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Eloxatin

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Eloxatin

CLINICAL PHARMACOLOGY

Mechanism of Action

Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo DACH platinum, which covalently bind with macromolecules. Both inter- and intrastrand Pt-DNA crosslinks are formed. Crosslinks are formed between the N7 positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific. In vivo studies have shown antitumor activity of oxaliplatin against colon carcinoma. In combination with 5-fluorouracil, oxaliplatin exhibits in vitro and in vivo antiproliferative activity greater than either compound alone in several tumor models [HT29 (colon), GR (mammary), and L1210 (leukemia)].

Pharmacokinetics

The reactive oxaliplatin derivatives are present as a fraction of the unbound platinum in plasma ultrafiltrate. The decline of ultrafilterable platinum levels following oxaliplatin administration is triphasic, characterized by two relatively short distribution phases (t½α; 0.43 hours and t½β; 16.8 hours) and a long terminal elimination phase (t½γ; 391 hours). Pharmacokinetic parameters obtained after a single 2-hour intravenous infusion of ELOXATIN at a dose of 85 mg/m² expressed as ultrafilterable platinum were Cmax of 0.814 mcg /mL and volume of distribution of 440 L.

Interpatient and intrapatient variability in ultrafilterable platinum exposure (AUC0-48hr) assessed over 3 cycles was moderate to low (23% and 6%, respectively). A pharmacodynamic relationship between platinum ultrafiltrate levels and clinical safety and effectiveness has not been established.

Distribution

At the end of a 2-hour infusion of ELOXATIN, approximately 15% of the administered platinum is present in the systemic circulation. The remaining 85% is rapidly distributed into tissues or eliminated in the urine. In patients, plasma protein binding of platinum is irreversible and is greater than 90%. The main binding proteins are albumin and gamma-globulins. Platinum also binds irreversibly and accumulates (approximately 2-fold) in erythrocytes, where it appears to have no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following 85 mg/m² every two weeks.

Metabolism

Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation. There is no evidence of cytochrome P450-mediated metabolism in vitro.

Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from patients, including several cytotoxic species (monochloro DACH platinum, dichloro DACH platinum, and monoaquo and diaquo DACH platinum) and a number of noncytotoxic, conjugated species.

Elimination

The major route of platinum elimination is renal excretion. At five days after a single 2-hour infusion of ELOXATIN, urinary elimination accounted for about 54% of the platinum eliminated, with fecal excretion accounting for only about 2%. Platinum was cleared from plasma at a rate (10 – 17 L/h) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/h). There was no significant effect of gender on the clearance of ultrafilterable platinum. The renal clearance of ultrafilterable platinum is significantly correlated with GFR.

Pharmacokinetics in Special Populations

Pediatric

[See Use In Specific Patient Populations].

Renal Impairment

A study was conducted in 38 patients with advanced GI cancer and varying degrees of renal impairment. Patients in the normal (creatinine clearance (CrCL) > 80 mL/min, N=11), mild (CrCL=50-80 mL/min, N=13), and moderate (CrCL=30-49 mL/min, N=10) groups were treated with 85 mg/m² ELOXATIN and those in the severe (CrCL < 30 mL/min, N=4) group were treated with 65 mg/m² ELOXATIN. The mean AUC of unbound platinum was 40%, 95%, and 342% higher in the mild, moderate, and severe groups, respectively, than in the normal group. Mean Cmax of unbound platinum appeared to be similar among the normal, mild and moderate renal function groups, but was 38% higher in the severe group than in the normal group. Caution should be exercised in renally impaired patients [see Use in Specific Populations]. The starting dose of ELOXATIN should be reduced in patients with severe renal impairment [see DOSAGE AND ADMINISTRATION].

Drug - Drug Interactions

No pharmacokinetic interaction between 85 mg/m² of ELOXATIN and infusional 5-fluorouracil has been observed in patients treated every 2 weeks, but increases of 5-fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m² of ELOXATIN administered every 3 weeks. In vitro, platinum was not displaced from plasma proteins by the following medications: erythromycin, salicylate, sodium valproate, granisetron, and paclitaxel. In vitro, oxaliplatin is not metabolized by, nor does it inhibit, human cytochrome P450 isoenzymes. No P450-mediated drug-drug interactions are therefore anticipated in patients. Since platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by co-administration of potentially nephrotoxic compounds, although this has not been specifically studied.

Clinical Studies

Combination Adjuvant Therapy with ELOXATIN and Infusional 5fluorouracil/leucovorin in Patients with Colon Cancer

An international, multicenter, randomized study compared the efficacy and evaluated the safety of ELOXATIN in combination with an infusional schedule of 5-fluorouracil/leucovorin to infusional 5-fluorouracil/leucovorin alone, in patients with stage II (Dukes' B2) or III (Dukes' C) colon cancer who had undergone complete resection of the primary tumor. The primary objective of the study was to compare the 3-year disease-free survival (DFS) in patients receiving ELOXATIN and infusional 5-fluorouracil/leucovorin to those receiving 5-fluorouracil/leucovorin alone. Patients were to be treated for a total of 6 months (i.e., 12 cycles). A total of 2246 patients were randomized; 1123 patients per study arm. Patients in the study had to be between 18 and 75 years of age, have histologically proven stage II (T3-T4 N0 M0; Dukes' B2) or III (any T N1-2 M0; Dukes' C) colon carcinoma (with the inferior pole of the tumor above the peritoneal reflection, i.e., ≥ 15 cm from the anal margin) and undergone (within 7 weeks prior to randomization) complete resection of the primary tumor without gross or microscopic evidence of residual disease. Patients had to have had no prior chemotherapy, immunotherapy or radiotherapy, and have an ECOG performance status of 0,1, or 2 (KPS ≥ 60%), absolute neutrophil count (ANC) > 1.5x109/L, platelets ≥ 100x109/L, serum creatinine ≤ 1.25 x ULN total bilirubin < 2 x ULN, AST/ALT < 2 x ULN and carcino-embyrogenic antigen (CEA) < 10 ng/mL. Patients with preexisting peripheral neuropathy (NCI grade ≥ 1) were ineligible for this trial.

The following table shows the dosing regimens for the two arms of the study.

Table 15 : Dosing Regimens in Adjuvant Therapy Study

Treatment Arm Dose Regimen
ELOXATIN + 5-FU/LV (FOLFOX4) (N =1123) Day 1: ELOXATIN: 85 mg/m² (2-hour infusion) + LV: 200 mg/m² (2-hour infusion), followed by 5-FU: 400 mg/m² (bolus), 600 mg/m² (22-hour infusion)
Day 2: LV: 200 mg/m² (2-hour infusion), followed by 5-FU: 400 mg/m² (bolus), 600 mg/m² (22-hour infusion)
every 2 weeks 12 cycles
5-FU/LV (N=1123) Day 1: LV: 200 mg/m² (2-hour infusion), followed by 5-FU: 400 mg/m² (bolus), 600 mg/m² (22-hour infusion)
Day 2: LV: 200 mg/m² (2-hour infusion), followed by 5-FU: 400 mg/m² (bolus), 600 mg/m² (22-hour infusion)
every 2 weeks 12 cycles

The following tables show the baseline characteristics and dosing of the patient population entered into this study. The baseline characteristics were well balanced between arms.

Table 16 : Patient Characteristics in Adjuvant Therapy Study

  ELOXATIN + infusional 5-FU/LV
N=1123
Infusional 5-FU/LV
N=1123
Sex: Male (%) 56.1 52.4
Female (%) 43.9 47.6
Median age (years) 61 60
< 65 years of age (%) 64.4 66.2
≥ 65 years of age (%) 35.6 33.8
Karnofsky Performance Status (KPS) (%)
100 29.7 30.5
90 52.2 53.9
80 4.4 3.3
70 13.2 11.9
≤ 60 0.6 0.4
Primary site (%)
Colon including cecum 54.6 54.4
Sigmoid 31.9 33.8
Recto sigmoid 12.9 10.9
Other including rectum 0.6 0.9
Bowel obstruction (%)
Yes 17.9 19.3
Perforation (%)
Yes 6.9 6.9
Stage at Randomization (%)
II (T=3,4 N=0, M=0) 40.1 39.9
III (T=any, N=1,2, M=0) 59.6 59.3
IV (T=any, N=any, M=1) 0.4 0.8
Staging – T (%)
T1 0.5 0.7
T2 4.5 4.8
T3 76 75.9
T4 19 18.5
Staging – N (%)
N0 40.2 39.9
N1 39.4 39.4
N2 20.4 20.7
Staging – M (%)
M1 0.4 0.8

Table 17 : Dosing in Adjuvant Therapy Study

  ELOXATIN + infusional 5-FU/LV
N=1108
Infusional 5-FU/LV
N=1111
Median Relative Dose Intensity (%)
  5-FU 84.4 97.7
  ELOXATIN 80.5 N/A
Median Number of Cycles 12 12
Median Number of cycles with ELOXATIN 11 N/A

The following table and figures summarize the disease-free survival (DFS) results in the overall randomized population and in patients with stage II and III disease based on an ITT analysis. The median duration of follow-up was approximately 77 months.

Table 18 : Summary of DFS analysis - ITT analysis

  ELOXATIN + Infusional 5-FU/LV Infusional 5-FU/LV
Parameter    
Overall
N 1123 1123
Number of events – relapse or death (%) 304 (27.1) 360 (32.1)
Disease-free survival % [95% CI] * 73.3 [70.7, 76.0] 67.4 [64.6, 70.2]
Hazard ratio [95% CI] ** 0.80 [0.68, 0.93]
Stratified Logrank test p=0.003
Stage III (Dukes' C)
N 672 675
Number of events –relapse or death (%) 226 (33.6) 271 (40.1)
Disease-free survival % [95% CI] * 66.4 [62.7, 70.0] 58.9 [55.2, 62.7]
Hazard ratio [95% CI] ** 0.78 [0.65, 0.93]
Logrank test p=0.005
Stage II (Dukes' B2)
N 451 448
Number of events – relapse or death (%) 78 (17.3) 89 (19.9)
Disease-free survival % [95% CI] * 83.7 [80.2, 87.1] 79.9 [76.2, 83.7]
Hazard ratio [95% CI] ** 0.84 [0.62, 1.14]
Logrank test p=0.258
Data cut off for disease free survival 1 June 2006
* Disease-free survival at 5 years
**A hazard ratio of less than 1.00 favors Eloxatin + Infusional 5-fluorouracil/leucovorin

In the overall and stage III colon cancer populations DFS was statistically significantly improved in the ELOXATIN combination arm compared to infusional 5-fluorouracil/leucovorin alone. However, a statistically significant improvement in DFS was not noted in Stage II patients.

Figure 2 shows the DFS Kaplan-Meier curves for the comparison of ELOXATIN and infusional 5-fluorouracil/leucovorin combination and infusional 5-fluorouracil/leucovorin alone for the overall population (ITT analysis).

Figure 3 shows the DFS Kaplan-Meier curves for the comparison of ELOXATIN and infusional 5-fluorouracil/leucovorin combination and infusional 5-fluorouracil/leucovorin alone in Stage III patients.

Figure 2 : DFS Kaplan-Meier curves by treatment arm (cutoff: 1 June 2006) – ITT population

Kaplan-Meier curves by treatment arm (cutoff: 1 June 2006) – ITT population - Illustration

Figure 3 : DFS Kaplan-Meier curves by treatment arm in Stage III patients (cutoff: 1 June 2006) – ITT population

DFS Kaplan-Meier curves by treatment arm in Stage III patients (cutoff: 1 June 2006) – ITT population -  Illustration

The following table summarizes the overall survival (OS) results in the overall randomized population and in patients with stage II and III disease, based on the ITT analysis.

Table 19 : Summary of OS analysis - ITT analysis

Parameter Eloxatin + Infusional 5-FU/LV Infusional 5-FU/LV
Overall
N 1123 1123
Number of death events (%) 245 (21.8) 283 (25.2)
Hazard ratio* [95% CI] 0.84 [0.71 , 1.00]
Stage III (Dukes' C)
N 672 675
Number of death events (%) 182 (27.1) 220 (32.6)
Hazard ratio* [95% CI] 0.80 [0.65 , 0.97]
Stage II (Dukes' B2)
N 451 448
Number of death events (%) 63 (14.0) 63 (14.1)
Hazard ratio* [95% CI] 1.00 [0.70 , 1.41]
*A hazard ratio of less than 1.00 favors Eloxatin + Infusional 5-fluorouracil/leucovorin
Data cut off for overall survival 16 January 2007

Combination Therapy with ELOXATIN and 5-fluorouracil/leucovorin in Patients Previously Untreated for Advanced Colorectal Cancer

A North American, multicenter, open-label, randomized controlled study was sponsored by the National Cancer Institute (NCI) as an intergroup study led by the North Central Cancer Treatment Group (NCCTG). The study had 7 arms at different times during its conduct, four of which were closed due to either changes in the standard of care, toxicity, or simplification. During the study, the control arm was changed to irinotecan plus 5-fluorouracil/leucovorin. The results reported below compared the efficacy and safety of two experimental regimens, ELOXATIN in combination with infusional 5-fluorouracil/leucovorin and a combination of ELOXATIN plus irinotecan, to an approved control regimen of irinotecan plus 5-fluorouracil/leucovorin in 795 concurrently randomized patients previously untreated for locally advanced or metastatic colorectal cancer. After completion of enrollment, the dose of irinotecan plus 5-fluorouracil/leucovorin was decreased due to toxicity. Patients had to be at least 18 years of age, have known locally advanced, locally recurrent, or metastatic colorectal adenocarcinoma not curable by surgery or amenable to radiation therapy with curative intent, histologically proven colorectal adenocarcinoma, measurable or evaluable disease, with an ECOG performance status 0,1, or 2. Patients had to have granulocyte count ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, hemoglobin ≥ 9.0 gm/dL, creatinine ≤ 1.5 x ULN, total bilirubin ≤ 1.5 mg/dL, AST ≤ 5 x ULN, and alkaline phosphatase ≤ 5 x ULN. Patients may have received adjuvant therapy for resected Stage II or III disease without recurrence within 12 months. The patients were stratified for ECOG performance status (0, 1 vs. 2), prior adjuvant chemotherapy (yes vs. no), prior immunotherapy (yes vs. no), and age ( < 65 vs. ≥ 65 years). Although no post study treatment was specified in the protocol, 65 to 72% of patients received additional post study chemotherapy after study treatment discontinuation on all arms. Fifty-eight percent of patients on the ELOXATIN plus 5-fluorouracil/leucovorin arm received an irinotecan-containing regimen and 23% of patients on the irinotecan plus 5-fluorouracil/leucovorin arm received oxaliplatin-containing regimens. Oxaliplatin was not commercially available during the trial.

The following table presents the dosing regimens of the three arms of the study.

Table 20 : Dosing Regimens in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial

Treatment Arm Dose Regimen
ELOXATIN + 5-FU/LV (FOLFOX4) (N=267) Day 1: ELOXATIN: 85 mg/m² (2-hour infusion) + LV 200 mg/m² (2-hour infusion), followed by 5-FU: 400 mg/m² (bolus), 600 mg/m² (22-hour infusion)
Day 2: LV 200 mg/m² (2-hour infusion), followed by 5-FU: 400 mg/m² (bolus), 600 mg/m² (22-hour infusion)
every 2 weeks
Irinotecan + 5-FU/LV (IFL) (N=264) Day 1: irinotecan 125 mg/m² as a 90–min infusion + LV 20 mg/m² as a 15-min infusion or intravenous push, followed by every 6 weeks
ELOXATIN + Irinotecan (IROX) (N=264) Day 1: ELOXATIN: 85 mg/m² intravenous (2 hour infusion) + irinotecan 200 mg/m² intravenous over 30 minutes every 3 weeks

The following table presents the demographics of the patient population entered into this study.

Table 21 : Patient Demographics in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial

  ELOXATIN + 5-FU/LV
N=267
Irinotecan + 5-FU/LV
N=264
ELOXATIN + irinotecan
N=264
Sex: Male (%) 58.8 65.2 61
  Female (%) 41.2 34.8 39
Median age (years) 61 61 61
< 65 years of age (%) 61 62 63
≥ 65 years of age (%) 39 38 37
ECOG (%)
0.1 94.4 95.5 94.7
2 5.6 4.5 5.3
Involved organs (%)
  Colon only 0.7 0.8 0.4
  Liver only 39.3 44.3 39
  Liver + other 41.2 38.6 40.9
  Lung only 6.4 3.8 5.3
  Other (including lymph nodes) 11.6 11 12.9
  Not reported 0.7 1.5 1.5
Prior radiation (%) 3 1.5 3
Prior surgery (%) 74.5 79.2 81.8
Prior adjuvant (%) 15.7 14.8 15.2

The length of a treatment cycle was 2 weeks for the ELOXATIN and 5-fluorouracil/leucovorin regimen; 6 weeks for the irinotecan plus 5-fluorouracil/leucovorin regimen; and 3 weeks for the ELOXATIN plus irinotecan regimen. The median number of cycles administered per patient was 10 (23.9 weeks) for the ELOXATIN and 5-fluorouracil/leucovorin regimen, 4 (23.6 weeks) for the irinotecan plus 5-fluorouracil/leucovorin regimen, and 7 (21.0 weeks) for the ELOXATIN plus irinotecan regimen. Patients treated with the ELOXATIN and 5-fluorouracil/leucovorin combination had a significantly longer time to tumor progression based on investigator assessment, longer overall survival, and a significantly higher confirmed response rate based on investigator assessment compared to patients given irinotecan plus 5-fluorouracil/leucovorin. The following table summarizes the efficacy results.

Table 22 : Summary of Efficacy

  ELOXATIN + 5-FU/LV
N=267
irinotecan + 5-FU/LV
N=264
ELOXATIN + irinotecan
N=264
Survival (ITT)
Number of deaths N (%) 155 (58.1) 192 (72.7) 175 (66.3)
Median survival (months) 19.4 14.6 17.6
Hazard Ratio and (95% confidence interval) 0.65 (0.53-0.80)*
P-value < 0.0001* - -
TTP (ITT, investigator assessment)
Percentage of progressors 82.8 81.8 89.4
Median TTP (months) 8.7 6.9 6.5
Hazard Ratio and (95% confidence interval) *** 0.74 (0.61-0.89)*
P-value 0.0014* - -
Response Rate (investigator assessment)**
Patients with measurable disease 210 212 215
Complete response N (%) 13 (6.2) 5 (2.4) 7 (3.3)
Partial response N (%) 82 (39.0) 64 (30.2) 67 (31.2)
Complete and partial response N (%) 95 (45.2) 69 (32.5) 74 (34.4)
95% confidence interval (38.5 – 52.0) (26.2 – 38.9) (28.1 – 40.8)
P-value 0.0080* - -
*Compared to irinotecan plus 5-fluorouracil/leucovorin (IFL) arm
**Based on all patients with measurable disease at baseline The numbers in the response rate and TTP analysis are based on unblinded investigator assessment.
***A hazard ratio of less than 1.00 favors Eloxatin + Infusional 5-fluorouracil/leucovorin

Figure 4 illustrates the Kaplan-Meier survival curves for the comparison of ELOXATIN and 5-fluorouracil/leucovorin combination and ELOXATIN plus irinotecan to irinotecan plus 5-fluorouracil/leucovorin.

Figure 4 : Kaplan-Meier Overall Survival by treatment arm

Kaplan-Meier Overall Survival by treatment arm - Illustration

A descriptive subgroup analysis demonstrated that the improvement in survival for ELOXATIN plus 5-fluorouracil/leucovorin compared to irinotecan plus 5-fluorouracil/leucovorin appeared to be maintained across age groups, prior adjuvant therapy, and number of organs involved. An estimated survival advantage in ELOXATIN plus 5-fluorouracil/leucovorin versus irinotecan plus 5-fluorouracil/leucovorin was seen in both genders; however it was greater among women than men. Insufficient subgroup sizes prevented analysis by race.

Combination Therapy with ELOXATIN and 5-fluorouracil/leucovorin in Previously Treated Patients with Advanced Colorectal Cancer

A multicenter, open-label, randomized, three-arm controlled study was conducted in the US and Canada comparing the efficacy and safety of ELOXATIN in combination with an infusional schedule of 5-fluorouracil/leucovorin to the same dose and schedule of 5-fluorouracil/leucovorin alone and to single agent oxaliplatin in patients with advanced colorectal cancer who had relapsed/progressed during or within 6 months of first-line therapy with bolus 5-fluorouracil/leucovorin and irinotecan. The study was intended to be analyzed for response rate after 450 patients were enrolled. Survival will be subsequently assessed in all patients enrolled in the completed study. Accrual to this study is complete, with 821 patients enrolled. Patients in the study had to be at least 18 years of age, have unresectable, measurable, histologically proven colorectal adenocarcinoma, with a Karnofsky performance status > 50%. Patients had to have SGOT(AST) and SGPT(ALT) ≤ 2x the institution's upper limit of normal (ULN), unless liver metastases were present and documented at baseline by CT or MRI scan, in which case ≤ 5x ULN was permitted. Patients had to have alkaline phosphatase ≤ 2x the institution's ULN, unless liver metastases were present and documented at baseline by CT or MRI scan, in which cases ≤ 5x ULN was permitted. Prior radiotherapy was permitted if it had been completed at least 3 weeks before randomization.

The dosing regimens of the three arms of the study are presented in the table below.

Table 23 : Dosing Regimens in Refractory and Relapsed Colorectal Cancer Clinical Trial

Treatment Arm Dose Regimen
ELOXATIN + 5-FU/LV (N =152) Day 1: ELOXATIN: 85 mg/m² (2-hour infusion) + LV 200 mg/m² (2-hour infusion), followed by 5-FU: 400 mg/m² (bolus), 600 mg/m² (22-hour infusion)
Day 2: LV 200 mg/m² (2-hour infusion), followed by 5-FU: 400 mg/m² (bolus), 600 mg/m² (22-hour infusion)
every 2 weeks
5-FU/LV (N=151) Day 1: LV 200 mg/m² (2-hour infusion), followed by 5-FU: 400 mg/m² (bolus), 600 mg/m² (22-hour infusion)
Day 2: LV 200 mg/m² (2-hour infusion), followed by 5-FU: 400 mg/m² (bolus), 600 mg/m² (22-hour infusion)
every 2 weeks
ELOXATIN (N=156) Day 1: ELOXATIN 85 mg/m² (2-hour infusion) every 2 weeks

Patients entered into the study for evaluation of response must have had at least one unidimensional lesion measuring ≥ 20mm using conventional CT or MRI scans, or ≥ 10mm using a spiral CT scan. Tumor response and progression were assessed every 3 cycles (6 weeks) using the Response Evaluation Criteria in Solid Tumors (RECIST) until radiological documentation of progression or for 13 months following the first dose of study drug(s), whichever came first. Confirmed responses were based on two tumor assessments separated by at least 4 weeks. The demographics of the patient population entered into this study are shown in the table below.

Table 24 : Patient Demographics in Refractory and Relapsed Colorectal Cancer Clinical Trial

  5-FU/LV
(N = 151)
ELOXATIN
(N = 156)
ELOXATIN + 5-FU/LV
(N = 152)
Sex: Male (%) 54.3 60.9 57.2
  Female (%) 45.7 39.1 42.8
Median age (years) 60 61 59
  Range 21-80 27-79 22-88
Race (%)
  Caucasian 87.4 84.6 88.8
  Black 7.9 7.1 5.9
  Asian 1.3 2.6 2.6
  Other 3.3 5.8 2.6
KPS (%)
  70 – 100 94.7 92.3 95.4
  50 – 60 2.6 4.5 2
  Not reported 2.6 3.2 2.6
Prior radiotherapy (%) 25.2 19.2 25
Prior pelvic radiation (%) 18.5 13.5 21.1
Number of metastatic sites (%)
  1 27.2 31.4 25.7
≥ 2 72.2 67.9 74.3
Liver involvement (%)
  Liver only 22.5 25.6 18.4
  Liver + other 60.3 59 53.3

The median number of cycles administered per patient was 6 for the ELOXATIN and 5-fluorouracil/leucovorin combination and 3 each for 5-fluorouracil/leucovorin alone and ELOXATIN alone.

Patients treated with the combination of ELOXATIN and 5-fluorouracil/leucovorin had an increased response rate compared to patients given 5-fluorouracil/leucovorin or oxaliplatin alone. The efficacy results are summarized in the tables below.

Table 25 : Response Rates (ITT Analysis)

Best Response 5-FU/LV
(N=151)
ELOXATIN
(N=156)
ELOXATIN + 5-FU/LV
(N=152)
CR 0 0 0
PR 0 2 (1%) 13 (9%)
p-value 0.0002 for 5-FU/LV vs. ELOXATIN + 5-FU/LV
95%CI 0-2.4% 0.2-4.6% 4.6-14.2%

Table 26 : Summary of Radiographic Time to Progression*

Arm 5-FU/LV
(N=151)
ELOXATIN
(N=156)
ELOXATIN + 5-FU/LV
(N=152)
No. of Progressors 74 101 50
No. of patients with no radiological evaluation beyond baseline 22 (15%) 16 (10%) 17 (11%)
Median TTP (months) 2.7 1.6 4.6
95% CI 1.8-3.0 1.4-2.7 4.2-6.1
*This is not an ITT analysis. Events were limited to radiographic disease progression documented by independent review of radiographs. Clinical progression was not included in this analysis, and 18% of patients were excluded from the analysis based on unavailability of the radiographs for independent review.

At the time of the interim analysis 49% of the radiographic progression events had occurred. In this interim analysis an estimated 2-month increase in median time to radiographic progression was observed compared to 5-fluorouracil/leucovorin alone.

Of the 13 patients who had tumor response to the combination of ELOXATIN and 5-fluorouracil/leucovorin, 5 were female and 8 were male, and responders included patients < 65 years old and ≥ 65 years old. The small number of non-Caucasian participants made efficacy analyses in these populations uninterpretable.

Last reviewed on RxList: 7/26/2013
This monograph has been modified to include the generic and brand name in many instances.

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