulocytopenia and thrombocytopenia were noted in cycle 1 of the 14-day schedule, all further patients received 21-day infusions, beginning at 0.3 mg/m2/day. Reversible, non-cumulative thrombocytopenia was dose-limiting with the 21-day infusion at the 0.5 mg/m2/day dose level, at which four of eight patients experienced grade 3-4 toxicity. There were no episodes of grade 4 thrombocytopenia at 0.4 mg/m2/day, although 2 of 14 patients developed grade 3 toxicity. Granulocytopenia occurred but was not dose-limiting. Only one patient treated with 0.4 mg/m2/day and two patients at the 0.5 mg/m2/day dose level experienced grade 3 neutropenia with 21-day infusion. There were no episodes of neutropenic sepsis. A heavily pretreated patient with synovial sarcoma and bilateral pulmonary metastases died of massive hemoptysis with a platelet count of 11,000/mm3. There were no other clinically significant hemorrhagic events related to grade 3-4 thrombocytopenia.
Results
Non-hematologic toxicity
A total of 38 patients received 80 cycles (median 2; range 1-8) of GG211 as part of this study; 37 were assessable for toxicity and response. One patient at the 0.5 mg/m2 dose level removed himself from study after three days of therapy to pursue treatment elsewhere and was not considered evaluable. There are no patients remaining on study. The demographic characteristics of the patients are listed in Table 1. The median age was 53, and
GG211 was generally well-tolerated. Non-hematologic toxicities included alopecia, nausea/vomiting, diarrhea, and fatigue but these were not dose-limiting. Five patients experienced grade 3 nausea/vomiting, but these symptoms were controlled with antiemetics in the majority of patients. Three patients developed grade 3 fatigue, and one patient experienced grade 3 diarrhea. Complications related to indwelling central venous catheters included
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Total entered/evaluable Sex Male Female Age Median Range Performance status Primary sites Colorectal Ovarian/endometrial NSCLC Sarcoma Breast Genitourinary Gastric Prior treatment Chemotherapy Chemotherapy/radiotherapy None
Table 2. Hematologic toxicities of GG211 during the first treatment cycle
342 Table 3 Summary of mean GG2I1 pharmacokinetic parameters by dose level." Dose n (mg/m 2 /d)
C ss (ng/ml)
0.3 0.3 0.3 0.4 0.5
0.22 0.27 0.37 0.35 0.40
1
x 7d x I4d x 21d x 21d x21d
± 0 04 ±0.03 ± 0 II ± 0.07
AUC 0 ., (ng h/ml)
T m a x (h)
31.4 ±6.0 97.9 ± 40.4 176 ± 1.01 151.8 ± 3 1 . 9 190.8 ± 3 8
5.3 7.8 7.5 8.4 13.4
±2.3 ±2.5 ±4.9 ±5.7 ±3.9
Clearance (ml/min/m 2 ) 991 ±216 752 ± 117 568 ±4.3 839 ± 272 887 ±141
+SD.
200
j<
100
4
Pharmacokinetics Thirty-seven patients had pharmacokinetic sampling performed during the first course of GG211 treatment. Data from 10 patients was unavailable for pharmacokinetic analysis and one patient did not receive one full course of therapy. Twenty of 27 patients with available data had pharmacokinetic parameters determined. Of the remaining seven patients, six had GG211 blood levels that were outwith the limit of detection of the HPLC assay and one had levels that exceeded the linear range of the HPLC assay. There were no significant differences in pharmacokinetic parameters between the three centers. Pharmacokinetic data from analyzed patients is presented in Table 3. Steady-state lactone GG211 blood concentrations, ranging from 0.17 to 0.64 ng/ml, were reached in most patients by day 4. AUC0.t increased with both duration of exposure and with increasing dose of GG211 (r2 = 0.76; Figure 2). Phanvacodynamics There was no clinically significant correlation between AUCo-t and fall in either neutrophil or platelet count. Likewise, in the patients receiving GG211 for 21 days there was no correlation between Css and myelosuppression. Responses There were partial responses observed in two patients. A 63-year-old woman with metastatic breast cancer whose previous treatments included epirubicin, 5-fluorouracil, tamoxifen, megace, and aminoglutethimide had regression in regional axillary lymph nodes, a left chest wall metastasis, and a skin metastasis on the left arm. She received four cycles of GG211 0.3 mg/m2/day (21-day infusion); treatment was discontinued after she developed catheter-related line sepsis. The other response occurred with 21-day infusion at the 0.4/mg/m2/day dose level. This 69-year-old woman with metastatic ovarian cancer experienced a partial response in cervi-
a
e
12
Total dosa (mg) Figure 2 GG2H lactone AUC versus total dose received in mg per cycle Note the linear increase
cal lymph nodes as well as a minor response at the site of a soft tissue metastasis. Her previous therapy included Taxol, carboplatin, and tamoxifen. Therapy was discontinued after four cycles of GG2H as a result of disease progression. Also, a 48-year-old woman with colorectal cancer and a 72-year-old woman with ovarian cancer maintained stable disease through eight cycles each of GG2H 14-day infusion at 0.3 mg/m2/day.
Discussion The clinical development of the camptothecins and the identification of their molecular target and mechanism of action represent an important advance in antineoplastic therapy. The semisynthetic derivatives CPT-11 and topotecan have been valuable additions to the armamentarium of the medical oncologist, and combination trials with these agents are in progress. The wholly synthetic camptothecin analogue GG211 demonstrated inhibition of topoisomerase I at nanomolar concentrations as well as greater water-solubility and antitumor potency than topotecan in preclinical studies [8]. The phase I development of GG211 to date has included the daily timesfive30-minute infusion and 72-hour continuous infusion schedules; an oral bioavailability study has also been reported [14, 19, 20]. Based on the superior efficacy with prolonged administration of topoisomerase I inhibitors in preclinical models, and clinical experience with prolonged exposure to 5-fluorouracil and the topoisomerase II inhibitor etoposide [25, 26], we investigated 21-day continuous infusion of GG211 in this study. We found GG211 to be safe and tolerable with 21-day continuous infusion and the recommended dose for phase II trials is 0.4 mg/irr/day, with thrombocytopenia as the predominant, dose-limiting toxicity. The dose-intensity achieved at the recommended
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line infections in six patients and subclavian vein thrombosis in two patients. Catheter sepsis resulted in the discontinuation of therapy in one patient.
343
The current study has confirmed activity of GG211 given by prolonged infusion at a tolerable dose. It is unclear whether this schedule would provide the increment in activity necessary for GG211 to be viewed as distinct from and superior to topotecan. However, data on schedule dependency of topotecan are disappointing and do not encourage the development of this ap-
14. Paz-Ares L, Kunka R, DeMaria D et al. A phase I clinical and pharmacokinetic study of the new topoisomerase inhibitor GI1472I1 given as a 72-hour continuous infusion. Br J Cancer 1998: in press. 15. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment. Cancer 1981; 47: 207-14. 16. Selinger K, Smith G, DepeeSetal. Determination of GI147211 in human blood by HPLC with fluorescence detection. J Pharm Biomed Anal 1995: 13: 1521-30.
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phase II dose is 1.68 mg/m /week, which is comparable proach. Liposome encapsulation represents one promisto that achieved in good-risk patients with 72-hour ing method of drug delivery. Emerson et al. demonstrated infusion at the phase II dose. The responses observed in GG211 liposomes to be more active and less rapidly the pretreated breast and ovarian cancer patients are cleared than free drug in animal models [32]: clinical encouraging. trials are anticipated. Pharmacokinetic studies revealed the kinetics of GG211 given by prolonged infusion to be linear. The Css achieved (0.17 to 0.64 ng/ml) was substantially lower Acknowledgement than that observed with 72-hour infusion of GG211 [14]. Nevertheless, these values are similar to the concentration Supported in part by grants from the Cancer Research of 0.59 ng/ml that achieves 50% growth inhibition in Campaign UK, The European School of Medical Oncolvitro [8]. These levels appear biologically active as anti- ogy, CA06927, CA 56036. proliferative toxicities were dose-limiting in the current study. The absence of pharmacodynamic relationships may in part be explained by the use of both different References doses and schedules of GG211. Phase II trials of GG211 in breast, small cell and non1. Hsiang Y-H, Hertzberg R, Hecht S et al. Camptothecin induces small-cell lung, colorectal and ovarian cancers have protein-linked DNA breaks via mammalian DNA topoisomerase been performed using the daily times five short infusion I. J Biol Chem 1985; 260: 14873-8. 2. Wang JC. DNA topoisomerases. Ann Rev Biochem 1985; 54: (1.2 mg/irr/day) schedule every 21 days. Van Oosterom 665-97. et al. reported an overall 18% response rate in 46 plati3. Hsiang Y-H, Lihou MG, Liu LF. Arrest of replication forks by num-pretreated ovarian cancer patients, and 41% overdrug-stabilized topoisomerase I-DNA cleavable complexes as a all maintained stable disease for at least two cycles [21]. mechanism of cell killing by camptothecin. Cancer Res 1989; 49: Preliminary data indicated activity in small-cell lung 5077-82. 4. Nitiss J, Wang JC. DNA topoisomerase-targeting antitumor drugs cancer, but only minor activity was noted in the breast can be studied in yeast. Proc Natl Acad Sci USA 1988, 85: 7501-5. and non-small-cell lung carcinoma trials, and no re5. Giovanella BC, Stehlin JS. Wall ME et al. DNA topoisomerase I sponses were observed in colorectal cancer patients [22targeted chemotherapy of human colon cancer xenografts. Sci24]. Myelosuppression, in the form of reversible, nonence 1989; 246. 1046-50. cumulative neutropenia was the principal toxicity with 6. Husain I, Mohler JL, Seigler HFet al. Elevation of topoisomerase this schedule. The data demonstrate that GG211 is an I messenger RNA, protein, and catalytic activity in human tumors: Demonstration of tumor-type specificity and implications agent with some activity, but are insufficient to deterfor cancer chemotherapy. Cancer Res 1994; 54: 539-46. mine if it has response characteristics that differ from 7. Muggia FM, Creaven PJ, Hansen HH et al. Phase I trial of weekly available topoisomerase I interactive agents. and daily treatment with camptothecin (NSC-100880): Correlation with preclinical studies. Cancer Chemother Rep 1972; 56: Indeed, recent in vitro and clinical data with pro515-21. longed exposure to topotecan might dampen the enthu8 Emerson DL, Besterman JM, Brown HR et al. In vivo antitumor siasm for pursuing the continuous infusion schedule for activity of two new seven-substituted water-soluble camptothecin GG211. Contrary to previous preclinical data, Danks et analogues. Cancer Res 1995; 55. 603-9. al. found no increase in cleavable complex formation or 9. Luzzio MJ, Besterman JM, Emerson DL et al. Synthesis and tumor inhibition with continuous exposure over interantitumor activity of novel water-soluble derivatives of camptothecin as specific inhibitors of topoisomerase I. J Med Chem mittent exposure to topotecan in the medulloblastoma 1995; 38: 395-401. cell lines they studied [27]. Similarly, in the clinic we 10. Emerson DL. Vuong A, Mclntyre G et al. In vivo efficacy of two found no improvement in efficacy with 21-day continuous new water-soluble camptothecin analogs in the human cancer infusion of topotecan over daily times five intermittent xenograft model. Proc Am Assoc Cancer Res 1993; 34: 419 (Abstr). dosing in our phase II studies in pancreatic and colo- 11. Burris III HA, Hanauske A-R, Johnson RK et al. Activity of rectal cancers (8% response rate in both trials) [28, 29]. topotecan, a new topoisomerase I inhibitor, against human tumor colony-forming units in vitro. 1 Natl Cancer Inst 1992; 84: 1816-20. Creemers et al. obtained similar data in colorectal cancer, and Mainwaring and colleagues recently reported 12. Hochster H, Liebes L, Speyer J et al. Phase I trial of low-dose continuous topotecan infusion in patients with cancer: An active response rates of 8% and 15% in non-small-cell lung and and well-tolerated regimen. J Clin Oncol 1994; 12: 553-9. breast cancer patients with 21-day infusion [30, 31]. 13. Hochster H, Speyer J, Wadler S et al. Activity of topotecan (TPT) Therefore, available evidence to date does not support 21-day infusion inplatinum treated ovarian cancer and pharmathe suggestion that topotecan's effects are enhanced by a codynamics of topo-1 depletion (A NYGOG study). Proc Eur Soc Med Oncol 1996; 21: 69 (Abstr). 21-day infusion.
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of medulloblastoma cells to topotecan produces growth inhibition equivalent to continuous exposure. Clin Cancer Res 1997; 3: 1731-8. Stevenson JP, Scher RM, Kosierowski R et al. Phase II trial of topotecan as a 21-day continuous infusion in patients with advanced or metastatic adenocarcinoma of the pancreas. Eur J Cancer 1998; 34: 1358-62. Hochster H, Ibrahim J, Liebes L et al. Phase II study of 21-day topotecan continuous infusion for metastatic colorectal cancer (ECOG study 4293). Proc Am Soc Clin Oncol 1997; 16: 290a (Abstr). Creemers GJ, Gerrits CJH, Schellens JHM et al. Phase II and pharmacologic study of topotecan administered as a 21-day continuous infusion to patients with colorectal cancer. J Clin Oncol 1996; 14: 2540-5. Mainwaring PM, Nicolson MC, Hickish T et al Continuous infusional topotecan in advanced breast and non-small-cell lung cancer: No evidence of increased efficacy. Br J Cancer 1997; 76: 1636-9. Emerson DL, Amirgahari N, Bendele R et al. NX-211, a liposomal formulation of lurtotecan demonstrates enhanced pharmacokinetic and antitumor activity. Proc Am Assoc Cancer Res 1998; 39. 278 (Abstr).
Received 11 September 1998, accepted 26 January 1999.
Correspondence to. J. P. Stevenson, MD University of Pennsylvania Presbyterian Medical Center 51 North 39th Street MAB-Suite 103 Philadelphia, PA 19104 USA E-mail: [email protected]
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17. Gibaldi M, Perrier D. Nonlinear pharmacokinetics. In Gibaldi M, Perrier D (ed): Pharmacokinetics. New York: Marcel Dekker 1984; 271-84. 18. Houghton PJ, Cheshire PJ, Hallman JC et al. Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4[l-piperidino]-lpiperidino)-carbonyloxycamptothecin against human tumor xenografts: Lack of cross-resistance in vivo tumors with acquired resistance to the topoisomerase I inhibitor 9-dimethylaminomethyl-10-camptothecin. Cancer Res 1993; 53: 2823-9. 19. Gerrits CJH, Creemers GJ, Schellens JHM et al. Phase I and pharmacological study of the new topoisomerase I inhibitor GI147211, using a daily x5 intravenous administration. Br J Cancer 1996; 73: 744-50. 20. Gerrits CJH, Schellens JH, Creemers GJ et al The bioavailabihty of oral GI147211 (GG211), a new topoisomerase I inhibitor. Br J Cancer 1997; 76: 946-51. 21. van Oosterom AT, Gore M, Calvert AH et al. Activity of GW211 (GI147211) in relapsed ovarian cancer, a phase II study. Proc Am Soc Clin Oncol 1997; 16: 349a (Abstr). 22. Heinrich B, Lehnert M, Cavalli Fet al. Phase II trial of GI147211 in locally advanced or metastatic non-small cell lung cancer (NSCLC): An EORTC-ECSG trial. Proc Am Soc Clin Oncol 1997; 16: 470a (Abstr). 23. Wanders J, ten Bokkel-Huinink WW, Heinrich B et al. Phase II studies with Gl-147211 in five different tumor types - preliminary results. Ann Oncol 1996; 7 (Supp 1): 131 (Abstr). 24 Wanders J, ten Bokkel-Huinink WW, Pavlidis N et al. Phase II studies with GI147211 (GI) in breast (B), colorectal (C) and nonsmall-cell lung cancer. Eur J Cancer 1997; 33 (Suppl 8): S158 (Abstr). 25 Lokich JJ, Ahlgren JD, Gullo JJ et al. A prospective randomized comparison of continuous infusion fiuorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: A MidAtlantic Oncology Program Study. J Clin Oncol 1989, 7: 425-32. 26. Comis RL. Oral etoposide in oncology: An evolving role Ann Oncol 1992; 3: 63-7. 27. Danks MK, Pawlik CA, Whipple DO et al. Intermittent exposure
Original article Phase I/pharmacokinetic study of the topoisomerase I inhibitor GG211 administered as a 21-day continuous infusion J. P. Stevenson,1 D. DeMaria, 2 J. Sludden,3 S. B. Kaye,3 L. Paz-Ares,3 L. B. Grochow,4 A. McDonald, 3 K. Selinger,5 P.Wissel,5 P. J. O'Dwyer 1 ' 2 & C. Twelves3
cytopenia was dose-limiting with 0.5 mg/rrr/day dosing but was not cumulative. Other grade 3-4 toxicities included neuBackground: Preclinical results support a prolonged schedule tropenia, nausea, vomiting, diarrhea, and fatigue. Partial reof administration for topoisomerase I inhibitors, and we have sponses occurred with 21-day infusion in two patients with previously demonstrated the safety and activity of the novel breast and ovarian cancer at the 0.3 and 0.4 mg/m2/day dose water-soluble topoisomerase I inhibitor GG211 when given as levels, respectively. Mean GG211 lactone Css ranged from 0.17 to 0.64 ng/ml. a 72-hour continuous infusion to cancer patients. Conclusion: The maximum tolerated dose of GG211 adminPatients and methods: In a three-center international phase I trial, 38 patients received GG211 doses from 0.3 to 0.5 istered as a 21-day continuous infusion is 0.4 mg/m2/day with mg/m2/day by continuous intravenous infusions for seven, 14, antitumor activity noted at tolerable doses. and 21 days. Patients' median performance status was 1; nearly half had colorectal cancer, and 35 patients had prior chemo- Key words: camptothecin analogues, GG211, continuous infusion, phase I trial, topoisomerase I inhibitors therapy. Results: The first patient cohort received 0.3 mg/rrr/day for seven days with no significant toxicities. Subsequent cohorts Abbreviations: Css - blood steady-state concentration; IC50 received continuous infusions for 14 and 21 days at this dose half-maximal inhibitory concentration; ECOG - Eastern level with only mild myelosuppression noted. Dose-escalation Cooperative Oncology Group; DLT - dose-limiting toxicity; on the 21-day schedule was then performed. No dose-limiting AUC - area under the concentration-time curve; HPLC toxicity occurred at the 0.4 mg/m2/day dose level. Thrombo- high-performance liquid chromatography Summary
Introduction
The camptothecins are novel cytotoxic agents which are the only well-characterized compounds to target the nuclear enzyme topoisomerase I [1]. The principal function of topoisomerase I is believed to be the relief of torsional strain produced in supercoiled DNA during processes which alter DNA topology such as replication and gene transcription [2]. Topoisomerase I binds covalently to double-stranded DNA and forms what is termed the 'cleavable complex' through the introduction of a single-strand break, allowing free rotation of DNA about the remaining phosphodiester bond. The camptothecins bind and stabilize the cleavable complex; double-strand breaks then result when the advancing replication fork encounters the persistent single-strand break [3]. The subsequent mechanism of cell death is not well understood, but double-strand breaks are major correlates of camptothecin cytotoxicity [4]. Topoisomerase I expression is greater than that of normal tissue in a range of cancer cell lines and surgical tumor specimens. Progres-
sive alterations in expression have also been described in tissues during malignant transformation, making topoisomerase I an attractive target for antineoplastic therapy [5, 6]. The development of camptothecin in the 1970s was limited by its insolubility in aqueous solutions and the occurrence of unpredictable bone marrow and bladder toxicity in early clinical trials [7]. Recently, the semisynthetic camptothecin analogues irinotecan (CPT-11) and topotecan have proven to be valuable in the clinic, given their solubility and tolerablility, as well as meaningful antitumor activity. GG211 (7-(4-methyl piperazinomethylene)-10,l 1 -ethylenedioxy-20-(S)-camptothecin) is a novel water-soluble synthetic camptothecin which displays potent topoisomerase I inhibition (Figure 1). Preclinical studies of GG211 in a range of tumor cell lines and xenografts revealed an antitumor profile similar to, but with two to five times the potency of, topotecan [8-10]. Interestingly, in two human colon xenografts, GG211 displayed a superior therapeutic index to topotecan [8], and this stimulated further preclinical and
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'University of Pennsylvania Cancer Center; 2Fox Chase Cancer Center, Philadelphia, PA, USA; 3CRC Department of Medical Oncology, University of Glasgow, Western Infirmary Hospital, Glasgow, UK; "Johns Hopkins Oncology Center, Baltimore, MD; 5Gla.\o Wellcome Research Inc., Research Triangle Park, NC, USA
340
2Hd
CH,(
O
clinical evaluation of the compound. GG211 had in vitro activity against HT-29 (colon), T47D (breast), LOX (melanoma), and SKOV3 (ovarian) cell lines, and against HT-29 and SW480 (colon), MX1 (breast), SKOV3, PC3 (prostate), and H460 (lung) xenografts in vivo. Hematologic and gastrointestinal toxicities predominated in animal studies, and were dose-dependent. Prolonged administration of topoisomerase I inhibitors in preclinical models produced superior activity over intermittent bolus dosing, suggesting schedule dependency [11, 18]. Hochster et al. have investigated 21-day continuous infusions of topotecan and demonstrated this to be a tolerable and active regimen. In their phase I study, responses occurred in breast, ovarian, renal, and non-small-cell lung cancers; bone marrow suppression (predominantly thrombocytopenia) was dose-limiting [12]. They reported a 43% response rate (one CR) in their phase II trial of 21-day topotecan infusion in platinum-pretreated ovarian cancer patients, and no grade 4 hematologic toxicity [13]. Continuous infusion schedules of GG211 are therefore warranted, especially as we have observed antitumor activity in our previous phase I study of 72-hour administration of GG211 as a continuous infusion [14]. Pharmacokinetic analyses from the 72-hour infusion trial indicated that mean GG211 lactone concentrations at steady-state increased with dose (range 0.24-1.24 ng/ml) with a mean terminal half-life of 7.5 hours. Based upon these promising results, we initiated this phase I trial to determine the toxicity, efficacy, and an appropriate phase II dose of GG211 when given to patients as a 21-day continuous intravenous infusion.
Patients and methods
Drug administration GG211 is stable as a concentrate or as a more dilute solution in 5% dextrose A uniform solution of 5% dextrose USP was the standard diluent in this study. GG21I was mixed with diluent to a total volume of 100 ml and administered as a seven-day continuous infusion using a calibrated ambulatory infusion pump. Drug containers and extension tubing were protected from light at all times. Aliquots of the administered solution were used to confirm the stability of GG211. GG2I1 infusions were administered for seven. 14, or 21 days according to the study design. Patients who received 14 or 21-day infusions had 50% and 33%, respectively, of the total GG211 dose administered in 100 ml over seven-day periods.
Study design In order to evaluate the safety and tolerability of GG211 when administered as a prolonged continuous infusion, length of infusion was extended in stepwise fashion. Cohorts of three to nine patients were entered into each treatment group. The starting dose of GG211 was 0.3 mg/m 2 /day administered for seven days, followed in the absence of DLT by infusions for 14 and then 21 days at the same daily dose. All subsequent patients received 21-day infusions and dose levels were escalated by 15% to 50% as tolerated. There was no dose escalation in individual patients. If at any time during treatment the neutrophil count fell to <750/mm 3 or platelet count $ 50,000/mm 3 the infusion was discontinued. Courses were repeated 14 days following the end of the previous infusion if laboratory values were adequate on day one of each cycle. If DLT was observed in any patient, an additional three patients were treated at that dose level. The maximum tolerated dose was denned as one dose level below that which produced DLT in a minimum of two of six patients. DLT was defined as the occurrence of any of the following: 1) an absolute neutrophil count <500/mm 3 or platelet count < 50,000/mm 3 for > 5 days; 2) an absolute neutrophil count < 500/mm 3 with fever requiring parenteral antibiotics or platelet count < 50,000/mm 3 requiring transfusion; 3) any non-hematologic toxicity > grade 3 excluding alopecia or emesis.
Patient population Pharmacokinetic sampling and analysis Patients were treated on this study between April 1995 and May 1996 as part of an international collaborative effort between Fox Chase Cancer Center, Johns Hopkins University Cancer Center, and the Cancer Research Campaign (CRC) Department of Medical Oncology at the University of Glasgow. Eligible patients were at least 18 years of age with histologically confirmed solid tumors that were refractory to standard therapy or for which no effective therapy was available. An
Blood and urine samples for the determination of GG211 pharmacokinetics were obtained from all patients during the first cycle. Blood samples (7 ml) were collected in heparinized tubes prior to infusion and on days 4 and 8 (seven-day infusion), days 4, 8, 11, and 15 (14-day infusion), or days 4,8.11,15.18, and 22 (21-day infusion). Blood samples were immediately placed on ice and stored at -20 C until analysis.
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Figure I. Structure of GG211 [7-(4-methyl piperazinomethylene)10,ll-ethylenedioxy-20-(S)-camptothecin].
ECOG performance status < 2 and a life expectancy > 3 months were required. All patients had recovered from prior treatment and had received no cytotoxic chemotherapy in the previous three weeks (six weeks for nitrosoureas or mitomycin C). Patients had adequate bone marrow function (neutrophils ^2000/mm 3 and platelets ^ 100,000/mm3), creatinine ^ 1.5 mg/dl, serum bilirubin < 1.5 mg/dl, and AST/ALT $ 4 times the upper limit of normal. All patients received information on the purpose and conduct of this study, and signed written informed consent. Pretreatment evaluation consisted of a history and physical examination, full blood count, serum electrolytes, creatinine and liver biochemistries, urinalysis, electrocardiogram, chest X-ray, and assessment of ECOG performance status. All patients had a central venous catheter placed prior to treatment. Blood counts were performed twice weekly, biochemical profiles were performed weekly, and patients were examined prior to every course. Toxicity during each treatment cycle was assigned according to the NCI Common Toxicity Criteria (Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, 1988). Lesions noted at baseline that were measured or evaluated by radiographic scan or x-ray were reviewed before each alternate course and evaluated for response according to standard criteria [15],
341 Table I. Patient characteristics. 38/37 Toxicity 23 15 53 27-72 0-2 18 6 4 4 3 2 1
Granulocytopenia 0.3 mg/m 2 x 7d 0.3 mg/m 2 x 14d 0.3 mg/m 2 x21d 0.4 mg/m 2 x 21d 0.5 mg/m 2 x21d Thrombocytopenia 0.3 mg/m 2 x 7d 0.3 mg/m 2 x 14d 0.3 mg/m 2 x21d 0.4 mg/m 2 x 21d 0.5 mg/m 2 x21d
n
Grade 1
Grade 2
Grade 3
Grade 4
3 8 5 14 7
0 1 0 1 1
0 1 0 0 3
0 0 0 1 1
0 0 0 0 0
3 8 5 14 7
0 1 0 1 0
0 0 0 2 0
0 0
0 0 0 0 2
0 1 2
27
GG211 lactone measurements were performed using a GLP validated HPLC assay [16]. GG211 was extracted from cold blood by a mixture of 1 :4 (v/v) acetonitrile and butylchloride. Samples were kept in an ice slurry bath prior to extraction to slow conversion of GG211 lactone to carboxylate. The organic phase was collected and evaporated down under a stream of nitrogen. The residue was reconstituted with a 1:4 (v/v) solution of acetonitrile and sodium phosphate buffer with a pH of 4. The solution was then injected onto an HPLC system equipped with a Cis extraction column and fluorescence detector. The range of the assay is 0.15 ng/ml to 100 ng/ml with sufficient precision and accuracy (CV < 10%). The mobile phase consisted of 25% acetonitrile and 10% ammonium acetate buffer pumped at 1.7 ml/min. The internal standard used the assay was 6,7-dimethoxy-4-methylcoumarin. Blood GG211 concentration versus time curves were evaluated using model independent methods [17]. AUC0-t was determined by WinNonlin (Scientific Consulting Inc., North Carolina, USA). The average steady-state concentration (Css) was determined by calculating the average GG211 concentration after steady-state was attained. Systemic blood clearance (CL) was estimated with the equation: CL = infusionrate/Css Pharmacokinetic and pharmacodynamic relationships were investigated using the sigmoid E max (Hill) equation of the following form: % decrease in neutrophils or platelets = 100 x (parameter) y/(parameter50) y + (parameter) y where the estimated parameters are the Hill constant (•/) and the pharmacokinetic parameters that produce the half-maximal Css. The data were fit to the above relationship using WinNonlin.
all had a good performance status. Nearly half of the patients had colorectal cancer and received 5-fluorouracil based chemotherapy. Most were not extensively pretreated; three patients were previously untreated, and 27 patients received ^ 2 chemotherapy regimens. Hematologic toxicity There were no significant toxicities noted in the first three patients treated with seven-day infusion of GG211 at 0.3 mg/m2/day (Table 2). Eight patients subsequently received 14-day infusions at this same dose level. As only grade 1-2 granulocytopenia and thrombocytopenia were noted in cycle 1 of the 14-day schedule, all further patients received 21-day infusions, beginning at 0.3 mg/m2/day. Reversible, non-cumulative thrombocytopenia was dose-limiting with the 21-day infusion at the 0.5 mg/m2/day dose level, at which four of eight patients experienced grade 3-4 toxicity. There were no episodes of grade 4 thrombocytopenia at 0.4 mg/m2/day, although 2 of 14 patients developed grade 3 toxicity. Granulocytopenia occurred but was not dose-limiting. Only one patient treated with 0.4 mg/m2/day and two patients at the 0.5 mg/m2/day dose level experienced grade 3 neutropenia with 21-day infusion. There were no episodes of neutropenic sepsis. A heavily pretreated patient with synovial sarcoma and bilateral pulmonary metastases died of massive hemoptysis with a platelet count of 11,000/mm3. There were no other clinically significant hemorrhagic events related to grade 3-4 thrombocytopenia.
Results
Non-hematologic toxicity
A total of 38 patients received 80 cycles (median 2; range 1-8) of GG211 as part of this study; 37 were assessable for toxicity and response. One patient at the 0.5 mg/m2 dose level removed himself from study after three days of therapy to pursue treatment elsewhere and was not considered evaluable. There are no patients remaining on study. The demographic characteristics of the patients are listed in Table 1. The median age was 53, and
GG211 was generally well-tolerated. Non-hematologic toxicities included alopecia, nausea/vomiting, diarrhea, and fatigue but these were not dose-limiting. Five patients experienced grade 3 nausea/vomiting, but these symptoms were controlled with antiemetics in the majority of patients. Three patients developed grade 3 fatigue, and one patient experienced grade 3 diarrhea. Complications related to indwelling central venous catheters included
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Total entered/evaluable Sex Male Female Age Median Range Performance status Primary sites Colorectal Ovarian/endometrial NSCLC Sarcoma Breast Genitourinary Gastric Prior treatment Chemotherapy Chemotherapy/radiotherapy None
Table 2. Hematologic toxicities of GG211 during the first treatment cycle
342 Table 3 Summary of mean GG2I1 pharmacokinetic parameters by dose level." Dose n (mg/m 2 /d)
C ss (ng/ml)
0.3 0.3 0.3 0.4 0.5
0.22 0.27 0.37 0.35 0.40
1
x 7d x I4d x 21d x 21d x21d
± 0 04 ±0.03 ± 0 II ± 0.07
AUC 0 ., (ng h/ml)
T m a x (h)
31.4 ±6.0 97.9 ± 40.4 176 ± 1.01 151.8 ± 3 1 . 9 190.8 ± 3 8
5.3 7.8 7.5 8.4 13.4
±2.3 ±2.5 ±4.9 ±5.7 ±3.9
Clearance (ml/min/m 2 ) 991 ±216 752 ± 117 568 ±4.3 839 ± 272 887 ±141
+SD.
200
j<
100
4
Pharmacokinetics Thirty-seven patients had pharmacokinetic sampling performed during the first course of GG211 treatment. Data from 10 patients was unavailable for pharmacokinetic analysis and one patient did not receive one full course of therapy. Twenty of 27 patients with available data had pharmacokinetic parameters determined. Of the remaining seven patients, six had GG211 blood levels that were outwith the limit of detection of the HPLC assay and one had levels that exceeded the linear range of the HPLC assay. There were no significant differences in pharmacokinetic parameters between the three centers. Pharmacokinetic data from analyzed patients is presented in Table 3. Steady-state lactone GG211 blood concentrations, ranging from 0.17 to 0.64 ng/ml, were reached in most patients by day 4. AUC0.t increased with both duration of exposure and with increasing dose of GG211 (r2 = 0.76; Figure 2). Phanvacodynamics There was no clinically significant correlation between AUCo-t and fall in either neutrophil or platelet count. Likewise, in the patients receiving GG211 for 21 days there was no correlation between Css and myelosuppression. Responses There were partial responses observed in two patients. A 63-year-old woman with metastatic breast cancer whose previous treatments included epirubicin, 5-fluorouracil, tamoxifen, megace, and aminoglutethimide had regression in regional axillary lymph nodes, a left chest wall metastasis, and a skin metastasis on the left arm. She received four cycles of GG211 0.3 mg/m2/day (21-day infusion); treatment was discontinued after she developed catheter-related line sepsis. The other response occurred with 21-day infusion at the 0.4/mg/m2/day dose level. This 69-year-old woman with metastatic ovarian cancer experienced a partial response in cervi-
a
e
12
Total dosa (mg) Figure 2 GG2H lactone AUC versus total dose received in mg per cycle Note the linear increase
cal lymph nodes as well as a minor response at the site of a soft tissue metastasis. Her previous therapy included Taxol, carboplatin, and tamoxifen. Therapy was discontinued after four cycles of GG2H as a result of disease progression. Also, a 48-year-old woman with colorectal cancer and a 72-year-old woman with ovarian cancer maintained stable disease through eight cycles each of GG2H 14-day infusion at 0.3 mg/m2/day.
Discussion The clinical development of the camptothecins and the identification of their molecular target and mechanism of action represent an important advance in antineoplastic therapy. The semisynthetic derivatives CPT-11 and topotecan have been valuable additions to the armamentarium of the medical oncologist, and combination trials with these agents are in progress. The wholly synthetic camptothecin analogue GG211 demonstrated inhibition of topoisomerase I at nanomolar concentrations as well as greater water-solubility and antitumor potency than topotecan in preclinical studies [8]. The phase I development of GG211 to date has included the daily timesfive30-minute infusion and 72-hour continuous infusion schedules; an oral bioavailability study has also been reported [14, 19, 20]. Based on the superior efficacy with prolonged administration of topoisomerase I inhibitors in preclinical models, and clinical experience with prolonged exposure to 5-fluorouracil and the topoisomerase II inhibitor etoposide [25, 26], we investigated 21-day continuous infusion of GG211 in this study. We found GG211 to be safe and tolerable with 21-day continuous infusion and the recommended dose for phase II trials is 0.4 mg/irr/day, with thrombocytopenia as the predominant, dose-limiting toxicity. The dose-intensity achieved at the recommended
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line infections in six patients and subclavian vein thrombosis in two patients. Catheter sepsis resulted in the discontinuation of therapy in one patient.
343
The current study has confirmed activity of GG211 given by prolonged infusion at a tolerable dose. It is unclear whether this schedule would provide the increment in activity necessary for GG211 to be viewed as distinct from and superior to topotecan. However, data on schedule dependency of topotecan are disappointing and do not encourage the development of this ap-
14. Paz-Ares L, Kunka R, DeMaria D et al. A phase I clinical and pharmacokinetic study of the new topoisomerase inhibitor GI1472I1 given as a 72-hour continuous infusion. Br J Cancer 1998: in press. 15. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment. Cancer 1981; 47: 207-14. 16. Selinger K, Smith G, DepeeSetal. Determination of GI147211 in human blood by HPLC with fluorescence detection. J Pharm Biomed Anal 1995: 13: 1521-30.
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phase II dose is 1.68 mg/m /week, which is comparable proach. Liposome encapsulation represents one promisto that achieved in good-risk patients with 72-hour ing method of drug delivery. Emerson et al. demonstrated infusion at the phase II dose. The responses observed in GG211 liposomes to be more active and less rapidly the pretreated breast and ovarian cancer patients are cleared than free drug in animal models [32]: clinical encouraging. trials are anticipated. Pharmacokinetic studies revealed the kinetics of GG211 given by prolonged infusion to be linear. The Css achieved (0.17 to 0.64 ng/ml) was substantially lower Acknowledgement than that observed with 72-hour infusion of GG211 [14]. Nevertheless, these values are similar to the concentration Supported in part by grants from the Cancer Research of 0.59 ng/ml that achieves 50% growth inhibition in Campaign UK, The European School of Medical Oncolvitro [8]. These levels appear biologically active as anti- ogy, CA06927, CA 56036. proliferative toxicities were dose-limiting in the current study. The absence of pharmacodynamic relationships may in part be explained by the use of both different References doses and schedules of GG211. Phase II trials of GG211 in breast, small cell and non1. Hsiang Y-H, Hertzberg R, Hecht S et al. Camptothecin induces small-cell lung, colorectal and ovarian cancers have protein-linked DNA breaks via mammalian DNA topoisomerase been performed using the daily times five short infusion I. J Biol Chem 1985; 260: 14873-8. 2. Wang JC. DNA topoisomerases. Ann Rev Biochem 1985; 54: (1.2 mg/irr/day) schedule every 21 days. Van Oosterom 665-97. et al. reported an overall 18% response rate in 46 plati3. Hsiang Y-H, Lihou MG, Liu LF. Arrest of replication forks by num-pretreated ovarian cancer patients, and 41% overdrug-stabilized topoisomerase I-DNA cleavable complexes as a all maintained stable disease for at least two cycles [21]. mechanism of cell killing by camptothecin. Cancer Res 1989; 49: Preliminary data indicated activity in small-cell lung 5077-82. 4. Nitiss J, Wang JC. DNA topoisomerase-targeting antitumor drugs cancer, but only minor activity was noted in the breast can be studied in yeast. Proc Natl Acad Sci USA 1988, 85: 7501-5. and non-small-cell lung carcinoma trials, and no re5. Giovanella BC, Stehlin JS. Wall ME et al. DNA topoisomerase I sponses were observed in colorectal cancer patients [22targeted chemotherapy of human colon cancer xenografts. Sci24]. Myelosuppression, in the form of reversible, nonence 1989; 246. 1046-50. cumulative neutropenia was the principal toxicity with 6. Husain I, Mohler JL, Seigler HFet al. Elevation of topoisomerase this schedule. The data demonstrate that GG211 is an I messenger RNA, protein, and catalytic activity in human tumors: Demonstration of tumor-type specificity and implications agent with some activity, but are insufficient to deterfor cancer chemotherapy. Cancer Res 1994; 54: 539-46. mine if it has response characteristics that differ from 7. Muggia FM, Creaven PJ, Hansen HH et al. Phase I trial of weekly available topoisomerase I interactive agents. and daily treatment with camptothecin (NSC-100880): Correlation with preclinical studies. Cancer Chemother Rep 1972; 56: Indeed, recent in vitro and clinical data with pro515-21. longed exposure to topotecan might dampen the enthu8 Emerson DL, Besterman JM, Brown HR et al. In vivo antitumor siasm for pursuing the continuous infusion schedule for activity of two new seven-substituted water-soluble camptothecin GG211. Contrary to previous preclinical data, Danks et analogues. Cancer Res 1995; 55. 603-9. al. found no increase in cleavable complex formation or 9. Luzzio MJ, Besterman JM, Emerson DL et al. Synthesis and tumor inhibition with continuous exposure over interantitumor activity of novel water-soluble derivatives of camptothecin as specific inhibitors of topoisomerase I. J Med Chem mittent exposure to topotecan in the medulloblastoma 1995; 38: 395-401. cell lines they studied [27]. Similarly, in the clinic we 10. Emerson DL. Vuong A, Mclntyre G et al. In vivo efficacy of two found no improvement in efficacy with 21-day continuous new water-soluble camptothecin analogs in the human cancer infusion of topotecan over daily times five intermittent xenograft model. Proc Am Assoc Cancer Res 1993; 34: 419 (Abstr). dosing in our phase II studies in pancreatic and colo- 11. Burris III HA, Hanauske A-R, Johnson RK et al. Activity of rectal cancers (8% response rate in both trials) [28, 29]. topotecan, a new topoisomerase I inhibitor, against human tumor colony-forming units in vitro. 1 Natl Cancer Inst 1992; 84: 1816-20. Creemers et al. obtained similar data in colorectal cancer, and Mainwaring and colleagues recently reported 12. Hochster H, Liebes L, Speyer J et al. Phase I trial of low-dose continuous topotecan infusion in patients with cancer: An active response rates of 8% and 15% in non-small-cell lung and and well-tolerated regimen. J Clin Oncol 1994; 12: 553-9. breast cancer patients with 21-day infusion [30, 31]. 13. Hochster H, Speyer J, Wadler S et al. Activity of topotecan (TPT) Therefore, available evidence to date does not support 21-day infusion inplatinum treated ovarian cancer and pharmathe suggestion that topotecan's effects are enhanced by a codynamics of topo-1 depletion (A NYGOG study). Proc Eur Soc Med Oncol 1996; 21: 69 (Abstr). 21-day infusion.
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Received 11 September 1998, accepted 26 January 1999.
Correspondence to. J. P. Stevenson, MD University of Pennsylvania Presbyterian Medical Center 51 North 39th Street MAB-Suite 103 Philadelphia, PA 19104 USA E-mail: [email protected]
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17. Gibaldi M, Perrier D. Nonlinear pharmacokinetics. In Gibaldi M, Perrier D (ed): Pharmacokinetics. New York: Marcel Dekker 1984; 271-84. 18. Houghton PJ, Cheshire PJ, Hallman JC et al. Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4[l-piperidino]-lpiperidino)-carbonyloxycamptothecin against human tumor xenografts: Lack of cross-resistance in vivo tumors with acquired resistance to the topoisomerase I inhibitor 9-dimethylaminomethyl-10-camptothecin. Cancer Res 1993; 53: 2823-9. 19. Gerrits CJH, Creemers GJ, Schellens JHM et al. Phase I and pharmacological study of the new topoisomerase I inhibitor GI147211, using a daily x5 intravenous administration. Br J Cancer 1996; 73: 744-50. 20. Gerrits CJH, Schellens JH, Creemers GJ et al The bioavailabihty of oral GI147211 (GG211), a new topoisomerase I inhibitor. Br J Cancer 1997; 76: 946-51. 21. van Oosterom AT, Gore M, Calvert AH et al. Activity of GW211 (GI147211) in relapsed ovarian cancer, a phase II study. Proc Am Soc Clin Oncol 1997; 16: 349a (Abstr). 22. Heinrich B, Lehnert M, Cavalli Fet al. Phase II trial of GI147211 in locally advanced or metastatic non-small cell lung cancer (NSCLC): An EORTC-ECSG trial. Proc Am Soc Clin Oncol 1997; 16: 470a (Abstr). 23. Wanders J, ten Bokkel-Huinink WW, Heinrich B et al. Phase II studies with Gl-147211 in five different tumor types - preliminary results. Ann Oncol 1996; 7 (Supp 1): 131 (Abstr). 24 Wanders J, ten Bokkel-Huinink WW, Pavlidis N et al. Phase II studies with GI147211 (GI) in breast (B), colorectal (C) and nonsmall-cell lung cancer. Eur J Cancer 1997; 33 (Suppl 8): S158 (Abstr). 25 Lokich JJ, Ahlgren JD, Gullo JJ et al. A prospective randomized comparison of continuous infusion fiuorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: A MidAtlantic Oncology Program Study. J Clin Oncol 1989, 7: 425-32. 26. Comis RL. Oral etoposide in oncology: An evolving role Ann Oncol 1992; 3: 63-7. 27. Danks MK, Pawlik CA, Whipple DO et al. Intermittent exposure