Leukine (Page 6 of 9)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis

Carcinogenicity and genetic toxicology studies have not been conducted with LEUKINE.

Impairment of Fertility

LEUKINE had no effect on fertility of female rabbits up to a dose of 200 mcg/kg/day.

The toxicology studies with up to 6 weeks of exposure to LEUKINE in sexually mature female and male cynomolgus monkeys did not reveal findings in male or female reproductive organs that would suggest impairment of fertility up to a dose of 200 mcg/kg/day. At 200 mcg/kg, the AUC exposure of LEUKINE was 8.8 to 11.4 times (monkeys) and 2.0 to 25.3 times (rabbits) the exposure in humans at the recommended clinical dose of 250 mcg/m2.

After the first administration, a dose of 200 mcg/kg/day corresponds to an AUC of approximately 11.4 (monkeys) and 25.3 (rabbits) times the exposures observed in patients treated with the clinical LEUKINE dose of 250 mcg/m2 ; however, due to the production of anti-LEUKINE antibodies with repeat administration, the AUC decreased to 8.8 (monkeys) and 2.0 (rabbits) times the clinical exposure by the end of the dosing periods.

14 CLINICAL STUDIES

14.1 Following Induction Chemotherapy for Acute Myelogenous Leukemia

The efficacy of LEUKINE in the treatment of AML was evaluated in a multicenter, randomized, double-blind placebo-controlled trial (study 305) of 99 newly-diagnosed adult patients, 55-70 years of age, receiving induction with or without consolidation. A combination of standard doses of daunorubicin (days 1-3) and ara-C (days 1-7) was administered during induction and high dose ara-C was administered days 1-6 as a single course of consolidation, if given. Bone marrow evaluation was performed on day 10 following induction chemotherapy. If hypoplasia with <5% blasts was not achieved, patients immediately received a second cycle of induction chemotherapy. If the bone marrow was hypoplastic with <5% blasts on day 10 or four days following the second cycle of induction chemotherapy, LEUKINE (250 mcg/m2 /day) or placebo was given intravenously over four hours each day, starting four days after the completion of chemotherapy. Study drug was continued until an ANC ≥1500 cells/mm3 for three consecutive days was attained or a maximum of 42 days. LEUKINE or placebo was also administered after the single course of consolidation chemotherapy if delivered (ara-C 3-6 weeks after induction following neutrophil recovery). Study drug was discontinued immediately if leukemic regrowth occurred.

LEUKINE significantly shortened the median duration of ANC <500 cells/mm3 by 4 days and <1000 cells/mm3 by 7 days following induction (see Table 5). Of patients receiving LEUKINE, 75% achieved ANC >500 cells/mm3 by day 16, compared to day 25 for patients receiving placebo. The proportion of patients receiving one cycle (70%) or two cycles (30%) of induction was similar in both treatment groups. LEUKINE significantly shortened the median times to neutrophil recovery whether one cycle (12 vs. 15 days) or two cycles (14 vs. 23 days) of induction chemotherapy was administered. Median times to platelet (>20,000 cells/mm3) and RBC transfusion independence were not significantly different between treatment groups.

Table 5: Hematological Recovery (in Days) in Patients with AML: Induction

a Patients with missing data censored

b p = Generalized Wilcoxon

c 2 patients on LEUKINE and 4 patients on placebo had missing values

d 2 patients on LEUKINE and 3 patients on placebo had missing values

e 4 patients on placebo had missing values

f 3 patients on LEUKINE and 4 patients on placebo had missing values

Dataset LEUKINE n=52a Median (25%, 75%) Placebo n=47 Median (25%, 75%) p-valueb
ANC >500/mm3 c 13 (11, 16) 17 (13, 25) 0.009
ANC >1000/mm3 d 14 (12, 18) 21 (13, 34) 0.003
PLT >20,000/mm3 e 11 (7, 14) 12 (9, >42) 0.10
RBCf 12 (9, 24) 14 (9, 42) 0.53

During the consolidation phase of treatment, LEUKINE did not shorten the median time to recovery of ANC to 500 cells/mm3 (13 days) or 1000 cells/mm3 (14.5 days) compared to placebo. There were no significant differences in time to platelet and RBC transfusion independence.

The incidence of severe infections and deaths associated with infections was significantly reduced in patients who received LEUKINE. During induction or consolidation, 27 of 52 patients receiving LEUKINE and 35 of 47 patients receiving placebo had at least one grade 3, 4 or 5 infection (p=0.02). Twenty-five patients receiving LEUKINE and 30 patients receiving placebo experienced severe and fatal infections during induction only. There were significantly fewer deaths from infectious causes in the LEUKINE arm (3 vs. 11, p=0.02). The majority of deaths in the placebo group were associated with fungal infections with pneumonia as the primary infection.

14.2 Autologous Peripheral Blood Progenitor Cell Mobilization and Collection

A retrospective review was conducted of data from adult patients with cancer undergoing collection of peripheral blood progenitor cells (PBPC) at a single transplant center. Mobilization of PBPC and myeloid reconstitution post transplant were compared between four groups of patients (n=196) receiving LEUKINE for mobilization and a historical control group who did not receive any mobilization treatment [progenitor cells collected by leukapheresis without mobilization (n=100)]. Sequential cohorts received LEUKINE. The cohorts differed by dose (125 or 250 mcg/m2 /day), route (IV over 24 hours or SC) and use of LEUKINE post transplant. Leukaphereses were initiated for all mobilization groups after the WBC reached 10,000 cells/mm3. Leukaphereses continued until both a minimum number of mononucleated cells (MNC) were collected (6.5 or 8.0 × 108 /kg body weight) and a minimum number of aphereses (5-8) were performed. Both minimum requirements varied by treatment cohort and planned conditioning regimen. If subjects failed to reach a WBC of 10,000 cells/mm3 by day 5, another cytokine was substituted for LEUKINE.

Marked mobilization effects were seen in patients administered the higher dose of LEUKINE (250 mcg/m2) either IV (n=63) or SC (n=41). PBPCs from patients treated at the 250 mcg/m2 /day dose had a significantly higher number of granulocyte-macrophage colony-forming units (CFU-GM) than those collected without mobilization. The mean value after thawing was 11.41 × 104 CFU-GM/kg for all LEUKINE-mobilized patients, compared to 0.96 × 104 /kg for the non-mobilized group. A similar difference was observed in the mean number of erythrocyte burst-forming units (BFU-E) collected (23.96 × 104 /kg for patients mobilized with 250 mcg/m2 doses of LEUKINE administered SC vs. 1.63 × 104 /kg for non-mobilized patients).

A second retrospective review of data from patients undergoing PBPC at another single transplant center was also conducted. LEUKINE was given SC at 250 mcg/m2 /day once a day (n=10) or twice a day (n=21) until completion of apheresis. Apheresis was begun on day 5 of LEUKINE administration and continued until the targeted MNC count of 9 × 108 /kg or CD34+ cell count of 1 × 106 /kg was reached. There was no difference in CD34+ cell count in patients receiving LEUKINE once or twice a day.

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