Oxaliplatin Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
Россия
  • Россия
  • Украина

Oxaliplatin Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: United States
Condition: Colorectal Carcinoma (Colorectal Cancer), Colorectal Cancer
Class: Alkylating agents
Form: Liquid solution, Intravenous (IV)
Ingredients: Oxaliplatin, water.

Description

Oxaliplatin Injection, USP is an antineoplastic agent with the molecular formula C8H14N2O4Pt and the chemical name is cis-[(1 R,2 R)-1,2-cyclohexanediamine-N,N’] [oxalato(2-)-O,O’] platinum. Oxaliplatin is an organoplatinum complex in which the platinum atom is complexed with 1,2- diaminocyclohexane(DACH) and with an oxalate ligand as a leaving group.

The molecular weight is 397.3. Oxaliplatin is slightly soluble in water at 6 mg/mL, very slightly soluble in methanol, and practically insoluble in ethanol and acetone.

Oxaliplatin Injection, USP is supplied in vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL. Water for injection is present as inactive ingredient.

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 (t1/2α; 0.43 hours and t1/2β; 16.8 hours) and a long terminal elimination phase (t1/2γ; 391 hours). Pharmacokinetic parameters obtained after a single 2-hour intravenous infusion of oxaliplatin 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 oxaliplatin, 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 oxaliplatin, 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 to 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 to 80 mL/min, N=13), and moderate (CrCL=30 to 49 mL/min, N=10) groups were treated with 85 mg/m2 oxaliplatin and those in the severe (CrCL < 30 mL/min, N=4) group were treated with 65 mg/m2 oxaliplatin. 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 oxaliplatin should be reduced in patients with severe renal impairment [see Dosage and Administration].

Drug - Drug Interactions

No pharmacokinetic interaction between 85 mg/m2 of Oxaliplatin 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 oxaliplatin 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of oxaliplatin. Oxaliplatin was not mutagenic to bacteria (Ames test) but was mutagenic to mammalian cells in vitro (L5178Y mouse lymphoma assay). Oxaliplatin was clastogenic both in vitro (chromosome aberration in human lymphocytes) and in vivo (mouse bone marrow micronucleus assay).

In a fertility study, male rats were given oxaliplatin at 0, 0.5, 1, or 2 mg/kg/day for five days every 21 days for a total of three cycles prior to mating with females that received two cycles of oxaliplatin on the same schedule. A dose of 2 mg/kg/day (less than one-seventh the recommended human dose on a body surface area basis) did not affect pregnancy rate, but caused developmental mortality (increased early resorptions, decreased live fetuses, decreased live births) and delayed growth (decreased fetal weight).

Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day x 5 days every 28 days for three cycles. A no effect level was not identified. This daily dose is approximately one-sixth of the recommended human dose on a body surface area basis.

Clinical Studies

Combination Adjuvant Therapy with Oxaliplatin and Infusional 5-Flurouracil/Leucovorin in Patients with Stage II or III Colon Cancer

An international, multicenter, randomized study compared the efficacy and evaluated the safety of oxaliplatin 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 oxaliplatin 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 N1–2M0; 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 ≥100×109/L, serum creatinine ≤ 1.25 × ULN total bilirubin < 2 × ULN, AST/ALT < 2 × 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 1 - Dosing Regimens in Adjuvant Therapy Study
Treatment ArmDoseRegimen
Oxaliplatin +
5-FU/LV
(FOLFOX4)
(N =1123)
Day 1: Oxaliplatin: 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 by5-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 2 - Patient Characteristics in Adjuvant Therapy Study
 Oxaliplatin + infusional
5-FU/LV
N=1123
Infusional
5-FU/LV
N=1123
Sex: Male (%)56.152.4
Female (%)43.947.6
Median age (years)61.060.0
<65 years of age (%)64.466.2
≥65 years of age (%)35.633.8
Karnofsky Performance Status (KPS) (%)
10029.730.5
9052.253.9
804.43.3
7013.211.9
≤600.60.4
Primary site (%)
Colon including cecum54.654.4
Sigmoid31.933.8
Recto sigmoid12.910.9
Other including rectum0.60.9
Bowel obstruction (%)
Yes17.919.3
Perforation (%)  
Yes6.96.9
Stage  at Randomization (%)  
II (T=3,4 N=0, M=0)40.139.9
III (T=any, N=1,2, M=0)59.659.3
IV (T=any, N=any, M=1)0.40.8
Staging – T  (%)
T10.50.7
T24.54.8
T376.075.9
T419.018.5
Staging – N (%)
N040.239.9
N139.439.4
N220.420.7
Staging – M (%)
M10.40.8
Table 3 - Dosing in Adjuvant Therapy Study
 Oxaliplatin + infusional
5-FU/LV
N=1108
Infusional
5-FU/LV
N=1111
Median Relative Dose Intensity (%)
5-FU84.497.7
Oxaliplatin80.5N/A
Median Number of Cycles1212
Median Number of cycles with Oxaliplatin11N/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 4 - Summary of DFS analysis – ITT analysis*
 Oxaliplatin + Infusional 5-
FU/LV
Infusional
5-FU/LV
Parameter  
Overall
N11231123
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 testp=0.003
Stage III (Dukes' C)
N672675
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 testp=0.005
Stage II (Dukes' B2)
N451448
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 testp=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 Oxaliplatin 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 oxaliplatin 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 oxaliplatin 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

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

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 5 - Summary of OS analysis - ITT analysis*
ParameterEloxatin + Infusional 5-FU/LVInfusional 5-FU/LV
Overall
N11231123
Number of death events (%)245 (21.8)283 (25.2)
Hazard ratio [95% CI]0.84 [0.71 , 1.00]
Stage III (Dukes' C)
N672675
Number of death events (%)182 (27.1)220 (32.6)
Hazard ratio [95% CI]0.80 [0.65 , 0.97]
Stage II (Dukes' B2)
N451448
Number of death events (%)63 (14.0)63 (14.1)
Hazard ratio[95% CI]1.00 [0.70 , 1.41]

*Data cut off for overall survival 16 January 2007

A hazard ratio of less than 1.00 favors Eloxatin + Infusional 5- fluorouracil/leucovorin

Combination Therapy with Oxaliplatin 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, oxaliplatin in combination with infusional 5- fluorouracil/leucovorin and a combination of oxaliplatin 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 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 oxaliplatin 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 6 – Dosing Regimens in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial
Treatment
Arm
DoseRegimen
Oxaliplatin
+
5-FU/LV
(FOLFOX4)
N=267)
Day 1: Oxaliplatin: 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:00 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 intravenouspush, followed by
5-FU 500 mg/m2 intravenousbolus weekly x 4
every 6
weeks
Oxaliplatin
+Irinotecan
(IROX)
N=264)
Day 1: Oxaliplatin: 85 mg/m2 intravenous(2-hour infusion) + irinotecan 200 mg/m2 intravenousover 30 minutesevery 3
weeks

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

Table 7 – Patient Demographics in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial
 Oxaliplatin +
5-FU/LV
(N=267)
irinotecan +
5-FU/LV
(N=264)
Oxaliplatin +
irinotecannbsp
N=264)
Sex: Male (%)58.865.261
 Female (%)41.234.839
Median age (years)616161
<65 years of age (%)616263
≥65 years of age (%)393837
ECOG (%)
0.194.495.594.7
25.64.55.3
Involved organs (%)
Colononly0.70.80.4
Liver only39.344.339
Liver + other41.238.640.9
Lung only6.43.85.3
Other (including lymph nodes)11.61112.9
Not reported0.71.51.5
Prior radiation (%)31.53
Prior surgery (%)74.579.281.8
Prior adjuvant (%)15.714.815.2

The length of a treatment cycle was 2 weeks for the oxaliplatin and 5-fluorouracil/leucovorin regimen; 6 weeks for the irinotecan plus 5-fluorouracil/leucovorin regimen; and 3 weeks for the oxaliplatin plus irinotecan regimen. The median number of cycles administered per patient was 10 (23.9 weeks) for the oxaliplatin and 5-fluorouracil/leucovorin regimen, 4 (23.6 weeks) for the irinotecan plus 5- fluorouracil/leucovorin regimen, and 7 (21 weeks) for the oxaliplatin plus irinotecan regimen. Patients treated with the oxaliplatin 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 8 – Summary of Efficacy *
 Oxaliplatin
+
5-FU/LV
(N=267)
irinotecan
+
5-FU/LV
(N=264)
Oxaliplatin
+
irinotecan
(N=264)
Survival (ITT)
Number of deaths N (%)155 (58.1)192 (72.7)175 (66.3)
Median survival (months)19.414.617.6
Hazard Ratio and (95% confidence interval)0.65 (0.53 to 0.8)
P-value<0.0001--
TTP (ITT, investigator assessment)
Percentage of progressors82.881.889.4
Median TTP (months)8.76.96.5
Hazard Ratio and (95% confidence interval)0.74 (0.61 to0.89)  
P-value0.0014--
Response Rate (investigator assessment)§
Patients with measurable disease210212215
Complete response N (%)13 (6.2)5 (2.4)7 (3.3)
Partial response N (%)82 (39)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 to 52)(26.2 to38.9)(28.1 to40.8)
P-value0.008--

*The numbers in the response rate and TTP analysis are based on unblinded investigator assessment.

Compared to irinotecan plus 5-fluorouracil/leucovorin (IFL) arm

A hazard ratio of less than 1 favors Oxaliplatin + Infusional 5-fluorouracil/leucovorin

§Based on all patients with measurable disease at baseline

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

Figure 4 – Kaplan-Meier Overall Survival by treatment arm

A descriptive subgroup analysis demonstrated that the improvement in survival for oxaliplatin 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 oxaliplatin 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 Oxaliplatin 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 oxaliplatin 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 9 – Dosing Regimens in Refractory and Relapsed Colorectal Cancer Clinical Trial
Treatment
Arm
DoseRegimen
Oxaliplatin +
5-FU/LV
(N =152)
Day 1: Oxaliplatin: 85 mg/m2 (2-hour infusion) + LV200 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
Oxaliplatin
(N=156)
Day 1: Oxaliplatin 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 10 – Patient Demographics  in Refractory and Relapsed Colorectal Cancer Clinical Trial
 5-FU/LV
(N = 151)
Oxaliplatin
(N = 156)
Oxaliplatin + 5-FU/LV
(N = 152)
Sex: Male (%)54.360.957.2
 Female (%)45.739.142.8
Median age (years)606159
Range21 to 8027 to 7922 to 88
Race (%)
Caucasian87.484.688.8
Black7.97.15.9
Asian1.32.62.6
Other3.35.82.6
KPS (%)
70 to 10094.792.395.4
50 to 602.64.52
Not reported2.63.22.6
Prior radiotherapy (%)25.219.225
Prior pelvic radiation (%)18.513.521.1
Number of metastatic sites (%)
127.231.425.7
≥272.267.974.3
Liver involvement (%)
Liver only22.525.618.4
Liver + other60.35953.3

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

Patients treated with the combination of oxaliplatin 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 11 - Response Rates (ITT Analysis)
Best Response5-FU/LV
(N=151)
Oxaliplatin
(N=156)
Oxaliplatin + 5 FU/LV
(N=152)
CR000
PR02 (1%)13 (9%)
p-value0.0002 for 5-FU/LV vs. Oxaliplatin + 5 FU/LV
95%CI0 to 2.4%0.2 to 4.6%4.6 to 14.2%
Table 12 - Summary of Radiographic Time to Progression*
Arm5-
FU/LV
(N=151)
Oxaliplatin
(N=156)
Oxaliplatin +5-
FU/LV
(N=152)
No. of Progressors7410150
No. of patients with no radiologicalevaluation beyond baseline22
(15%)
16
(10%)
17
(11%)
Median TTP (months)2.71.64.6
95% CI1.8 to 31.4 to 2.74.2 to 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 oxaliplatin 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.