"The U.S. Food and Drug Administration today granted accelerated approval to Lynparza (olaparib), a new drug treatment for women with advanced ovarian cancer associated with defective BRCA genes, as detected by an FDA-approved test.
Mechanism Of Action
Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S-phase boundary. Gemcitabine is metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate deoxynucleoside triphosphates for DNA synthesis, resulting in reductions in deoxynucleotide concentrations, including dCTP. Gemcitabine triphosphate competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP by the action of the diphosphate enhances the incorporation of gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strands, which eventually results in the initiation of apoptotic cell death.
Absorption And Distribution
The pharmacokinetics of gemcitabine were examined in 353 patients, with various solid tumors. Pharmacokinetic parameters were derived using data from patients treated for varying durations of therapy given weekly with periodic rest weeks and using both short infusions ( < 70 minutes) and long infusions (70 to 285 minutes). The total Gemzar dose varied from 500 to 3600 mg/m².
The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m² following infusions lasting < 70 minutes. For long infusions, the volume of distribution rose to 370 L/m².
Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. Population pharmacokinetic analyses of combined single and multiple dose studies showed that the volume of distribution of gemcitabine was significantly influenced by duration of infusion and gender. Gemcitabine plasma protein binding is negligible.
Gemcitabine disposition was studied in 5 patients who received a single 1000 mg/m²/30 minute infusion of radiolabeled drug. Within one (1) week, 92% to 98% of the dose was recovered, almost entirely in the urine. Gemcitabine ( < 10%) and the inactive uracil metabolite, 2´-deoxy-2´,2´-difluorouridine (dFdU), accounted for 99% of the excreted dose. The metabolite dFdU is also found in plasma.
The active metabolite, gemcitabine triphosphate, can be extracted from peripheral blood mononuclear cells. The half-life of the terminal phase for gemcitabine triphosphate from mononuclear cells ranges from 1.7 to 19.4 hours.
Clearance of gemcitabine was affected by age and gender. The lower clearance in women and the elderly results in higher concentrations of gemcitabine for any given dose. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations. Table 10 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and gender.
Table 10: Gemcitabine Clearance and Half-Life for the
|Age||Clearance Men (L/hr/m²)||Clearance Women (L/hr/m²)||Half-Lifea Men (min)||Half-Lifea Women (min)|
|a Half-life for patients receiving < 70 minute infusion.|
Gemcitabine half-life for short infusions ranged from 42 to 94 minutes, and the value for long infusions varied from 245 to 638 minutes, depending on age and gender, reflecting a greatly increased volume of distribution with longer infusions.
When Gemzar (1250 mg/m² on Days 1 and 8) and cisplatin (75 mg/m² on Day 1) were administered in NSCLC patients, the clearance of gemcitabine on Day 1 was 128 L/hr/m² and on Day 8 was 107 L/hr/m². Analysis of data from metastatic breast cancer patients shows that, on average, Gemzar has little or no effect on the pharmacokinetics (clearance and half-life) of paclitaxel and paclitaxel has little or no effect on the pharmacokinetics of gemcitabine. Data from NSCLC patients demonstrate that Gemzar and carboplatin given in combination does not alter the pharmacokinetics of gemcitabine or carboplatin compared to administration of either single agent. However, due to wide confidence intervals and small sample size, interpatient variability may be observed.
The safety and efficacy of Gemzar 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 Gemzar 1000 mg/m² on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after Gemzar 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 Gemzar 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 Gemzar for treatment of disease progression. There was no significant difference in overall survival between the treatment arms.
Table 11: Randomized Trial of Gemzar plus Carboplatin
versus Carboplatin in Ovarian Cancer – Baseline Demographics and Clinical
|Number of randomized patients||178||178|
|Median age, years||59||58|
|Range||36 to 78||21 to 81|
|Baseline ECOG performance status 0-1a||94%||95%|
|> 12 months||59%||60%|
|a 5 patients on Gemzar plus carboplatin arm
and 4 patients on carboplatin arm with no baseline Eastern Cooperative Oncology
Group (ECOG) performance status.
b 2 on Gemzar plus carboplatin arm and 1 on carboplatin arm had platinum-free interval < 6 months.
Table 12: Randomized Trial of Gemzar plus Carboplatin
versus Carboplatin in Ovarian Cancer – Efficacy Outcomes
|Progression-free Survival Median (95% CIa) months||8.6 (8.0, 9.7)||5.8 (5.2, 7.1)|
|Hazard Ratio (95% CI)||0.72 (0.57, 0.90)|
|Median (95% CI) months||18.0 (16.2, 20.3)||17.3 (15.2, 19.3)|
|Hazard Ratio (95% CI)||0.98 (0.78, 1.24)|
|Overall Response Rate||47.2%||30.9%|
|PR plus PRNMe||32.6%||24.7%|
|Independently Reviewed Overall Response Ratef||46.3%||35.6%|
|PR plus PRNMe||37.2%||31.7%|
|a CI=confidence interval.
b Log rank, unadjusted.
c Chi square.
d CR=Complete response.
e PR plus PRNM=Partial response plus partial response, non-measurable disease.
f Independently reviewed cohort - Gemzar/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 Gemzar plus Carboplatin versus Carboplatin in Ovarian Cancer
The safety and efficacy of Gemzar 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 Gemzar 1250 mg/m² on Days 1 and 8 of a 21-day cycle and paclitaxel 175 mg/m² administered prior to Gemzar 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.
A total of 529 patients were enrolled; 267 were randomized to Gemzar and paclitaxel and 262 to paclitaxel alone. Demographic and baseline characteristics were similar between treatment arms (see Table 13). Efficacy results are presented in Table 13 and Figure 2. The addition of Gemzar 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 13: Randomized Trial of Gemzar plus Paclitaxel
versus Paclitaxel in Breast Cancer
|Number of patients||267||262|
|Median age (years)||53||52|
|Range||26 to 83||26 to 75|
|Baseline KPSa ≥ 90||70%||74%|
|Number of tumor sites|
|Time to Documented Disease Progressionb|
|Median in months(95% CI)||5.2
|Hazard Ratio (95% CI)||0.650 (0.524, 0.805)|
|p-value||p < 0.0001|
|Median Survival in months(95% CI)||18.6
|Hazard Ratio (95% CI)||0.86 (0.71, 1.04)|
|Overall Response Rate(95% CI)||40.8%
|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 Gemzar plus Paclitaxel versus Paclitaxel Breast Cancer
Non-Small Cell Lung Cancer (NSCLC)
The safety and efficacy of Gemzar was evaluated in two randomized, multicenter trials.
A multinational, randomized trial compared Gemzar plus 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 Gemzar 1000 mg/m² on Days 1, 8, and 15 of a 28-day cycle with cisplatin 100 mg/m² administered on Day 1 of each cycle or to receive cisplatin 100 mg/m² on Day 1 of each 28-day cycle. The primary efficacy outcome measure was overall survival. A total of 522 patients were enrolled at clinical centers in Europe, the US, and Canada. Patient demographics and baseline characteristics (shown in Table 14) 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 Gemzar plus cisplatin arm having adenocarcinoma. Efficacy results are presented in Table 14 and Figure 3 for overall survival.
A randomized (1:1), multicenter trial was conducted in 135 patients with Stage IIIB or IV NSCLC. Patients were randomized to receive Gemzar 1250 mg/m² on Days 1 and 8, and cisplatin 100 mg/m² on Day 1 of a 21-day cycle or to receive etoposide 100 mg/m² intravenously on Days 1, 2, and 3 and cisplatin 100 mg/m² on Day 1 of a 21 -day cycle.
There was no significant difference in survival between the two treatment arms (Log rank p=0.18, two- sided, see Table 14). The median survival was 8.7 months for the Gemzar plus cisplatin arm versus 7.0 months for the etoposide plus cisplatin arm. Median time to disease progression for the Gemzar plus cisplatin arm was 5.0 months compared to 4.1 months on the etoposide plus cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the Gemzar plus cisplatin arm was 33% compared to 14% on the etoposide plus cisplatin arm (Fisher's Exact p=0.01, two-sided).
Figure 3: Kaplan-Meier Survival Curve in Gemzar plus
Cisplatin versus Cisplatin in Patients with NSCLC Study (N=522).
Table 14: Randomized Trials of Gemzar plus Cisplatin
in Patients with NSCLC
|Trial Treatment Arm||28-day Schedulea||21-day Scheduleb|
|Gemzar plus Cisplatin||Cisplatin||Gemzar plus Cisplatin||Etoposide plus Cisplatin|
|Number of patients||260||262||69||66|
|Median age, years||62||63||58||60|
|Range||36 to 88||35 to 79||33 to 76||35 to 75|
|Baseline KPSd 70 to 80||41%||44%||45%||52%|
|Baseline KPSd 90 to100||57%||55%||55%||49%|
|Median in months||9.0||7.6||8.7||7.0|
|(95% CIe) months||8.2, 11.0||6.6, 8.8||7.8, 10.1||6.0, 9.7|
|Time to Disease|
|Median in months||5.2||3.7||5.0||4.1|
|(95% CIe) months||4.2, 5.7||3.0, 4.3||4.2, 6.4||2.4, 4.5|
|p-valuef||p < 0.0001||p=0.01|
|a 28-day schedule — Gemzar plus cisplatin:
Gemzar 1000 mg/m² on Days 1, 8, and 15 and cisplatin 100 mg/m² on Day 1 every
28 days; Single-agent cisplatin: cisplatin 100 mg/m² on Day 1 every 28 days.
b 21-day schedule — Gemzar plus cisplatin: Gemzar 1250 mg/m² on Days 1 and 8 and cisplatin 100 mg/m² on Day 1 every 21 days; Etoposide plus Cisplatin: cisplatin 100 mg/m² on Day 1 and intravenous etoposide 100 mg/m² on Days 1, 2, and 3 every 21 days.
c N/A Not applicable.
d Karnofsky Performance Status.
e CI=confidence intervals.
f p-value two-sided Fisher's Exact test for difference in binomial proportions; log rank test for time-to-event analyses.
The safety and efficacy of Gemzar was evaluated in two trials, a randomized, single-blind, two-arm, activecontrolled trial 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 conducted in patients with locally advanced or metastatic pancreatic cancer previously treated with 5-FU or a 5-FU-containing regimen. The first trial randomized patients to receive Gemzar 1000 mg/m² intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles (n=63) or to 5-fluorouracil (5-FU) 600 mg/m² intravenously over 30 minutes once weekly (n=63). In the second trial, all patients received Gemzar 1000 mg/m² intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles.
The primary 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.
- 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.
The randomized trial enrolled 126 patients across 17 sites in the US and Canada. The demographic and entry characteristics were similar between the arms (Table 15). The efficacy outcome results are shown in Table 15 and for overall survival in Figure 4. Patients treated with Gemzar had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to those randomized to receive 5-FU. No confirmed objective tumor responses were observed in either treatment arm.
Table 15: Randomized Trial of Gemzar versus
5-Fluorouracil in Pancreatic Cancer
|Number of patients||63||63|
|Median age||62 years||61 years|
|Range||37 to 79||36 to 77|
|Stage IV disease||71%||76%|
|Baseline KPSa ≤ 70||70%||68%|
|Clinical benefit response||22.2%||4.8%|
|Median||5.7 months||4.2 months|
|(95% CI)||(4.7, 6.9)||(3.1, 5.1)|
|Time to Disease Progression|
|Median||2.1 months||0.9 months|
|(95% CI)||(1.9, 3.4)||(0.9, 1.1)|
|a Karnofsky Performance Status.
b 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.
Figure 4: Kaplan-Meier Survival Curve.
Last reviewed on RxList: 5/23/2016
This monograph has been modified to include the generic and brand name in many instances.
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