DX-895If, a hexacyclic synthetic water-soluble derivative of camptothecin, is a novel topo 1 inhibitor with in vitro activity against a wide spectrum of human malignant cell lines. In terms of tumor cell growth inhibition, topo 1 activity inhibition, and DNA fragmentation, DX-8951fis more potent than other topo 1 inhibitors including topotecan. Cell lines cross-resistant to CPT-11 and topotecan retain sensitivity to DX-8951f. We have previously reported on the activity of DX-8951 f in a human AML SCID mouse model - this: activity was schedule dependent and DX-8951 f has significant activity against CNS leukaemia in this model. (Vey et al Clin Ça Res 6: 731-736: 2000). We conducted a Phase I study of DX-8951 f in adult and pédiatrie patients (pts) with primary refractory or relapsed acute myeloid (AML) or lymphocytic (ALL) leukemia, myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP). DX-895 If was given as an intravenous infusion over 30 minutes daily for 5 days every 3-4 weeks. The starting dose was 0.6 mg/m2/d (3.0 mg/m2/course). Twentyfive pts (AML: 21; MDS: 1; ALL: 2; CML-BP: 1), median age 54 years, were treated on study. Stomatitis was the dose limiting toxicity (DLT). The recommended dose for further single agent studies was defined as 0.9 mg/nr/day x 5. Dose (Number patients treated) Grade 3/4 Stomatitis Grade 3/4 Diarrhea Grade 3/4 Other 0.6(4) 000 0.9(9) I 0 0 1.2(3) 200 1.35(2) 200 0.9 x 7 (7) 1 0 2 DX-895 If exhibited antileukemic activity, as reflected by the finding of marrow hypoplasia (<20% cellularity with <5% blasts) at day 14 to 28 in over 60% of AML pts. Two AML patients achieved hématologie improvement. DX-895 If will now be investigated as a single agent in better prognosis AML pts, in AML when combined with Ara-C, and in other hematological malignancies.
|Original language||English (US)|
|Issue number||11 PART I|
|State||Published - Dec 1 2000|
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