Phase I study of UCN-01 and perifosine in patients with relapsed and refractory acute leukemias and high-risk myelodysplastic syndrome

• Published in: Investigational new drugs Vol. 31; no. 5; pp. 1217 - 1227
• Main Authors: Gojo, Ivana, Perl, Alexander, Luger, Selina, Baer, Maria R., Norsworthy, Kelly J., Bauer, Kenneth S., Tidwell, Michael, Fleckinger, Stephanie, Carroll, Martin, Sausville, Edward A.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.10.2013; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Analysis; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Apoptosis; Biological and medical sciences; Cancer therapies; Cell growth; Dose-Response Relationship, Drug; Drug dosages; Drug Resistance, Neoplasm; Female; General aspects; Growth factors; Hematologic and hematopoietic diseases; Humans; Kinases; Leukemia; Leukemia - drug therapy; Leukemia - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Leukocytes, Mononuclear - metabolism; Male; Maximum Tolerated Dose; Medical prognosis; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Myelodysplastic syndromes; Myelodysplastic Syndromes - drug therapy; Myelodysplastic Syndromes - metabolism; Oncology; Pharmaceutical sciences; Pharmacodynamics; Pharmacokinetics; Pharmacology. Drug treatments; Pharmacology/Toxicology; Phase I Studies; Phosphorylation; Phosphorylcholine - administration & dosage; Phosphorylcholine - adverse effects; Phosphorylcholine - analogs & derivatives; Phosphorylcholine - pharmacokinetics; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Proto-Oncogene Proteins c-akt - metabolism; Staurosporine - administration & dosage; Staurosporine - adverse effects; Staurosporine - analogs & derivatives; Staurosporine - pharmacokinetics; Studies; Toxicity; Treatment Outcome; Young Adult; Acute leukemia; Perifosine; Akt inhibition; UCN-01; Antineoplastic agent; Human; High risk; Drug combination; Relapse; Treatment resistance; Toxicity; Akt protein kinase; Malignant hemopathy; Maximum tolerated dose; Myelodysplastic syndrome; Treatment; Phase I trial; Inhibitor; Pharmacokinetics; Cancer
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-013-9937-8

Summary Background The PI3K-Akt pathway is frequently activated in acute leukemias and represents an important therapeutic target. UCN-01 and perifosine are known to inhibit Akt activation. Methods The primary objective of this phase I study was to determine the maximum tolerated dose (MTD) of UCN-01 given in combination with perifosine in patients with advanced acute leukemias and myelodysplastic syndrome. Secondary objectives included safety, pharmacokinetics, pharmacodynamics, and efficacy. Perifosine 150 mg every 6 h was given orally on day 1 followed by 100 mg once a day continuously in 28-day cycles. UCN-01 was given intravenously over 3 h on day 4 at three dose levels (DL1 = 40 mg/m 2 ; DL2 = 65 mg/m 2 ; DL3 = 90 mg/m 2 ). Results Thirteen patients were treated (DL1, n  = 6; DL2, n  = 4; DL3, n  = 3) according to a traditional “3 + 3” design. Two patients at the DL3 experienced dose-limiting toxicity including grade 3–4 pericardial effusion, hypotension, hyperglycemia, hyperkalemia, constitutional symptoms and grade 5 pneumonitis. Other frequent toxicities were grade 1–2 nausea, diarrhea, vomiting, fatigue and hyperglycemia. The MTD was determined to be UCN-01 65 mg/m 2 with perifosine 100 mg a day. No appreciable direct Akt inhibition could be demonstrated in patients’ mononuclear cells using Western blot, however, reduced phosphorylation of the downstream target ribosomal protein S6 in leukemic blasts was noted by intracellular flow cytometry. No objective responses were observed on this study. Conclusion UCN-01 and perifosine can be safely administered, but this regimen lacked clinical efficacy. This approach may have failed because of insufficient Akt inhibition in vivo.