UFT/Leucovorin Plus Irinotecan in Advanced or Metastatic Colorectal Cancer

ABSTRACT: UFT (with leucovorin) and irinotecan both have single-agent activity in colorectal cancer, with non–cross-resistant mechanisms of action. Combining these drugs would be anticipated to increase response rates while maintaining the advantages of a regimen based on an orally administered fluoropyrimidine. This trial aims to determine the maximum tolerated dose, side-effect profile, dose-limiting toxicity, and response rate for the combination of UFT plus leucovorin, and irinotecan. The design is for an initial phase I study investigating escalating doses of UFT (250 to 350 mg/m²/d) and irinotecan (200 to 300 mg/m²) with fixed doses of leucovorin at 90 mg/d, in up to five cohorts of six patients each. UFT and leucovorin are given orally on days 1 to 14 of a 21-day cycle and irinotecan is given intravenously on day 1. The maximum tolerated dose is defined as the dose at which three of six patients in a cohort have a dose-limiting toxicity in the first cycle of treatment. In the second part of the study, the cohort below that experiencing maximum tolerated dose will be expanded up to a total of 20 patients in order to assess further the toxicity and response rate (phase II). To date, 17 assessable patients have been recruited, with a median age of 64 years (range: 35–80 years). At the first dose level (UFT 250 mg/m²/d and irinotecan 200 mg/m²), no dose-limiting toxicities were seen, and in cohort 2 (UFT 250 mg/m²/d and irinotecan 250 mg/m²), there was one grade 3 diarrhea. In cohort 3 (UFT 250 mg/m²/d and irinotecan 300 mg/m²), currently there have been two grade 3/4 toxicities (both neutropenic fever). Thus, the maximum tolerated dose has not yet been reached. Response has been assessed in the first six patients, with three having partial response, two having stable disease, and one having progressive disease (response rate 50%). We conclude that this regimen appears feasible with acceptable toxicity at these dose levels. There is also evidence of significant anti-tumor activity similar to that seen with other fluoropyrimidine-based combination regimens but without the requirement for indwelling catheters or inpatient admission. [ONCOLOGY 14(Suppl 9):28-31, 2000]

Introduction

Colorectal cancer has been treated primarily with single-agent fluorouracil (5-FU) for many years. Combination therapy with new, non–cross-resistant drugs is now being explored. One such agent is irinotecan (Camptosar, CPT-11), an inhibitor of the nuclear enzyme topoisomerase I, via its active metabolite SN-38. In second-line treatment of 5-FU–resistant colorectal cancer, single-agent irinotecan is associated with a survival advantage over best supportive care.[1] In a study of first-line treatment of colorectal cancer using an every-3-week regimen, a response rate of 18.8% was achieved, which did not differ from the response in 5-FU–pretreated patients, supporting the premise of non–cross-resistance.[2]

To date, trials of combination 5-FU (with or without leucovorin) plus irinotecan have been encouraging, with reported results showing response and time to disease progression advantages over 5-FU alone.[3,4] As reported last year at the annual meeting of the American Society of Clinical Oncology, there is also a survival advantage with this combination (16.8 months for irinotecan/5-FU/leucovorin vs 14 months for 5-FU/leucovorin, P = .03).[4] Delayed diarrhea and hematologic effects are the major dose-limiting toxicities of irinotecan.

In addition to the opportunities provided by the development of such new agents, the renewed interest in oral formulations of 5-FU, especially in combination with dihydropyrimidine dehydrogenase inhibitors, has provided the impetus for novel combination regimens. One such oral agent is UFT (a combination of the 5-FU prodrug tegafur and uracil). Clinical trials of UFT have shown that its clinical activity appears similar to standard 5-FU regimens when combined with leucovorin. Furthermore, in addition to the ease of oral delivery, there is a toxicity advantage, with less associated myelosuppression.

A recently reported phase III study comparing UFT (300 mg/m²/d) and oral leucovorin (75 to 90 mg/d) administered for 28 days of a 35-day cycle to the standard Mayo regimen (5-FU at 425 mg/m²/d plus leucovorin at 20 mg/m²/d IV × 5, every 4 weeks) has supported these conclusions, with grade 3 or 4 neutropenia recorded in 1% of patients receiving UFT plus oral leucovorin (a combination being developed under the trade name Orzel) vs 56% for those receiving the Mayo schedule (P < .0001).[5] Toxicities are diarrhea, nausea, and vomiting. This study also showed no statistical difference between the response rates of the two groups. Thus, given the evidence that UFT plus leucovorin appears to be comparable to 5-FU plus leucovorin, and that combination regimens are usually superior to single agents, this trial was designed to explore the substitution of an oral 5-FU prodrug in combination with irinotecan.

Study Design

This study has a nonrandomized, open-label design. The primary objectives of the dual-center phase I/II trial are to determine the maximum tolerated dose, establish a recommended starting dose for subsequent study, and assess the side-effect profile and dose-limiting toxicity of this combination. A secondary objective will be to determine the response rate in this group of patients with advanced colorectal cancer. Evidence from prior irinotecan/5-FU combination studies was used to decide the dose schedule. A number of different dose schedules have been investigated in phase I trials, which are summarized in Table 1.[6-10]

As the schedules for UFT involve administering the drug for prolonged periods, varying from 14 to 28 days, a 3-week regimen was designed in which UFT is administered daily for 14 days, with irinotecan on day 1, followed by a 7-day rest. The recommended starting dose for single-agent irinotecan is 350 mg/m² every 3 weeks (a schedule that is widely used in Europe). The first cohort of six patients received irinotecan 200 mg/m² intravenously over 90 minutes on day 1.

As can be seen in Table 1, it appears that irinotecan can be administered at or near single-agent levels in combination with 5-FU; therefore, dose escalation of irinotecan was the initial step. UFT in a 14-day schedule has been administered at doses ranging from 350 to 400 mg/m²/d,[11] usually with a 14-day rest period. As this regimen is to be administered every 3 weeks with the rest period reduced to 7 days, a starting dose of 250 mg/m²/d was considered appropriate. Leucovorin was used for biomodulation at a constant dose of 90 mg/d for 14 days. A summary of the planned dose levels appears in Table 2.

The first patient of each cohort will undergo at least 1 week of treatment before other patients in the cohort can be entered. There will be six patients per dose level, and if three of six patients experience dose-limiting toxicity at any given dose level, this will be defined as the maximum tolerated dose. In addition, if two of the first three patients experience dose-limiting toxicity, then this dose level will also be defined as the maximum tolerated dose. The dose level below subsequently will be expanded to include an additional 14 patients and will define the recommended dose level for future study.

The dose-limiting toxicities are defined as follows: (1) grade 3/4 neutropenia complicated by fever > 38°C; (2) use of intravenous antibiotics; (3) grade 3/4 diarrhea; (4) grade 4 thrombocytopenia prolonged or complicated by bleeding or requiring platelet transfusion; (5) grade 3/4 neutropenia or thrombocytopenia lasting more than 7 days; (6) grade 3/4 nonhematologic toxicity, with the exception of alopecia, nausea, and vomiting; (7) grade ³ 2 renal, hepatic, cardiac, or pulmonary toxicity; (8) treatment delay of ³ 2 weeks prior to the start of the next cycle of treatment.

Patients with advanced or metastatic histologically confirmed colorectal cancer are eligible for inclusion in this study. Disease must be measurable and at least 1 cm in dimension. Previous adjuvant chemotherapy is allowed if it was administered 6 months prior to confirmation of advanced disease, but otherwise treatment will be in chemotherapy-naive patients. Standard biochemical and hematologic parameters are required, and the patient should be at a performance status of 0 to 2 (ECOG). Patients with malabsorption, Crohn’s disease, or ulcerative colitis are excluded.

The schedule consists of a 3-week regimen of irinotecan on day 1 and UFT plus leucovorin on days 1 through 14. UFT plus leucovorin is administered 1 hour prior to the irinotecan dose on day 1. UFT is subsequently administered in three divided doses per day for 14 days, followed by a 7-day rest period (Figure 1).

Given previous experience with irinotecan, patients are instructed to take loperamide at the first sign of a loose stool and continue at 2 mg per 2 hours until 12 hours after the last liquid stool. If symptoms have not resolved within 48 hours, patients should be hospitalized and given ciprofloxacin (Cipro). Ciprofloxacin is also given if diarrhea occurs with neutropenia. Atropine sulfate 0.25 mg is given subcutaneously each cycle to prevent acute cholinergic syndrome. Prophylactic antiemetics (excluding 5-HT₃ receptor antagonists in the first cycle) are routinely given prior to irinotecan administration.

Tumor assessment with computed tomographic (CT) scanning will occur prior to treatment and after the third and sixth cycles. Patients must receive two cycles to be evaluable for response. If response is documented, then CT scanning is repeated at least 4 weeks after the previous CT scan and subsequently every 2 months. All patients will be evaluated for toxicity, which is assessed using the Common Toxicity Criteria (CTC), after at least one dose of study medication.

Results

To date, 18 patients have been enrolled, with 17 eligible for toxicity assessment and six eligible for response. Patient number 4 withdrew from the study without having received chemotherapy. One other patient was withdrawn due to dose-limiting toxicity (neutropenia > 7 days). Patient characteristics are summarized in Table 3. Median age is 64.5 years. Two of the 17 patients are 80 years of age. Of these 17 patients, six have had a final tumor assessment after six cycles. Although the confirmatory scan is pending, preliminary results indicate partial responses in three of six patients, stable disease in two, and progressive disease in one patient. Two of the three responses occurred at the lowest dose level.

Treatment has been generally well tolerated, with the greatest percentage of toxicity being of CTC grade 1/2. The majority of reported toxicity is from diarrhea, fatigue, alopecia, and nausea. A dose-limiting toxicity has been reported at dose levels 2 and 3, and at the time of this report two of five patients at dose level 3 have experienced a dose-limiting toxicity. Overall toxicity is summarized in Table 4.

In addition to toxicity assessable according to CTC, four patients have reported symptoms of indigestion and two patients have experienced the acute cholinergic syndrome related to irinotecan infusion. There have been two episodes of accidental overdoses of UFT. One patient (cohort 2) experienced grade 4 diarrhea after taking an excessive dose for 7 days. The second patient did not experience excessive toxicity as the period of overdose was minimal. Both patients were on a variable tid dose (eg, 200/100/200 mg).

Conclusions

Although results are preliminary, some tentative conclusions can be drawn at this stage. The regimen appears to have significant activity, with three of the six assessable patients achieving a partial response, two of these occurring at the lowest dose level. In addition, at this point only one patient has had documented progressive disease.

The toxicity data so far would seem to be predictable, with the majority having some degree of diarrhea, although this is mostly grade 1 or 2. Lethargy and alopecia, which are reported with irinotecan, are also frequent findings. Grade 3 or 4 neutropenia has appeared relatively frequently, but is generally tolerated without associated significant infection (4 of the 17 patients). One benefit of this combination may be reduced hematologic toxicity, and the results so far appear to support this. In previous phase I trials of irinotecan and 5-FU, the reported frequency of grade 3 to 4 neutropenia was over 60%.[9,12] However, it seems likely that neutropenia, in combination with diarrhea, will constitute the dose-limiting toxicity.

 One point to note is the occurrence of accidental overdose, which highlights the importance of education and monitoring when using oral chemotherapy agents, particularly when there is a variable dose schedule required.

The maximum tolerated dose has not yet been reached, and the plan is to complete the current cohort at dose level 3, and, if tolerated without dose-limiting toxicity, escalation to the next dose level is envisaged. Following the determination of the maximum tolerated dose, the dose level below will be expanded to 20 patients (ie, an additional 14 patients will be entered). An assessment of cumulative toxicity will then be possible.

Given the promising results so far, final assessments of overall response rate, and more importantly the tolerability of this regimen in the setting of a phase I trial, are awaited with interest. Assuming the results are satisfactory, this combination will be explored on a larger scale in future phase II/III studies.

References:

1. Cunningham D, Pyrhönen S, James JD, et al: Randomised trial of irinotecan plus best supportive care (BSC) versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413-1418, 1998.

2. Rougier P, Bugat R, Douillard J-Y, et al: Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemonaive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 15:251-260, 1997.

3. Saltz LB, Locker PK, Pirotta N, et al: Weekly irinotecan (CPT-11), leucovorin (LV), and fluorouracil (FU) is superior to daily × 5 LV/FU in patients (PTS) with previously untreated metastatic colorectal cancer (CRC) (abstract 898). Proc Am Soc Clin Oncol 18:233a, 1999.

4. Douillard J-Y, Cunningham D, Roth AD, et al: A randomized phase III trial comparing irinotecan (IRI) + 5-FU/folinic acid (FA) to the same schedule of 5-FU/FA in patients (pts) with metastatic colorectal cancer (MCRC) as front line chemotherapy (CT) (abstract 899). Proc Am Soc Clin Oncol 18:233a, 1999.

5. Pazdur R, Douillard J-Y, Skillings JR, et al: Multicenter phase III study of 5-fluorouracil (5-FU) or UFT in combination with leucovorin (LV) in patients with metastatic colorectal cancer (abstract). Proc Am Soc Clin Oncol 18:1009, 1999.

6. Shimada Y: Topoisomerase I inhibitor: Combination chemotherapy with CPT-11 in gastrointestinal cancers (abstract 37). 2nd International Conference on Biology, Prevention and Treatment of Gastrointestinal Malignancies. Köln, Germany, January 9–12, 1995.

7. Saltz L, Kanowitz J, Kemeny N, et al: Phase I clinical and pharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patients with advanced solid tumours. J Clin Oncol 14:2959-2967, 1996.

8. Falcone A, Danesi R, Allegrini G, et al: Escalating dose irinotecan (CPT-11) immediately prior or after 5-fluorouracil (5-FU) 48-hour infusion + leucovorin (LV): Pharmacokinetic and pharmacodynamic interactions in chemotherapy–naive metastatic colorectal cancer patients (abstract 924). Proc Am Soc Clin Oncol 18:241a, 1999.

9. Ducreux M, Ychou M, Seitz J-F, et al: Irinotecan with bolus fluorouracil, continuous-infusion fluorouracil, and high-dose leucovorin every 2 weeks (LV5FU2 regimen): A clinical dose-finding and pharmacokinetic study in patients with pretreated metastatic colorectal cancer. J Clin Oncol 17:2901-2908, 1999.

10. Sastre J, Paz-Ares L, Diaz-Rubin, et al: Phase I dose finding study of irinotecan (CPT-11) over a short infusion combined with a fixed dose of 5-fluorouracil (5-FU) over a protracted IV infusion in patients with advanced solid tumors (abstract 775). Proc Am Soc Clin Oncol 18:201a, 1998.

11. Pazdur R, Lassere Y, Diaz-Canton E, et al: Phase I trials of uracil-tegafur (UFT) using 5- and 28-day administration schedules: Demonstration of schedule-dependent toxicities. Anticancer Drugs 7:728-733, 1996.

12. Comella P, Casaretti R, De Vita F, et al: Concurrent irinotecan and 5-fluorouracil plus levo-folinic acid every other week in the first line management of advanced colorectal carcinoma: A phase I study of the Southern Italy Cooperative Oncology Group. Ann Oncol 10:915-921, 1999.