Phase I study of a novel pro-apoptotic drug R-etodolac in patients with B-cell chronic lymphocytic leukemia

• Published in: Investigational new drugs 2008-04, Vol.26 (2), p.139-149
• Main Authors: Jensen, Markus, Engert, Andreas, Weissinger, Florian, Knauf, Wolfgang, Kimby, Eva, Poynton, Christopher, Oliff, Ira Anton, Rummel, Mathias J., Österborg, Anders
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Aged; Alanine Transaminase - drug effects; Anemia; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Apoptosis; Apoptosis - drug effects; Arthritis; Cancer therapies; Chemotherapy; Clinical outcomes; Clinical trials; Creatinine; Dose-Response Relationship, Drug; Drug dosages; Etodolac - administration & dosage; Etodolac - adverse effects; Etodolac - pharmacokinetics; Female; Half-Life; Humans; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Lymphocytes; Lymphocytes - drug effects; Male; Maximum Tolerated Dose; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Middle Aged; Nonsteroidal anti-inflammatory drugs; Oncology; Patients; Pharmacology; Pharmacology/Toxicology; Phase I Studies; Thrombocytopenia
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-007-9106-z

Summary R-etodolac is a novel pro-apoptotic agent with potential antitumor activity against B-cell chronic lymphocytic leukemia (B-CLL). This phase I clinical trial was conducted to determine the tolerability, safety, and maximum tolerated dose (MTD) of R-etodolac, administered orally twice a day (BID), in patients with B-CLL. Secondary objectives included evaluating clinical response, pharmacodynamic activity (reduction of lymphocytes), and pharmacokinetic (PK) profile. Forty-three patients were enrolled in the study. The most frequently reported adverse events were diarrhea, rash, pruritus, and headache. Increases in alanine aminotransferase (ALT) were also observed. Adverse events were generally mild and self-limiting, although in an apparent dose–response relationship, grade 2 and 3 gastrointestinal toxicities and grade 3 skin toxicities were reported with the highest dose regimens (1,800 and 2,400 mg BID). Hematologic toxicity was rare. The MTD was determined to be 1,200 mg BID. PK results indicated that oral absorption of R-etodolac was rapid (time to maximum concentration ranged from 2 to 4 h), and the half-life ranged from 5 to 7 h. The increase in maximum concentration, however, was not proportional to the increase in dose. R-etodolac significantly reduced absolute lymphocyte count (ALC) in B-CLL patients in a dose-dependent manner up to 1,800 mg BID and caused partial responses in 2 patients. Further study of R-etodolac as a possible new maintenance therapy or as a part of combination therapy of B-CLL appears warranted.