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

figure1
(click image for full-size original)

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

figure2
(click image for full-size original)

Figure 2: Kaplan–Meier Curve of Time to Documented Disease Progression in Gemcitabine For Injection Plus Paclitaxel versus Paclitaxel Breast Cancer Study (N=529)

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2024. All Rights Reserved.