Phase 1 study of PTK787 ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome

• Published in: Leukemia Vol. 20; no. 6; pp. 952 - 957
• Main Authors: ROBOZ, G. J, GILES, F. J, LAURENT, D, FELDMAN, E. J, LIST, A. F, CORTES, J. E, CARLIN, R, KOWALSKI, M, BILIC, S, MASSON, E, ROSAMILIA, M, SCHUSTER, M. W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01.06.2006; Nature Publishing Group
• Subjects: Acute Disease; Acute myeloid leukemia; Adult; Aged; Aged, 80 and over; Angiogenesis inhibitors; Anorexia; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Bone marrow; c-Kit protein; Cell Proliferation - drug effects; Chemotherapy; Cohort Studies; Diarrhea; Dosage; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme inhibitors; Female; Growth factors; Hematologic and hematopoietic diseases; Humans; Hypertension; Kinases; KIT protein; Lethargy; Leukemia; Leukemia, Myeloid - diagnosis; Leukemia, Myeloid - drug therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - diagnosis; Myelodysplastic Syndromes - drug therapy; Nausea; Oral administration; Patients; Peripheral blood; Pharmacokinetics; Pharmacology; Phthalazines - administration & dosage; Phthalazines - adverse effects; Phthalazines - pharmacology; Phthalazines - therapeutic use; Platelet-derived growth factor; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase receptors; Pruritus; Pyridines - administration & dosage; Pyridines - adverse effects; Pyridines - pharmacology; Pyridines - therapeutic use; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptors; Remission; Safety; Steady state; Toxicity; Treatment Outcome; Tyrosine; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular endothelial growth factor receptors; Vomiting; myelodysplastic syndrome: VEGF; Vascular endothelium growth factor; Treatment; Hematology; Tyrosine kinase inhibitor; Acute; Phase I trial; Receptor tyrosine kinase; Malignant hemopathy; Myelodysplastic syndrome; Acute myelocytic leukemia
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2404213

PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase and the c-kit protein tyrosine kinase. The objective of this Phase I study was to evaluate the safety, tolerability, biologic activity and pharmacologic profile of PTK/ZK administered orally, twice daily, on a continuous dosing schedule in patients with primary refractory or relapsed acute myeloid leukemia (AML), secondary AML, poor-prognosis de novo AML or advanced myelodysplastic syndrome (MDS). Acute myeloid leukemia patients for whom PTK/ZK monotherapy was ineffective could receive PTK/ZK combined with standard induction chemotherapy. Sixty-three patients received PTK/ZK at doses of 500-1000 mg orally b.i.d. Safety and pharmacokinetic data were collected. Responses were evaluated according to standard bone marrow and peripheral blood criteria. At 1000 mg b.i.d., dose-limiting toxicities of lethargy, hypertension, nausea, emesis and anorexia were observed. Other adverse events related to PTK/ZK were dizziness, weakness, fatigue, diarrhea and pruritus; these were generally mild and reversible. Pharmacokinetic data showed that steady state was reached by day 14, there was no accumulation with repeat dosing and there was no significant increase in exposure at steady state beyond the maximum tolerated dose (MTD). Complete remission was observed in five of 17 AML patients treated with PTK/ZK combined with chemotherapy. In conclusion, the MTD of PTK/ZK is 750 mg orally b.i.d. The drug is generally well tolerated and can be given in combination with chemotherapy for patients with MDS and AML.