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• W2553523735 abstract "Abstract XIAP (X-linked Inhibitor of Apoptosis protein) is an inhibitor of caspases 3 and 9 that is over-expressed in AML and may contribute to chemoresistance. We report a phase I/II trial of the XIAP antisense oligonucleotide AEG35156 in combination with reinduction chemotherapy in AML patients in first relapse after a short (≤ 6 months) initial CR or with primary refractory disease. In the phase I portion of the study, 24 patients were treated with escalating doses of AEG35156 (12 to 250 mg/m2) on days 1–3 by IV infusion over 2 hours followed by idarubicin (12mg/m2 on days 4–6) and cytarabine (1.5g/m2 by continuous infusion on days 4–7 (patients age < 65) and days 4–6 (patients > 65 years)). AEG35156 was continued weekly following reinduction chemotherapy until treatment failure. In the phase II portion, 27 patients with treated with the protocol at the highest planned AEG35156 dose level of 350 mg/m2. In the phase I study, 13 patients were in first relapse with CR1 ≤ 6 months, 10 were primary refractory to 2 induction regimens, and 1 was primary refractory to 1 induction regimen. In the phase II study, 7 patients were in first relapse, 11 were primary refractory to 2 induction regimens, and 9 were primary refractory to 1 induction regimen. The most frequent adverse events related to protocol therapy were febrile neutropenia, and mostly Grade 1–2 nausea/vomiting, peripheral edema and diarrhea. The incidence of Phase I and II adverse event rates were similar except for 2 cases of Grade 3–4 peripheral neuropathy in the Phase II study that occurred in responding patients after repeated AEG35156 administration at 350 mg/m2. In the phase I study, 2/24 patients died during induction from septicemia and renal failure. In the phase II study, 4/27 died; one each from respiratory failure and AML progression and two from septicemia complications. In the phase I study, the one patient refractory to a single induction regimen achieved CR (total response rate for the 24 phase I patients = 4%). In the Phase II portion of the study, 41% of patients responded (7 CRs and 4 CRps): 4/7 in first relapse, 7/9 refractory to 1 induction regimen, and 0/11 refractory to 2 inductions. PK analysis demonstrated a dose-proportional increase in plasma AEG35156 Cmax up to 83μg/ml at 350mg/m2. Pharmacodynamic studies evaluated the ability of AEG35156 to knockdown its target. Blasts from peripheral blood were isolated from 22 Phase I/II patients. Total mRNA was isolated and levels of XIAP mRNA quantified by Q-RTPCR. XIAP mRNA knockdown was detected after AEG35156 administration and the frequency of knockdown was related to the dose of AEG35156. During the initial 3 days of AEG35156 administration, > 30% target knockdown was observed in 1/9 (11%) patients receiving AEG35156 < 110 mg/m2 and 11/13 (85%) receiving ≥ 110 mg/m2AEG35156. At the highest dose level of 350mg/m2, 4/6 (67%) patients had > 75% decrease in XIAP mRNA. In summary, AEG35156 was well tolerated up to the highest planned dose level (350 mg/m2) in combination with idarubicin and cytarabine chemotherapy except for two episodes of peripheral neuropathy at 350 mg/m2. At the highest dose levels, AEG35156 reproducibly reduced levels of XIAP mRNA in circulating blasts. The combination of AEG35156 with idarubicin and cytarabine was not efficacious in AML patients refractory to more than 1 prior induction attempt but produced remissions in patients who had not responded to a single induction therapy or were in first relapse after a short initial CR. Thus, these data support the continued clinical evaluation of AEG35156 as part of an early reinduction strategy for patients with relapsed/refractory AML." @default.
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• W2553523735 date "2008-11-16" @default.
• W2553523735 modified "2023-09-28" @default.
• W2553523735 title "Phase 1/2 Trial of the XIAP Antisense Oligonucleotide (AEG35156) in Combination with Idarubicin and Cytarabine in Patients with Relapsed/Refractory AML" @default.
• W2553523735 doi "https://doi.org/10.1182/blood.v112.11.764.764" @default.
• W2553523735 hasPublicationYear "2008" @default.
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