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© 2001 American Society for Clinical Oncology Phase I Trial of the Combination of Irinotecan, Paclitaxel, and Carboplatin in Patients With Advanced Non–Small-Cell Lung CancerFrom the University of North Carolina, Chapel Hill, NC; Indiana University, Indianapolis, IN; Pharmacia Corp, Peapack, NJ; University of Southern California/Norris Cancer Center, and Cedars-Sinai Medical Center, Los Angeles, CA; and Pharmacia Corp, Milan, Italy. Address reprint requests to Mark A. Socinski, MD, Director, Multidisciplinary Thoracic Oncology Program, University of North Carolina at Chapel Hill, 3009 Old Clinic Building, CB# 7305, Chapel Hill, NC 27599; email: socinski{at}med.unc.edu
PURPOSE: To determine the maximum-tolerated dose, toxicities, and dose suitable for phase II/III trials of irinotecan (CPT-11) combined with paclitaxel and carboplatin in patients with advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC were enrolled to this multicenter, phase I study. The initial regimen was paclitaxel 225 mg/m2/3 h, followed by carboplatin area under the curve (AUC) 6 over 30 minutes on day 1, and CPT-11 starting at 40 mg/m2 over 90 minutes, days 1 and 8, every 3 weeks. Dose-limiting toxicity occurred in three of seven patients. The regimen was amended, with doses reduced to paclitaxel 175 mg/m2/3 h, carboplatin AUC 5 and CPT-11 at 40 mg/m2, all on day 1 every 3 weeks. Dose escalation of CPT-11 proceeded to 80 mg/m2 then 125 mg/m2 before dose-limiting toxicities were experienced. Subsequent patients received an intermediate CPT-11 dose of 100 mg/m2. RESULTS: Thirty-three patients were enrolled; 32 patients were assessable for safety, and 31 were assessable for tumor response. The primary first-cycle dose-limiting toxicities were neutropenia and diarrhea. The most common grade 3/4 toxicity observed during all cycles was neutropenia (16 patients [50%], with six [19%] developing neutropenic fever). Objective tumor response was observed in 39% (12/31, 95% confidence interval, 22% to 58%). The median time to tumor progression was 6.8 months, median survival 11.0 months, and 1-year survival probability 0.46. CONCLUSION: CPT-11 100 mg/m2, paclitaxel 175 mg/m2, and carboplatin AUC 5 given every 3 weeks can be safely administered in patients with advanced NSCLC. Neutropenia and diarrhea are the dose-limiting toxicities. The combination shows appreciable activity, and survival data are favorable.
LUNG CANCER is the leading cause of cancer deaths in the United States in both men and women.1 Approximately 172,000 new cases and 160,000 deaths from this disease were expected in 2000. Non–small-cell lung cancer (NSCLC) accounts for approximately 75% of lung cancer cases and is associated with a 5-year survival rate for all stages of 13%. Most patients (70%) with newly diagnosed NSCLC have inoperable locally advanced or metastatic stage IIIB/IV disease at the time of diagnosis.2 As a result, systemic treatment has become standard to obtain disease control, palliate symptoms, and extend life. Cisplatin-based combination chemotherapy has been the standard of care in the treatment of advanced NSCLC.3 A recent meta-analysis showed that cisplatin-based combination chemotherapy clearly prolongs survival, and several reports also show this therapy can have a palliative effect on disease-related symptoms.4-8 The cisplatin analog, carboplatin, has also shown activity in the therapy of NSCLC9 and has been considered an attractive alternative to cisplatin for the outpatient treatment of NSCLC because of its manageable toxicity profile and ease of administration. In three randomized comparisons of the two agents used in combination chemotherapy for advanced NSCLC, there were no significant differences in response rate or survival; however, patients receiving carboplatin experienced significantly less toxicity than those treated with cisplatin.10-12 Although most earlier studies used cisplatin or carboplatin in conjunction with a plant alkaloid, such as etoposide,10,13 several new agents, including the antimitotic agent, paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ), have been considered for combination with platinum as treatment for NSCLC. Both single-agent studies of paclitaxel14-17 and trials using paclitaxel in combination with carboplatin have demonstrated promising activity.18-21 In a phase I/II study at the University of Southern California Norris Cancer Center, a 3-hour infusion of paclitaxel 225 mg/m2 combined with an area under the curve (AUC) of 6 for carboplatin given every 3 weeks was found to be a well-tolerated and highly active regimen in this disease.22,23 Dose-limiting toxicity (DLT) consisted primarily of mild to moderate arthralgias/myalgias or cumulative sensory neuropathy. Myelosuppression was mild and rarely dose-limiting. These results suggested that incorporation of a third agent, such as irinotecan (CPT-11, Camptosar; Pharmacia Corp, Peapack, NJ), might be possible. CPT-11 is a water-soluble prodrug that is metabolized in vivo to an active cytotoxic metabolite, SN-38. SN-38 binds to topoisomerase I, an enzyme that relieves torsional strain in DNA during DNA replication or transcription and stabilizes topoisomerase I in a complex with DNA. During cell division, DNA replication forks collide with these enzyme-DNA complexes, resulting in double-stranded DNA breaks and subsequent programmed cell death.24,25 Several clinical studies of CPT-11 alone or CPT-11 in combination with other chemotherapeutic agents have documented promising activity in NSCLC.26-34 The most common combination used was cisplatin given in a dose of 60 to 80 mg/m2 on day 1 of each cycle of treatment, with CPT-11 30 to 100 mg/m2 given for 3 consecutive weeks (days 1, 8, and 15) every 4 weeks.31-33 The primary DLTs of CPT-11 in these trials were diarrhea and neutropenia. On the basis of the mechanistic differences in the actions of carboplatin, paclitaxel, and CPT-11, their demonstrated antitumor activity in NSCLC, and dosing information derived from prior studies, this phase I dose-escalation trial was designed. The specific objectives of the trial were to determine the maximum-tolerated dose (MTD) and the dose suitable for phase II trials of CPT-11 combined with fixed doses of paclitaxel and carboplatin, to evaluate the toxicities of this regimen, and to obtain preliminary information regarding the efficacy of the triplet combination in patients with NSCLC.
Patient Selection Adult patients were enrolled onto the study if they met the following criteria: (1) a histologic or cytologic diagnosis of NSCLC; (2) stage IIIB (malignant pleural/pericardial effusions or supraclavicular adenopathy) or IV disease (patients with recurrent disease that was stage IIIB or IV on restaging after surgery were eligible); (3) performance status of 0, 1, or 2 on the Southwest Oncology Group (SWOG) scale with a predicted life expectancy of at least 12 weeks; (4) measurable or nonmeasurable but assessable disease, at least one area of which had not been subject to prior irradiation; (5) no prior chemotherapy; (6) any previous radiation therapy had been completed more than 3 weeks before enrollment and the patient had recovered from any adverse effects; (7) any brain metastases had been treated with radiation and/or surgery with radiographic and clinical evidence of improvement; and (8) adequate organ function as documented by a WBC count  3.5 x 109/L, an absolute neutrophil count 1.5 x 109/L, platelet count 100 x 109/L, hemoglobin 9 g/dL; total serum bilirubin  1.25 the institutional upper limit of normal, hepatic transaminase less than 3 x the institutional upper limit of normal, and a calculated creatinine clearance 50 mL/min.35 Patients were not eligible for study enrollment if they had any of the following: (1) active or uncontrolled infection; (2) significant cardiovascular disease (uncontrolled hypertension, unstable angina, active congestive heart failure, myocardial infarction within the previous year, or uncontrolled serious arrhythmia); (3) prior malignancies, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient had been disease-free for 5 years; (4) evidence of peripheral neuropathy; (5) a history of seizures or use of phenytoin or phenobarbital prophylaxis; (6) pneumonitis or uncontrolled large pleural effusions; (7) uncontrolled diabetes mellitus; or (8) pregnancy, lactation, or refusal to use effective contraception. All study candidates were required to provide written informed consent as approved by local institutional review boards before initiation of any study procedures.
Treatment Plan As described in Fig 1, the initial schedule of drug administration (regimen 1) consisted of day 1 treatment with fixed doses of paclitaxel (225 mg/m2) and carboplatin (AUC of 6).36 CPT-11 was administered at a starting dose level of 40 mg/m2, with treatment to be given on days 1 and 8. After three of the first seven patients developed DLT with regimen 1, the protocol was amended; in regimen 2, patients received lower starting doses of paclitaxel (175 mg/m2) and carboplatin (AUC of 5) with the same infusion times and sequence of administration. The CPT-11 schedule was altered to give the 90-minute infusion only on day 1 at planned starting dose levels of 40, 80, and 125 mg/m2. In both regimens, treatment continued at planned intervals of 3 weeks for six cycles or until patients had disease progression, developed unacceptable drug toxicity not responding to dosage modification or supportive therapy, or withdrew consent.
Prevention of paclitaxel reactions consisted of dexamethasone 20 mg orally on the evening before chemotherapy and again on the morning of treatment, and IV diphenhydramine 50 mg and either cimetidine 300 mg or ranitidine 50 mg 30 minutes before paclitaxel. Cholinergic symptoms occurring during or shortly after receiving CPT-11 could be treated with IV or subcutaneous atropine 0.25 to 1 mg.37,38 IV administration of dexamethasone 10 mg, either ondansetron 32 mg or granisetron 10 µg/kg, and lorazepam 1 to 2 mg were suggested as components of the pretreatment antiemetic regimen. Oral dexamethasone 4 mg every 12 hours for eight doses was used prophylactically if grade 2 arthralgias/myalgias occurred, with the addition of ibuprofen 600 to 800 mg four times per day as needed. Patients were instructed to begin taking loperamide at the first sign of diarrhea that occurred more than 12 hours after CPT-11 administration. Prophylactic colony-stimulating factor use was not allowed in the first course and was discouraged during subsequent courses of treatment.
Dose Escalation and Definition of MTD and DLT
Toxicities were graded using the National Cancer Institute common toxicity criteria, version 1.0. DLT was defined as first-course neutropenic fever (
Dose Modifications
Patient Evaluation Before treatment, patients underwent medical history and physical examination, ECG, laboratory evaluation (complete blood cell count, serum chemistries, and pregnancy testing for women of childbearing potential), and baseline tumor measurements. Before each 3-week course, patients underwent a medical history and physical examination and serum chemistries were obtained. Assessments before treatment administration and during rest-weeks included complete blood cell count and medical history.
Patients were to have repeated tumor evaluations at least every 6 weeks. Tumor response was assessed according to modified World Health Organization criteria (ie, measurable disease, nonmeasurable but assessable disease, nonassessable disease; complete response, partial response, stable disease [including the subset of minor response, comprising
Statistics
Patient Characteristics A total of 33 patients were enrolled between November 5, 1996, and December 15, 1997, and the data cutoff date was set at November 1999. One patient experienced grade 3/4 hypersensitivity to paclitaxel before receiving any carboplatin or CPT-11 and was discontinued from protocol therapy. As a result, 32 patients were considered fully assessable for safety associated with use of all three chemotherapy agents. One additional patient did not have measurable disease. As a consequence, 31 patients were assessable for tumor response. Among the 32 patients who could be assessed for safety ( Table 2), the median age was 56 years and the population was balanced by sex. Performance status was relatively good for most patients; 29 (90.6%) had a SWOG performance score of 0 or 1, and 3 (9.4%) had a performance status of 2. The majority of patients (68.8%) had stage IV disease. None of the patients had undergone prior chemotherapy. Eight patients (25%) had undergone an attempt at primary surgical resection. Six (19%) had received prior radiotherapy; the site of irradiation was the chest in four patients and the brain in two patients.
Multiple sites of disease were measured in 21 (67.7%) of the 31 patients assessable for response. The predominant site of measurable disease was the lung.
Dose Escalation and Determination of First-Course MTD and DLT
Seven patients were enrolled to receive 40 mg/m2 of CPT-11 on days 1 and 8 of the first cycle. Three of these patients experienced DLTs, including neutropenic fever and grade 4 diarrhea, and a paclitaxel-related grade 3 neuropathy. In addition, three of seven patients required dose reduction or omission on day 8 during cycle 1. At this point, the study was amended because the first dose level with regimen 1 was considered to exceed the MTD. The initial premise, that CPT-11 could be added to full-dose carboplatin and paclitaxel, was felt to be incorrect. It was decided that the doses of carboplatin and paclitaxel should be lowered and that CPT-11 treatment should be given only on day 1. At the first dose level (40 mg/m2) of regimen 2, three patients were initially enrolled. One patient, while not experiencing DLT, died of unknown causes during the second course. During expansion of the cohort, several patients presented simultaneously at different sites, and so a total of nine patients were accrued to this dose level. One patient had neutropenic fever and another had grade 4 diarrhea. It was decided that this dose level was tolerable, because only two of nine patients (ie, fewer than 33%) experienced first-course DLT. Five patients were then treated at the second CPT-11 dose level (80 mg/m2). None of these five patients experienced DLT. Escalation to the next CPT-11 dose level (125 mg/m2) in regimen 2 proceeded; four patients were initially enrolled, and one of them developed grade 4 diarrhea. As a consequence, additional patients were added. Because of rapid accrual at the study sites, four additional patients were included in this cohort. Among these patients, one experienced neutropenic fever/infection and one experienced grade 4 diarrhea. Because three of eight (ie, greater than 33%) patients at this dose level experienced DLT, it was felt that the MTD had been exceeded. The decision was made to enroll patients at an intermediate CPT-11 dose level of 100 mg/m2. Three patients were accrued and none experienced DLT. As a consequence, this dose level was felt to represent the MTD and the recommended phase II dose level for future phase II trials. The DLTs observed in this portion of the study were primarily related to neutropenia and diarrhea. All of the patients were sufficiently recovered from any first-course toxicities by day 21 or 28 to be able to receive treatment, so protracted toxicity did not play a role in determining the MTD.
Treatment Administration and Toxicities During All Cycles of Treatment
Table 4 lists the overall incidence of grade 3/4 hematologic and nonhematologic toxicities for all patients treated on this trial. The most frequent adverse events observed were consistent with those expected in patients receiving any of the drugs individually. Grade 3/4 myelosuppressive adverse events occurring in
Two patients died within 30 days of receiving treatment on this study. Of these, one patient died at home of unknown causes and the other patient, whose death was unrelated to study medication, suffered from severe peripheral vascular disease which led to a stroke; this patient had experienced a partial tumor response at the time of his death.
Because the median age of patients in this study was 56 years, which is generally younger than NSCLC patients enrolled in most phase II/III cooperative group trials, we performed an analysis of toxicity based on age (
Efficacy Objective tumor response was observed and confirmed in 39% (12 of 31; 95% CI, 22% to 58%) of patients. Because this was a phase I trial, rigorous response confirmation was not requisite. However, in seven additional patients, objective response was observed during at least one on-study evaluation but was not confirmed 4 to 6 weeks later by a subsequent follow-up assessment. Considering both confirmed and unconfirmed responses, 19 of 31 patients were observed to have objective evidence of response (61%; 95% CI, 22% to 58%).
Best responses included three complete responses (all confirmed) and 16 partial responses (nine confirmed). Stable disease was observed in 26% of patients (eight of 31), and, of this group, two patients (7%) achieved a minor tumor response (
Median time to response was 1.4 months (range, 1.2 to 2.8 months), and median duration of response from the time of first evidence of objective response was 7.2 months (range, 2.9 to 22.2+ months). Median time to tumor progression was 6.8 months (range, 0.7 to 23.6+ months), and median survival was 11.0 months (range, 1.3 to 34.9 months). The probability of survival at 1 and 2 years was 0.46 (95% CI, 0.29 to 0.64) and 0.18 (95% CI, 0.03 to 0.34), respectively. A Kaplan-Meier survival curve for the 32 assessable patients is shown in Fig 2.
Combination chemotherapy containing a platinum has become the standard of care in the palliative treatment of advanced NSCLC.3 Platinum-based regimens have been shown to improve survival and palliate symptoms, thereby improving the overall quality of life for patients with advanced NSCLC.4-8,40 The survival gains have been real but modest, with a 2-month improvement in median survival and a 10% improvement in 1-year survival.4 Recently, several new agents with substantial single-agent activity have been developed in NSCLC. Phase III trials evaluating these new agents either alone or in combination with cisplatin have shown improved response rates, quality of life, and/or survival compared with best supportive care41-44 or cisplatin alone,45-47 confirming the therapeutic gain associated with combination therapy of advanced NSCLC. Phase II studies assessing paclitaxel combined with cisplatin48 or carboplatin18-21 have resulted in response rates ranging from 26% to 54%, with median survivals of 8.7 to 10.8 months. Phase III trials of cisplatin or carboplatin in combination with paclitaxel have yielded mixed survival results when compared with the standard regimens of either cisplatin/etoposide49,50 or cisplatin/vinorelbine.51 Based on the phase II and III data, the combination of carboplatin/paclitaxel has become a standard regimen in the treatment of advanced NSCLC.52 In a recent survey of medical oncologists in the United States, this regimen was the most widely favored option for first-line chemotherapy in all stages of NSCLC.53 CPT-11 is a topoisomerase I inhibitor with substantial activity in advanced NSCLC, either alone or in combination with cisplatin.26-34 Preclinical data suggest that the addition of CPT-11 may provide clinical benefit to the combination of carboplatin/paclitaxel. It has been hypothesized that exposing cells to a topoisomerase I inhibitor during repair of platinum-induced DNA adducts might accentuate platinum activity.54 In fact, synergistic cytotoxicity between platinum and CPT-11 has been demonstrated in cell culture studies, involving multiple cell lines and in mice bearing human lung tumor xenografts.55 Likewise, SN-38, the active metabolic of CPT-11, produced additive cytotoxicity in combination with paclitaxel in an in vitro study with an NSCLC cell line.56 Based on the rationale provided by these clinical and preclinical findings, this phase I dose-escalation trial evaluated whether CPT-11 could be added to an established regimen of carboplatin (AUC of 6) and paclitaxel (225 mg/m2) given on day 1 every 3 weeks. The original hypothesis was that addition of CPT-11 might be accomplished without any attenuation in the starting doses of the other agents. In fact, despite the moderate initial dose of CPT-11 (40 mg/m2 on days 1 and 8), excessive neutropenic complications in five of seven patients and the occurrence of grade 4 diarrhea in one patient proved that this regimen would not be tolerable. Subsequent reduction in the starting doses of paclitaxel (175 mg/m2) and carboplatin (AUC of 5) allowed safe escalation of CPT-11 to a starting dose level of 100 mg/m2, with all therapy given on day 1. Administration of day 8 CPT-11 in this second regimen was abandoned to avoid unintended day 8 dose modifications and omissions during determination of the CPT-11 MTD, to maximize any potential synergy between the agents, and to simplify the schedule. With these modifications, the CPT-11 starting dose could be escalated to 125 mg/m2 on day 1 before DLT (consisting of diarrhea and neutropenic sepsis). Evaluation of repeated courses of therapy with this modified regimen revealed it to be quite well tolerated. A median number of six cycles were administered, and delays in treatment were seen in only 20% of cycles, primarily because of neutropenia. First-cycle DLTs, when encountered during the dose escalation, consisted primarily of grade 4 neutropenia (three of 32 patients, or 9%) and grade 4 diarrhea (four of 32, or 13%). It is tempting to postulate that the toxicity results suggest the potential for clinical synergy; certainly neutropenia might be an expected complication of any of the three agents, but diarrhea is commonly only associated with CPT-11, and the occurrence of any grade 4 diarrhea at these CPT-11 dose levels is somewhat surprising. Alternatively, a pharmacologic interaction is conceivable; future testing of pharmacokinetics might shed light on any alteration in disposition of the drugs but would not necessarily reveal whether intracellular interactions were occurring. The doses of paclitaxel and carboplatin achieved in this final regimen are likely to be adequate for activity based on past studies.57 In the only trial that has addressed paclitaxel dose on the 3-hour infusion schedule in combination with carboplatin, no difference in survival was demonstrated between the 175 mg/m2 and 225 mg/m2 dose levels.57 There was a suggestion that time to progression was significantly improved (median 4.3 months for 175 mg/m2 v 6.4 months for 225 mg/m2, respectively, P = .044) for the higher dose of paclitaxel. However, our median time to progression with the addition of CPT-11 to the doublet of carboplatin and paclitaxel at 175 mg/m2 was 6.8 months. The CPT-11 dose that could be delivered on this schedule was reduced compared with that usually given when the drug is administered alone. The 100 mg/m2 starting dose is approximately one third of the 300 to 350 mg/m2 single-agent starting dose used in every-3-week regimens in patients with colorectal cancer.58,59 However, inducing potentially synergistic activity via different mechanisms, even at somewhat reduced doses, may be preferable to giving single agents alone. This hypothesis is supported by the promising antitumor activity observed in this phase I trial; 39% of patients (12 of 31) had confirmed objective responses, 22% of patients (seven of 31) had unconfirmed objective responses, and an additional 7% (two of 31) had minor responses with a reduction in tumor area of 44% and 36%, respectively. This level of activity obviously compares favorably with response rates observed in prior experience with combinations of two drugs in other uncontrolled trials. It is conceivable that such positive effects are a function of the generally good performance status among the patients participating in the study and the known activity of the paclitaxel/carboplatin combination. However, the high response rate and the median survival of 11 months are sufficiently encouraging to suggest that further study of the combination in phase II trials is warranted. In summary, this United States, multicenter, phase I trial has identified a regimen of paclitaxel 175 mg/m2, carboplatin AUC of 5, and CPT-11 100 mg/m2 that can be given every 3 weeks. DLT with this regimen is diarrhea and neutropenia. The tolerability of this three-drug regimen and evidence of activity observed in NSCLC suggest that this combination should be developed further. A phase II trial in advanced NSCLC with this regimen is ongoing to assess the safety and efficacy of this triplet combination. Potential indications might include cancers of the head and neck, esophagus, stomach, ovary, and other sites for which each of the three component agents are known to be active.
Supported in part by a grant-in-aid from Pharmacia Corp, Peapack, NJ. We thank Mary Fitzjohn and Janet Lawing for their expert assistance in the preparation of this manuscript.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
