Topotecan (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity testing of topotecan has not been performed. Topotecan is known to be genotoxic to mammalian cells and is a probable carcinogen. Topotecan was mutagenic to L5178Y mouse lymphoma cells and clastogenic to cultured human lymphocytes with and without metabolic activation. It was also clastogenic to mouse bone marrow. Topotecan did not cause mutations in bacterial cells.

Topotecan given to female rats prior to mating at an intravenous dose of 1.4 mg/m2 [about equal to the clinical dose based on body surface area (BSA)] caused superovulation possibly related to inhibition of follicular atresia. This dose given to pregnant female rats also caused increased pre-implantation loss. Studies in dogs given at an intravenous dose of 0.4 mg/m2 (about 0.25 times the clinical dose based on BSA) of topotecan daily for a month suggest that treatment may cause an increase in the incidence of multinucleated spermatogonial giant cells in the testes.

14 CLINICAL STUDIES

14.1 Ovarian Cancer

The efficacy of topotecan was evaluated in two clinical trials of 223 patients with metastatic ovarian cancer. All patients had disease that had recurred on, or was unresponsive to, a platinum-containing regimen. Patients in these trials received an initial dose of 1.5 mg/m2 as an intravenous infusion for 5 consecutive days, starting on Day 1 of a 21 day cycle.

One trial (Study 039) was a randomized trial of 112 patients who received topotecan and of 114 patients who received paclitaxel (175 mg/m2 intravenously over 3 hours on Day 1 of a 21 day cycle). All patients had recurrent ovarian cancer after a platinum-containing regimen or had not responded to at least 1 prior platinum-containing regimen. Patients who did not respond to the trial therapy, or who progressed, could be given the alternative treatment. The efficacy outcome measures were overall response rate, response duration, time to progression, and overall survival (OS).

The results of the trial did not show statistically significant improvements in response rates, response duration, time to progression, and OS as shown in Table 4.

Table 4. Efficacy Results in Ovarian Cancer in Study 039

Parameter

Topotecan

(n = 112)

Paclitaxel (n = 114)

Overall response rate (95% CI)

21% (13%, 28%)

14% (8%, 20%)

Complete response rate

5%

3%

Partial response rate

16%

11%

Response durationa (months)

Median (95% CI)

6 (5.1, 7.6)

5 (3.7, 7.8)

Time to progression (months)

Median (95% CI)

Hazard ratio (95% CI)

4.4 (2.8, 5.4) 3.4 (2.7, 4.2)

0.76 (0.57, 1.02)

Overall survival (months)

14.5 (10.7, 16.5) 12.2 (9.7, 15.8)

Median (95% CI)

Hazard ratio (95% CI)

0.97 (0.71, 1.34)

Abbreviation: CI, confidence interval.

a The calculation for response duration was based on the interval between first response and time to progression.

The median time to response was 7.6 weeks (3.1 weeks to 5 months) with topotecan compared with 6 weeks (2.4 weeks to 4.1 months) with paclitaxel. In the cross-over phase, 13% of 61 patients who received topotecan after paclitaxel had a partial response and 10% of 49 patients who received paclitaxel after topotecan had a response (2 complete responses).

Topotecan was active in ovarian cancer patients who had developed resistance to platinum-containing therapy, defined as tumor progression while on, or tumor relapse within 6 months after completion of, a platinum-containing regimen. One complete and 6 partial responses were seen in 60 patients, for a response rate of 12%. In the same trial, there were no complete responders and 4 partial responders on the paclitaxel arm, for a response rate of 7%.

Topotecan was also studied in an open-label, non-comparative trial in 111 patients with recurrent ovarian cancer after treatment with a platinum-containing regimen, or who had not responded to 1 prior platinum-containing regimen. The response rate was 14% (95% CI: 7%, 20%). The median duration of response was 5 months (4.6 weeks to 9.6 months). The time to progression was 2.6 months (5 days to 1.4 years). The median survival was 1.3 years (1.4 weeks, to 2.2 years).

14.2 Small Cell Lung Cancer

The efficacy of topotecan was evaluated in 426 patients with recurrent or progressive small cell lung cancer (SCLC) in a randomized, comparative trial and in 3 single-arm trials.

Randomized Comparative Trial

In a randomized, comparative trial, 211 patients were randomized 1:1 to receive topotecan (1.5 mg/m2 once daily intravenously for 5 days starting on Day 1 of a 21 day cycle) or CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2 , vincristine 2 mg administered sequentially on Day 1 of a 21 day cycle). All patients were considered sensitive to first-line chemotherapy (responders who then subsequently progressed greater than or equal to 60 days after completion of first-line therapy). A total of 77% of patients treated with topotecan and 79% of patients treated with CAV received platinum/etoposide with or without other agents as first-line chemotherapy. The efficacy outcome measures were overall response rate, response duration, time to progression or OS.

The results of the trial did not show statistically significant improvements in response rate, response duration, time to progression, or OS as shown in Table 5.

Table 5. Efficacy Results in Patients with Small Cell Lung Cancer Sensitive to First-Line Chemotherapy in Study 090

Parameter

Topotecan

(n = 107)

CAV b

(n = 104)

Overall response rate (95% CI)

24% (16%, 32%)

18% (11%, 26%)

Complete response rate

0%

1%

Partial response rate

24%

17%

Response duration a (months)

Median (95% CI)

3.3 (3, 4.1)

3.5 (3, 5.3)

Time to progression (months)

3.1 (2.6, 4.1) 2.8 (2.5, 3.2)

Median (95% CI)

Hazard ratio (95% CI)

0.92 (0.69, 1.22)

Overall survival (months)

5.8 (4.7, 6.8) 5.7 (5, 7)

Median (95% CI)

Hazard ratio (95% CI)

1.04 (0.78, 1.39)

Abbreviations: CI, confidence interval.

a The calculation for duration of response was based on the interval between first response and time to progression.

b CAV = cyclophosphamide, doxorubicin and vincristine.

The median time to response was similar in both arms: topotecan, 6 weeks (2.4 weeks to 3.6 months) versus CAV, 6 weeks (5.1 weeks to 4.2 months).

Changes on a disease-related symptom scale are presented in Table 6. It should be noted that not all patients had all symptoms, nor did all patients respond to all questions. Each symptom was rated on a 4-category scale with an improvement defined as a change in 1 category from baseline sustained over 2 courses. Limitations in interpretation of the rating scale and responses preclude formal statistical analysis.

Table 6. Symptom Improvementa in Patients with Small Cell Lung Cancer in Study 090

Symptom

Topotecan

(n = 107)

CAV

(n = 104)

n b

(%)

n b

(%)

Shortness of breath

68

28

61

7

Interference with daily activity

67

27

63

11

Fatigue

70

23

65

9

Hoarseness

40

33

38

13

Cough

69

25

61

15

Insomnia

57

33

53

19

Anorexia

56

32

57

16

Chest pain

44

25

41

17

Hemoptysis

15

27

12

33

a Defined as improvement sustained over at least 2 courses compared with baseline.

b Number of patients with baseline and at least 1 post-baseline assessment.

Single-Arm Trials

Topotecan was also studied in three open-label, non-comparative trials (Studies 014, 092 and 053) in a total of 319 patients with recurrent or progressive SCLC after treatment with first-line chemotherapy. In all three trials, patients were stratified as either sensitive (responders who then subsequently progressed greater than or equal to 90 days after completion of first-line therapy) or refractory (no response to first-line chemotherapy or who responded to first-line therapy and then progressed within 90 days of completing first-line therapy). Response rates ranged from 11% to 31% for sensitive patients and 2% to 7% for refractory patients. Median time to progression and median survival were similar in all three trials and the comparative trial.

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