Irinotecan Hydrochloride (Page 6 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies with irinotecan were not conducted. Rats were, however, administered intravenous doses of 2 mg/kg or 25 mg/kg irinotecan once per week for 13 weeks (in separate studies, the 25 mg/kg dose produced an irinotecan C_max and AUC that were about 7.0 times and 1.3 times the respective values in patients administered 125 mg/m² weekly) and were then allowed to recover for 91 weeks. Under these conditions, there was a significant linear trend with dose for the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas. Irinotecan was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (micronucleus test in mice). Neither irinotecan nor its active metabolite SN-38 was mutagenic in the in vitro Ames assay.

No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan in doses of up to 6 mg/kg/day to rats and rabbits; however, atrophy of male reproductive organs was observed after multiple daily irinotecan doses both in rodents at 20 mg/kg and in dogs at 0.4 mg/kg. In separate studies in rodents, this dose produced an irinotecan C_max and AUC about 5 and 1 times, respectively, of the corresponding values in patients administered 125 mg/m² weekly. In dogs this dose produced an irinotecan C_max and AUC about one-half and 1/15^th , respectively, of the corresponding values in patients administered 125 mg/m² weekly.

14 CLINICAL STUDIES

Irinotecan has been studied in clinical trials as a single agent [see Dosage and Administration (2)]. Weekly and once-every-3-week dosage schedules were used for the single-agent irinotecan studies. Clinical studies single-agent use are described below.

14.1 Metastatic Colorectal Cancer

Second-Line Therapy After 5-FU-Based Treatment

4 Weekly Doses on a 6-Week Cycle: Studies 3, 4, and 5

Data from three open-label, single-agent, clinical studies, involving a total of 304 patients in 59 centers, support the use of irinotecan hydrochloride in the treatment of patients with metastatic cancer of the colon or rectum that has recurred or progressed following treatment with 5-FU-based therapy. These studies were designed to evaluate tumor response rate and do not provide information on effects on survival and disease-related symptoms. In each study, irinotecan hydrochloride was administered in repeated 6-week cycles consisting of a 90-minute intravenous infusion once weekly for 4 weeks, followed by a 2-week rest period. Starting doses of irinotecan hydrochloride in these trials were 100, 125, or 150 mg/m² , but the 150-mg/m² dose was poorly tolerated (due to high rates of grade 4 late diarrhea and febrile neutropenia). Study 3 enrolled 48 patients and was conducted by a single investigator at several regional hospitals. Study 4 was a multicenter study conducted by the North Central Cancer Treatment Group. All 90 patients enrolled in Study 4 received a starting dose of 125 mg/m². Study 5 was a multicenter study that enrolled 166 patients from 30 institutions. The initial dose in Study 5 was 125 mg/m² but was reduced to 100 mg/m² because the toxicity seen at the 125-mg/m² dose was perceived to be greater than that seen in previous studies. All patients in these studies had metastatic colorectal cancer, and the majority had disease that recurred or progressed following a 5-FU-based regimen administered for metastatic disease. The results of the individual studies are shown in Table 11.

Table 11. Weekly Dosage Schedule: Study Results

a  Nine patients received 150 mg/m2 as a starting dose; two (22.2%) responded to irinotecan hydrochloride.
b Relative dose intensity for irinotecan hydrochloride. Based on planned dose intensity of 100, 83.3, and 66.7 mg/m2 /wk corresponding with 150, 125, and 100 mg/m 2 starting doses, respectively.
c Confirmed ≥ 4 to 6 weeks after first evidence of objective response.
	Study
	3	4	5
Number of Patients	48	90	64	102
Starting Dose (mg/m2 /week × 4)	125a	125	125	100
Demographics and Treatment Administration
Female/Male (%)	46/54	36/64	50/50	51/49
Median Age in years (range)	63 (29–78)	63 (32–81)	61 (42–84)	64 (25–84)
Ethnic Origin (%)
White	79	96	81	91
African American	12	4	11	5
Hispanic	8	0	8	2
Oriental/Asian	0	0	0	2
Performance Status (%)
0	60	38	59	44
1	38	48	33	51
2	2	14	8	5
Primary Tumor (%)
Colon	100	71	89	87
Rectum	0	29	11	8
Unknown	0	0	0	5
Prior 5-FU Therapy (%)
For Metastatic Disease	81	66	73	68
≤6 months after Adjuvant	15	7	27	28
>6 months after Adjuvant	2	16	0	2
Classification Unknown	2	12	0	3
Prior Pelvic/Abdominal Irradiation (%)
Yes	3	29	0	0
Other	0	9	2	4
None	97	62	98	96
Duration of Treatment with Irinotecan hydrochloride injection (median, months)	5	4	4	3
Relative Dose Intensity b (median %)	74	67	73	81
Efficacy
Confirmed Objective Response Rate (%)c (95% CI)	21(9.3–32.3)	13(6.3–20.4)	14(5.5–22.6)	9(3.3–14.3)
Time to Response (median, months)	2.6	1.5	2.8	2.8
Response Duration (median, months)	6.4	5.9	5.6	6.4
Survival (median, months)	10.4	8.1	10.7	9.3
1-Year Survival (%)	46	31	45	43

In the intent-to-treat analysis of the pooled data across all three studies, 193 of the 304 patients began therapy at the recommended starting dose of 125 mg/m². Among these 193 patients, 2 complete and 27 partial responses were observed, for an overall response rate of 15.0% (95% Confidence Interval [CI], 10.0% to 20.1%) at this starting dose. A considerably lower response rate was seen with a starting dose of 100 mg/m². The majority of responses were observed within the first two cycles of therapy, but responses did occur in later cycles of treatment (one response was observed after the eighth cycle). The median response duration for patients beginning therapy at 125 mg/m² was 5.8 months (range, 2.6 to 15.1 months). Of the 304 patients treated in the three studies, response rates to irinotecan hydrochloride were similar in males and females and among patients older and younger than 65 years. Rates were also similar in patients with cancer of the colon or cancer of the rectum and in patients with single and multiple metastatic sites. The response rate was 18.5% in patients with a performance status of 0 and 8.2% in patients with a performance status of 1 or 2. Patients with a performance status of 3 or 4 have not been studied. Over half of the patients responding to irinotecan hydrochloride had not responded to prior 5-FU. Patients who had received previous irradiation to the pelvis responded to irinotecan hydrochloride at approximately the same rate as those who had not previously received irradiation.

Once-Every-3-Week Dosage Schedule

Single Arm Study: Study 6

Data from an open-label, single-agent, single-arm, multicenter, clinical study involving a total of 132 patients support a once every-3-week dosage schedule of irinotecan in the treatment of patients with metastatic cancer of the colon or rectum that recurred or progressed following treatment with 5-FU. Patients received a starting dose of 350 mg/m² given by 30-minute intravenous infusion once every 3 weeks. Among the 132 previously treated patients in this trial, the intent-to-treat response rate was 12.1% (95% CI, 7.0% to 18.1%).

Randomized Studies: Studies 7 and 8

Two multicenter, randomized, clinical studies further support the use of irinotecan given by the once-every-3-week dosage schedule in patients with metastatic colorectal cancer whose disease has recurred or progressed following prior 5-FU therapy. In Study 7, second-line irinotecan therapy plus best supportive care was compared with best supportive care alone. In Study 8, second-line irinotecan therapy was compared with infusional 5-FU-based therapy. In both studies, irinotecan was administered intravenously at a starting dose of 350 mg/m² over 90 minutes once every 3 weeks. The starting dose was 300 mg/m² for patients who were 70 years and older or who had a performance status of 2. The highest total dose permitted was 700 mg. Dose reductions and/or administration delays were permitted in the event of severe hematologic and/or nonhematologic toxicities while on treatment. Best supportive care was provided to patients in both arms of Study 7 and included antibiotics, analgesics, corticosteroids, transfusions, psychotherapy, or any other symptomatic therapy as clinically indicated. In both studies, concomitant medications such as antiemetics, atropine, and loperamide were given to patients for prophylaxis and/or management of symptoms from treatment. If late diarrhea persisted for greater than 24 hours despite loperamide, a 7-day course of fluoroquinolone antibiotic prophylaxis was given. Patients in the control arm of the Study 8 received one of the following 5-FU regimens: (1) LV, 200 mg/m² IV over 2 hours; followed by 5-FU, 400 mg/m² IV bolus; followed by 5-FU, 600 mg/m² continuous IV infusion over 22 hours on days 1 and 2 every 2 weeks; (2) 5-FU, 250 to 300 mg/m² /day protracted continuous IV infusion until toxicity; (3) 5-FU, 2.6 to 3 g/m² IV over 24 hours every week for 6 weeks with or without LV, 20 to 500 mg/m² /day every week IV for 6 weeks with 2-week rest between cycles. Patients were to be followed every 3 to 6 weeks for 1 year.

A total of 535 patients were randomized in the two studies at 94 centers. The primary endpoint in both studies was survival. The studies demonstrated a significant overall survival advantage for irinotecan compared with best supportive care (p=0.0001) and infusional 5-FU-based therapy (p=0.035) as shown in Figures 3 and 4. In Study 7, median survival for patients treated with irinotecan was 9.2 months compared with 6.5 months for patients receiving best supportive care. In Study 8, median survival for patients treated with irinotecan was 10.8 months compared with 8.5 months for patients receiving infusional 5-FU-based therapy. Multiple regression analyses determined that patients’ baseline characteristics also had a significant effect on survival. When adjusted for performance status and other baseline prognostic factors, survival among patients treated with irinotecan remained significantly longer than in the control populations (p=0.001 for Study 7 and p=0.017 for Study 8). Measurements of pain, performance status, and weight loss were collected prospectively in the two studies; however, the plan for the analysis of these data was defined retrospectively. When comparing irinotecan with best supportive care in Study 7, this analysis showed a statistically significant advantage for irinotecan, with longer time to development of pain (6.9 months versus 2.0 months), time to performance status deterioration (5.7 months versus 3.3 months), and time to > 5% weight loss (6.4 months versus 4.2 months). Additionally, 33.3% (33/99) of patients with a baseline performance status of 1 or 2 showed an improvement in performance status when treated with irinotecan versus 11.3% (7/62) of patients receiving best supportive care (p=0.002). Because of the inclusion of patients with non-measurable disease, intent-to-treat response rates could not be assessed.

Table 12. Once-Every-3-Week Dosage Schedule: Study Results

a BSC = best supportive care
b Relative dose intensity for irinotecan based on planned dose intensity of 116.7 and 100 mg/m2 /wk corresponding with 350 and 300 mg/m2 starting doses, respectively.
	Study 7		Study 8
	Irinotecan	BSCa	Irinotecan	5-FU
Number of patients	189	90	127	129
Demographics and treatment administration
Female/Male (%)	32/68	42/58	43/57	35/65
Median age in years (range)	59 (22–75)	62 (34–75)	58 (30–75)	58 (25–75)
Performance status (%)
0	47	31	58	54
1	39	46	35	43
2	14	23	8	3
Primary tumor (%)
Colon	55	52	57	62
Rectum	45	48	43	38
Prior 5-FU therapy (%)
For metastatic disease	70	63	58	68
As adjuvant treatment	30	37	42	32
Prior irradiation (%)	26	27	18	20
Duration of study treatment (median, months) (Log-rank test)	4.1	—	4.2(p=0.02)	2.8
Relative dose intensity (median %) b	94	—	95	81–99
Survival
Survival (median, months) (Log-rank test)	9.2(p=0.0001)	6.5	10.8(p=0.035)	8.5

In the two randomized studies, the EORTC QLQ-C30 instrument was utilized. At the start of each cycle of therapy, patients completed a questionnaire consisting of 30 questions, such as “Did pain interfere with daily activities?” (1 = Not at All, to 4 = Very Much) and “Do you have any trouble taking a long walk?” (Yes or No). The answers from the 30 questions were converted into 15 subscales, that were scored from 0 to 100, and the global health status subscale that was derived from two questions about the patient’s sense of general well being in the past week. The results as summarized in Table 13 are based on patients’ worst post-baseline scores. In Study 7, a multivariate analysis and univariate analyses of the individual subscales were performed and corrected for multivariate testing. Patients receiving irinotecan reported significantly better results for the global health status, on two of five functional subscales, and on four of nine symptom subscales. As expected, patients receiving irinotecan noted significantly more diarrhea than those receiving best supportive care. In Study 8, the multivariate analysis on all 15 subscales did not indicate a statistically significant difference between irinotecan and infusional 5-FU.

Table 13. EORTC QLQ-C30: Mean Worst Post-Baseline Score^a

a  For the five functional subscales and global health status subscale, higher scores imply better functioning, whereas, on the nine symptom subscales, higher scores imply more severe symptoms. The subscale scores of each patient were collected at each visit until the patient dropped out of the study.
QLD-C30 Subscale	Study 7			Study 8
	Irinotecan	BSC	p-value	Irinotecan	5-FU	p-value
Global health status	47	37	0.03	53	52	0.9
Functional scales
Cognitive	77	68	0.07	79	83	0.9
Emotional	68	64	0.4	64	68	0.9
Social	58	47	0.06	65	67	0.9
Physical	60	40	0.0003	66	66	0.9
Role	53	35	0.02	54	57	0.9
Symptom Scales
Fatigue	51	63	0.03	47	46	0.9
Appetite loss	37	57	0.0007	35	38	0.9
Pain assessment	41	56	0.009	38	34	0.9
Insomnia	39	47	0.3	39	33	0.9
Constipation	28	41	0.03	25	19	0.9
Dyspnea	31	40	0.2	25	24	0.9
Nausea/Vomiting	27	29	0.5	25	16	0.09
Financial impact	22	26	0.5	24	15	0.3
Diarrhea	32	19	0.01	32	22	0.2