A phase I study of tipifarnib combined with conventional induction and consolidation therapy for previously untreated patients with acute myeloid leukemia aged 60 years and over

• Published in: Leukemia Vol. 23; no. 4; pp. 631 - 634
• Main Authors: Brandwein, J M, Leber, B F, Howson-Jan, K, Schimmer, A D, Schuh, A C, Gupta, V, Yee, K W L, Wright, J, Moore, M, MacAlpine, K, Minden, M D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2009; Nature Publishing Group
• Subjects: Acute myeloid leukemia; Aged; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - toxicity; Arrhythmia; Biological and medical sciences; Cancer Research; Chemotherapy, Combination; Consolidation; Critical Care Medicine; Cytarabine; Cytarabine - administration & dosage; Cytogenetics; Daunorubicin; Daunorubicin - administration & dosage; Diarrhea; Drug-Related Side Effects and Adverse Reactions; Drugs; Enterocolitis; Gastrointestinal Diseases - chemically induced; Health aspects; Hematologic and hematopoietic diseases; Hematology; Humans; Hyperbilirubinemia; Induction therapy; Intensive; Internal Medicine; Intravenous administration; Leukemia; Leukemia, Myeloid, Acute - complications; Leukemia, Myeloid, Acute - drug therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Maximum Tolerated Dose; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Neutropenia; Oncology; original-article; Quinolones - administration & dosage; Quinolones - toxicity; Recovery; Remission; Remission Induction; Toxicity; United States; acute myeloid leukemia; chemotherapy; farnesyltransferase inhibitors; Antineoplastic agent; Human; Drug combination; Acute myelogenous leukemia; Hematology; Enzyme; Transferases; Enzyme inhibitor; Tipifarnib; Malignant hemopathy; Farnesyl-diphosphate farnesyltransferase; Consolidation treatment; Induction treatment; Chemotherapy; Treatment; Phase I trial; Elderly; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2008.341

Patients aged 60 years and over with previously untreated acute myeloid leukemia were enrolled in a Phase I study combining tipifarnib with standard induction therapy. The regimen consisted of cytarabine 100 mg/m
2
/day continuous intravenous (i.v.) infusion on days 1–7, daunorubicin 60 mg/m
2
/day i.v. push × 3 on days 6–8 and tipifarnib twice daily on days 6–15. Tipifarnib was escalated over four dose levels (200, 300, 400 and 600 mg). Patients achieving complete response (CR) were eligible to receive one consolidation using the same regimen. The following dose-limiting toxicities (DLTs) were identified during induction: dose level I: 2/6 (hyperbilirubinemia, respiratory arrest), level II: 0/3, level III: 0/3 and level IV: 4/10 (one each of diarrhea, neutropenic enterocolitis, arrhythmia and delayed hematologic recovery post-consolidation). There were no DLTs due to delayed hematologic recovery post-induction. Of 22 evaluable patients, there were 10 CR, 2 morphologic leukemia-free state (MLFS), 2 partial remission (PR) and 8 non-responders. Of seven patients with adverse risk cytogenetics, there were four CR/MLFS and one PR. In summary, this regimen was well tolerated and the maximum tolerated dose was not reached, although somewhat more severe gastrointestinal toxicity was seen at dose level IV. Tipifarnib 600 mg b.i.d. is considered the recommended dose for further study using this regimen.