Gemcitabine (Page 5 of 7)
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term animal studies to evaluate the carcinogenic potential of gemcitabine for injection have not been conducted. Gemcitabine was mutagenic in an in vitro mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay. Gemcitabine IP doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/m2 basis) in male mice had an effect on fertility with moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day administered intravenously (about 1/200 the human dose on a mg/m2 basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1300 the human dose on a mg/m2 basis).
14 CLINICAL STUDIES
14.1 Ovarian Cancer
The safety and efficacy of gemcitabine for injection was studied in a randomized trial of 356 women with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either gemcitabine for injection 1000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after gemcitabine for injection infusion on Day 1 of each cycle (n=178) or to carboplatin AUC 5 administered on Day 1 of each 21-day cycle (n=178). The primary efficacy outcome measure was progression free survival (PFS).
Patient characteristics are shown in Table 11. The addition of gemcitabine for injection to carboplatin resulted in statistically significant improvements in PFS and overall response rate as shown in Table 12 and Figure 1. Approximately 75% of patients in each arm received additional chemotherapy for disease progression; 13 of 120 patients in the carboplatin alone arm received gemcitabine for injection for treatment of disease progression. There was no significant difference in overall survival between the treatment arms.
Table 11: Randomized Trial of Gemcitabine For Injection plus Carboplatin versus Carboplatin in Ovarian Cancer — Baseline Demographics and Clinical Characteristics
Gemcitabine For Injection/Carboplatin | Carboplatin | |
Number of randomized patients | 178 | 178 |
Median age, years | 59 | 58 |
Range | 36 to 78 | 21 to 81 |
Baseline ECOG performance status 0 to 1a | 94% | 95% |
Disease Status | ||
Evaluable | 8% | 3% |
Bidimensionally measurable | 92% | 96% |
Platinum–free intervalb | ||
6 to 12 months | 40% | 40% |
>12 months | 59% | 60% |
First–line therapy | ||
Platinum–taxane combination | 70% | 71% |
Platinum–non–taxane combination | 29% | 28% |
Platinum monotherapy | 1% | 1% |
a 5 patients on gemcitabine for injection plus carboplatin arm and 4 patients on carboplatin arm with no baseline Eastern Cooperative Oncology Group (ECOG) performance status.
b 2 on gemcitabine for injection plus carboplatin arm and 1 on carboplatin arm had platinum-free interval <6 months.
Table 12: Randomized Trial of Gemcitabine For Injection plus Carboplatin versus Carboplatin in Ovarian Cancer — Efficacy Outcomes
Gemcitabine For Injection/Carboplatin (N=178) | Carboplatin (N=178) | |
Progression-free Survival Median (95% CIa) months | 8.6 (8, 9.7) | 5.8 (5.2, 7.1) |
Hazard Ratio (95%, C.I.) | 0.72 (0.57, 0.90) | |
p-valueb | p=0.0038 | |
Overall Survival Median (95% CI) months | 18 (16.2, 20.3) | 17.3 (15.2, 19.3) |
Hazard Ratio (95% CI) | 0.98 (0.78, 1.24) | |
p-valueb | p=0.8977 | |
Investigator Reviewed Overall Response Rate | 47.2% | 30.9% |
p-valuee | p=0.0016 | |
CRd PR plus PRNMe | 14.6%32.6% | 6.2%24.7% |
Independently Reviewed Overall Response Ratef | 46.3% | 35.6% |
p-valuee | p=0.11 | |
CRd PR plus PRNMe | 9.1%37.2% | 4%31.7% |
a CI=confidence interval
b Complete response
c Partial response plus partial response, non-measurable disease
d log Rank, unadjusted
e chi Square
f Independently reviewed cohort –gemcitabine for injection/carboplatin (n=121), carboplatin (n=101); independent reviewers unable to measure disease detected by sonography or physical exam
Figure 1: Kaplan–Meier Curve of Progression Free Survival in Gemcitabine For Injection Plus Carboplatin Versus Carboplatin in Ovarian Cancer (N=356)
14.2 Breast Cancer
The safety and efficacy of gemcitabine for injection were evaluated in a multi-national, randomized, open-label trial conducted in women receiving initial treatment for metastatic breast cancer in women who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated. Patients were randomized to receive gemcitabine for injection 1250 mg/m2 on Days 1 and 8 of a 21-day cycle and paclitaxel 175 mg/m2 administered prior to gemcitabine for injection on Day 1 of each cycle (n=267) or to receive paclitaxel 175 mg/m2 was administered on Day 1 of each 21-day cycle (n=262). The primary efficacy outcome measure was time to documented disease progression.
Table 13: Randomized Trial of Gemcitabine For Injection plus Paclitaxel versus Paclitaxel in Breast Cancer
Gemcitabine For Injection/Paclitaxel | Paclitaxel | |
Number of patients | 267 | 262 |
Demographic/Entry Characteristics Median age (years) Range | 53 26 to 83 | 52 26 to 75 |
Metastatic disease | 97% | 97% |
Baseline KPSa ≥90 | 70% | 74% |
Number of tumor sites 1 to 2 ≥ 3 | 57% 43% | 59% 41% |
Visceral disease | 73% | 73% |
Prior anthracycline | 97% | 96% |
Efficacy Outcomes | ||
Time to Documented Disease Progressionb | ||
Median in months (95% CI) | 5.2 (4.2, 5.6) | 2.9 (2.6, 3.7) |
Hazard Ratio (95% CI) | 0.650 (0.524, 0.805) | |
p-value | p<0.0001 | |
Overall Survivalc | ||
Median Survival in months (95% CI) | 18.6 (16.5, 20.7) | 15.8 (14.1, 17.3) |
Hazard Ratio (95% CI) | 0.86 (0.71, 1.04) | |
p-value | Not Significant | |
Overall Response Rate (95% CI) | 40.8% (34.9, 46.7) | 22.1% (17.1, 27.2) |
p-value | p<0.0001 |
a Karnofsky Performance Status.
b These represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm. c Based on the ITT population
Figure 2: Kaplan–Meier Curve of Time to Documented Disease Progression in Gemcitabine For Injection Plus Paclitaxel versus Paclitaxel Breast Cancer Study (N=529)
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