Phase I Study of XL-119, a Rebeccamycin Analog, in Patients with Refractory Hematological Malignancies.

XL-119, a water soluble analog of the antibiotic agent rebeccamycin, has demonstrated broad spectrum antitumor activity in preclinical studies, including P388 and L1210 leukemia in murine models. XL-119 intercalates DNA, and inhibits topo II activity by a unique highly potent mechanism which renders it active in etoposide-resistant A549 and HCT 116 leukemia cell lines. On a Phase I study in patients with refractory hematological malignancies XL 119 was given as a 60 minute IV infusion, on D1–5 of 21 day cycles. The starting dose for the initial cohort was 140 mg/m²/d with planned escalation by 20% increments in the setting of a standard 3+3 design. A total of 28 patients (pts) have been treated to date. Three, 5, 3, 6, 3, and 8 have been enrolled to dose levels (DL) of 140, 160, 180, 200, 220 and 240 mg/m²/d, respectively. Median age was 57 years (range 19–82). Median ECOG status 1 (range, 0–2). Diagnoses included: AML (22 pts), MDS (1 pt) and ALL (5pts). AML was either primary refractory or at an advanced relapse state and had failed a median of 3 prior salvage treatments (range 1–10). The pt with MDS had received 4 prior therapies. Pts with ALL had received a median of 3 prior therapies. Dose limiting toxicities (DLTs) were observed in evaluable patients at the following dose levels: 1 patient at 200 mg/m² experienced DLTs: grade 3 hand-foot syndrome and grade 4 mucositis. An expansion of this dose level yielded no further incidences of DLT. 1 patient at 240mg/m² experienced DLT with grade 3 mucositis. The cohort was expanded without observation of additional DLTs. Dose level 260 mg/m² is currently being explored with 2 patients too early for full evaluation. Two patients with refractory AML achieved a significant elimination of marrow blasts and received a second cycle of therapy. Twenty-four of 28 patients had transient reductions in peripheral blood blasts. XL 119 is a well-tolerated myelosuppressive agent which warrants further study in patients with hematological malignancies.