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

Publication ,  Journal Article
Rizzieri, D; LoRusso, S; Tse, W; Khan, K; Advani, A; Moore, J; Karsten, V; Cahill, A; Gerson, SL
Published in: Clin Lymphoma Myeloma Leuk
June 2010

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.

Duke Scholars

Published In

Clin Lymphoma Myeloma Leuk

DOI

EISSN

2152-2669

Publication Date

June 2010

Volume

10

Issue

3

Start / End Page

211 / 216

Location

United States

Related Subject Headings

  • Young Adult
  • Temozolomide
  • Sulfonamides
  • O(6)-Methylguanine-DNA Methyltransferase
  • Neoplasm Recurrence, Local
  • Middle Aged
  • Maximum Tolerated Dose
  • Male
  • Leukemia
  • Hydrazines
 

Citation

APA
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MLA
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Rizzieri, D., LoRusso, S., Tse, W., Khan, K., Advani, A., Moore, J., … Gerson, S. L. (2010). Phase I study of temozolomide and laromustine (VNP40101M) in patients with relapsed or refractory leukemia. Clin Lymphoma Myeloma Leuk, 10(3), 211–216. https://doi.org/10.3816/CLML.2010.n.033
Rizzieri, David, Samantha LoRusso, William Tse, Khuda Khan, Anjali Advani, Joseph Moore, Verena Karsten, Ann Cahill, and Stanton L. Gerson. “Phase I study of temozolomide and laromustine (VNP40101M) in patients with relapsed or refractory leukemia.Clin Lymphoma Myeloma Leuk 10, no. 3 (June 2010): 211–16. https://doi.org/10.3816/CLML.2010.n.033.
Rizzieri D, LoRusso S, Tse W, Khan K, Advani A, Moore J, et al. Phase I study of temozolomide and laromustine (VNP40101M) in patients with relapsed or refractory leukemia. Clin Lymphoma Myeloma Leuk. 2010 Jun;10(3):211–6.
Rizzieri, David, et al. “Phase I study of temozolomide and laromustine (VNP40101M) in patients with relapsed or refractory leukemia.Clin Lymphoma Myeloma Leuk, vol. 10, no. 3, June 2010, pp. 211–16. Pubmed, doi:10.3816/CLML.2010.n.033.
Rizzieri D, LoRusso S, Tse W, Khan K, Advani A, Moore J, Karsten V, Cahill A, Gerson SL. Phase I study of temozolomide and laromustine (VNP40101M) in patients with relapsed or refractory leukemia. Clin Lymphoma Myeloma Leuk. 2010 Jun;10(3):211–216.
Journal cover image

Published In

Clin Lymphoma Myeloma Leuk

DOI

EISSN

2152-2669

Publication Date

June 2010

Volume

10

Issue

3

Start / End Page

211 / 216

Location

United States

Related Subject Headings

  • Young Adult
  • Temozolomide
  • Sulfonamides
  • O(6)-Methylguanine-DNA Methyltransferase
  • Neoplasm Recurrence, Local
  • Middle Aged
  • Maximum Tolerated Dose
  • Male
  • Leukemia
  • Hydrazines