14 CLINICAL STUDIES

14.1 Pediatrics

Elitek was administered in three studies to 265 patients with acute leukemia or non-Hodgkin's lymphoma. These clinical studies were largely limited to pediatric patients (246 of 265). Elitek was administered as a 30-minute infusion once (n=251) or twice (n=14) daily at a dose of 0.15 or 0.2 mg/kg/dose (total daily dose 0.2–0.4 mg/kg/day). Elitek was administered prior to and concurrent with antitumor therapy, which consisted of either systemic chemotherapy (n=196) or steroids (n=69).

Study 1

Study 1 was a randomized, open-label, controlled study conducted at six institutions, in which 52 pediatric patients were randomized to receive either Elitek (n=27) or allopurinol (n=25). The dose of allopurinol varied according to local institutional practice. Elitek was administered as an intravenous infusion over 30 minutes once (n=26) or twice (n=1) daily at a dose of 0.2 mg/kg/dose (total daily dose 0.2–0.4 mg/kg/day). Initiation of dosing was permitted at any time between 4 to 48 hours before the start of antitumor therapy and could be continued for 5 to 7 days after initiation of antitumor therapy. Patients were stratified at randomization on the basis of underlying malignant disease (leukemia or lymphoma) and baseline serum or plasma uric acid levels (<8 mg/dL and ≥8 mg/dL). The primary study objective was to demonstrate a greater reduction in uric acid concentration over 96 hours (AUC0–96 hr) in the Elitek group as compared to the allopurinol group. Uric acid AUC0–96 hr was defined as the area under the curve for plasma uric acid levels (mg hr/dL), measured from the last value prior to the first dose of Elitek until 96 hours after that first dose. Plasma uric acid levels were used for all uric acid AUC0–96 hr calculations [see Warnings and Precautions (5.4)].

The demographics of the two study arms (Elitek vs allopurinol) were as follows: age <13 years (82% vs 76%), males (59% vs 72%), Caucasian (59% vs 72%), ECOG performance status 0 (89% vs 84%), and leukemia (74% vs 76%). The median interval, in hours, between initiation of Elitek and of antitumor treatment was 20 hours, with a range of 70 hours before to 10 hours after the initiation of antitumor treatment (n=24, data not reported for 3 patients).

The uric acid AUC0–96 hr was significantly lower in the Elitek group (128 ± s.e. 14 mg hr/dL) as compared to the allopurinol group (328 ± s.e. 26 mg hr/dL). All but one patient in the Elitek arm had reduction and maintenance of uric acid levels to within or below the normal range during the treatment. The incidence of renal dysfunction was similar in the two study arms; one patient in the allopurinol arm developed acute renal failure.

Study 2

Study 2 was a multi-institutional, single-arm study conducted in 89 pediatric and 18 adult patients with hematologic malignancies. Patients received Elitek at a dose of 0.15 mg/kg/day. The primary efficacy objective was determination of the proportion of patients with maintained plasma uric acid concentration at 48 hours where maintenance of uric acid concentration was defined as: 1) achievement of uric acid concentration ≤6.5 mg/dL (patients <13 years) or ≤7.5 mg/dL (patients ≥13 years) within a designated time point (48 hours) from initiation of Elitek and maintained until 24 hours after the last administration of study drug; and 2) control of uric acid level without the need for allopurinol or other agents.

The study population demographics were: age <13 years (76%), males (61%), Caucasian (91%), ECOG performance status=0 (92%), and leukemia (89%).

The proportion of patients with maintenance of uric acid concentration at 48 hours in Study 2 was 99% (106/107).

Study 3

Study 3 was a multi-institutional, single-arm study conducted in 130 pediatric patients and 1 adult patient with hematologic malignancies. Patients received Elitek at either a dose of 0.15 mg/kg/day (n=12) or 0.2 mg/kg/day (n=119). The primary efficacy objective was determination of the proportion of patients with maintained plasma uric acid concentration at 48 hours as defined for Study 2 above.

The study population demographics were: age <13 years (76%), Caucasian (83%), males (67%), ECOG=0 (67%), and leukemia (88%).

The proportion of patients with maintenance of uric acid concentration at 48 hours in Study 3 was 92% in the 0.15 mg/kg group (n=12) and 95% in the 0.2 mg/kg group (n=119).

Pooled Analyses of Studies 1, 2, and 3

Data from the 3 studies (n=265) were pooled and analyzed according to the plasma uric acid levels over time. The pretreatment plasma uric acid concentration was ≥8 mg/dL in 61 patients and was <8 mg/dL in 200 patients. The median uric acid concentration at baseline, at 4 hours following the first dose of Elitek, and the per-patient fall in plasma uric acid concentration from baseline to 4 hours, were calculated in those patients with both pretreatment and 4-hour post-treatment values. Among patients with pretreatment uric acid ≥8 mg/dL (baseline median 10.6 mg/dL [range 8.1-36.4]), the median per-patient change in plasma uric acid concentration by 4 hours after the first dose was a decrease of 9.1 mg/dL (0.3-19.3 mg/dL). Among the patients with a pretreatment plasma uric acid level <8 mg/dL (baseline median 4.6 mg/dL [range 0.2-7.9 mg/dL]), the median per-patient change in plasma uric acid concentration by 4 hours after the first dose was a decrease of 4.1 mg/dL (0.1-7.6 mg/dL).

Figure 1: Box and Whisker Plot of Uric Acid Concentration at Designated Time Blocks – Elitek Administration Began Immediately after Baseline

Figure 1 is a box and whisker plot of plasma uric acid levels inclusive of 261 of the 265 Elitek-treated patients from Studies 1, 2, and 3. Of the 261 evaluable patients, plasma uric acid concentration was maintained (see Study 2 for the definition of uric acid concentration maintenance) by 4 hours for 92% of patients (240/261), by 24 hours for 93% of patients (245/261), by 48 hours for 97% of patients (254/261), by 72 hours for 99% of patients (260/261), and by 96 hours for 100% of patients (261/261). Of the subset of 61 patients whose plasma uric acid level was elevated at baseline (≥8 mg/dL), plasma uric acid concentration was maintained by 4 hours for 72% of patients (44/61), by 24 hours for 80% of patients (49/61), by 48 hours for 92% of patients (56/61), by 72 hours for 98% of patients (60/61), and by 96 hours for 100% (61/61).

14.2 Studies in Adults

A total of 342 adults with either leukemia, lymphoma, or other hematologic malignancy received Elitek in five studies (one randomized study, Study 4, and four uncontrolled studies). Across the five studies, Elitek was administered at a dose of 0.15 mg/kg/day (n=38) or 0.2 mg/kg/day (n=304).

Study 4 was a randomized (1:1:1), multi-center, open-label study conducted in patients with leukemia, lymphoma, and solid tumor malignancies at risk for hyperuricemia and TLS. A total of 275 adult patients received at least one dose of study drug. The median age was 56 years, 62% were males, 80% were Caucasian, 66% had leukemia, 29% had lymphoma; 18% were hyperuricemic (uric acid >7.5 mg/dL) at study entry. Patients in Arm A received Elitek for 5 days (n=92). Patients in Arm B received Elitek from day 1 through day 3 followed by oral allopurinol from day 3 through day 5 (overlap on day 3: Elitek and allopurinol administered approximately 12 hours apart) (n=92). Patients in Arm C received oral allopurinol for 5 days (n=91). Elitek was administered at the dose of 0.2 mg/kg/day as a 30-minute infusion once daily. Allopurinol was administered orally at the dose of 300 mg once a day. Patients were eligible for the study if they were either at high risk or potential risk for TLS. The major endpoint of this study was the uric acid response rate defined as the proportion of patients with plasma uric acid levels ≤7.5 mg/dL from day 3 to day 7, after initiation of antihyperuricemic treatment.

Table 2 presents the response rates in the three treatment arms. The response rate in arm A was significantly greater than in arm C (p=0.0009). The response rate was higher for arm B compared to arm C; this difference was not statistically significant.

Table 2: Summary of Response Rates
	Arm A Elitek n=92	Arm B Elitek/Allopurinol n=92	Arm C Allopurinol n=91
Response Rate % (95% CI)	87% (80%, 94%)	78% (70%, 87%)	66% (56%, 76%)
Nonresponse Rate %	13%	22%	34%
Failed to control uric acid	0	0	11%
Hyperuricemic treatment extended beyond 5 days	0	6.5%	4.4%
Missing uric acid samples	13%	15%	19%

There were no patients with documented failure to control uric acid in arms A or B. In arm C, 34% of patients did not have a uric acid response; 11% due to failure to control uric acid and 4.4% due to the need for extended antihyperuricemic treatment.

Box and whisker plots of uric acid over time for the patient population (Figure 2) show that in the two arms containing Elitek, uric acid levels were ≤2 mg/dL in 96% of patients at 4 hours of the day 1 dose.

Figure 2: Uric Acid Concentration Over Time – Patient Population Box and Whisker Plot

Tumor Lysis Syndrome (TLS)

Clinical TLS was defined by changes in at least two or more laboratory parameters for hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia and at least one of the following events occurring within 7 days of treatment: renal failure/injury, need for renal dialysis, and/or serum creatinine increase >1.5 ULN, arrhythmia or seizure. Clinical TLS occurred in 3% of Elitek-treated patients, 3% of Elitek/allopurinol-treated patients, and 4% of allopurinol-treated patients.