An Open-Label Randomized Phase 2 Study of the X-Linked Inhibitor of Apoptosis (XIAP) Antisense AEG35156 Given in Combination With High-dose Cytarabine and Idarubicin in AML Following Failure of a Single Standard Dose Cytarabine Based Frontline Induction Regimen

To determine if AEG35156 can enhance the combined complete remission (CR) and CR with incomplete platelet recovery (CRp) rate of high-dose cytarabine and idarubicin in AML following failure of a single standard dose cytarabine based frontline induction regimen.

开始日期2009-11-01

申办/合作机构

Aegera Therapeutics, Inc.

EUCTR2009-011254-18-BG / Not yet recruitingN/A

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Comparing the Safety and Efficacy of AEG33773 versus Placebo in Patients with Painful Diabetic Peripheral Neuropathy - n/a

开始日期2009-10-02

申办/合作机构

Aegera Therapeutics, Inc.

NCT00882869 / Completed临床1/2期

A Phase 1-2, Open-Label Study of The X-Linked Inhibitor of Apoptosis (XIAP) Antisense AEG35156 in Combination With Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC)

AEG35156 is a second generation antisense which targets XIAP mRNA to lower XIAP levels and the apoptotic threshold of cancer cells, enhancing their sensitivity to intrinsic death and chemotherapy. Advanced HCC is an attractive target for AEG35156 since XIAP is highly expressed in HCC and may prevent cancer cells from undergoing apoptosis. Second generation antisense molecules are known to accumulate in liver where AEG35156 may down regulate XIAP protein expression in HCC cells thus promoting their apoptotic death.

开始日期2009-03-01

申办/合作机构

Aegera Therapeutics, Inc.

[+1]

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2010-04-15·Cancer Research

Abstract 139: The identification of potent inhibitor of apoptosis protein (IAP) inhibitors for clinical development

作者: Patel, Harshila ; Romeo, Andrea ; Gillard, John ; Ashdown, Helen ; Humphreys, R ; Boudreault, Alain ; Laurent, Alain ; Methot, Danielle ; Morris, Stephen J. ; Jerome, Lori ; Jaquith, James ; Devalaraja, M ; Maltais, Stephane ; Hewitt, Kim ; Durkin, Jon

AbstractThe inhibitor of apoptosis proteins (IAPs) are important regulators of cell death. Over-expression of IAPs, including XIAP, cIAP1 and cIAP2, predicts poor patient outcome in several types of cancer. XIAP binds to and inhibits caspases 3, 7 and 9. Inhibition of IAP function can enhance cell death in tumor cells. Inhibition of IAPs is being explored clinically with XIAP anti-sense (AEG35156) and small molecule inhibitor (HGS1029) strategies.We describe small molecule inhibitors of the IAPs that have been designed to bind to the homologous BIR3 domains on the IAPs, which is the site of binding of second mitochondria-derived activator of caspase (SMAC). Structure-activity trends of IAP inhibitors were evaluated for binding potency and selectivity towards IAP BIR domains and analyzed for their ability to sensitize cancer cells to death alone or in conjunction with the agonistic TRAIL receptor 1 monoclonal antibody, mapatumumab, or chemotherapeutic agents.Bridging selected compounds at various sites led to compounds with binding affinities for IAPs in the picomolar range. In cellular assays, IAP inhibitor compounds caused rapid and robust loss of cIAP1, consistent with stimulation of E3 ligase activity. In vitro cytotoxicity assays demonstrated sensitization of tumor cell lines to co-treatment with mapatumumab or chemotherapy at low nanomolar concentrations.In vitro ADME studies were conducted in multiple species to select stable molecules which were negative in CYP and hERG binding assays. Selected compounds had high protein binding in plasma from multiple species. IV administration in mice resulted in Cmax values in excess of the EC50 required for cancer cell death in vitro.Efficacy of lead compounds was demonstrated against several xenograft tumor models as single agents and in combination with either mapatumumab or conventional chemotherapeutics. This led to the identification of a highly potent compound series from which a clinical development candidate, HGS1029, was selected.Solid tumor and lymphoid malignancies Phase 1 cancer trials with HGS1029 have been initiated.Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 139.

2008-11-16·Blood

Phase 1/2 Trial of the XIAP Antisense Oligonucleotide (AEG35156) in Combination with Idarubicin and Cytarabine in Patients with Relapsed/Refractory AML

作者: Carter, Bing ; Schimmer, Aaron D ; Altman, Jessica K ; Morris, Stephen ; Schiller, Gary J. ; Tallman, Martin S. ; Borthakur, Gautam ; Kassis, Jeannine ; Jacob, Christine ; Andreeff, Michael ; Estey, Elihu H ; Jolivet, Jacques ; Karp, Judith E.

AbstractXIAP (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.

2008-11-16·Blood

Pharmacodynamic Study of Phase 1/2 Trial of the XIAP Antisense Oligonucleotide (AEG35156) in Combination with Chemotherapy in Patients with Relapsed/Refractory AML.

作者: Borthakur, Gautam ; Kantarjian, Hagop M. ; Konopleva, Marina ; Morris, Stephen ; Carter, Bing Z. ; Byrd, Anna L. ; Mak, Duncan H. ; Andreeff, Michael ; Estey, Elihu

AbstractXIAP, a potent cellular inhibitor of caspases 3 and 9, is highly expressed in various malignant cells including AML cells and contributes to chemoresistance. A phase 1/2 trial of the XIAP antisense oligonucleotide AEG35156 in combination with chemotherapy in AML patients in first relapse after a short (< 6 months) initial CR or with primary refractory disease was conducted (Schimmer A et al., abstract #, ASH 2008). Here we report the pharmacodynamic studies of patients in this trial treated at M. D. Anderson Cancer Center. A total of 13 patients were treated at our institution: 5 in the phase 1 study with escalating doses of AEG35156 (12mg/m2 to 350 mg/m2) and 8 in the phase 2 study with a fixed dose of AEG35156 (350 mg/m2). Patients in both phases were treated with AEG35156 on days 1–3 by IV infusion over 2 hours followed by idarubicin on days 4–6 (12mg/m2 over 30 min) 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 for 4 weeks following re-induction chemotherapy. Blood samples were collected from each patient at screening, days 1–5 before the daily treatment, and day 28–35 post chemotherapies. XIAP mRNA levels (patients 102, 105, 106, 107, 109, 110, and 111) were determined in CD3/CD19-depleted mononuclear cells by real time RT-PCR. Apoptosis induction in RBC-lysed whole blood (all the patients except 105, 109, 113, and 114) was measured by Annexin V positivity and/or changes in mitochondrial membrane potential (MMP) whenever samples were available. XIAP mRNA knockdown was evident with increasing doses of AEG35156. No decrease of XIAP mRNA was found in patient 102 (dose 24 mg/m2) who did not respond to the treatment, while more than 60% of XIAP mRNA reduction was detected in patient 105 (dose 165 mg/m2) who achieved CR. XIAP mRNA was knocked down significantly in all phase 2 patients analyzed. XIAP mRNA levels were reduced by 90% or more in patients 106, 107, 109, and 110 and about 50% in patient 111. Importantly, 3 of these 5 patients achieved CR (107, 110, and 111). No apoptosis induction was detected in patients 101 (dose 12 mg/m2) and 102. A large increase of MMP-low but not of Annexin V positive cells by AEG35156 alone was detected in patient 103 (dose 48 mg/m2) especially in the CD34+38- stem cell compartment. Interestingly, apoptosis was induced by AEG35156 alone in patient 104 (dose 48 mg/m2) measured by both Annexin V positivity (33.6% on day 3 versus 14.7% on day 1 before the treatment) and changes in MMP (45.3% on day 3 versus 31.0% on day 1 before the treatment). Again, the induction was more pronounced in CD34+38- stem cells than CD34+38+ progenitor cells and bulk leukemic cells. Among the phase 2 patients, no induction in apoptosis was found in patient 106. Although no apoptosis induction was detected in bulk leukemic cells and CD34+38+ progenitor cells in patients 107, 110, and 111, a major induction in apoptosis was found in CD34+38- stem cells of all these three patients on day 2, 24 hours after first AEG35156 infusion. It is noteworthy that all three patients achieved CR with the treatment. Profound apoptosis induction was observed on day 2 in bulk as well as progenitor and stem cells in patient 115 and the patient achieved CR after one induction course. In summary, AEG35156, at the dose of 350 mg/m2, is effective in knocking down XIAP mRNA levels in circulating blasts. This is accompanied by the induction of apoptosis preferentially in the CD34+38- stem cell compartment. This observation needs to be further investigated when more patients are evaluated. Knockdown of XIAP has to be confirmed at the protein levels in future studies.

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