A Phase I Trial of Ara-C, Topotecan, and Gemtuzumab Ozogamicin (Mylotarg®) for Advanced MDS and Secondary or Relapsed AML.

The outlook for most pts with advanced MDS and secondary or relapsed AML is poor, given the limited efficacy of conventional chemotherapy. While allogeneic SCT is potentially curative, many pts are not candidates for myeloablative transplants, and newer reduced intensity conditioning approaches applicable to older pts are generally less effective unless pts are in remission. We designed a Phase I dose escalation study to examine the safety and efficacy of combining chemotherapy with the anti-CD33 mAb conjugate, Gemtuzumab Ozogamicin (GO) as induction therapy for high risk MDS and AML. Design and study population: Between 11/01 and 2/04, 19 pts were assigned to receive Ara-C 2 g/m2 over 4 hours daily, days 1–5; Topotecan 1.5 mg/m2 by continuous infusion daily, days 1–5; and GO on day 6 at a dose of 3, 4.5, or 6 mg/m2; the protocol included an option for a second dose of GO (at ½ of the day 6 dose) on the basis of results of the day 14 BM exam. Primary safety endpoints were Gr 4 or unexpected non-hematologic toxicities, or death within 30 days of treatment. The primary efficacy endpoint was CR, defined as complete morphologic, flow cytometric, and cytogenetic remission. The study population included 10 pts with advanced MDS (IPSS score ≥1.5), 6 with AML following MDS, and 3 with relapsed AML. All pts had blasts demonstrating CD33 expression. Median pt age was 64 yrs (37–77). Results: Table 1 summarizes results at each dose level. Assigned treatment was delivered in 17 of the 19 pts; 2 pts did not receive GO because of pneumonia (1pt), and elevated LFT’s (1 pt). Infections accounted for the majority of non-hematologic complications, with 6 bacteremic episodes, 1 case of mild typhlitis, and 2 pneumonias. There was only one case of Gr 4 liver toxicity in the single pt who received a second dose of GO. There were two early deaths (10%), including a sudden death on day 20 in a pt who had an MI related to the GO infusion. At the 6 mg/m2 dose level, 3 of 6 pts treated with a single dose of GO experienced Gr IV–V non-hematologic toxicities (1 sudden death, 2 reversible but prolonged delirium). Based on intent to treat, 9 of the 19 pts (47%) achieved CR following therapy. With median follow-up of 311 d (161–889), 8 of the 19 pts were alive at last follow-up, 4 in CR. Five pts went on to allogeneic SCT; 3 are alive and disease-free 199, 219, and 713 days following treatment, and two died of transplant-related complications. None experienced VOD or other unexpected toxicities following SCT. Conclusions: These results compare favorably with those observed with standard induction therapy for MDS/secondary AML, and the safety data support the feasibility of combining GO with chemotherapy. Other combination studies have typically utilized a GO dose of 9 mg/m2 given prior to chemotherapy, and unacceptable toxicities have frequently been observed. In this study, GO doses of 3 and 4.5 mg/m2 administered after chemotherapy were well tolerated. At the 6 mg/m2 dose level, 4 of 7 pts experienced serious toxicities, meeting criteria for declaring the MTD to be a single dose of 4.5 mg/m2. A Phase II study at the 4.5 mg/m2 dose is planned to assess efficacy. ATGO: Outcomes by Dose Level | GO Dose (mg/m2) | n | CR (%) | # DLT’s | TRM (%) | |:----------------------------------:| -- | ------ | ------- | -------- | | * One pt received a 2nd dose of GO | | 3 | 8 | 5 (62) | 1 | 1 (12.5) | | 4.5 | 4 | 2 (50) | | | | 6 | 7 | 2 (28) | 4* | 1 (14) | | All pts | 19 | 9 (47) | 5 | 2 (10.5) |