docetaxel in patients with advanced solid tumors

Lung Cancer 37 (2002) 213
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Phase I study of weekly CPT-11 (irinotecan)/docetaxel in patients with advanced solid tumors A. Font, J.M. Sanchez, R. Rosell *, M. Taron, E. Martinez, M. Guillot, J.L. Manzano, M. Margeli, A. Barnadas, A. Abad Medical Oncology Service, Hospital Germans Trias i Pujol, Ctra Canyet, s/n, 08916 Badalona, Barcelona, Spain Received 14 November 2001; received in revised form 8 March 2002; accepted 19 March 2002

Abstract Based on the synergistic cytotoxicity demonstrated in vitro by topoisomerase I inhibitors followed by docetaxel and the feasibility of giving both drugs on a weekly schedule avoiding overlapping toxicities, we designed a phase I trial of weekly CPT-11 (irinotecan)/ docetaxel to determine the dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) of this combination. Eighteen patients with advanced solid tumors treated with at least one prior chemotherapy regimen were included in this trial. CPT-11 was administered as a 90-min (intravenous) IV infusion followed immediately by docetaxel as a 30-min IV infusion. Both drugs were given on days 1, 8 and 15 in 4-week cycles. Four escalating dose levels of CPT-11/docetaxel (level I: 60/20 mg/m2, level II: 60/25 mg/ m2, level III: 70/25 mg/m2, and level IV: 70/30 mg/m2) were studied. Forty-seven cycles were administered (range, 1
/5 courses) with a median number of 2.6 cycles per patient. Grade 4 leukopenia was the DLT reached at dose-level IV (CPT-11/docetaxel 70/30 mg/ m2). Four patients had grade 3 anemia at dose levels III (two patients) and IV (two patients), while grade 3/4 thrombocytopenia was not seen. Grade 3/4 non-hematologic toxicities included grade 3 diarrhea in two patients (dose levels II and IV), grade 3 asthenia in one patient (dose level II) and grade 3 stomatitis in one patient (dose level I). The recommended dose of this weekly schedule is CPT11 70 mg/m2 and docetaxel 25 mg/m2. DLT of this regimen is leukopenia, although toxicity is manageable at the recommended dose level. The activity of this regimen is being evaluated in a phase II study in previously treated patients with advanced non-small cell lung cancer. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Chemotherapy; Docetaxel; Irinotecan; Maximum tolerated dose; Phase I; Toxicity

1. Introduction CPT-11 (irinotecan) is a water-soluble camptothecin derivative that inhibits topoisomerase I by stabilizing the enzyme
/DNA cleavable complex and thus causes single-strand DNA breaks and subsequent cell death. Several studies have shown that CPT-11 possesses a wide spectrum of activity in human tumors, including colorectal, lung, ovarian and gastric cancers, leukemia, and non-Hodgkin’s lymphoma. The dose-limiting toxicity (DLT) when given as a single agent on a 3-week schedule as a 30
/90-min IV infusion was late diarrhea

* Corresponding author. Tel.: /34-93-497-8925; fax: /34-93-4978950 E-mail address: [email protected] (R. Rosell).

and febrile neutropenia [1]. However, CPT-11 administered on a weekly schedule has been shown to have a favorable toxicity profile, with a lower incidence of grade 3
/4 diarrhea [2], increasing the feasibility of combination with other drugs. Docetaxel, a member of the taxoid family of compounds, disrupts mitosis by the promotion of abnormal microtubular assembly and the suppression of the depolymerization of microtubular bundles to free tubulin [3]. As a single agent, docetaxel has demonstrated significant antitumor activity against both chemotherapy-naive and chemotherapy-pretreated relapsed malignancies, including non-small cell lung cancer (NSCLC), breast cancer, urothelial cancer, and ovarian cancer. To date, in most studies, the recommended dose of docetaxel has been 70
/100 mg/m2 as a 1-h IV infusion every 3 weeks. The DLT reported with this dose is neutrope-

0169-5002/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 2 ) 0 0 0 8 1 - 8

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nia [4]. In contrast, when docetaxel is given on a weekly schedule, the toxicity profile changes and the DLT is asthenia, while hematological toxicity is not relevant [5]. The weekly administration of docetaxel seems to be well tolerated, leading to a higher dose intensity and more frequent exposure to the drug. A wealth of evidence suggests that the combination of CPT-11 and docetaxel is synergistic. The cytotoxic mechanism of topoisomerase I inhibitors acts during the S-phase of the cell cycle and induces G2/M-phase cell arrest [6]; cells in G2/M phase are particularly sensitive to the cytotoxic effect of docetaxel. Chou et al demonstrated the synergistic cytotoxicity of topotecan, a topoisomerase-directed agent, and paclitaxel in a human teratocarcinoma cell line [7]. SN-38 also produced additive cytotoxicity when combined with paclitaxel in lung cancer cell lines [8]. Furthermore, in our experience, synergistic activity was obtained with the sequential administration of topotecan followed by docetaxel in the SKBr3 human breast cancer cell line. This combination was synergistic when docetaxel was administered at the time of the greatest topotecan-induced G2/M-phase cell arrest [9]. The objectives of this phase I study were to determine the maximum tolerated dose (MTD) of the combination of weekly CPT-11 and docetaxel, to describe the DLT, and to establish the recommended dose for phase II studies.

2. Patients and methods 2.1. Patient selection Patients were eligible if they had advanced or metastatic solid tumors refractory to conventional therapy treated with at least one previous chemotherapy regimen. Eligibility criteria also included: age
/18 years; Karnofsky index
/60%; life expectancy of at least 12 weeks; and adequate bone marrow (platelets
/100 /109 cells/l, absolute neutrophil count (ANC)
/1.5 /109 cells/l), hepatic (total bilirubin within normal limits, aspartate transaminase B/2.0 times normal), and renal (serum creatinine B/1.5 times the upper limit of normal) functions. Patients had to have discontinued previous chemotherapy for at least 4 weeks. Prior radiotherapy to pelvis or abdomen was not allowed because of the increased risk of diarrhea induced by CPT-11. No major clinical neuropathy
/grade 1, according to National Cancer Institute criteria, was allowed. This study was approved by the hospital ethics committee. 2.2. Treatment plan CPT-11 was administered IV over 90 min followed immediately by docetaxel administered IV over 30 min.

Four escalating dose levels of CPT-11/docetaxel (60/20, 60/25, 70/25, 80/30 mg/m2) were studied. The dose escalation scheme was arbitrary. Dose escalation was not allowed in individual patients. Chemotherapy was given on days 1, 8 and 15. The regimen was repeated every 28 days. Treatment administration was given if ANC and platelets were
/1.5 /109 and
/100/109 cells/l, respectively, with non-hematological toxicity B/ grade 2 (excluding nausea/vomiting and alopecia). Otherwise, treatment was delayed for 1 week. If these conditions were still not met on day 35, treatment was discontinued and toxicity was considered to be doselimiting. Patients were medicated with dexamethasone 20 mg IV before chemotherapy; and antiemetic prophylaxis consisted of ondansetron 8 mg IV before and after treatment. Cholinergic symptoms (diarrhea, sweating, salivation, or abdominal cramping) that occurred within 1 hour after receiving CPT-11 could be treated with atropine (1 mg intravenously or as indicated). All patients were instructed to begin taking loperamide at the first sign of diarrhea that occurred more than 12 h after they received CPT-11, following the standard recommendations for CPT-11-induced late-onset diarrhea: 4 mg at the first onset of diarrhea, then 2 mg every 2 h around the clock until diarrhea-free for at least 12 h. Prophylactic use of colony-stimulating factors (CSFs) was not permitted. The DLT were defined as follows: ANC B/0.5 /109 cells/l or leukocyte countB/1.0 /109 cells/l for
/5 days; febrile neutropenia (fever
/38 8C with ANC B/0.5 / 109 cells/l); platelet countB/25/109 cells/l; diarrhea of grade 3 or greater; and other non-hematologic toxicity (except for nausea and vomiting, alopecia, and general fatigue) of grade 3 or greater. At least three patients were to be included at each dose level. If a patient experienced a DLT during the first cycle, then the number of patients at that level was increased to six. The MTD was defined as the dose level at which at least two of the six patients developed the DLT during the first course of treatment.

2.3. Evaluation at baseline and during treatment Complete patient histories, physical examinations, complete blood cell counts, serum electrolytes, and chemistries were performed at baseline and before each course of chemotherapy. Complete blood cell counts were performed weekly while patients were on study. Chest X-rays and computed tomography were performed at baseline and after every two cycles of therapy to assess tumor response. Patients were evaluated for toxicity weekly while on study.

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3. Results 3.1. Patient characteristics Eighteen patients were enrolled between May 1999 and January 2000. Patient characteristics are listed in Table 1. The median age was 56 years (range, 39
/74 years). Performance status was relatively good for most patients; the Karnofsky index was 70% for ten patients (55%), 80% for six patients (33%), and 90% for two patients (12%). The most common tumors were NSCLC (seven patients) and small cell lung cancer (seven patients). At study entry, 13 patients (72%) had metastatic disease, and five (28%) had locally advanced disease. All patients had received prior chemotherapy. Eleven patients (61%) had received one prior chemotherapy regimen (median number of cycles, five; range, 3
/9). Table 1 Patient characteristics Characteristic

No. of patients (%)

No. of patients

18

Gender Male Female

15 (83%) 3 (17%)

Median age (range)

56 (39
/74)

Performance status 70% 80% 90%

10 (55%) 6 (33%) 2 (12%)

Tumor type NSCLC SCLC HNSCC Esophagus/gastric No of previous regimens 1 2 3 4 5 Prior chemotherapy Cisplatin/etoposide Cisplatin/vinorelbine Cisplatin/gemcitabine Carboplatin/paclitaxel Cisplatin/gemcitabine/docetaxel Gemcitabine Paclitaxel or docetaxel MIC Paclitaxel/gemcitabine Cisplatin/fluorouracil

7 7 2 2

(38%) (38%) (12%) (12%)

11 (61%) 5 (27%) 1
/ 1

No. of cycles Median (range) 5 (3
/9) 4 (1
/6) Total 7
/ Total 12

7 2 2 4 3 2 4 1 1 1

NSCLC, non-small-cell lung cancer; SCLC, small-cell lung cancer; HNSCC, head and neck squamous cell carcinoma; MIC, mitomycin, ifosfamide, cisplatin.

215

Five patients (28%) had received two prior regimens; for the second regimen, patients received a median of four cycles (range, 1
/6). Only one patient had received three prior regimens (five cycles as first-line, two as secondline, and two as third-line). Finally, one patient had received five previous regimens (total of 12 cycles) (Table 1). Eight patients (44%) had received prior thoracic radiotherapy of 50 Gy or more (four NSCLC and four small-cell lung cancer; four patients at dose level I, three at level III, and one at level IV). All patients were eligible and assessable for toxicity. 3.2. Dose escalation and determination of first-course MTD and DLT A total number of 47 cycles was administered among four levels of the combination. The median number of cycles given was 2.6 (range, 1
/5 cycles); six patients received one, three received two, five received three, and four received five cycles. Table 2 lists the number of patients treated and number of courses administered by dose level as well as the DLT observed in the first cycle. At the first dose level (60/20 mg/m2), one patient developed grade 3 stomatitis, and three more patients were included in this cohort. No additional DLT was observed and further dose escalation was carried out. At dose level II, three patients were accrued and none experienced DLT; likewise, at dose level III, only one patient had a grade 3 anemia after the first cycle and required red blood cell transfusion. Six patients were included at level IV (70/30 mg/m2). Two patients developed DLT at this dose level. The first patient experienced febrile neutropenia during the first cycle, recovered, developed a bilateral pneumonia and died. The second patient had grade 4 leukopenia and died from septic shock caused by infected ascites. In addition, a third patient included at this level was hospitalized due to grade 2 diarrhea and died from septic shock in the absence of concomitant neutropenia during the infection. Thus, grade 4 leukopenia was considered the DLT and MTD was established at dose level IV (CPT-11 70 mg/m2 and docetaxel 30 mg/m2). The dose level recommended for future phase II trials is CPT-11 70 mg/m2 and docetaxel 25 mg/m2. 3.3. Toxicities during all cycles of treatment Table 3 list the overall incidence of hematologic and non-hematologic toxicities for all patients treated on this trial. The most frequent non-dose-limiting hematologic toxicity was anemia. Four patients had grade 3 anemia (two at dose level III and two at dose level IV); however, many patients entered the trial with some degree of anemia and it is difficult to determine to what degree this was treatment-related. Toxic effects on platelets

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Table 2 Dose escalation scheme and dose limiting toxicity Dose level

CPT-11/Doc (mg/m2)

No. of pts

No. of cycles

No of pts DLT

DLT

I II III IV

60/20 60/25 70/25 70/30

6 3 3 6

11 13 12 11

1 0 0 2

G3 stomatitis
/
/ Febrile neutropenia (1) G4 leukopenia (1)

were modest; only one patient (dose level IV) in one course of chemotherapy had grade 2 thrombocytopenia. No grade 3 or 4 leukopenia was noted below dose level IV (Table 3). Diarrhea (two patients), nausea and vomiting (one patient), stomatitis (one patient) and asthenia (one patient) were the only non-hematologic grade 3/4 adverse events observed (Table 3). During the treatment, dose reductions and/or dose omissions due to toxicity were not required.

3.4. Tumor responses A partial response lasting 3 months was observed in a patient with metastatic NSCLC treated at dose level III. Three additional patients had stable disease for at least two cycles of therapy (one patient with NSCLC, one with small cell lung cancer, and one with head and neck cancer).

4. Discussion Table 3 Toxicity Hematologic toxicity

Dose level

Total no of patients

I 6

II 3

III 3

IV 6

Leukopenia Grade 1
/2 Grade 3 Grade 4

1
/
/


/
/
/

1
/
/


/
/ 2

Neutropenic fever


/


/


/

1

Thrombocytopenia Grade 1
/2 Grade 3 Grade 4


/
/
/


/
/
/


/
/
/

1
/
/

Anemia Grade 1
/2 Grade 3 Grade 4


/
/
/


/
/
/


/ 2
/

3 2
/

Non-hematological toxicity Stomatitis Grade 1
/2 Grade 3 Grade 4


/ 1
/


/
/
/


/
/
/


/
/
/

Diarrhea Grade 1
/2 Grade 3 Grade 4

2
/
/

2 1
/

1
/
/

2 1
/

Nausea/vomiting Grade 1
/2 Grade 3 Grade 4


/
/
/


/ 1
/


/
/
/

1
/
/

Asthenia Grade 1
/2 Grade 3 Grade 4


/
/
/

1 1
/


/
/
/

2
/
/

We designed this phase I trial to determine the DLT and MTD of a weekly CPT-11/docetaxel schedule in previously treated patients. The DLT was leukopenia and the recommended dose for phase II studies was established at dose level III (CPT-11/docetaxel 70/25 mg/m2). To date, five phase I trials (Table 4) have assessed the CPT-11/docetaxel combination given on different schedules. Two studies carried out in previously treated patients analyzed CPT-11/docetaxel on a 3-week schedule [10,11]; a third study assessed weekly CPT-11 plus docetaxel given on day 2 every 4 weeks in patients with advanced NSCLC [12]. However, only our study and one by Rich et al. [13] have given both drugs on a weekly schedule. However, in the Rich study, the sequence of drug administration (docetaxel followed by CPT-11) was the opposite of that in our study and the MTD has not yet been established at the dose level of docetaxel/ CPT-11 of 35/50 mg/m2 [13]. In our experience, in human tumor-derived cell lines, the administration of topoisomerase I inhibitors followed by docetaxel was synergistic [9], but Kaufmann et al. found that the combination of topotecan and paclitaxel was antagonistic in a human NSCLC cell line [14]. Administration of CPT-11 before docetaxel may decrease docetaxel clearance because both drugs are metabolized by cytochrome P450 3A4 (CYP3A4). However, in the Adjei et al. study [10], the administration of CPT-11 before docetaxel led to a significant increase in docetaxel clearance, perhaps due to the fact that dexamethasone, a potent inducer of CYP3A4, was given before and after docetaxel administration. In the Couteau et al. study [11], docetaxel was given before

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217

Table 4 Summary of phase I studies with CPT-11 and docetaxel Study

Schedule

MTD

DLT

RD

Couteau, 2000 Adjei, 2000 Masuda, 2000 Rich, 1999 Present study

Doc/CPT-11 (d 1 q 3 wks) CPT-11/Doc (d 1 q 3 wks) CPT-11 (d 1,8,15) Doc (d 2) Doc/CPT-11 (wkly) CPT-11/Doc (wkly)

70/250 200/65 60/50
35/50 70/30

Neutropenia Neutropenia Neutropenia and diarrhea N.A Leukopenia

60/275 160/65 50/50
35/50 70/25

Doc, docetaxel; NA, not achieved; RD, recommended dose.

CPT-11, and no relevant interaction between the drugs was observed. Interestingly, the recommended dose for CPT-11 in the Adjei et al study was significantly lower than that in the Couteau et al study (CPT-11 160 vs. 250 mg/m2), while the recommended dose of docetaxel was similar in both studies (65 vs. 60 mg/m2). These results suggest that the toxicity profile of the CPT-11/docetaxel combination may be related to sequence of administration. In both our study and the three published phase I trials with the CPT-11/docetaxel regimen [10
/12], neutropenia was the DLT. In the Adjei et al. study [10], the ANC nadir at the recommended dose level (CPT-11/ docetaxel 160/65 mg/m2) was only 0.5 /109 cells/l, Couteau et al. [11] reported 85% of patients with grade 3/4 neutropenia, and Masuda et al. found 90% of patients with grade 2 or greater neutropenia. Diarrhea was the most important non-hematologic toxicity in all three studies. In the Adjei et al. study, 14 of 18 patients had diarrhea, and in the Couteau et al. study, late diarrhea occurred in 95% and early diarrhea in 50% of patients. The high incidence of diarrhea in the trials giving CPT-11/docetaxel on a 3-week schedule [10,11] seems to be related to the CPT-11 dose, since significant diarrhea is uncommon with docetaxel monotherapy [15]. However, in the study by Millward et al. [16], where patients were treated with cisplatin and docetaxel, grade 3 and 4 diarrhea occurred in 21% of patients. This finding suggests that a combination with docetaxel can increase the risk of diarrhea in CPT-11 regimens. In our study, the incidence of diarrhea was very low; only two patients (11%) had grade 3 diarrhea, and grade 4 diarrhea was not observed. At the recommended dose level, none of the three patients treated had grade 2 or higher diarrhea in the 12 cycles of treatment given. Regarding hematologic toxicity, although leukopenia was the DLT, no grade 3/4 leukopenia or thrombocytopenia was observed in the 12 patients treated below the MTD dose level. These results confirm that weekly CPT-11/docetaxel is a feasible regimen with a good toxicity profile. Furthermore, the dose intensity achieved in our study for CPT-11 and docetaxel is similar to that obtained in the Adjei et al. study [10] and substantially higher than that achieved in the Masuda et al. study [12].

A better understanding of the genetic factors involved in the metabolism of CPT-11 could be useful in predicting the toxicity and activity of this drug. Several enzymes are involved in the metabolic activation and detoxification of CPT-11. Once tissue carboxylesterase transforms CPT-11 into SN-38, the major mechanism of detoxification is through glucuronidation by UDPglucorunosyltransferase (UGT) 1A1 enzyme. Polymorphisms in the UGT1A1 gene, regarding the length of a TATA box sequence in the promoter region, have been described [17]. Prior studies have demonstrated that there is a correlation between UGT1A1 genotypes and SN-38 glucuronidation [18]; thus, variant genotypes will increase the toxicity by CPT-11 because of the excessive accumulation of the active metabolite SN-38 due to a decrease of glucuronidation. In fact, in a recent study carried out in patients with different tumor types treated with CPT-11, a significant correlation between UGT1A1 polymorphisms and severe toxicity (leukopenia and/or diarrhea) with CPT-11 was found [19]. CPT-11 and docetaxel have demonstrated antitumor activity in previously treated advanced NSCLC patients [10,11] as well as in chemonaive NSCLC patients [12,20]. In our institution, a phase II trial in previously treated NSCLC patients given weekly CPT-11/docetaxel at the recommended doses established in this phase I trial is ongoing. An analysis of UGT1A1 polymorphisms has been performed in blood samples of these patients to predict the toxicity and activity of this CPT-11 regimen [21].

Acknowledgements This study was not supported by any grants.

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