Rationale and Dose-Finding Studies of the Combination of Irinotecan and a Taxane on a Weekly Schedule

ABSTRACT: Cisplatin (Platinol)-based chemotherapy has been the standardsystemic therapy for both non-small-cell and small-cell lung cancer for thepast 2 decades, though the efficacy and benefit remain modest. Recently, severalnovel agents have been introduced that have single-agent activity comparable tocisplatin and offer the possibility of improved therapy for lung cancer.Camptothecin and taxane derivatives are associated with both differentmechanisms of action and nonhematologic toxicities, and have demonstratedadditive or synergistic activity when used in combination in preclinicalstudies. We review pertinent clinical studies of these agents in lung cancer andpresent our experience in combining irinotecan (Camptosar, CPT-11) with taxaneson a weekly schedule in dose-finding and efficacy studies. When chemotherapy isdelivered for 4 consecutive weeks followed by a 2-week rest, hematologictoxicity is dose limiting and most prominent during weeks 3 and 4. Doseintensification is feasible if the schedule is modified so the chemotherapy isgiven on days 1 and 8, with cycles repeated every 3 weeks. The most commonnonhematologic toxicities remain asthenia, neuropathy, and diarrhea. Futurestudies will explore and better define the role of these drug combinations inthe treatment of lung cancer. [ONCOLOGY 15(Suppl 1):25-30, 2001]IntroductionCisplatin (Platinol)-based chemotherapyhas been the foundation of the treatment of lung cancer for over 2 decades.Several new classes of agents, or analogs of existing drugs, that havesingle-agent activity comparable to cisplatin have recently been introduced. Twoclasses of new drugs that have significant activity in both small-cell and non-small-celllung cancer are the camptothecins and the taxanes.

Introduction

Cisplatin (Platinol)-based chemotherapyhas been the foundation of the treatment of lung cancer for over 2 decades.Several new classes of agents, or analogs of existing drugs, that havesingle-agent activity comparable to cisplatin have recently been introduced. Twoclasses of new drugs that have significant activity in both small-cell and non-small-celllung cancer are the camptothecins and the taxanes.

Taxanes in Non-Small-CellLung Cancer

Taxanes preferentially bind to microtubules, inhibiting dynamicreorganization of the microtubular network, leading to the arrest of cells intheG2/M phase of the cell cycle.[1] Both paclitaxel (Taxol) and docetaxel(Taxotere) are drugs active against non-small-cell lung cancer, and eachproduces a single-agent response rate of approximately 20%.

The Eastern Cooperative Oncology Group (ECOG) performed arandomized study comparing cisplatin/etoposide to cisplatin/paclitaxel.[2]Patients were randomized to three arms: control (cisplatin/etoposide),paclitaxel 135 (cisplatin and paclitaxel as a 24-hour infusion at 135 mg/m² percycle), and paclitaxel 250 (cisplatin and paclitaxel as a 24-hour infusion at250 mg/m² per cycle with granulocyte colony-stimulating factor [G-CSF] support).Survival was better in both paclitaxel-containing arms than in the control arm,but the difference reached standard levels of statistical significance only ifresults of the two paclitaxel-containing groups were combined (1-year survivalof 39% vs 32%, P = .048).

Patient tolerance and preservation of quality of life werefairly comparable with the different regimens. Preliminary results of a studycomparing the combination of carboplatin (Paraplatin)/paclitaxel tocisplatin/etoposide reported comparable survival.[3] Febrile neutropeniadeveloped less frequently in the patients treated with carboplatin/paclitaxel,but myalgia and neuropathy were more common.

The Southwest Oncology Group (SWOG) has reported the preliminaryresults of a study that compared carboplatin/paclitaxel to cisplatin/vinorelbine(Navelbine).[4] No difference in survival was noted. However, fewer patientsdropped out of the carboplatin/paclitaxel arm due to toxicity, suggesting thatthis regimen was better tolerated. The ECOG has also conducted a large study(E1594) comparing four of the newer platinum-containing regimens. This studycompared the combinations of cisplatin/paclitaxel to cisplatin/gemcitabine(Gemzar) to cisplatin/docetaxel to carboplatin/paclitaxel.[5]

A total of 1,163 patients were treated, and survival wascomparable in the four arms. The median survival ranged from 7.4 to 8.2 months,and 1-year survival ranged from 31% to 36%. Taken together, these studiessuggest that platinum-containing chemotherapy regimens that include one of thenewer drugs, such as a taxane, offer advantages to regimens that contain olderagents (ie, etoposide). Whether or not there are clinically importantdifferences if a platinum drug is combined with a taxane or with another one ofthe newer drugs, such as gemcitabine, has not been established.

For patients who have received prior platinum-containingchemotherapy, docetaxel is one of the few agents that have demonstratedactivity. Shepherd and colleagues randomized previously treated patients (one ormore regimens) to docetaxel or to best supportive care.[6] Overall, bothsurvival (time to progression and median survival) and quality of life werebetter in the patients who received treatment with docetaxel.[7] A study byFossella and coworkers randomized 373 previously treated patients to docetaxel100 (docetaxel at 100 mg/m² per cycle), docetaxel 75 (docetaxel at 75mg/m² percycle), or a control arm of vinorelbine or ifosfamide (Ifex).[8] Previoustreatment with paclitaxel was permitted, and 37% of the patients had receivedthis drug as part of their prior therapy.

Based on an intention-to-treat analysis, survival at 1 year inthe docetaxel 75 group (32%) was superior to the other two arms (21% and 19% inthe docetaxel 100 and control group [P = .025 vs control], respectively). Inboth docetaxel arms progression-free survival and quality of life wereimproved.[9] An analysis attempting to adjust for the effects of poststudytreatment suggested a survival advantage for both docetaxel arms.

Taxanes in Small-CellLung Cancer

Two phase II studies have examined the role of single-agentpaclitaxel in patients with previously untreated extensive-stage small-cell lungcancer.[10,11] The ECOG reported a response rate of 34%, but life-threateninggrade 4 leukopenia occurred in 56% of the patients.[10] A second trial,conducted by the North Central Cancer Treatment Group (NCCTG), administeredpaclitaxel on a similar schedule, but with the addition of G-CSF.[11] Theresponse rate was similar (53%), and the incidence of severe leukopenia wasreduced to 14%.

One study has examined the activity of paclitaxel in patientsrefractory to chemotherapy, defined as a relapse within 3 months of thecompletion of previous therapy.[12] Nearly half of the patients enrolled in thisstudy had received prior platinum-containing chemotherapy. In 21 assessablepatients, 7 achieved a partial response, for an objective response rate of 29%.There were two early deaths and two toxic deaths in the trial, and the mediansurvival of assessable patients was 100 days. This study suggests thatpaclitaxel is a useful, active drug in the management of refractory small-celllung cancer.

When combined with cisplatin, paclitaxel has shown substantialactivity in small-cell lung cancer. A phase II study by Nair et al inchemotherapy-naive patients assessed paclitaxel at an initial dose of 135 mg/m²,later escalated to 175 mg/m², with cisplatin at 75mg/m².[13] Patients thatdeveloped progressive disease were crossed over to cisplatin and etoposide.Fifteen of 21 (71%) evaluable patients in the lower paclitaxel arm and 39 of 44(89%) evaluable patients in the higher paclitaxel arm demonstrated a response totreatment.

Docetaxel has been evaluated in small-cell lung cancer in asmall number of phase II trials. The National Cancer Institute of Canadaevaluated docetaxel in chemotherapy-naive patients with extensive disease at adose of 75 mg/m² every 3 weeks.[14] Twelve patients were evaluable for response,of which only one demonstrated a partial response (12-week duration), resultingin a disappointing response rate of 8%. A subsequent SWOG study utilized ahigher dose of docetaxel at 100 mg/m² every 3 weeks. In 46 eligible patientswith untreated extensive-stage small-cell lung cancer, a response rate of 26%,with a median survival of 9 months, was reported.[15] In 34 previously treatedpatients, a European Organization for Research and Treatment of Cancer (EORTC)study reported a response rate of 25%.[16]

Irinotecan in Non-Small-Cell Lung Cancer

In previously untreated patients, irinotecan (Camptosar, CPT-11)has demonstrated a single-agent response rate of 15% to 32%.[17] Response ratesin previously treated patients have been comparable to other chemotherapy drugsand ranged from 0% to 14%. The main toxicities were neutropenia and diarrhea.Pulmonary toxicity, presumably due to a hypersensitivity reaction, occurred in8% of patients in one phase II study.[18] Similar to the results in studies ofcolorectal cancer, both the weekly schedule of administration of irinotecan andthe single dose every 3 weeks appear to yield comparable activity and sideeffects.[17]

The combination of irinotecan and cisplatin has been reported toshow significant antitumor activity in untreated patients, with response ratesranging between 31% and 55%.[17,19,20] Dose reductions are common whenirinotecan is given on a weekly schedule and cisplatin is administered onceevery 4 weeks. Schedules in which cisplatin is given in divided doses weeklytogether with irinotecan may be better tolerated and are equally effective.[21]

Two randomized phase III studies from Japan have compared thecombination of cisplatin and irinotecan to a standard regimen in patients withpreviously untreated non-small-cell lung cancer. In the study by Masuda andcolleagues, 398 patients were randomized to cisplatin/irinotecan, irinotecanalone, or a control arm consisting of cisplatin and vindesine; 378 wereevaluable for response, survival, and toxicity.[22] In a study by Niho andcoworkers, 203 eligible patients were evaluated for responses and toxicity tocisplatin/irinotecan or cisplatin/vindesine regimens.[23] Although nodifferences in survival were detected individually in these studies, an analysisthat combined the data showed that patients treated with cisplatin/irinotecanhad a significantly better survival at 1 year than patients treated with thecontrolled regimen.[24]

Irinotecan in Small-CellLung Cancer

Irinotecan has also shown promising results in small-cell lungcancer, but has not yet been as extensively evaluated as topotecan (Hycamtin) inthis disease. In previously treated patients, response rates to irinotecan haveranged from 16% to 47%, reflecting differences in the patient populationevaluated and perhaps the schedule of drug administration.[17,25] There arelimited data on the single-agent activity of irinotecan in chemotherapy-naivepatients with small-cell lung cancer. In an early Japanese trial, Negoro andcoworkers reported a response rate of 50% in eight previously untreated patientswith small-cell lung cancer who were treated with weekly irinotecan.[26]

A recent Japanese randomized trial compared the combination ofirinotecan/cisplatin to etoposide/cisplatin in extensive-stage small-cell lungcancer.[27] The schedule of irinotecan was 60 mg/m² days 1, 8, and 15, withcisplatin at 60 mg/m² day 1, administered every 4 weeks. The study was closedwhen the second interim analysis showed a survival advantage for theirinotecan-containing arm. The overall response rate (89% vs 67%), mediansurvival time, and 1-year survival (60% vs 40%) were superior for patientstreated with the irinotecan-based chemotherapy.

Irinotecan/cisplatin also produced a lower incidence of severegrade 3/4 neutropenia and thrombocytopenia, but more treatment-related deathswere seen with this combination (four vs one). Nearly half of the patients onthe irinotecan/cisplatin arm did not receive the scheduled irinotecan on day 15due to toxicity. Confirmatory phase III trials with the combination ofirinotecan/cisplatin are being planned in the United States using both theJapanese regimen and a regimen in which the schedule is modified to irinotecanat 65 mg/m² days 1 and 8, plus cisplatin at 30mg/m² days 1 and 8, every 3weeks.

Irinotecan in CombinationWith Paclitaxel

Results of preclinical data investigating the combination of acamptothecin and a taxane have been mixed, though most studies reported anadditive or synergistic effect.[28-30] Sequencing of the chemotherapy may beimportant, with pretreatment with a low dose of a taxane capable of potentiatingthe cytotoxicity of camptothecins in a model system.[31] Based on theestablished antineoplastic activity against lung cancer as single agents,nonoverlapping nonhematologic toxicity profiles, and at least additivitydemonstrated in most preclinical models, we are investigating the combination ofirinotecan and taxane derivatives.

We completed a dose-finding study to determine the maximumtolerated dose and toxicity of irinotecan and paclitaxel when both drugs weregiven on a weekly schedule.[32] In this study we also evaluated whether thesequence of drug administration affected the elimination of irinotecan.Paclitaxel was administered at a dose of 75 mg/m² over 1 hour. The starting doseof irinotecan was 50 mg/m² over 90 minutes, and it was escalated in successivegroups of patients according to a standard phase I design. The treatment wasadministered weekly for 4 weeks followed by a rest period of 2 weeks.

Results

There were 21 patients enrolled in this trial and treated for atotal of 53 cycles. Two patients were treated at the second dose level ofirinotecan at 65 mg/m², and both developed hematologic dose-limiting toxicities.The other patients were treated with a starting dose of irinotecan at 50 mg/m²,which was declared to be the maximum tolerated dose. A total of 50 cycles weredelivered at this dose; the average number of cycles delivered was 3. Onepatient had the irinotecan dose reduced by 25% on the third cycle due to grade 2diarrhea.

Overall, the regimen was tolerated well, and toxicities werenoncumulative, with the most prominent toxicity being neutropenia. Most patientsrequired dose delays at weeks 3 and 4 because of insufficient hematologicrecovery (see Figure 1); diarrhea at week 4 caused a delay in five cycles.Overall, only 26% of the cycles were delivered within the planned 6 weeks. Inpatients that completed one or more cycles of chemotherapy, the mean actual dosedelivery/planned dose was 86%, reflecting the average delivery of thechemotherapy over 7 weeks instead of 6.

The common nonhematologic toxicities consisted of diarrhea,neuropathy, and malaise. Serious nonhematologic toxicity occurred in only 6% ofthe 50 cycles delivered at the recommended dose and consisted of nausea (2),diarrhea (1), and fatigue (1). Among patients in whom the sequence of drugadministration was reversed on cycle 2, there was no difference in thepharmacokinetics of irinotecan, nor were there differences in the observed sideeffects. This suggested that on this schedule, there were no significant druginteractions between irinotecan and paclitaxel. In contrast, other investigatorsfound that irinotecan was more slowly eliminated from the plasma whenadministered before paclitaxel, compared to when irinotecan was given alone.[33]

One patient with metastatic cholangiocarcinoma refractory tofluorouracil (5-FU) chemotherapy achieved a partial response that lasted 26weeks. Seventeen patients had stabilization of disease that lasted ³ 3 months,and five of these patients achieved stabilization for > 6 months. All threepatients with non-small-cell lung cancer had stabilization of their diseasethat lasted 11, 16, and 25 weeks. The median overall survival for all patientsevaluated was 22 weeks.

Phase II Study in Non-Small-Cell Lung Cancer

In designing the phase II study protocol, a few modificationswere made to the treatment design. Based on the pattern of hematologic toxicity,the regimen was modified to a 2 weeks on, 1 week off schedule, and theneutrophil count required for treatment within a cycle was reduced from1,500/µL to 1,200/µL. In addition, the sequence of paclitaxel followed byirinotecan was used for all treatment cycles. In anticipation that this schedulewould be better tolerated, a dose escalation of irinotecan by 20% (to 60 mg/m²)was permitted.

Eligibility criteria for the study included histologicallyconfirmed metastatic non-small-cell lung cancer with measurable or evaluabledisease, an ECOG performance status ≤ 2, and a life expectancy of 3 months.Distant metastases or the presence of a malignant pleural effusion was required.Patients with central nervous system metastases were eligible, provided thecentral nervous system disease remained stable for at least 4 weeks followingcompletion of surgery or radiation therapy. If prior radiation had beenadministered, no more than 20% of the marrow could be encompassed within theradiation portals. All patients had adequate baseline organ function as definedby an absolute neutrophil count (ANC) ³ 1,500/µL, platelet count >100,000/µL, creatinine clearance ³ 70 mL/min,and total bilirubin ≤ 2.0 mg/dL.

Results

Ten patients have been enrolled in this phase II study, and datafrom seven have been analyzed. A total of 31 cycles of therapy were delivered.Six of these patients were evaluable for disease response. One patient achieveda partial response that has lasted for more than 24 weeks, and two patients hada minor response (one of these patients progressed during the 18th week oftreatment, and one developed progressive brain metastases at 15 weeks). Onepatient had stable disease lasting 25 weeks.

Overall, this treatment was well tolerated by patients.Hematologic toxicities were mild, with only two cycles (4%) delayed due to agrade 3 hematologic toxicity (one patient with a reduction in neutrophil countand hemoglobin, another with a reduction only in neutrophil count). Nosignificant thrombocytopenia was observed. No serious nonhematologic toxicitieshave been recorded. Moderate fatigue occurred in two patients. Mild fatigue,nausea, and neuropathy were reported in 39%, 16%, and 12% of cycles,respectively. Dose reduction was necessary in one patient beginning in cycle 3.The dose of irinotecan was increased to 60 mg/m2 in two patients. The delivereddose intensity was 97% of the planned dose intensity.

Irinotecan in CombinationWith Docetaxel

We are also conducting a dose-finding study to determine themaximum tolerated dose and toxicity of this drug combination when bothirinotecan and docetaxel are given on a weekly schedule.[34] Eligibilitycriteria for the study included a histologically confirmed metastaticmalignancy, an ECOG performance status ≤ 2, and a life expectancy of ³ 3months. The patients must have achieved full recovery from the effects of anyprior surgery and received no treatment with wide-range radiation within 4 weeksof study entry with radiation therapy to no more than 20% of the bone marrow.

All patients had adequate baseline organ function, as defined byan ANC ³ 1,500/µL, platelet count ³ 100,000/µL, and creatinine clearance ³55 mL/min. Because of the delayed clearance and increased risk of toxicityobserved in patients with hepatic dysfunction who are treated with docetaxel, atotal bilirubin < 1.2 mg/dL and no more than moderate elevation of livertransaminases were required.

Treatment Plan

In the first phase of this study, treatment was administeredweekly for 4 weeks, followed by a rest period of 2 weeks. The dose of irinotecanwas fixed, and docetaxel was escalated in successive groups of patientsaccording to a standard phase I design (see Table1). Docetaxel was administeredat a starting dose of 25 mg/m² over 60 minutes, followed immediately byirinotecan at a dose of 50 mg/m² over 30 minutes. Patients were premedicatedwith oral dexamethasone at 8 mg approximately 12 hours before and 12 hours afterthe dose of docetaxel. They received antiemetics consisting of granisetron(Kytril) at 10 µg/kg and dexamethasone at 10 mg 30 minutes before the start oftherapy on each treatment day.

During a cycle, treatment was administered on days 8, 15, and 22if the ANC was ³ 1,200/µL, the platelet count was ³ 50,000/µL, and there wasno nonhematologic drug-related toxicity worse than grade 1. Patients developinga grade 2 hematologic toxicity or a nonhematologic drug toxicity worse thangrade 1 were continued on treatment with a 20% dose reduction.

Results

There were 28 patients enrolled in the first phase of thistrial, and a preliminary analysis of the first 26 patients has been completed.The median age was 59 (range: 36 to 76 years), and 21 (81%) were males. In thispatient population, four dose levels of docetaxel that ranged from 25 to 40 mg/m² were evaluated. There were nine patients treated on the fourth dose levelof docetaxel (40 mg/m²); they received a total of 21 cycles. Althoughdose-limiting toxicity was not observed during the first cycle in any of thesepatients, seven patients developed serious toxicity during treatment, fourpatients required a dose reduction, three patients were hospitalized, and onepatient died suddenly of a presumed cardiac event. Consequently, 35 mg/m² wasdetermined to be the optimal dose, and the number of patients treated on thisdose level was expanded to ensure that it could be delivered safely for multiplecycles.

The common nonhematologic toxicities consisted of nausea,diarrhea, and fatigue. Serious nonhematologic toxicity occurred in 4 of 21cycles (19%) at dose level 4, and 4 of 32 cycles (13%) at dose level 3. Seriousneutropenia occurred in only 5 of 53 cycles (9%) at dose levels 3 and 4, andthere was no significant toxicity to the other marrow elements. Twelve of thepatients enrolled had non-small-cell lung cancer, and 4 of these patients hadstabilization of disease that lasted from 18 to 36 weeks.

Similar to findings with the regimen of irinotecan/paclitaxel,toxicities in this study became most prominent during weeks 3 and 4 of thetreatment cycle. Consequently, the second phase of the protocol will determinethe optimal dose on a 2 weeks on, 1 week off schedule. In this second phase, thedose of docetaxel was fixed at 35 mg/m² and the dose of irinotecan escalated ina standard phase I design; a total of 14 patients have been treated. At a doseof 60 mg/m², one of seven patients experienced a dose-limiting toxicity. At 65mg/m², one of four patients experienced dose-limiting toxicity. Further patientsare being accrued at this dose level.

Conclusions

A drug regimen that includes a camptothecin and a taxane on aweekly schedule is attractive for several reasons: both of these classes ofagents are active in lung cancer, the mechanism of action and the spectrum ofnonhematologic toxicity is different, and most of the preclinical studiessuggest that the combination is additive or synergistic. A weekly schedule ofchemotherapy allows more careful monitoring and adjustment of dose to minimizetoxicity. Activity has been identified in several settings, including non-small-celllung cancer when paclitaxel is given on a weekly schedule to patients who wereresistant to paclitaxel that was delivered once every 3 weeks.[35] This wouldsuggest that weekly administration is a more effective schedule for this drug.

The recommended dose of irinotecan on a 4 week on, 2 week offschedule was 125 mg/m², though the median dose intensity achieved was only 67%to 74% of the planned dose intensity, with diarrhea being the most prominentside effect. A phase I study that assessed paclitaxel weekly has delivered dosesas high as 175 mg/m² for 6 weeks followed by a 2-week rest, though doseattenuation due to cumulative neuropathy was required in one-third of thepatients.[36] Docetaxel has been given on a weekly schedule for 6 consecutiveweeks followed by a 2-week break.[37] The recommended dose on this phase Ischedule was 36 mg/m², with the limiting toxicity consisting of fatigue andasthenia, rather than myelosuppression. Diarrhea and neuropathy were notprominent in our studies of irinotecan and paclitaxel due to the lower doses ofeach agent employed. However, asthenia and fatigue also proved to be prominenttoxicities in our investigation of the combination of irinotecan and docetaxel.

There have been a limited number of other studies evaluating thecombination of irinotecan and a taxane in lung cancer. Rushing conducted a phaseI/II nonrandomized open-label dose-finding study, and defined the doses foririnotecan as 60 mg/m² and paclitaxel as 50mg/m² when both drugs were given for3 consecutive weeks followed by a 1-week rest.[38] Activity was observed in fiveof seven patients with relapsed small-cell lung cancer, including three completeremissions.

Masuda and colleagues recently reported a dose-finding study ofthe combination of docetaxel and irinotecan in 32 patients with non-small-celllung cancer.[39]. They identified a recommended dose of docetaxel at 50 mg/m² onday 2, and irinotecan at 50 mg/m² on days 1, 8, and 15, with cycles ofchemotherapy repeated every 4 weeks. There were 11 partial responses (37%) among30 evaluable patients. In both studies, a substantial reduction in the dose ofeach chemotherapy agent was necessary compared to the doses feasible when thedrugs are used alone.

This has been a frequent observation in the development ofcombination chemotherapy regimens that include a camptothecin. In our studiesusing slightly different schedules of irinotecan and paclitaxel, we achieveddose-intensity comparable to that of Rushing in a mixed population of previouslytreated patients. Compared to Masuda and coworkers, we have been able toincrease the dose intensity for the combination of irinotecan and docetaxel.This may be related to differences in schedule, since we administered both drugsweekly, and also to the use of grade 3 rather than grade 2 diarrhea as adose-limiting toxicity (as used in the Japanese study).

The role of irinotecan in the management of lung cancer remainsto be more fully defined. Taxanes have already established an important role inthis disease. Combinations of irinotecan and a taxane derivative deserve furtherexploration in both non-small-cell and small-cell lung cancer.

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