Keratinocyte Growth Factor Factor (Palifermin) in Combination with Tacrolimus and Methotrexate for the Prevention of Acute Graft-Vs-Host Disease (aGVHD) in Patients at High Risk of Agvhd.

In murine BMT systems, the administration of palifermin reduces small bowel damage and serum systemic inflammatory mediators resulting in less clinical aGVHD while preserving graft-vs-leukemia and improving leukemia free survival. We initiated a phase I schedule escalation trial of palifermin plus standard aGVHD prophylaxis (tacrolimus and 5 mg/m² methotrexate on days 1, 3, 6, and 11) in patients with an unrelated or HLA mismatched donor who are at high risk for developing aGVHD. All study patients (n=35) had high risk hematologic malignancies and received a fully myeloablative conditioning regimen. Palifermin (60 mcg/kg/day intravenously) was administered for 3 consecutive days prior to the conditioning regimen, and then for 3 consecutive days each week starting Day 0, escalating by 6 doses per cohort, to a maximum of 36 doses. There were 6 cohorts, and each cohort had at least 2 patients. Dose schedules were escalated to the next cohort as long as the dose limiting toxicity (DLT) rate for the current cohort was less than 20% as determined by statistical analysis using a modified form of the continual reassessment method. A DLT was defined as any grade 3 or 4 nonhematologic toxicity that was possibly, probably, or definitely related to palifermin occurring within 14 days of receiving the final dose of palifermin. Nine DLTs were observed (table), and all patients were fully evaluable for aGVHD. In 20 patients, palifermin was not administered through engraftment—three patients completed palifermin prior to engraftment by protocol design (early cohorts), eight patients were removed from study due to DLTs, and nine patients discontinued palifermin by preference of either patient or physician. In this group of 20, 7 (35%) developed grade 3–4 aGVHD. In the other group of 15 patients, palifermin was administered through the time of neutrophil engraftment and only 3 (20%) developed grade 3–4 aGVHD. Mortality at 100 days for subjects who did not receive palifermin through engraftment was 30±10% compared to14±9% for patients who received palifermin through engraftment (p=NS). When adjusted for the interaction of palifermin administration with the number of methotrexate doses given (1–2 vs. 3–4), administration of palifermin through the time of engraftment was associated with improved survival (p = 0.02). Disease status at time of transplant (advanced vs non-advanced) and degree of HLA disparity (5/6 vs 6/6) did not alter the association. These preliminary data suggest that the administration of palifermin through the time of engraftment possibly has a survival benefit in patients at high risk for acute GVHD, perhaps mediated through an interaction with methotrexate.

Dose Limiting Toxicities