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Eloxatin Description

Eloxatin™ (oxaliplatin for injection) is an antineoplastic agent with the molecular formula C8H14N2O4Pt and the chemical name of cis-[(1R,2R)-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. Eloxatin is supplied in vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free lyophilized powder for reconstitution. Lactose monohydrate is present as an inactive ingredient at 450 mg and 900 mg in the 50 mg and 100 mg dosage strengths, respectively.

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.

Pharmacology

In vivo studies have shown antitumor activity of oxaliplatin against colon carcinoma. In combination with 5-fluorouracil (5-FU), 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)].

Human 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 IV infusion of Eloxatin at a dose of 85 mg/m2 expressed as ultrafilterable platinum were Cmax of 0.814 µg/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 (see ADVERSE REACTIONS).

Pharmacokinetics in Special Populations

The AUC0–48hr of platinum in the plasma ultrafiltrate increases as renal function decreases. The AUC0–48hr of platinum in patients with mild (creatinine clearance, CLcr 50 to 80 mL/min), moderate (CLcr 30 to <50 mL/min) and severe renal (CLcr<30 mL/min) impairment is increased by about 60, 140 and 190%, respectively, compared to patients with normal renal function (CLcr>80 mL/min) (see PRECAUTIONS and ADVERSE REACTIONS).

No pharmacokinetic interaction between 85 mg/m2 of Eloxatin and infusional 5-FU has been observed in patients treated every 2 weeks, but increases of 5-FU 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 5-FU/LV in Patients with Stage II or III Colon Cancer

An international, multicenter, randomized study compared the efficacy and evaluated the safety of Eloxatin in combination with an infusional schedule of 5-FU/LV to infusional 5-FU/LV 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-FU/LV to those receiving 5-FU/LV 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) > 1.5×109/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.

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.

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.

In the overall study population DFS was statistically significantly improved in the Eloxatin combination arm compared to infusional 5-FU/LV alone. A statistically significant improvement in DFS was noted in Stage III patients, but not in Stage II patients.

Figure 1 shows the Kaplan-Meier DFS curves for the comparison of Eloxatin and infusional 5-FU/LV combination and infusional 5-FU/LV alone for the overall population (ITT analysis). Figure 2 shows the Kaplan-Meier DFS curves for the comparison of Eloxatin and infusional 5-FU/LV combination and infusional 5-FU/LV alone for the Stage III Subgroup.

Figure 1 - Kaplan-Meier DFS curves by treatment arm for Overall Population

Figure 2 - Kaplan-Meier DFS curves by treatment arm for Stage III Subgroup

Survival data were not mature at the time of the analysis with a median follow-up of 47 months. No statistically significant difference in overall survival [Hazard Ratio 0.89 (95% CI 0.72, 1.09) p=0.236] was shown between the two treatment arms in the entire population or in the Stage II [Hazard Ratio 0.98 (95% CI 0.63, 1.53) p=0.94] or Stage III [Hazard Ratio 0.86 (95%CI 0.68, 1.08) p=0.196] subgroups.

A descriptive subgroup analysis demonstrated that the improvement in DFS for the Eloxatin combination arm compared to the infusional 5-FU/LV alone arm appeared to be maintained across genders. The effect of Eloxatin on disease free survival benefit in patients ≥65 years of age was not conclusive. Insufficient subgroup sizes prevented analysis by race.

Combination Therapy with Eloxatin and 5-FU/LV 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-FU/LV. The results reported below compared the efficacy and safety of two experimental regimens, Eloxatin in combination with infusional 5-FU/LV and a combination of Eloxatin plus irinotecan, to an approved control regimen of irinotecan plus 5-FU/LV in 795 concurrently randomized patients previously untreated for locally advanced or metastatic colorectal cancer. After completion of enrollment, the dose of irinotecan plus 5-FU/LV 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 × 109/L, platelets ≥ 100 × 109/L, hemoglobin ≥9.0 gm/dL, creatinine ≤ 1.5 × ULN, total bilirubin ≤ 1.5 mg/dL, AST ≤ 5 × ULN, and alkaline phosphatase ≤ 5 × 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-FU/LV arm received an irinotecan-containing regimen and 23% of patients on the irinotecan plus 5-FU/LV 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.

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

The length of a treatment cycle was 2 weeks for the Eloxatin and 5-FU/LV regimen; 6 weeks for the irinotecan plus 5-FU/LV 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-FU/LV regimen, 4 (23.6 weeks) for the irinotecan plus 5-FU/LV regimen, and 7 (21.0 weeks) for the Eloxatin plus irinotecan regimen. Patients treated with the Eloxatin and 5-FU/LV 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-FU/LV. The following table summarizes the efficacy results.

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

Figure 3 illustrates the Kaplan-Meier survival curves for the comparison of Eloxatin and 5-FU/LV combination and Eloxatin plus irinotecan to irinotecan plus 5-FU/LV.

Figure 3 – Kaplan-Meier Overall Survival by treatment arm

A descriptive subgroup analysis demonstrated that the improvement in survival for Eloxatin plus 5-FU/LV compared to irinotecan plus 5-FU/LV appeared to be maintained across age groups, prior adjuvant therapy, and number of organs involved. An estimated survival advantage in Eloxatin plus 5-FU/LV versus irinotecan plus 5-FU/LV 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-FU/LV 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-FU/LV to the same dose and schedule of 5-FU/LV 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-FU/LV 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) ≤2× 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 ≤ 5× ULN was permitted. Patients had to have alkaline phosphatase ≤2× the institution's ULN, unless liver metastases were present and documented at baseline by CT or MRI scan, in which cases ≤5× 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.

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.

The median number of cycles administered per patient was 6 for the Eloxatin and 5-FU/LV combination and 3 each for 5-FU/LV alone and Eloxatin alone.

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

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-FU/LV alone.

Of the 13 patients who had tumor response to the combination of Eloxatin and 5-FU/LV, 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.

Indications and Usage for Eloxatin

Eloxatin, used in combination with infusional 5-FU/LV, is indicated for adjuvant treatment of stage III colon cancer patients who have undergone complete resection of the primary tumor. The indication is based on an improvement in disease-free survival, with no demonstrated benefit in overall survival after a median follow up of 4 years.

Eloxatin, used in combination with infusional 5-FU/LV, is indicated for the treatment of advanced carcinoma of the colon or rectum.

Contraindications

Eloxatin should not be administered to patients with a history of known allergy to Eloxatin or other platinum compounds.

Warnings

As in the case for other platinum compounds, hypersensitivity and anaphylactic/anaphylactoid reactions to Eloxatin have been reported (see ADVERSE REACTIONS). These allergic reactions were similar in nature and severity to those reported with other platinum-containing compounds, i.e., rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension. These reactions occur within minutes of administration and should be managed with appropriate supportive therapy. Drug-related deaths associated with platinum compounds from this reaction have been reported.

Pregnancy Category D

Eloxatin may cause fetal harm when administered to a pregnant woman. Pregnant rats were administered 1 mg/kg/day oxaliplatin (less than one-tenth the recommended human dose based on body surface area) during gestation days 1–5 (pre-implantation), 6–10, or 11–16 (during organogenesis). Oxaliplatin caused developmental mortality (increased early resorptions) when administered on days 6–10 and 11&ndash

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