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GEMCITABINE - SOLUTION (gemcitabine injection) Clinical Studies

14 CLINICAL STUDIES

14.1 Ovarian Cancer

The efficacy of gemcitabine was evaluated in a randomized trial (Study 1) conducted in 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 1000 mg/m2 on Days 1 and 8 of each 21-day cycle with carboplatin AUC 4 on Day 1 after gemcitabine administration (n = 178) or carboplatin AUC 5 on Day 1 of each 21-day cycle (n = 178). The major efficacy outcome measure was progression-free survival (PFS).

A total of 356 patients were enrolled. Demographics and baseline characteristics are shown in Table 16. Efficacy results are presented in Table 17 and Figure 1. The addition of gemcitabine to carboplatin resulted in statistically significant improvements in PFS and overall response rate. 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 treatment of disease progression. There was no significant difference in overall survival between the treatment arms.

Table 16: Baseline Demographics and Clinical Characteristics for Study 1
Gemcitabine/Carboplatin
(N=178)
Carboplatin
(N=178)
*
5 patients on gemcitabine/carboplatin arm and 4 patients on carboplatin arm had no baseline Eastern Cooperative Oncology Group (ECOG) performance status.
2 patients on gemcitabine/carboplatin arm and 1 patient on carboplatin arm had platinum-free interval <6 months.
Median age, years 59 58
  Range 36 to 78 21 to 81
Baseline ECOG performance status 0–1* 94% 95%
Disease Status
  Evaluable 8% 3%
  Bidimensionally measurable 92% 96%
Platinum-free interval
  6–12 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%
Table 17: Efficacy Results in Study 1
Efficacy Parameter Gemcitabine/Carboplatin
(N=178)
Carboplatin
(N=178)
*
CI=confidence interval.
Log rank, unadjusted.
Chi square.
§
CR=Complete response
PR with PRNM=Partial response with partial response, non-measurable disease
#
Independently reviewed cohort - gemcitabine/carboplatin (n=121), carboplatin (n=101); independent reviewers unable to measure disease detected by sonography or physical exam.
Progression-Free Survival
  Median (95% CI *) in months 8.6 (8.0, 9.7) 5.8 (5.2, 7.1)
  Hazard Ratio (95% CI) 0.72 (0.57, 0.90)
p=value p=0.0038
Overall Survival
  Median (95% CI) in months 18.0 (16.2, 20.3) 17.3 (15.2, 19.3)
  Hazard Ratio (95% CI) 0.98 (0.78, 1.24)
p=value p=0.8977
Overall Response Rate by Investigator Review 47.2% 30.9%
p=value p=0.0016
CR§ 14.6% 6.2%
  PR with PRNM 32.6% 24.7%
Overall Response Rate by Independent Review# 46.3% 35.6%
p=value p=0.11
  CR§ 9.1% 4.0%
  PR with PRNM 37.2% 31.7%
Figure 1: Kaplan-Meier Curves for Progression-Free Survival in Study 1
Figure 1

14.2 Breast Cancer

The efficacy of gemcitabine was evaluated in a multinational, randomized, open-label trial conducted in women receiving initial treatment for metastatic breast cancer and who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated.

Patients were randomized to receive gemcitabine 1250 mg/m2 on Days 1 and 8 of each 21-day cycle with paclitaxel 175 mg/m2 administered on Day 1 before gemcitabine administration (n = 267) or paclitaxel 175 mg/m2 on Day 1 of each 21-day cycle (n = 262). The major efficacy outcome measure was time to documented disease progression.

A total of 529 patients were enrolled. Demographic and baseline characteristics were similar between treatment arms (Table 18).

Efficacy results are presented in Table 19 and Figure 2. The addition of gemcitabine to paclitaxel resulted in statistically significant improvement in time to documented disease progression and overall response rate compared to paclitaxel alone. There was no significant difference in overall survival.

Table 18: Baseline Demographics and Clinical Characteristics for Study 2
Gemcitabine/Paclitaxel
(N=267)
Paclitaxel
(N=262)
*
Karnofsky Performance Status.
Median age, years 53 52
  Range 26 to 83 26 to 75
Metastatic disease 97% 97%
Baseline KPS*≥90 70% 74%
Number of tumor sites
  1–2 57% 59%
  ≥3 43% 41%
Visceral disease 73% 73%
Prior anthracycline 97% 96%
Table 19: Efficacy Results in Study 2
Efficacy Parameter Gemcitabine/Paclitaxel
(N=267)
Paclitaxel
(N=262)
*
These represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm.
Based on the ITT population.
Time to Documented Disease Progression*
  Median (95% CI) in months 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 Survival
  Median (95% CI) in months 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
Figure 2: Kaplan-Meier Curves for Time to Documented Disease Progression in Study 2
Figure 2

14.3 Non-Small Cell Lung Cancer

The efficacy of gemcitabine was evaluated in two randomized, multicenter trials.

Study 3: 28-Day Schedule

A multinational, randomized trial (Study 3) compared gemcitabine with cisplatin to cisplatin alone in the treatment of patients with inoperable Stage IIIA, IIIB, or IV NSCLC who had not received prior chemotherapy. Patients were randomized to receive either gemcitabine 1000 mg/m2 on Days 1, 8, and 15 of each 28-day cycle with cisplatin 100 mg/m2 on Day 1 after gemcitabine administration (N=260) or cisplatin 100 mg/m2 on Day 1 of each 28-day cycle (N=262). The major efficacy outcome measure was overall survival.

A total of 522 patients were enrolled. Demographics and baseline characteristics (Table 20) were similar between arms with the exception of histologic subtype of NSCLC, with 48% of patients on the cisplatin arm and 37% of patients on the gemcitabine with cisplatin arm having adenocarcinoma.

Efficacy results are presented in Table 21 and Figure 3.

Study 4: 21-Day Schedule

A randomized (1:1), multicenter trial (Study 4) was conducted in patients with Stage IIIB or IV NSCLC. Patients were randomized to receive gemcitabine 1250 mg/m2 on Days 1 and 8 of each 21-day cycle with cisplatin 100 mg/m2 on Day 1 after gemcitabine administration or etoposide 100 mg/m2 intravenously on Days 1, 2, and 3 with cisplatin 100 mg/m2 on Day 1 of each 21-day cycle. The major efficacy outcome measure was response rate.

A total of 135 patients were enrolled. Demographics and baseline characteristics are summarized in Table 20.

Efficacy results are presented in Table 21. There was no significant difference in survival between the two treatment arms. The median survival was 8.7 months for the gemcitabine with cisplatin arm versus 7 months for the etoposide with cisplatin arm. Median time to disease progression for the gemcitabine with cisplatin arm was 5 months compared to 4.1 months on the etoposide with cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the gemcitabine with cisplatin arm was 33% compared to 14% on the etoposide with cisplatin arm (Fisher's Exact p=0.01, two-sided).

Figure 3: Kaplan-Meier Curves for Overall Survival in Study 3
Figure 3
Table 20: Baseline Demographics and Clinical Characteristics for Studies 3 and 4
Trial 28-day Schedule (Study 3) 21-day Schedule (Study 4)
Gemcitabine/Cisplatin
(N=260)
Cisplatin
(N=262)
Gemcitabine/Cisplatin
(N=69)
Etoposide/Cisplatin
(N=66)
*
N/A Not applicable.
Karnofsky Performance Status.
Male 70% 71% 93% 92%
Median age, years 62 63 58 60
Range 36 to 88 35 to 79 33 to 76 35 to 75
Stage IIIA 7% 7% N/A* N/A*
Stage IIIB 26% 23% 48% 52%
Stage IV 67% 70% 52% 49%
Baseline KPS 70 to 80 41% 44% 45% 52%
Baseline KPS 90 to 100 57% 55% 55% 49%
Table 21: Efficacy Results for Studies 3 and 4
Trial 28-day Schedule (Study 3) 21-day Schedule (Study 4)
Efficacy Parameter Gemcitabine/Cisplatin
(N=260)
Cisplatin
(N=262)
Gemcitabine/Cisplatin
(N=69)
Etoposide/Cisplatin
(N=66)
*
CI=confidence intervals.
p-value two-sided Fisher's Exact test for difference in binomial proportions;log rank test for time-to-event analyses.
Survival
  Median (95% CI*) in months 9.0 (8.2, 11.0) 7.6 (6.6, 8.8) 8.7 (7.8, 10.1) 7.0 (6.0, 9.7)
  p-value p=0.008 p=0.18
Time to Disease Progression
  Median (95% CI*) in months 5.2 (4.2, 5.7) 3.7 (3.0, 4.3) 5.0 (4.2, 6.4) 4.1 (2.4, 4.5)
  p-value p=0.009 p=0.015
Tumor Response 26% 10% 33% 14%
  p-value p<0.0001 p=0.01

14.4 Pancreatic Cancer

The efficacy of gemcitabine was evaluated in two trials (Studies 5 and 6), a randomized, single-blind, two-arm, active-controlled trial (Study 5) conducted in patients with locally advanced or metastatic pancreatic cancer who had received no prior chemotherapy and in a single-arm, open-label, multicenter trial (Study 6) conducted in patients with locally advanced or metastatic pancreatic cancer previously treated with fluorouracil or a fluorouracil-containing regimen. In Study 5, patients were randomized to receive either gemcitabine 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly for 3 consecutive weeks every 28-days in subsequent cycles (n=63) or fluorouracil 600 mg/m2 intravenously over 30 minutes once weekly (n=63). In Study 6, all patients received gemcitabine 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly for 3 consecutive weeks every 28-days in subsequent cycles.

The major efficacy outcome measure in both trials was "clinical benefit response". A patient was considered to have had a clinical benefit response if either of the following occurred:

  • The patient achieved a ≥50% reduction in pain intensity (Memorial Pain Assessment Card) or analgesic consumption, or a 20-point or greater improvement in performance status (Karnofsky Performance Status) for a period of at least 4 consecutive weeks, without showing any sustained worsening in any of the other parameters. Sustained worsening was defined as 4 consecutive weeks with either any increase in pain intensity or analgesic consumption or a 20-point decrease in performance status occurring during the first 12 weeks of therapy.

OR

  • The patient was stable on all of the aforementioned parameters, and showed a marked, sustained weight gain (≥7% increase maintained for ≥4 weeks) not due to fluid accumulation.

Study 5 enrolled 126 patients. Demographics and baseline characteristics were similar between the arms (Table 22).

The efficacy results are shown in Table 23 and Figure 4. Patients treated with gemcitabine had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to those randomized to receive fluorouracil. No confirmed objective tumor responses were observed in either treatment arm.

Table 22: Baseline Demographics and Clinical Characteristics for Study 5
Gemcitabine
(N=63)
Fluorouracil
(N=63)
*
Karnofsky Performance Status.
Male 54% 54%
Median age 62 years 61 years
Range 37 to 79 36 to 77
Stage IV disease 71% 76%
Baseline KPS*≤70 70% 68%
Table 23: Efficacy Results in Study 5
Efficacy Parameter Gemcitabine
(N=63)
Fluorouracil
(N=63)
*
p-value for clinical benefit response calculated using the two-sided test for difference in binomial proportions. All other p-values are calculated using log rank test.
Clinical Benefit Response 22.2% 4.8%
  p-value* p=0.004
Overall Survival
  Median (95% CI) in months 5.7 (4.7, 6.9) 4.2 (3.1, 5.1)
  p-value* p=0.0009
Time to Disease Progression
  Median (95% CI) in months 2.1 (1.9, 3.4) 0.9 (0.9, 1.1)
  p-value* p=0.0013
Figure 4: Kaplan-Meier Curves for Overall Survival in Study 5
Figure 4

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