Irinotecan Plus 5-FU and Leucovorin in Advanced Colorectal Cancer: North American Trials

North American Clinical Trials

There are four reports of North American studies in which irinotecan(Drug information on irinotecan), 5-FU, and leucovorin have been combined either simultaneously, sequentially, or in an alternating fashion. In all of the American regimens reported to date, 5-FU was given by intermittent bolus injection or short (< 2-hour) infusion. European trials of the three-drug combination are described elsewhere in this monograph . A number of European trials administered the 5-FU as a short infusion over 22 to 48 hours in a manner similar to the schedules commonly used when 5-FU and leucovorin are given without concomitant irinotecan.

The simultaneous schedule was tested in one phase I North American trial, which recruited patients with advanced solid tumors. Additional patients were accrued at the MTD to provide an early evaluation of the regimen’s activity and toxicity. This simultaneous schedule is now being tested as one of the experimental arms of a phase III randomized trial in advanced colorectal cancer. The sequential approach was the subject of one phase I trial, which closed after accruing nine patients, and an ongoing phase I trial in patients with advanced solid tumors, which is currently enrolling subjects. The alternating schedule was tested in a phase II trial in patients with previously untreated advanced colorectal cancer.

Simultaneous Administration Schedule

Trial of Saltz et al--Saltz et al at Memorial Sloan-Kettering Cancer Center developed a program to find the MTD of a combined regimen of irinotecan given with 5-FU and leucovorin. This regimen was based on the administration schedule of irinotecan that is currently FDA approved and that is most often employed in US patients with advanced colorectal cancer.[19] This empirically derived regimen prescribed escalating doses of irinotecan as a 90-minute infusion given weekly for 4 consecutive weeks followed by a 2-week rest. Low-dose leucovorin (fixed dose of 20 mg/m²/d) was given as an intravenous bolus as soon as the irinotecan infusion was completed and immediately preceding bolus 5-FU. Doses of 5-FU were also escalated in typical phase I trial fashion as new patients were recruited and the trial proceeded. Low-dose leucovorin was chosen in an attempt to minimize diarrhea related to 5-FU and leucovorin in the face of simultaneous use of another diarrhea-producing agent, irinotecan.

A secondary goal of this study was to further investigate the finding by Sasaki et al that 5-FU may inhibit conversion of irinotecan to SN-38.[20] To test for this potential drug interaction, patients were given only irinotecan on the first day of the first treatment week. Blood samples for irinotecan and SN-38 pharmacokinetics were collected over 24 hours. Then, on day 2, 5-FU and leucovorin were administered. Thereafter, except on the first day of the second cycle of therapy, all three drugs were given one after the other in sequence, irinotecan, leucovorin, and 5-FU.

At the second week of the study, blood samples for irinotecan and SN-38 pharmacokinetics were collected, and pharmacokinetic parameters were compared to levels seen after administration of irinotecan alone. On the first day of the second cycle of therapy (week 7) leucovorin and 5-FU were given just before irinotecan was administered, and irinotecan and SN-38 pharmacokinetic blood samples were again collected.

Twenty-seven patients were treated with escalating doses and an additional 15 patients were treated at the MTDs, for a total of 42 patients enrolled in this study. The vast majority of registrants had colorectal cancer (38/42). Of the patients with colorectal cancer, two thirds had received one or more prior chemotherapy regimens.

The MTDs were determined to be 125 mg/m²/d of irinotecan, 20 mg/m²/d of leucovorin, and 500 mg/m²/d of 5-FU. Neutropenia and diarrhea were dose limiting. Among the 17 evaluable patients who were treated at the MTDs, 29% experienced grade 4 neutropenia and 18% had grade 4 diarrhea.

The pharmacokinetic goals of the study were to determine whether the maximal concentration and area under the concentration-time curve (AUC) of SN-38 and irinotecan varied based on the sequence of drug administration. No differences were discerned when irinotecan was given alone, before, or after 5-FU plus leucovorin. There also was no correlation between the SN-38 AUC and the magnitude of granulocytopenia observed. A small but significant decrease in SN-38 AUC was observed by Saltz, but this was not clinically significant.

Although response was not the primary end point of this study, tumor responses were observed. In the 35 evaluable patients (out of 38 entered) who had metastatic colorectal cancer and measurable disease, a response rate of 17% was observed. This included patients treated at less than the MTD and may have underestimated the true response rate. In addition, only 12 previously untreated patients were included in the series, two of whom responded to treatment.

Currently, Saltz and colleagues, in conjunction with investigators at Pharmacia and Upjohn, are conducting a trial that randomly assigns patients with previously untreated measurable colon cancer to one of three treatment arms; (1) irinotecan alone, (2) irinotecan, 5-FU, and leucovorin as described above, or (3) 5-FU and leucovorin. As of January 1998, over 500 of the 660 patients needed to meet the study’s goals have been enrolled. It is likely that the results will be available in 1999 or shortly thereafter.

Doses Used in Simultaneous Schedule--It is notable that the dose of irinotecan (125 mg/m²/d) that can be given concomitantly with 5-FU is identical to the dose that can be administered safely when the drug is given as a single agent, while the dose of 5-FU that can be given concomitantly with irinotecan is five sixths of the dose used for monotherapy (500 mg/m²/d instead of 600 mg/m²/d). The leucovorin dose, which is used to modulate 5-FU in the weekly regimen of 600 mg/m²/d, is 500 mg/m²/d rather than the 20 mg/m²/d employed in the Saltz regimen. It is difficult to determine whether the difference in the leucovorin dose is of clinical importance. The potential for overlapping toxicity has not proven to be as problematic in this schedule as was anticipated.

Since the drugs are administered simultaneously in the Saltz regimen, it does not take advantage of the potential synergistic effects of sequential administration of irinotecan 24 hours before 5-FU noted in vitro and discussed above. (These findings were reported after the initiation of the Saltz trial.) However, because there is more experience with the Saltz regimen than with other regimens that combine irinotecan, 5-FU, and leucovorin, plans are under way to evaluate the Saltz regimen in the adjuvant setting. A randomized trial in which the combination will be compared to a 5-FU and leucovorin-containing regimen in patients with resected stage III colon cancer is being designed.

Sequential Administration

Trial of Parnes et al--Parnes and colleagues attempted a phase I trial in which leucovorin (500 mg/m²/d) and 5-FU (500 mg/m²/d) were administered weekly, with doses of irinotecan escalated for 4 consecutive weeks in 6-week cycles.[21] Irinotecan was administered over 90 minutes 48 hours prior to 5-FU on the first and fourth weeks of treatment beginning at a dose of 25 mg/m²/d. Grade 4 diarrhea proved to be dose limiting at a dose of 50 mg/m²/d, and only nine patients were entered on the study. The authors concluded that this dosing strategy was unproductive and recommended the investigation of other schedules. The higher dose of leucovorin used in this trial may have led to the increased severity of diarrhea seen here as compared to that seen by Saltz.

Mayo Clinic Trial--A phase I trial that combines irinotecan with 5-FU and leucovorin is in progress at the Mayo Clinic.[22] The drugs are given sequentially, based on the work of Mullany et al. In the Mayo Clinic program, irinotecan is given as a 90-minute intravenous infusion on day 1. This is followed, after a 24-hour interval, by leucovorin, given as a standard 20-mg/m²/d bolus, which is followed immediately by 5-FU as a 90-minute intravenous infusion on days 2 through 5. Doses of both irinotecan and 5-FU are escalated according to typical phase I trial design, wherein three patients are accrued and followed for toxicity at each dose level before increasing the doses of either agent.

Like the Saltz regimen, which is based on a commonly used schedule for administration of single-agent irinotecan, the Mayo Clinic trial repeats treatments every 3 weeks in an attempt to replicate the every 3 week schedule of irinotecan that is often given in Europe and that was used in a previous Mayo Clinic phase I study. In that phase I trial of single-agent irinotecan administered every 3 weeks, the MTD was 320 mg/m²/d.[23]

The MTDs of the three drugs in combination in the current Mayo Clinic phase I trial have not been reached. As of January 1998, 28 patients have been enrolled in the current trial. The primary tumor sites are colorectal cancer in 18 patients, other gastrointestinal cancers in 5 patients, breast cancers in 2 patients, head and neck cancer in 1 patient, and lung cancers in 2 patients. The median number of cycles to date is 4, with a range of 1 to 19 cycles. The current cohort is being treated at doses of 250 mg/m²/d of irinotecan, 20 mg/m²/d of leucovorin, and 350 mg/m²/d of 5-FU.

Toxicity to date has included one patient with grade 3 and one patient with grade 4 diarrhea. One case each of grade 3 and grade 4 neutropenia has been noted. Other toxicities have included one case of grade 3 fatigue and one case of grade 3 dyspnea.

Response is not the primary trial end point of this study. Although responses have been observed, the response data will not be reported in detail until the trial has concluded and a phase II dose can be recommended.