A 2-Part Phase I Study in Patients with Solid or Hematologic Malignancies: Dose Proportionality of Subcutaneous (SC) Azacitidine (AZA) and Pharmacokinetics of SC AZA in Patients with Severe Renal Impairment,
Authors: Laille Eric , Mita Alain C. , Goel Sanjay , Gabrail Nashat Y. , Schwarz Joseph , Beach CL 
Published: October 2019

Abstract
Abstract 3480

Background:
The recommended starting dose for all patients receiving SC AZA is 75 mg/m2 daily for 7 days in 28-day cycles. If no response is observed, the dose may be increased to 100 mg/m2. Conversely, if cytopenias do not adequately resolve between dosing cycles, AZA dose may be reduced. Similarly, because AZA and its metabolites are primarily excreted by the kidneys, patients with renal impairment may require monitoring for elevations of BUN or serum creatinine (cr), in which case the next AZA treatment cycle should be delayed until values return to baseline and the next AZA dose should be reduced by 50% (Vidaza® prescribing information, 2011). Currently, the pharmacokinetics (PK) of SC AZA in reduced (<75 mg/m2) or increased (100 mg/m2) doses, and AZA exposure at the recommended dose in patients with renal impairment, are unknown.

Objectives:
To assess the dose proportionality of AZA PK after single SC doses ranging from 25 to 100 mg/m2, and to determine the effect of renal impairment on AZA PK after single and multiple (5 days) SC doses of 75 mg/m2. Also, the safety and tolerability of AZA in patients with severe renal impairment were determined.

Methods:
This 2-part multicenter, randomized, open-label study included patients with solid or hematologic malignancies. Part 1 was a 4-treatment, parallel-group evaluation of the dose proportionality of SC AZA in patients with normal renal function (cr clearance [CLcr] >80 mL/min/1.73 m2, Cockcroft-Gault equation adjusted for body surface area). Patients were randomized to receive a single dose of 25-, 50-, 75-, or 100-mg/m2 SC AZA. Blood and urine samples were collected before dosing and at various time points up to 8 hours post-dose. The 75 mg/m2 dosing group in Part 1 received an additional 4 days of AZA treatment and blood and urine were collected from these patients on the same schedule on Day 5. For Part 2, patients with severe renal impairment (CLcr <30 mL/min/1.73 m2) received SC AZA 75 mg/m2 for 5 consecutive days. PK parameters were determined using non-compartmental methods. Patients could continue to receive treatment with AZA (75 mg/m2/d SC x 7d q 28 days) in an extension phase for up to 6 cycles (patients were followed for safety only).

Results:
At the time of this analysis, 21 patients were enrolled and were included in safety evaluations, with PK data available for 18 patients. At baseline, median ages of patients with normal renal function (n=17) or severe renal impairment (n=4) were 61 years (range: 38–76) and 71 years (range: 54–90), respectively. Of patients with normal renal function, 12 (70%) had solid tumors, 4 had MDS (RAEB-t [n=2], RA, RARS), and 1 had multiple myeloma. Of patients with severe renal impairment, 2 (50%) had solid tumors, 1 had CMML, and 1 had MDS (RA). In Part 1, 14 patients were randomized to either 25 mg/m2 (n=4), 50 mg/m2 (n=4), 75 mg/m2 (n=3), or 100 mg/m2 (n=3). Mean [±SD] AUC0-∞ in the 25-, 50-, 75-, and 100 mg/m2 dose groups were 490 [146], 895 [300], 1270 [480], and 1410 [212] ng*hr/mL, respectively. Preliminary results show AZA is dose proportional across the 25–100 mg/m2dose range (Figure 1). In Part 2, on Days 1 and 5 of 5 consecutive days of SC AZA administration, AZA was rapidly absorbed by patients with severe renal impairment, reaching Cmax within 0.75 hours post-dose. AZA concentration decreased thereafter in a pseudobiphasic manner (Figure 2). Similar profiles were observed in patients with normal renal function who received the same dose. Mean [±SD] AUC0-∞ values after a 75 mg/m2 SC AZA dose on Day 1 were 1270 [480] ng*hr/mL in patients with normal renal function and 1630 [913] ng*hr/mL in patients with severely impaired renal function. On Day 5, mean AUC0-∞ values were 901 [92] and 1280 [728] ng*hr/mL, respectively. Similar observations were noted for Cmax. No accumulation of AZA was noted on Day 5 in either group. High inter-patient variability was noted in both groups (% coefficient of variation up to ∼82%). Patients with or without renal impairment did not show unusual or unexpected adverse events.

Conclusions:
AZA is dose-proportional over the 25–100 mg/m2 dosing range. PK parameters from patients with severe renal impairment treated with multiple doses of AZA 75 mg/m2 SC were comparable to those obtained from patients with normal renal function. Treatment with AZA 75 mg/m2 SC over multiple days was safe and well tolerated in this small group of patients with normal renal function or severe renal impairment.

Disclosures:
Laille: Celgene Corporation: Employment, Equity Ownership. Goel:Celgene: Research Funding. Schwarz:Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership.