A Phase I Study of Cloretazine® and Temozolomide in Patients with Hematologic Malignancies.
Background: In recent single agent Phase I trials, both Cloretazine® (VNP40101M) and temozolomide (TMZ) have shown activity in relapsed leukemia with minimal non-hematologic toxicity (Giles et al, 2004, Seiter et al, 2002). The cytotoxic activity of Cloretazine and TMZ have been attributed to the alkylation at the O6 position of guanine leading to a futile cycle of misincorporation of thymidine and ineffective mismatch repair. In addition, activation of Cloretazine generates different alkylating and isocyanate species that produce DNA cross linkages leading to DNA strand breaks and apoptosis. Repair of Cloretazine and TMZ induced alkylation lesions have been attributed to the expression and irreversible activity of enzyme O6 alkylguanine DNA alkyltranferase (AGT). It has been shown that TMZ administered to patients once or twice daily can reduce AGT levels in tumor cells; therefore depletion of AGT by TMZ may sensitize cells to Cloretazine and result in synergistic anti-tumor activity.
Methods: Cloretazine given after TMZ priming is currently evaluated in a Phase I dose escalation study. Patients are eligible if they have relapsed or refractory leukemia (ECOG 0–2). TMZ was given orally starting at a dose of 200 mg twice daily for 5 doses. Cloretazine is given intravenously on day 3, 2–4 hours after the last dose of TMZ starting at 100 mg/m2. Dose escalation of TMZ was guided by AGT depletion in leukemic blasts assessed by enzyme assay and HPLC (Gerson et al, 1985). Leukemia response is assessed according for standard criteria for CR and CRp (Cheson et al, 2003).
Results: Thirty-two patients have been treated in the first 5 cohorts (I: 200mg TMZ +100mg/m2 Cloretazine n=7, II: 300mg TMZ+100mg/m2 Cloretazine n=6, III: 300mg TMZ + 200mg/m2 Cloretazine n=3, IV: 300 mg TMZ + 300mg/m2 Cloretazine n=7, V: 300 mg TMZ + 400mg/m2 Cloretazine n=9). Median age of the patients is 62 years (range 27–80), M:F = 20:12. Treatment with 300mg TMZ x 5 doses resulted in >90% depletion of AGT levels in 5 of 6 patients in cohort II and was fixed for subsequent dose escalation with Cloretazine. Myelosuppression was the most frequent adverse event occurring in 10/32 (30%) of treated patients (6 Grade 3–4 neutropenia, 4 Grade 3–4 thrombocytopenia). Non-hematologic toxicity has been minimal. To date, two patients treated with TMZ 300mg x 5 and Cloretazine 400 mg/m2 have experienced dose-limiting toxicity: Grade 3 pulmonary hemorrhage and Grade 3 neutropenic colitis in Cohort V and no unexpected toxicities were observed. Three early deaths occurred within 30 days (9.4%), all attributed to progressive disease. Responses are as follows: CR=3, CRp=1, and HI=2 for an overall response rate of 18.8%. The study is ongoing.
Conclusions: Cloretazine® in combination with TMZ is tolerable and manageable. Evidence of anti-tumor effect has already been observed suggesting the combination of Cloretazine® and TMZ may potentiate their antileukemic activity.
Rizzieri, DA; Tse, W; Khan, KD; Advani, A; Donze, J; Karsten, V; Geller, RB; Gerson, SL
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