New combinations of chemotherapy agents with favorable toxicity. Phase I Evaluation of Docetaxel and Topotecan for Patients with Advanced Solid Tumors

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1 2240 Phase I Evaluation of Docetaxel and Topotecan for Patients with Advanced Solid Tumors Anne S. Tsao, M.D. 1 Dong M. Shin, M.D. 2 J. Lynn Palmer, Ph.D. 3 Jin S. Lee, M.D. 4 Bonnie S. Glisson, M.D. 1 1 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 2 Department of Hematology/Oncology, Emory University, Atlanta, Georgia. 3 Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 4 National Cancer Center Hospital, Kyonggi, Republic of Korea. BACKGROUND. The authors administered a combination of docetaxel and topotecan with granulocyte colony-stimulating factor (G-CSF) support in a Phase I study to define the maximum tolerated dose (MTD) of this regimen. METHODS. Patients with advanced-stage solid tumors were eligible for this trial if they had a Zubrod performance status of 2 and normal renal, hepatic, and bone marrow function. No previous therapy with taxanes or topoisomerase inhibitors was allowed. The authors administered both docetaxel and topotecan in a doseescalated manner until the MTD was reached. Docetaxel was given on Day 1 of each cycle before topotecan, which was administered intravenously on Days 1 3. Granulocyte colony-stimulating factor (G-CSF) support with 5 g/kg subcutaneous injections was initiated on Day 4 and continued until the absolute granulocyte count recovered to 2000/ L. Treatment cycles were repeated every 21 days. RESULTS. Of the 11 patients enrolled in the current study, all were evaluable for toxicity and 10 were evaluable for response. A median of three treatment cycles was received (range, one to nine treatment cycles). The dose-limiting toxicity was Grade 4 (according to the National Cancer Institute Common Toxicity Criteria for Adverse Events [version 2.0]). neutropenia with fever. The MTD was 75 mg/m 2 of docetaxel on Day 1 and 1.4 mg/m 2 of topotecan on Days 1 3. There was one complete response and one partial response in patients with nasopharyngeal carcinoma and one partial response in a patient with small cell lung carcinoma (SCLC). The response durations were 24 weeks, 29 weeks, and 244 weeks, respectively. At the time of last follow-up, both patients with nasopharyngeal carcinoma were still alive at 241 weeks and 244 weeks, respectively. CONCLUSIONS. This trial demonstrated that a regimen of docetaxel and topotecan with G-CSF support was generally well tolerated and had promising activity in patients with nasopharyngeal and SCLC. Cancer 2004;100: American Cancer Society. Supported in part by Grant CA from the National Cancer Institute and by a grant-in-aid from Aventis Pharmaceuticals (B.S.G.). Address for reprints: Bonnie S. Glisson, M.D., Department of Thoracic/Head and Neck Medical Oncology, P.O. Box 432, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030; Fax: (713) ; bglisson@mdanderson.org Received January 26, 2004; revision received February 20, 2004; accepted February 26, KEYWORDS: docetaxel, topotecan, nasopharyngeal carcinoma, small cell lung carcinoma. New combinations of chemotherapy agents with favorable toxicity profiles and nonoverlapping mechanisms of action are needed to treat patients with cancer. Taxanes and topoisomerase I inhibitors have broad single-agent activity against solid tumors. Docetaxel is a semisynthetic agent extracted from the needles of the European yew tree, Taxus baccata. 1 The active antitumor component is a diterpenoid from the taxane family that promotes tubulin assembly into microtubules and prevents depolymerization to free tubulin. This activity leads cells to accumulate in the M-phase of the cell cycle. 2,3 In murine models with human tumor xenografts, docetaxel showed promising antitumor activity. 4,5 Results of human Phase I trials established the maximum tolerated dose (MTD) of docetaxel as American Cancer Society DOI /cncr Published online 19 April 2004 in Wiley InterScience (

2 Docetaxel and Topotecan for Solid Tumors/Tsao et al mg/m 2 every 21 days, with the dose-limiting toxicity (DLT) being neutropenia. Other toxicities include alopecia, mucositis, fatigue, sensory neuropathy, fluid retention, rash, and hypersensitivity reactions. 6 8 Docetaxel has subsequently demonstrated antitumor activity against breast, nonsmall cell lung, small cell lung (SCLC), head and neck, ovarian, and gastric carcinomas Topotecan, a semisynthetic camptothecin analog derived from Camptotheca acuminata targets topoisomerase I, a nuclear enzyme that reduces torsional stress of supercoiled DNA and exposes selected DNA regions for replication, recombination, and transcription. 12 Topotecan is S-phase specific and covalently binds to double-stranded DNA to produce an intermediary single-strand break that then decreases torsional strain. 13 Normally, when the torsional strain is alleviated, topoisomerase I rejoins the cleaved strand of DNA and dissociates from the relaxed double helix, but binding of topotecan leads to stabilization of the transient topoisomerase I DNA complex and inhibits religation of DNA strands and reformation of DNA Exposure of the topotecan topoisomerase I DNA complex to the replication fork can lead to irreversible double-stranded breaks and cell death. 17 Topotecan antitumor activity has been reported in human SCLC, ovarian, prostate, brain, and hematologic carcinomas Several dosing regimens for topotecan have been investigated, but the one most frequently studied is a 30-minute infusion on 5 consecutive days, repeated every 3 weeks. Phase I trials have established the MTD of topotecan at 1.5 mg/m 2 per day for this dosing schedule. 14,21 24 The DLT for all administered forms of topotecan is neutropenia, which is often associated with thrombocytopenia. Less frequent toxicities include nausea, emesis, fatigue, mucositis, elevated serum transaminase concentrations, fever, and rash. 14 Topotecan is currently approved as a second-line therapy for advanced ovarian and small cell lung carcinomas. 25,26 Because both docetaxel and topotecan have single-agent activity against solid tumors, a rationale to combine these two agents with their novel mechanisms of action has emerged. A preclinical study of SKBr-3 cell lines showed that the combination of topotecan and docetaxel is synergistic when docetaxel is administered at the time of the highest topotecaninduced G 2 -phase cell arrest. 27 However, based on the overlapping DLT of both drugs (i.e., neutropenia), delivery of effective doses in a combination regimen was predicted to be difficult. We conducted a Phase I trial of docetaxel and topotecan with routine granulocyte colony-stimulating factor (G-CSF) support to identify the MTD and characterize the toxicity of this regimen. MATERIALS AND METHODS Patient Selection Patients were eligible for the current study if they met the following criteria: age 18 years, histologic diagnosis of a malignant solid tumor, a measurable or assessable lesion, 1 previous chemotherapy regimen for metastatic disease, a performance status of 2 on the Zubrod performance scale, life expectancy of 3 months, adequate bone marrow function (absolute granulocyte count 1500/ L and a platelet count 140,000/ L), adequate renal function (serum creatinine level 1.5 mg/dl or calculated or actual creatinine clearance 50 ml/min), and adequate hepatic function (serum bilirubin level 1.0 mg/dl and aspartate aminotransferase [AST] level 2.5 times the upper limit of normal [ULN] if the alkaline phosphatase [AP] level was the ULN; the AP level could be no more than 4 times the ULN; otherwise, the AST level had to be 1.5 times the ULN and the AP level had to be 2.5 times the ULN). Although previous radiation treatment was permitted, all chemotherapy or radiation was required to be completed 4 weeks before study entry. Patients were ineligible for this trial if they had previous exposure to docetaxel or topotecan, symptomatic brain metastasis, serious infectious diseases, or active concurrent malignancies. They were also ineligible if they were lactating, pregnant, or wished to become pregnant, or if they had a history of drug allergy or psychiatric or medical problems severe enough to prevent compliance with the protocol. Patients with no history of previous therapy were eligible for this trial only if they were not eligible for protocols of higher priority. All patients entering the current study were informed of the investigational nature of the treatment and its potential adverse effects and were required to provide written informed consent. The University of Texas M. D. Anderson Cancer Center (Houston, TX) institutional review board approved this trial. Dosage and Drug Administration Docetaxel (Taxotere; Aventis, Bridgewater, NJ) was supplied as a concentrated sterile solution (40 mg of docetaxel/ml in polysorbate 80). The appropriate amount of drug was reconstituted in 250 ml of 5% dextrose solution or 0.9% saline solution, for a final solution concentration of mg docetaxel/ml. To prevent anaphylactic or fluid retention reactions to docetaxel, all patients received premedication with 8 mg of dexamethasone twice daily beginning the day before each treatment cycle for 3 days. Docetaxel was

3 2242 CANCER May 15, 2004 / Volume 100 / Number 10 TABLE 1 Dose Levels Dose level Docetaxel (Day 1) Dose (mg/m 2 ) Topotecan (Days 1 3) Total no. of patients treated at this dose level Total no. of courses administered intravenously as a 1-hour infusion on Day 1 of each cycle. Topotecan (Hycamptin; Smith- Kline Beecham Pharmaceuticals, Philadelphia, PA) was then administered as a 0.5-hour infusion on Days 1 3 of each cycle. Cycles were repeated every 21 days as long as adequate hematologic function was present and nonhematologic toxicities had resolved to Grade 1 or less. To determine the MTD of the drugs in combination, at least three patients were to be treated at each dose level. Docetaxel was administered on Day 1 and topotecan was administered on Days 1 3. Dose levels are listed in Table 1. The initial cohort was treated at dose level 0. G-CSF support with 5- g/kg subcutaneous injections was initiated on Day 4 and continued until a neutrophil nadir occurred and the absolute granulocyte count recovered to 2000/ L. Dose Escalation Procedure The current study was designed to escalate the doses of both docetaxel and topotecan until the MTD was reached (Table 1). Toxicities were graded according to the National Cancer Institute s Common Toxicity Criteria for Adverse Events (version 2.0). DLT was defined as febrile neutropenia (fever of 38.5 C with an absolute neutrophil count [ANC] 1000/ L), Grade 4 neutropenia (ANC 500/ L) for 7 days duration, Grade 4 thrombocytopenia, or Grade 3 or 4 nonhematologic toxicity (excluding alopecia). The following dose escalation scheme was planned. For example, if the first cohort of three patients did not experience DLT in the first cycle, the next cohort began treatment at the next higher dose level. Each patient cohort was monitored for DLT for 3 weeks before any patient received additional treatment at the next dose level. If one patient in the cohort experienced DLT, an additional three patients were enrolled at that dose level. If only one of six patients enrolled at the same dose level experienced a DLT, the next patient cohort would be started at the next higher dose level. The MTD was defined as the dose level that caused a DLT in two of six patients or the dose level immediately below the one that caused a DLT in three or more patients. If hepatic function was compromised (i.e., serum bilirubin concentration greater than the ULN and AP and AST concentrations 5 times the ULN), therapy was withheld for 3 weeks until recovery occurred. Once the hepatic function was normalized, docetaxel was readministered but with a 25% dose reduction. If no recovery of hepatic function occurred within 3 weeks, patients were removed from the trial. When there was less severe hepatic toxicity (bilirubin level the ULN, AP concentration 5 times the ULN, and AST concentration times the ULN), the dose of docetaxel was reduced by 25% in the next cycle of treatment. Any patient who experienced Grade 3 or 4 neurotoxicity, symptomatic fluid retention, or anaphylaxis was removed from the protocol. Patient Evaluation Pretreatment evaluations consisted of a detailed medical history, a physical examination including assessment of performance status (according to Zubrod criteria), baseline radiography obtained within 28 days of registration, and laboratory testing performed within 7 days of registration. Routine laboratory tests included a complete blood count (CBC) with differential; a platelet count; concentrations of albumin, calcium, electrolytes, blood urea nitrogen (BUN), creatinine, AP, total bilirubin, lactate dehydrogenase (LDH), and AST concentrations; and a pregnancy test (serum or urine) for women of childbearing potential. While receiving chemotherapy, patients were monitored at least once weekly with a CBC with differential and a platelet count. Before every cycle of chemotherapy, measurement of serum levels of sodium, potassium, BUN, creatinine, AP, LDH, AST, and total bilirubin concentrations was performed and a physical examination was completed. All relevant information regarding drug dosages, tumor response, laboratory examinations, and treatment-related toxicities also was recorded before each cycle of therapy. If evaluable or measurable disease was present on a patient s previous chest radiograph, another film was obtained before each cycle. Otherwise, radiographic images were repeated every three cycles to evaluate the disease response. Response and Toxicity Criteria Objective radiographic responses were classified according to the World Health Organization bidimensional criteria as a complete (CR), partial (PR), or minor response, stable disease (SD), or as progressive disease (PD). 28 Survival duration was calculated from

4 Docetaxel and Topotecan for Solid Tumors/Tsao et al TABLE 2 Patient and Tumor Characteristics Characteristics No. of patients Total 11 Males 9 Females 2 Race White 7 Hispanic 2 African American 1 Asian 1 ECOG performance status Age Mean 57.5 yrs Median (range) 56 yr (50 69 yrs) No. of patients with previous chemotherapy One regimen 10 No. of patients with previous radiation 7 No. of patients with previous immunotherapy 1 No. of patients with previous surgical resection 4 Tumor types Adenocarcinoma of the lung 2 Nonsmall cell lung carcinoma 1 Mesothelioma, epithelial 1 Nasopharyngeal carcinoma 2 Small cell carcinoma of the lung 2 Squamous cell carcinoma of the head, neck, or skin 3 ECOG: Eastern Cooperative Oncology Group. the first day of treatment until the date of death or last contact with the patient. Patients were removed from the trial in the event of unmanageable toxicity, serious abnormalities in laboratory values, or PD, or at the discretion of the treating physician. RESULTS Patient Characteristics Eleven patients with advanced-stage solid tumors were enrolled between July 1998 and January 1999 and they received 46 cycles of chemotherapy. Ten of the 11 patients were evaluable for response. The baseline characteristics of the patients and their tumor types are listed in Table 2. Treatment Patients received a median of three cycles of therapy (range, one to nine cycles). Thirteen courses of chemotherapy were delivered at dose level 0, 32 courses at dose level 1, and 1 course at dose level 2 (Table 1). Three patients initially received therapy at dose level 0, seven patients at dose level 1, and one patient at dose level 2. Two patients required dose reductions after the first cycle of therapy, one of whom required TABLE 3 Hematologic Toxicity a Toxic effects No. of patients by dose level (no. of courses) Grade 4 neutropenia 2 (4) 8 (23) 1 (1) Neutropenia fever 0 2 (2) 0 Grade 3/4 anemia Grade 3/4 thrombocytopenia 1 (1) 2 (8) 0 Grade 5 (death) 1 b /1 0 0 a Data are expressed as the number of patients (number of courses). b Febrile neutropenic death. an additional dose reduction after the second cycle of therapy. Evaluation of Toxicity Eleven patients were evaluable for toxicity. The first cohort of three patients tolerated dose level 0 without experiencing a DLT so we treated the next three patients at dose level 1. Because one of them experienced febrile neutropenia, we treated an additional three patients at this dose level and did not observe further DLTs. Therefore, the next cohort was treated at dose level 2. After one patient received the first cycle of chemotherapy at dose level 2, the patient who had experienced febrile neutropenia at dose level 1 was treated with a second cycle of therapy at dose level 0. Unfortunately, this patient developed neutropenic sepsis and subsequently died. Because of concerns regarding myelosuppressive toxicity, the patient who had received initial therapy at dose level 2 received his second treatment at dose level 1. In addition, Patient 11 was being evaluated for the trial at this time and was entered at dose level 1, summing to a total of seven patients in this cohort. Only one further episode of neutropenic fever was observed at dose level 1, occurring during the ninth cycle of therapy. Grade 4 neutropenia occurred in 72% of the cycles at this dose level. Given this finding and the one treatment-related death, dose level 1 was declared the MTD. The most common toxicity from this regimen was neutropenia (Table 3). Grade 4 neutropenia was experienced by 9 of the 11 patients. Only two of five patients developed Grade 4 neutropenia at dose level 0. However, all patients at dose levels 1 and 2 experienced Grade 4 neutropenia. Thrombocytopenia was less common. Grade 4 thrombocytopenia was observed in the patient who died of neutropenic sepsis. Two of eight patients at dose level 1 developed Grade 3 thrombocytopenia.

5 2244 CANCER May 15, 2004 / Volume 100 / Number 10 TABLE 4 Nonhematologic Toxicity Toxic effect a Grade 1 Grade 2 Grade 3 Arthralgia 3 (7) 1 (1) 0 Cough 2 (6) 2 (2) 0 Edema 5 (8) 0 0 Fatigue 6 (13) 3 (5) 0 Infection 0 1 (1) 2 (2) Nausea 4 (9) 1 (2) 1 (1) Sensory neuropathy 3 (13) 0 0 Emesis 3 (9) 1 (3) 0 a Toxic effects experienced by two or more patients, expressed as the number of patients (number of courses). At all doses, the most prevalent nonhematologic toxic effects were fatigue, edema, and nausea/emesis (Table 4). No Grade 4 nonhematologic toxicities were observed nor were episodes of docetaxel hypersensitivity or anaphylaxis. Evaluation of Response Tumors in three patients responded to the treatment regimen, with one CR and two PRs. One additional patient had SD and six patients had PD. The patients who responded or had disease stabilization with therapy received additional therapy. Two patients received nine cycles and two other patients received six cycles of treatment. The responses were observed in the two patients with nasopharyngeal carcinoma (one CR and one PR) and in one of the patients with SCLC (one PR). The response durations were 24 weeks, 29 weeks, and 244 weeks, respectively. The two patients with nasopharyngeal carcinoma were alive at the time of last follow-up at 241 weeks and 244 weeks, respectively, one of whom remained in complete disease remission. Disease was stable for 78 weeks in one patient with squamous cell skin carcinoma. In the two responding patients with nasopharyngeal carcinoma, both received neoadjuvant therapy with cisplatin and 5-fluorouracil (5-FU) and radiotherapy as their primary treatment. One patient with T4N3 disease progressed during chemotherapy treatment and received definitive radiotherapy followed by surgical salvage of cervical lymph nodes. Three years later, the patient experienced pulmonary metastases and was enrolled on our protocol. The second patient with nasopharyngeal carcinoma (T4N2) received neoadjuvant cisplatin and 5-FU followed by concomitant chemoradiotherapy. This patient experienced local disease recurrence 2 years later before beginning treatment on our trial. The responding patient with SCLC was treated with four cycles of carboplatin and etoposide with a PR before developing brain metastasis. She was treated with whole-brain and chest radiotherapy. Disease progression in the liver prompted protocol enrollment. The patient with skin squamous cell carcinoma was treated with surgical resection and adjuvant interferon and 13-cis retinoic acid before multifocal cutaneous recurrent disease was identified. DISCUSSION Based on promising preclinical and clinical data, we evaluated the combination of docetaxel and topotecan in a Phase I study. As expected, the DLT was Grade 4 neutropenia with fever. Although this toxic effect was experienced in only 3 of 32 courses at the MTD, 1 patient died of neutropenic infection and Grade 4 neutropenia was observed uniformly at this dose level. Based on these results, we determined the MTD for this regimen to be 75 mg/m 2 of docetaxel on Day 1 and 1.4 mg/m 2 of topotecan on Days 1 3 with G-CSF support. Previous studies have evaluated the sequence of administration of this drug regimen. Zamboni et al. 36 reported that giving topotecan on Days 1 4 and docetaxel on Day 4 led to a 50% decrease in docetaxel clearance and a subsequent increase in neutropenia. Other hematologic toxicities, such as thrombocytopenia, were not affected. In this pharmacokinetic study, the dose of docetaxel was escalated on alternating days (1 or 4) and 0.75 mg/m 2 of topotecan was given on Days 1 4 of each cycle, with G-CSF support. The MTD was defined as 80 mg/m 2 of docetaxel given on Day 1 and 0.75 mg/m 2 of topotecan given on Days 1 4 as reported by Tkaczuk et al. 35 The current study suggested that topotecan inhibits the CYP3A4 metabolism of docetaxel, but no effect of docetaxel on topotecan clearance was observed. Although we did not study the latter effect, we administered docetaxel only on Day 1 of each cycle, which should minimize any adverse effect on topotecan clearance. The total MTD of topotecan that we defined with the 3-day schedule (4.2 mg) is also higher than that used in the trial by Zamboni et al. (3 mg). 36 The results of the current study demonstrated that the administration of docetaxel and topotecan with G-CSF support is a feasible regimen in patients with advanced-stage solid tumors. This combination regimen was generally well tolerated and showed promising activity in patients with nasopharyngeal and SCLC. At nearly 5 years from study enrollment, 1 patient with nasopharyngeal carcinoma remained in complete disease remission. Further studies are clearly warranted to assess the efficacy of this combination.

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