Phase II Trial of Irinotecan in Patients with Progressive or Rapidly Recurrent Colorectal Cancer

Rothenberg ML, Eckardt JG, Kuhn GS, et al. Journal of Clinical Oncology. 1996;14(4):1128-1135

A phase II, open-label trial of CAMPTOSAR Injection (irinotecan hydrochloride injection) demonstrated objective tumor response.

Patients

Patients had measurable metastatic colorectal cancer that had recurred or progressed despite prior treatment with one 5-FU-based regimen.

77% of the patients had progressive disease during 5-FU-based therapy

23% had progressive or recurrent disease within 6 months of 5-FU-based therapy

All 48 patients were evaluated for toxicity and survival, 43 were evaluable for response

Six-Week Treatment Cycle

Irinotecan 125 to 150 mg/m² IV q week x 4 followed by a 2-week rest continued until tumor progression.

median number of courses = 3.5
(range 1 to 13)

Table 1. - Response to Irinotecan Therapy
Response	Number

Overall response (or) CR PR Median response duration	10/43 (23%) 1/43 (2%) 9/43 (21%) 6 months (range 2 to 13 months)

Table 1. - Response to Irinotecan Therapy

Response

Number

Overall response (or)
CR
PR

Median response duration

10/43 (23%)
1/43 (2%)
9/43 (21%)

6 months (range 2 to 13 months)

Median survival for the entire group of 48 patients was 10.4 months

Measures implemented in this trial substantially reduced the incidence of severe diarrhea.

Use of an irinotecan starting dose of 125 mg/m²/wk
Adoption of a prompt, intensive course of loperamide at the earliest symptoms

The incidence of grade 4 diarrhea for patients beginning therapy at 125 mg/m²/wk fell from 14% of 42 courses before these measures were taken to 4% of 113 courses after they were implemented.

Dose Selection

An earlier phase I trial recommended a phase II starting dose of 150 mg/m²/wk. However, the phase II protocol was amended to use a starting dose of 125 mg/m²/wk after an unacceptably high rate of toxicity occurred at the 150-mg/m²; dose.

Table 2. - Severe Diarrhea Observed at Two Dose Levels
Dose Level	Number Treated	Grade 4 Diarrhea
150 mg/m²/wk	9	4/9 (44%)
125 mg/m²/wk	39	9/39 (23%)

Standardized Management

A standardized approach for prompt and aggressive treatment of late-onset diarrhea (diarrhea that occurred >12 hours after irinotecan administration) was adopted after the first 65 courses were administered to the first 30 patients.

Table 3. - Diarrhea Management Adopted in the Trial
Diarrhea	Management
During or shortly after irinotecan infusion	Atropine 1 mg IV
Late-onset diarrhea in the initial 65 courses	No standard approach to treatment
Late-onset diarrhea in the final 145 courses of treatment	At the first sign of diarrhea: loperamide 4 mg po, followed by 2 mg po q 2 hours (4 mg po q 4 hours at night) until complete resolution lasting 12 hours

Table 4. - Incidence of Grade 4 Late-Onset Diarrhea Following Adoption of the Loperamide Regimen
Irinotecan Dose	Grade 4 Diarrhea
No Standard Regimen	Standardized Loperamide Management
All patients (150 or 125 mg/m²/wk) 125 mg/m²/wk dose	11/65 courses (17%) 6/42 courses (14%)	7/145 courses (5%) 5/113 courses (4%)

Table 4. - Incidence of Grade 4 Late-Onset Diarrhea Following Adoption of the Loperamide Regimen

Irinotecan Dose

Grade 4 Diarrhea

No Standard Regimen

Standardized Loperamide Management

All patients
(150 or 125 mg/m²/wk)
125 mg/m²/wk dose

11/65 courses (17%)

6/42 courses (14%)

7/145 courses (5%)

5/113 courses (4%)

Toxicity

Grades 3 and 4 diarrhea had the most frequent non-hematologic toxicity, with a median time to onset of the late diarrhea of 10 days from the initiation of a course of therapy.

Neutropenia was the most common hematologic toxicity, with a median onset of 15 days.

Table 5. - Irinotecan Toxicity by Patient Worst Grade Experienced During Any Cycle of Therapy (n=48)
Toxicity	No. Pts With grade 3 (%)	No. Pts With grade 4 (%)
Non-hematologic
Abdominal pain	1 (2%)	0
Asthenia	3 (6%)	0
Increased alk phosphatase	2 (4%)	0
Increased bilirubin	3 (6%)	0
Increased creatinine	1 (2%)	1 (2%)
Dehydration	2 (4%)	0
Diarrhea	5 (10%)	13 (27%)
Malaise	1 (2%)	0
Nausea	5 (10%)	0
Vomiting	6 (13%)	2 (4%)
Hematologic
Anemia	4 (8%)	1 (2%)
Leukopenia	10 (2 %)	2 (4%)
Neutropenia	7 (15%)	8 (17%)
Thrombocytopenia	1 (2%)	0

Conclusion

Virtually all patients diagnosed with metastatic colorectal cancer will develop progressive disease following`5-FU-based therapy, thus a need exists for agents with activity in this setting.

Irinotecan appears to have significant activity against colorectal cancer that has progressed during or shortly after 5-FU-based therapy.

Irinotecan responses tend to be durable and do not appear to be influenced by the duration of prior 5-FU therapy.

Diarrhea, the most frequent dose-limiting toxicity to this therapy, can be substantially reduced through the early initiation and protracted administration of loperamide.

See the package insert for full prescribing information.


© 1996 Pharmacia & Upjohn Company		USX 5742.00 August 1996

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