Phase I study of temozolomide and laromustine (VNP40101M) in patients with relapsed or refractory leukemia.

Abstract

PURPOSE:

Although alkylators are known to be effective against some myeloid leukemias, resistance is often mediated via O6-alkylguanine-DNA alkyltransferase (AGT). Temozolomide's inhibition of AGT may sensitize leukemia cells to the novel alkylator laromustine. We conducted a phase I translational study to evaluate the toxicities and estimate the maximum tolerated dose (MTD) of laromustine when administered with temozolomide (TMZ) in patients with hematologic malignancies.

PATIENTS AND METHODS:

TMZ was delivered twice daily for 5 doses followed by a single infusion of laromustine. The target TMZ dose was the dose that would reliably result in > 90% AGT depletion. Once the target TMZ dose was identified, the laromustine dose was escalated. A total of 35 patients with relapsed/refractory leukemia were treated.

RESULTS:

Treatment with TMZ 300 mg for 5 doses resulted in > 90% depletion of AGT levels in 5 of 6 patients. The MTD of the combination was established at TMZ 1500 mg and laromustine 300 mg/m2. Three of the 7 patients assayed from cohort 1 achieved > 90% depletion of AGT activity (range, 77%-100% depletion; median, 88%). Five of 6 patients enrolled in cohort 2 achieved > 90% depletion of AGT activity (range, 92%-100% depletion; median, 93.5%). This established that the 300-mg dose of TMZ (1500 mg total) would be maintained in subsequent cohorts. The majority of adverse events were primarily hematologic, with infectious and pulmonary complications also noted. Three (9%) of the patients with previous refractory disease achieved a complete remission, and 5 (14%) of the patients achieved a morphologic, leukemia-free, but persistent hypocellular bone marrow status.

CONCLUSION:

Laromustine in combination with TMZ is tolerable and manageable at doses that predictably suppress AGT. Reliable TMZ-induced inhibition of AGT was observed in doses that are clinically tolerable. Evidence of antitumor effect was observed with this combination, suggesting that further efficacy studies should be performed.

• Authors: David Rizzieri, Samantha LoRusso, William Tse, Khuda Khan, Anjali Advani, Joseph Moore, Verena Karsten, Ann Cahill, Stanton L Gerson
• Journal: Clinical lymphoma, myeloma & leukemia (Clin Lymphoma Myeloma Leuk) Vol. 10 Issue 3 Pg. 211-6 (Jun 2010) ISSN: 2152-2669 [Electronic] United States
• PMID: 20511167 (Publication Type: Clinical Trial, Phase I, Historical Article, Journal Article)

Chemical References

• Hydrazines
• Sulfonamides
• laromustine
• Dacarbazine
• O(6)-Methylguanine-DNA Methyltransferase
• Temozolomide

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Dacarbazine (administration & dosage, adverse effects, analogs & derivatives)
• Female
• History, 16th Century
• Humans
• Hydrazines (administration & dosage, adverse effects)
• Leukemia (drug therapy)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Recurrence, Local (drug therapy)
• O(6)-Methylguanine-DNA Methyltransferase (antagonists & inhibitors, drug effects)
• Sulfonamides (administration & dosage, adverse effects)
• Temozolomide
• Young Adult