Phase I/II Study of Weekly Irinotecan and Paclitaxel in Patients With SCLC

Phase I/II Study of Weekly Irinotecan and Paclitaxel in Patients With SCLC

ABSTRACT: This phase I/II nonrandomized, open-label study was designed to assess the safety and benefit of sequencing irinotecan (Camptosar, CPT-11) plus paclitaxel (Taxol) immediately after cisplatin (Platinol)/etoposide (VePesid, VP-16) or carboplatin (Paraplatin)/etoposide in patients with extensive small-cell lung cancer (SCLC). Ten patients were evaluable in phase I; all had previously been treated with cisplatin and etoposide, and five of the 10 had also previously received carboplatin and paclitaxel. All 10 patients were given a fixed dose of irinotecan (60 mg/m²) and escalating doses of paclitaxel weekly for 3 weeks. Three patients had grade 4 toxicities, one at the lowest dose level of paclitaxel (15 mg/m²). Two patients had grade 3 toxicities. The dose-limiting toxicity occurred at the 60 mg/m² paclitaxel dose level, when the performance status of both patients in that group decreased to 60 (Karnofsky scale). Two patients had progressive disease after 1 month of treatment and did not receive cycle 2. Three of seven patients evaluable for response had complete remissions. A fourth patient had resolution of lymphangitic metastases and resolution of a partial small bowel obstruction but did not have measurable disease. The fifth patient had a partial remission. The ongoing phase II portion of the study is restricted to previously untreated patients who will receive at least one cycle of either cisplatin or carboplatin in combination with etoposide followed by irinotecan at 60 mg/m² and paclitaxel at 50 mg/m² dosed once weekly for 3 weeks. [ONCOLOGY 14(Suppl 5):63-66, 2000]


European and American studies over the past 10 years have shown that the net benefit of the change to newer platinum (cisplatin [Platinol], carboplatin [Paraplatin]) and etoposide (VePesid, VP-16) combinations in the treatment of small-cell lung cancer (SCLC) is only a 1-month improvement in median survival.[1,2] Moreover, early mortality is increasing among patients given higher doses of newer chemotherapeutic agents to treat extensive disease.[3,4] Although there is continuing enthusiasm for regimens in which platinum and etoposide are combined with paclitaxel (Taxol), a recurring problem in the treatment of extensive-disease SCLC (ED-SCLC) is finding a regimen that provides increased efficacy as measured by a complete remission rate of 25% or greater, an overall response rate of 75% or more, median survival over 11 months, and greater tolerability, defined as less than 35% treatment-associated grade 3/4 toxicities.

Rapid Sequencing

We have studied the serial responses of patients with SCLC who have been treated with CAV (cyclophosphamide/Adriamycin [doxorubicin]/vincristine) as well as cisplatin and etoposide given for two courses. With either treatment, the median percentage of tumor shrinkage with the first course was 56%. By the second course, significant chemoresistance was evident, even among patients who initially had a good response. A diminishing response to sequential courses of chemotherapy has likewise been observed in a randomized study of patients with ED-SCLC by Shevlin et al[5] who compared the efficacy of three vs six courses of chemotherapy. No additional survival benefit resulted from treatment after the first three courses were concluded. Similar results were reported by Bleehen et al in another randomized study in this patient population.[6] Collectively, these data provide evidence that the first three courses of chemotherapy are the most important, and that even an initially effective regimen can be improved upon by substituting a second, equally effective regimen by at least the third course of treatment.

Integration of New Treatments

When the regimen is changed after course 2 for SCLC patients with extensive disease who respond well to the initial treatment and after course 1 for poor responders, the new regimen might include a platinum compound (cisplatin or carboplatin) combined with etoposide followed by a topoisomerase-I inhibitor and a taxane. Arguably, other effective combinations could include a taxane and a topoisomerase-II inhibitor followed by a platin and topoisomerase-I inhibitor, but in view of the wide acceptance of the platin plus etoposide combination, it is easier to gain acceptance of this regimen for the initial treatment (course 1 and 2), to be followed by a topoisomerase-I inhibitor plus a taxane.

The need for new combinations that will improve the efficacy of chemotherapy in SCLC without compromising safety is evident. To that end, we have undertaken a study that incorporates weekly dosing and rapid sequencing of the irinotecan and paclitaxel doublet following induction therapy with a platinum and etoposide combination.

The response rates of both irinotecan and paclitaxel in patients with extensive disease previously treated with platinum and etoposide indicate that these two agents deserve to be studied in combination in this population. In addition, as shown in previous phase I/II studies, the combination of irinotecan at a dose of 60 mg/m² and cisplatin is well tolerated. Further, data confirming the efficacy and safety of paclitaxel given once per week suggest that a weekly treatment schedule would allow an optimal response to treatment with the irinotecan and paclitaxel doublet with a tolerable toxicity profile.[7]

Phase I Study

The first phase of our nonrandomized, open-label phase I/II study (1998-1999)[8] was designed to define the maximum tolerated dose of paclitaxel when combined with a minimum fixed dose of irinotecan in the treatment of extensive disease SCLC. Assessment of treatment response was a secondary objective. Patients were eligible provided they had a diagnosis of small-cell anaplastic carcinoma of the lung. Patients either had relapsed from previous treatment without receiving subsequent salvage chemotherapy or were newly diagnosed and pretreated with at least one induction cycle consisting of cisplatin (administered at a dose of 80 mg/m2 given on day 1) and etoposide (administered at a dose of 100 mg/m² on days 1, 2, and 3) every 3 weeks for two cycles. All patients received a fixed dose of irinotecan (60 mg/m²) as a 45-minute infusion and paclitaxel at doses escalating from 15 (dose level 1) to 30 (dose level 2) to 50 (dose level 3) and finally to 60 mg/m² (dose level 4). Both drugs were given weekly on days 1, 8, and 15 of the first month of treatment and on days 28, 35, and 42 of the second. No patient was entered at more than one paclitaxel dose level; routine use of growth factors was not allowed. All patients entered into the study were at least 18 years of age and all were required to provide informed consent.


Ten of the 19 patients entered into the study were considered evaluable for toxicity and response. All had previously been treated with cisplatin and etoposide. Five patients had also received carboplatin and paclitaxel. Two patients were evaluable for toxicity at dose level 1, three patients each at dose levels 2 and 3, and two patients at dose level 4. Two patients had evidence of progressive disease after 1 month of treatment and did not receive cycle 2.


There were two patients who died on the study: one had a sudden demise related to acute shortness of breath unassociated with other toxicity; the second died of sepsis associated with leukopenia.

Four patients had grade 3/4 toxicities (one patient had both grade 3 and 4 toxicities) (Table 1).

The dose-limiting toxicity occurred at level 4 (paclitaxel 60 mg/m²) when the Karnofsky performance status of both patients in the treatment group declined to 60; thereafter the maximum tolerated dose of paclitaxel was defined as 50 mg/m², and that was the dose of paclitaxel subsequently given in the phase II portion of the study.


Complete remissions were achieved by three of seven patients evaluable for response. A fourth patient had resolution of lymphangitic metastases and of a small bowel obstruction. A fifth patient had a partial remission. Responses were seen in patients previously treated with paclitaxel. One patient achieved a complete response with the study regimen, even though the weekly dose of paclitaxel was only 15 mg/m².

Phase II Study

The second phase of our study is currently underway. The efficacy parameters include overall response rate (³ 75%), complete remission rate (³ 25%), median survival (³ 12 months), and toxicity (< 40% grade 3/4). Entry is restricted to previously untreated patients with a histologic diagnosis of ED-SCLC who will receive at least one cycle of either cisplatin or carboplatin plus etoposide before initiation of the study treatment. In addition, patients must be at least 18 years of age; have a performance status of 0 to 2 or ³ 70 (Karnofsky); and adequate hematologic, renal, hepatic, and cardiovascular function. All patients must give informed consent.

While they may not receive any other investigational medicines concomitantly, patients previously treated with radiation therapy or chemotherapy for other malignancies are not excluded, if the previous treatment was completed at least 12 months before entering this study and the patients are free of any previous malignancy. Prospective patients are excluded, if they have an active or uncontrolled chronic disease or infection, severe malnutrition, chronic diarrhea or intractable emesis, evidence of cardiovascular disease, or active concurrent cancer. All patients of reproductive potential are refused unless they agree to an effective contraceptive method. All eligible premenopausal women with childbearing potential must have a negative pregnancy test at entry, and must not breastfeed while participating in the study.

All registered patients receive either of the following induction regimens 3 days per week every 3 weeks for one or two cycles: cisplatin (60 to 80 mg/m² IV) and etoposide (60 to 120 mg/m² IV), or carboplatin (area-under-curve [AUC] 5 or 6 IV) and etoposide (60 to 120 mg/m² IV). After completing the induction therapy, patient response is assessed by computerized tomography (CT) scan, after which two cycles of study medication are given weekly for 3 of every 4 weeks: irinotecan (60 mg/m² IV) and paclitaxel (50 mg/m² IV). Paclitaxel is given first by 30-minute infusion followed by irinotecan given by 45-minute infusion. Dose modifications, dose omissions, antibiotic therapy, and G-CSF support are instituted based on neutrophil counts (Tables 2, 3, 4, 5).

Patient Accrual

Fifteen patients will initially be entered in phase II; if one or more responses are observed in the first group of patients, another 38 patients will be accrued. Results of studies incorporating triplet combinations of platinum and etoposide with either irinotecan or paclitaxel may ultimately demonstrate that the standard treatment of cisplatin and etoposide that we use for reference may need to be replaced. However, the high response rate and the safety of our current regimen, as demonstrated in the phase I portion of the study, suggest that it may be a valid treatment option for newly diagnosed patients with limited or extensive SCLC.


1. Chute JP, Venzon DJ, Hankins L, et al: Outcome of patients with small-cell lung cancer during 20 years of clinical research at the US National Cancer Institute. Mayo Clin Proc 72:901-912, 1997.

2. Lassen UN, Hirsch FR, Østerlind K, et al: Outcome of combination chemotherapy in extensive stage small-cell lung cancer: Any treatment related progress? Lung Cancer 20:151-160, 1998.

3. Lassen UN, Østerlind K, Hirsch FR, et al: Early death during chemotherapy in patients with small-cell lung cancer: Derivation of a prognostic index for toxic death and progression. Br J Cancer 79:515-519, 1999.

4. Murray N, Livingston R, Shepherd F, et al: A randomized study of CODE plus thoracic irradiation versus alternating CAV/EP for extensive-stage small-cell lung cancer (ESCLC): An Intergroup study of the National Cancer Institute of Canada and the Southwest Oncology Group (abstract). Lung Cancer 18:6, 1997.

5. Shevin PM, Stead ML, Brown JM, et al: A randomized trial of three versus six courses of etoposide, ifosfamide, mesna and vincristine in small-cell lung cancer. Lung Cancer 18(suppl 1):8, 1997.

6. Bleehen NM, Girling DJ, Machin D, et al: A randomised trial of three or six courses of etoposide/cyclophosphamide/methotrexate and vincristine or six courses of etoposide and ifosfamide in small-cell lung cancer (SCLC) I: Survival and prognostic factors. Medical Research Council Lung Cancer Working Party. Br J Cancer 68:1150-1156, 1993.

7. Akerley W, Choy H, Safran H, et al: Weekly paclitaxel—marked activity, diminished toxicity and platelet stimulating effect. Lung Cancer 18:19-20, 1997.

8. Rushing DA: Phase I study of the combination of irinotecan (CPT-11) and paclitaxel (Taxol) in previously treated patients (pts) with small-cell carcinoma of the lung (SCCL) (abstract 1867). Proc Am Soc Clin Oncol 18:484a, 1999.

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