Final report of phase I/II study of PR104, a hypoxia-activated pro-drug, in relapsed/refractory acute leukemia
| Autor: | Tapan M. Kadia, Andrew Coveler, Peter F. Thall, Stefan Faderl, John Gutheil, Naval Daver, William R. Wilson, Hagop M. Kantarjian, Marina Konopleva, Elias Jabbour, Steven M. Kornblau, Jorge E. Cortes, Naveen Pemmaraju, Hoang Q. Nguyen, Elihu H. Estey, Cecilia Ysabel Arana Yi, Deborah A. Thomas, Farhad Ravandi, Teresa J. Melink, Gautam Borthakur |
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| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | Journal of Clinical Oncology. 31:7074-7074 |
| ISSN: | 1527-7755 0732-183X |
| Popis: | 7074 Background: Hypoxia is prevalent in leukemia bone marrow (BM) microenvironment, suggesting its role as a therapeutic target. PR104 is a pro-drug activated by hypoxia-dependent reductases and by hypoxia-independent aldo-ketoreductase 1C3 (AKR1C3). Methods: Patients (pts) with relapsed/refractory AML (n=40) after 1 or 2 prior treatments; or ALL (n=10) after any number of prior treatments received PR104 as a 1-hr i.v. infusion q 2 weeks. Biomarkers for hypoxia and AKR1C3 were assessed. Results: Pts received PR104 at doses of 1.1 (n=6), 1.6 (n=1), 2.2 (n=1), 3 (n=20) and 4 gm/m2 (n=22) for a median of 1 cycle (range, 1 – 3 cycles). 17 pts had PR104 doses assigned using an adaptive method using toxicity-response trade-offs, patient age, and prior remission duration, and 33 pts were assigned doses by investigators for cohort expansion at 3 and 4gm/m2. Most common treatment-related grade 3/4 adverse events included myelosupression (anemia 44%, neutropenia 56%, thrombocytopenia 52%), febrile neutropenia (22%), infection (22%) and enterocolitis (14%). 3 (14%) PR104-related deaths occurred at the 4 gm/m2 dose level: hepatic failure (n=1), enterocolitis (n=1) and pneumonia (n=1). 49 of 50 pts were evaluable for response. No CRs were seen at doses < 3 gm/m2. 10 of 31 AML pts (32%, (0.19, 0.5)% CI) and 2 of 10 ALL pts (20%, (0.06,0.51)% CI) at 3 or 4 gm/m2 had responses (CR, n=1; CRp, n=5; morphologic leukemia-free state (MLFS), n=6). In AML pts with 1 prior treatment, responses were seen in 7 of 21 pts (CR, n=1; CRp, n=3; MLFS, n=3). Median overall survival of all pts treated at 3 and 4 gm/m2 was 72 days, and of pts who achieved CR/CRp/MLFS 143 days. 3 pts with AML (MLFS, n=2; CRp, n=1) and 1 with B-ALL (CRp, n=1) underwent allogeneic stem cell transplantation. Biomarker studies showed hypoxia in the BM; and levels of AKR1C3 in leukemic blasts did not correlate with responses (Benito et al., ASH 2012). Conclusions: PR104 administered at doses 3 to 4x the solid tumor MTD had moderate toxicity (most commonly myelosuppression and enterocolitis) in pts with relapsed/refractory AML and ALL. Evidence of activity supports continued evaluation of hypoxia-activated cytotoxins in acute leukemias. Clinical trial information: NCT01037556. |
| Databáze: | OpenAIRE |
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