The Experts below are selected from a list of 348 Experts worldwide ranked by ideXlab platform

Jorge E. Cortes - One of the best experts on this subject based on the ideXlab platform.

  • subcutaneous omacetaxine mepesuccinate in patients with chronic phase chronic myeloid leukemia previously treated with 2 or more tyrosine kinase inhibitors including imatinib
    Clinical Lymphoma Myeloma & Leukemia, 2013
    Co-Authors: Jorge E. Cortes, Luke P Akard, Franck E Nicolini, Meir Wetzler, Jeffrey H Lipton, Nisha Nanda, Annie Claude Benichou, Adam R Craig, Janis Leonoudakis, Jean H Khoury
    Abstract:

    Abstract Introduction Omacetaxine mepesuccinate (omacetaxine) is a first-in-class Cephalotaxine that has demonstrated efficacy in CML. In this analysis we evaluated omacetaxine in CML patients with resistance or intolerance to 2 or more tyrosine kinase inhibitors (TKIs). Patients and Methods Data were pooled from 2 phase II trials of subcutaneous omacetaxine, administered at 1.25 mg/m 2 twice daily for 14 consecutive days every 28 days until response, then for 7 days every 28 days as maintenance. Patients with resistance or intolerance to imatinib and at least 1 other approved TKI (dasatinib and/or nilotinib) were included; results for patients in chronic phase (CP) are reported here. Major cytogenetic response (MCyR) was the primary end point. Results Eighty-one patients with CML-CP (median age, 59 years; range, 26-83 years) were included in the analysis. All patients previously received imatinib, 69 (85%) previously received dasatinib, and 48 (59%) previously received nilotinib. Median omacetaxine exposure was 7.5 months (range, 0.03-38.6 months), with 13 patients ongoing. MCyR was reported in 16 patients (20%; one-sided 95% lower confidence limit, 12.8%), including 8 complete responses; median duration was 17.7 months (95% confidence interval, 4.1 months – not reached). Fifty-six patients (69%) achieved and/or maintained hematologic response for at least 8 weeks; median duration was 12.2 months (range, 8.4-26.2 months). Median failure-free and overall survival were 9.6 months and 34 months, respectively. Toxicity was mainly hematologic: the most common grade 3/4 adverse events were thrombocytopenia (67%), neutropenia (47%), and anemia (37%). Conclusion Omacetaxine produced clinically meaningful responses with acceptable tolerability in patients with CML-CP previously treated with 2 or more TKIs.

  • predictive factors associated with achievement of major cytogenetic response mcyr to omacetaxine mepesuccinate among patients with chronic phase chronic myeloid leukemia cml cp
    Journal of Clinical Oncology, 2013
    Co-Authors: Meir Wetzler, Hanna Jean Khoury, Hagop M. Kantarjian, Adam Craig, Luke P Akard, Franck E Nicolini, Jeffrey H Lipton, Michele Baccarani, Jorge E. Cortes
    Abstract:

    7088 Background: Omacetaxine mepesuccinate (OMA), a first-in-class Cephalotaxine, is a protein synthesis inhibitor not dependent on Bcr-Abl signaling. OMA has shown clinical activity in CML patient...

  • phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors
    American Journal of Hematology, 2013
    Co-Authors: Jorge E. Cortes, Meir Wetzler, Annie Claude Benichou, Raghunadharao Digumarti, Adam R Craig, Purvish M Parikh, J H Lipton, Andreas Hochhaus, F E Nicolini, Hagop M. Kantarjian
    Abstract:

    Omacetaxine mepesuccinate (omacetaxine) is a first-in-class Cephalotaxine with a unique mode of action, independent of BCR-ABL, that has shown promising activity in patients with chronic myeloid leukemia (CML). This multicenter, noncomparative, open-label phase 2 study evaluated the efficacy and safety of subcutaneous omacetaxine in CML patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs); results in patients in chronic phase are reported here. Patients received subcutaneous omacetaxine 1.25 mg/m2 twice daily days 1–14 every 28 days until hematologic response (up to a maximum of six cycles), then days 1–7 every 28 days as maintenance. Primary endpoints were rates of hematologic response lasting >8 weeks and major cytogenetic response (MCyR). Forty-six patients were enrolled: all had received imatinib, 83% had received dasatinib, and 57% nilotinib. A median 4.5 cycles of omacetaxine were administered (range, 1–36). Hematologic response was achieved or maintained in 31 patients (67%); median response duration was 7.0 months. Ten patients (22%) achieved MCyR, including 2 (4%) complete cytogenetic responses. Median progression-free survival was 7.0 months [95% confidence interval (CI), 5.9–8.9 months], and overall survival was 30.1 months (95% CI, 20.3 months—not reached). Grade 3/4 hematologic toxicity included thrombocytopenia (54%), neutropenia (48%), and anemia (33%). Nonhematologic adverse events were predominantly grade 1/2 and included diarrhea (44%), nausea (30%), fatigue (24%), pyrexia (20%), headache (20%), and asthenia (20%). Subcutaneous omacetaxine may offer clinical benefit to patients with chronic-phase CML with resistance or intolerance to multiple TKI therapies. Am. J. Hematol. 88:350–354, 2013. © 2013 Wiley Periodicals, Inc.

  • long term follow up of ongoing patients in 2 studies of omacetaxine mepesuccinate for chronic myeloid leukemia
    Blood, 2012
    Co-Authors: Hagop M. Kantarjian, Adam Craig, Luke P Akard, Franck E Nicolini, Meir Wetzler, Jeffrey H Lipton, Michele Baccarani, Laurence Legros, Krzysztof Warzocha, Jorge E. Cortes
    Abstract:

    Abstract 2787 Background Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is an investigational, first-in-class Cephalotaxine, a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine reduces levels of multiple oncoproteins, including Bcr-Abl, and induces apoptosis in leukemic stem cells. It has shown clinical activity and adequate tolerability in two phase 2, open-label studies of chronic myeloid leukemia (CML), the first in patients with a history of the T315I Bcr-Abl mutation (enrolled September 2006 through March 2010) and the second in patients with resistance or intolerance to ≥2 approved tyrosine kinase inhibitors (TKIs; enrolled March 2007 through June 2009). This ad hoc analysis presents the efficacy and safety results of patients in the phase 2 studies who remained on omacetaxine as of March 31, 2012. Methods Efficacy and safety data were pooled from patients with CML chronic phase (CML-CP) and CML accelerated phase (CML-AP) who received omacetaxine in either of the phase 2 studies and had not discontinued omacetaxine as of March 31, 2012. Omacetaxine 1.25 mg/m 2 was given subcutaneously twice daily up to 14 consecutive days per 28-day cycle for induction and at the same dosage for up to 7 days/cycle as maintenance. Results Of the 203 patients enrolled in the 2 studies (108 CML-CP, 51 CML-AP, and 44 CML blast phase), 9 CML-CP patients (median 35 cycles [range 26–53]) and 2 CML-AP patients (median 20.5 cycles [range 19–22]) continue to receive omacetaxine. Median age of ongoing CML-CP patients at baseline was 61 years (range 45–73); 7 were male. Median age of ongoing CML-AP patients was 58 years (range 48–67); all were male. For CML-CP patients, the median number of dosing days was 137 (range 68–342) over a median of 35 cycles (range 26–53); the 2 CML-AP patients had 189 and 277 dosing days during 19 and 22 cycles, respectively. Other baseline clinical characteristics are presented in the Table. Seven of the CML-CP patients achieved MCyR, including 6 complete responses. One CML-CP patient achieved a minimal cytogenetic response and 1 had no response. No CML-AP patient achieved MCyR. Time to onset of MCyR for the CML-CP patients were Six CML-CP patients were in CHR at baseline and 3 achieved CHR within 3 months. One CML-AP patient achieved CHR at All patients had at least 1 AE and 1 serious AE. The most common AEs were anemia (11/11), thrombocytopenia (9/11), neutropenia (6/11), nausea (7/11), diarrhea or fatigue (5/11 each), and headache (4/11). Grade 3/4 AEs occurred in 10 (91%) patients. The most common were hematologic: thrombocytopenia (79% \(79\) CML-CP, 100% \(22\) CML-AP), anemia (67% \(49\) CML-CP, 100% \(22\) CML-AP), and neutropenia (56% \(59\) CML-CP, 0% \(02\) CML-AP). Leukopenia and pancytopenia were reported in 1 patient each in the CML-AP group. Blast crisis, which was deemed treatment-related, was reported in 1 patient in the CML-AP group; this patient was discontinued. No deaths were reported. Conclusions A subset of heavily pretreated patients with CP or AP CML who participated in phase 2 studies of omacetaxine were able to continue omacetaxine for up to 53 cycles and experience durable major cytogenetic and hematologic responses. Grade 3/4 AEs were primarily hematologic and consistent with the known safety profile of omacetaxine. Disclosures: Kantarjian: ChemGenex (Teva): Research Funding. Off Label Use: Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine has shown clinical activity in 2 studies of chronic myeloid leukemia (CML), one in patients with a history of the T315I Bcr-Abl mutation and the other in patients failing at least 2 tyrosine kinase inhibitors. Baccarani: Teva: Research Funding. Nicolini: BMS: Research Funding, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Teva: Speakers Bureau. Wetzler: Teva: Membership on an entity9s Board of Directors or advisory committees; BMS: Research Funding. Akard: Merck: Research Funding; Pfizer: Research Funding; Eisai: Speakers Bureau; Millenium: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Ariad: Research Funding; Teva: Research Funding. Legros: Celgene: Speakers Bureau; BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Craig: Teva: Consultancy. Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Chemgenex (Teva): Consultancy, Research Funding; Deciphera: Research Funding.

  • blast phase chronic myeloid leukemia a pooled analysis of subcutaneous omacetaxine mepesuccinate in treatment resistant patients
    Blood, 2012
    Co-Authors: Jean H Khoury, Jorge E. Cortes, Hagop M. Kantarjian, Adam Craig, Meir Wetzler, Jeffrey H Lipton, Michele Baccarani, Dan Douer, Luke P Akard
    Abstract:

    Abstract 3753 Background Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is a first-in-class Cephalotaxine. Omacetaxine is a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine reduces levels of multiple oncoproteins, including Bcr-Abl, and induces apoptosis in leukemic stem cells. Omacetaxine has shown clinical activity and adequate tolerability in two phase 2, open-label, international, multicenter studies in patients with chronic myeloid leukemia (CML): the first in patients with history of T315I mutation who had failed prior imatinib and the second in patients with resistance or intolerance to ≥2 tyrosine kinase inhibitors (TKIs). This is a pooled analysis of the efficacy and safety data of omacetaxine in patients with CML in the blast phase (BP). Methods Data from patients with CML-BP were included from two phase 2 studies. All patients received omacetaxine 1.25 mg/m2 subcutaneously twice daily for up to 14 consecutive days every 28 days for induction and the same dosage for up to 7 days every 28 days as maintenance. The number of consecutive days of dosing could be adjusted, as clinically indicated. Recombinant growth factor support was allowed in the event of febrile neutropenia. The primary outcome measures were major hematologic response (MaHR) and major cytogenetic response (MCyR). MaHR was defined as complete hematologic response (CHR) lasting ≥4 weeks, no evidence of leukemia, or return to chronic phase. MCyR included confirmed or unconfirmed complete or partial response. Secondary endpoints included duration of response, time to disease progression, overall survival and safety. Results Forty-four patients with CML-BP (median age 53.5 years [range, 19–68]) received treatment with omacetaxine. Forty-two patients (96%) had ECOG status ≤2. All but 1 patient had prior treatment with imatinib; 5 (11%) patients received imatinib only, 20 (45%) received 2 approved TKIs (imatinib, dasatinib, or nilotinib), and 19 (43%) were treated with all 3 approved TKIs. Most common non-TKI agents included hydroxyurea in 18/44 (41%), anthracyclines and related agents in 17 (39%), cytarabine in 14 (32%), and interferons in 11 (25%). Mutation analysis was not performed per protocol; however, point mutations were detected in 23 patients, and 17 (74%) of these had the T315I mutation. No mutations were identified in 7 patients and 14 were not assessed for mutations. The median number of cycles of omacetaxine administered was 2 (range 1–12) with a median duration of exposure of 1.5 months (range 0–13.8). Four patients (9%) had a MaHR (3 with CHR and 1 returned to chronic phase); additional 2 patients had hematologic improvement as a best response. No patient achieved MCyR; 3 patients (7%) achieved a minimal cytogenetic response. Median duration of MaHR was 1.7 months (range 1.7–4.9 months). Median survival was 3.5 months (95% CI 2.2–4.5); in 4 patients with MaHR, median survival was not reached as of >1 year of follow-up by Kaplan-Meier analysis (95% CI 2.4 to not reached) versus 3.5 months (95% CI 2.2–3.9) in patients without MaHR (Figure). Median time to disease progression was 2.2 months (95% CI 1.5–2.9). Grade 3/4 laboratory hematologic toxicities included thrombocytopenia (43/44 patients), anemia (36/44), neutropenia (36/44), and leukopenia (29/44), with most of the thrombocytopenia and neutropenia toxicities occurring in earlier cycles and attenuating in later cycles. The most common (≥5%) grade 3/4 nonhematologic AEs were hypercalcemia and bone pain (4/44 each), followed by confusional state (3/44). The most common reasons for discontinuation were progressive disease (21 patients) and death (14 patients); 2 patients discontinued due to AEs. One patient discontinued due to transfer for stem cell transplantation (7 cycles received on study over 6.7 months). Nineteen deaths occurred on study and 19 during follow-up; disease progression was the most common cause (25/38). One death was deemed related to the study drug (sepsis). Conclusions Among heavily pretreated patients with CML-BP who had failed prior TKI therapy, omacetaxine demonstrated limited activity, although 13% of patients had hematologic improvement, 2 patients had responses with duration longer than one year. Most grade 3/4 events were hematologic; grade 3/4 nonhematologic AEs were less common. Support: Teva Pharmaceutical Industries Ltd. Disclosures: Off Label Use: Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine has shown clinical activity in 2 studies of chronic myeloid leukemia (CML), one in patients with a history of the T315I Bcr-Abl mutation and the other in patients failing at least 2 tyrosine kinase inhibitors. Cortes:Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Chemgenex (Teva): Consultancy, Research Funding; Deciphera: Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Wetzler:BMS: Research Funding; Teva: Membership on an entity9s Board of Directors or advisory committees. Baccarani:Teva: Research Funding. Douer:Teva: Consultancy. Craig:Teva: Consultancy. Kantarjian:ChemGenex (Teva): Research Funding. Akard:Celgene: Research Funding, Speakers Bureau; Millenium: Speakers Bureau; Eisai: Speakers Bureau; Pfizer: Research Funding; Merck: Research Funding; Ariad: Research Funding; Teva: Research Funding; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

Hagop M. Kantarjian - One of the best experts on this subject based on the ideXlab platform.

  • predictive factors associated with achievement of major cytogenetic response mcyr to omacetaxine mepesuccinate among patients with chronic phase chronic myeloid leukemia cml cp
    Journal of Clinical Oncology, 2013
    Co-Authors: Meir Wetzler, Hanna Jean Khoury, Hagop M. Kantarjian, Adam Craig, Luke P Akard, Franck E Nicolini, Jeffrey H Lipton, Michele Baccarani, Jorge E. Cortes
    Abstract:

    7088 Background: Omacetaxine mepesuccinate (OMA), a first-in-class Cephalotaxine, is a protein synthesis inhibitor not dependent on Bcr-Abl signaling. OMA has shown clinical activity in CML patient...

  • post hoc analysis of sustained efficacy tolerability of 12 cycles of omacetaxine mepesuccinate in chronic myeloid leukemia cml
    Journal of Clinical Oncology, 2013
    Co-Authors: Delphine Rea, Hanna Jean Khoury, Hagop M. Kantarjian, Luke P Akard, Franck E Nicolini, Meir Wetzler, Jeffrey H Lipton, Mauricette Michallet, Agnes Guercibresler, Charles Chuah
    Abstract:

    7066 Background: Subcutaneous omacetaxine mepesuccinate (OMA), a first-in-class Cephalotaxine, inhibits protein synthesis independent of Bcr-Abl signaling. It showed clinical activity in 2 phase II, open-label CML trials, 1 in patients with a T315I Bcr-Abl mutation failing imatinib, and 1 in patients failing ≥2 tyrosine kinase inhibitors (TKIs). Methods: This post hoc analysis pooled patients with chronic phase (CP) or accelerated phase (AP) from the 2 trials. 28-day cycles of OMA 1.25 mg/m2BID were given ≤14 days for induction, ≤7 days as maintenance with dose delay/change as needed. Primary endpoints were major cytogenetic response (MCyR) for CP and complete hematologic response (CHR) for AP. Adverse events (AEs) were assessed. Results: Of 108 CP and 51 AP patients from the 2 trials, 31 (29%) CP and 7 (14%) AP patients received ≥12 cycles (Table). At baseline in the ≥12-cycle groups, most CP (median age 59 y) and AP patients (median age 67 y) had received hydroxyurea (17/31, 4/7) and ≥2 TKIs (22/31, 5/7...

  • phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors
    American Journal of Hematology, 2013
    Co-Authors: Jorge E. Cortes, Meir Wetzler, Annie Claude Benichou, Raghunadharao Digumarti, Adam R Craig, Purvish M Parikh, J H Lipton, Andreas Hochhaus, F E Nicolini, Hagop M. Kantarjian
    Abstract:

    Omacetaxine mepesuccinate (omacetaxine) is a first-in-class Cephalotaxine with a unique mode of action, independent of BCR-ABL, that has shown promising activity in patients with chronic myeloid leukemia (CML). This multicenter, noncomparative, open-label phase 2 study evaluated the efficacy and safety of subcutaneous omacetaxine in CML patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs); results in patients in chronic phase are reported here. Patients received subcutaneous omacetaxine 1.25 mg/m2 twice daily days 1–14 every 28 days until hematologic response (up to a maximum of six cycles), then days 1–7 every 28 days as maintenance. Primary endpoints were rates of hematologic response lasting >8 weeks and major cytogenetic response (MCyR). Forty-six patients were enrolled: all had received imatinib, 83% had received dasatinib, and 57% nilotinib. A median 4.5 cycles of omacetaxine were administered (range, 1–36). Hematologic response was achieved or maintained in 31 patients (67%); median response duration was 7.0 months. Ten patients (22%) achieved MCyR, including 2 (4%) complete cytogenetic responses. Median progression-free survival was 7.0 months [95% confidence interval (CI), 5.9–8.9 months], and overall survival was 30.1 months (95% CI, 20.3 months—not reached). Grade 3/4 hematologic toxicity included thrombocytopenia (54%), neutropenia (48%), and anemia (33%). Nonhematologic adverse events were predominantly grade 1/2 and included diarrhea (44%), nausea (30%), fatigue (24%), pyrexia (20%), headache (20%), and asthenia (20%). Subcutaneous omacetaxine may offer clinical benefit to patients with chronic-phase CML with resistance or intolerance to multiple TKI therapies. Am. J. Hematol. 88:350–354, 2013. © 2013 Wiley Periodicals, Inc.

  • long term follow up of ongoing patients in 2 studies of omacetaxine mepesuccinate for chronic myeloid leukemia
    Blood, 2012
    Co-Authors: Hagop M. Kantarjian, Adam Craig, Luke P Akard, Franck E Nicolini, Meir Wetzler, Jeffrey H Lipton, Michele Baccarani, Laurence Legros, Krzysztof Warzocha, Jorge E. Cortes
    Abstract:

    Abstract 2787 Background Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is an investigational, first-in-class Cephalotaxine, a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine reduces levels of multiple oncoproteins, including Bcr-Abl, and induces apoptosis in leukemic stem cells. It has shown clinical activity and adequate tolerability in two phase 2, open-label studies of chronic myeloid leukemia (CML), the first in patients with a history of the T315I Bcr-Abl mutation (enrolled September 2006 through March 2010) and the second in patients with resistance or intolerance to ≥2 approved tyrosine kinase inhibitors (TKIs; enrolled March 2007 through June 2009). This ad hoc analysis presents the efficacy and safety results of patients in the phase 2 studies who remained on omacetaxine as of March 31, 2012. Methods Efficacy and safety data were pooled from patients with CML chronic phase (CML-CP) and CML accelerated phase (CML-AP) who received omacetaxine in either of the phase 2 studies and had not discontinued omacetaxine as of March 31, 2012. Omacetaxine 1.25 mg/m 2 was given subcutaneously twice daily up to 14 consecutive days per 28-day cycle for induction and at the same dosage for up to 7 days/cycle as maintenance. Results Of the 203 patients enrolled in the 2 studies (108 CML-CP, 51 CML-AP, and 44 CML blast phase), 9 CML-CP patients (median 35 cycles [range 26–53]) and 2 CML-AP patients (median 20.5 cycles [range 19–22]) continue to receive omacetaxine. Median age of ongoing CML-CP patients at baseline was 61 years (range 45–73); 7 were male. Median age of ongoing CML-AP patients was 58 years (range 48–67); all were male. For CML-CP patients, the median number of dosing days was 137 (range 68–342) over a median of 35 cycles (range 26–53); the 2 CML-AP patients had 189 and 277 dosing days during 19 and 22 cycles, respectively. Other baseline clinical characteristics are presented in the Table. Seven of the CML-CP patients achieved MCyR, including 6 complete responses. One CML-CP patient achieved a minimal cytogenetic response and 1 had no response. No CML-AP patient achieved MCyR. Time to onset of MCyR for the CML-CP patients were Six CML-CP patients were in CHR at baseline and 3 achieved CHR within 3 months. One CML-AP patient achieved CHR at All patients had at least 1 AE and 1 serious AE. The most common AEs were anemia (11/11), thrombocytopenia (9/11), neutropenia (6/11), nausea (7/11), diarrhea or fatigue (5/11 each), and headache (4/11). Grade 3/4 AEs occurred in 10 (91%) patients. The most common were hematologic: thrombocytopenia (79% \(79\) CML-CP, 100% \(22\) CML-AP), anemia (67% \(49\) CML-CP, 100% \(22\) CML-AP), and neutropenia (56% \(59\) CML-CP, 0% \(02\) CML-AP). Leukopenia and pancytopenia were reported in 1 patient each in the CML-AP group. Blast crisis, which was deemed treatment-related, was reported in 1 patient in the CML-AP group; this patient was discontinued. No deaths were reported. Conclusions A subset of heavily pretreated patients with CP or AP CML who participated in phase 2 studies of omacetaxine were able to continue omacetaxine for up to 53 cycles and experience durable major cytogenetic and hematologic responses. Grade 3/4 AEs were primarily hematologic and consistent with the known safety profile of omacetaxine. Disclosures: Kantarjian: ChemGenex (Teva): Research Funding. Off Label Use: Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine has shown clinical activity in 2 studies of chronic myeloid leukemia (CML), one in patients with a history of the T315I Bcr-Abl mutation and the other in patients failing at least 2 tyrosine kinase inhibitors. Baccarani: Teva: Research Funding. Nicolini: BMS: Research Funding, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Teva: Speakers Bureau. Wetzler: Teva: Membership on an entity9s Board of Directors or advisory committees; BMS: Research Funding. Akard: Merck: Research Funding; Pfizer: Research Funding; Eisai: Speakers Bureau; Millenium: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Ariad: Research Funding; Teva: Research Funding. Legros: Celgene: Speakers Bureau; BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Craig: Teva: Consultancy. Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Chemgenex (Teva): Consultancy, Research Funding; Deciphera: Research Funding.

  • blast phase chronic myeloid leukemia a pooled analysis of subcutaneous omacetaxine mepesuccinate in treatment resistant patients
    Blood, 2012
    Co-Authors: Jean H Khoury, Jorge E. Cortes, Hagop M. Kantarjian, Adam Craig, Meir Wetzler, Jeffrey H Lipton, Michele Baccarani, Dan Douer, Luke P Akard
    Abstract:

    Abstract 3753 Background Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is a first-in-class Cephalotaxine. Omacetaxine is a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine reduces levels of multiple oncoproteins, including Bcr-Abl, and induces apoptosis in leukemic stem cells. Omacetaxine has shown clinical activity and adequate tolerability in two phase 2, open-label, international, multicenter studies in patients with chronic myeloid leukemia (CML): the first in patients with history of T315I mutation who had failed prior imatinib and the second in patients with resistance or intolerance to ≥2 tyrosine kinase inhibitors (TKIs). This is a pooled analysis of the efficacy and safety data of omacetaxine in patients with CML in the blast phase (BP). Methods Data from patients with CML-BP were included from two phase 2 studies. All patients received omacetaxine 1.25 mg/m2 subcutaneously twice daily for up to 14 consecutive days every 28 days for induction and the same dosage for up to 7 days every 28 days as maintenance. The number of consecutive days of dosing could be adjusted, as clinically indicated. Recombinant growth factor support was allowed in the event of febrile neutropenia. The primary outcome measures were major hematologic response (MaHR) and major cytogenetic response (MCyR). MaHR was defined as complete hematologic response (CHR) lasting ≥4 weeks, no evidence of leukemia, or return to chronic phase. MCyR included confirmed or unconfirmed complete or partial response. Secondary endpoints included duration of response, time to disease progression, overall survival and safety. Results Forty-four patients with CML-BP (median age 53.5 years [range, 19–68]) received treatment with omacetaxine. Forty-two patients (96%) had ECOG status ≤2. All but 1 patient had prior treatment with imatinib; 5 (11%) patients received imatinib only, 20 (45%) received 2 approved TKIs (imatinib, dasatinib, or nilotinib), and 19 (43%) were treated with all 3 approved TKIs. Most common non-TKI agents included hydroxyurea in 18/44 (41%), anthracyclines and related agents in 17 (39%), cytarabine in 14 (32%), and interferons in 11 (25%). Mutation analysis was not performed per protocol; however, point mutations were detected in 23 patients, and 17 (74%) of these had the T315I mutation. No mutations were identified in 7 patients and 14 were not assessed for mutations. The median number of cycles of omacetaxine administered was 2 (range 1–12) with a median duration of exposure of 1.5 months (range 0–13.8). Four patients (9%) had a MaHR (3 with CHR and 1 returned to chronic phase); additional 2 patients had hematologic improvement as a best response. No patient achieved MCyR; 3 patients (7%) achieved a minimal cytogenetic response. Median duration of MaHR was 1.7 months (range 1.7–4.9 months). Median survival was 3.5 months (95% CI 2.2–4.5); in 4 patients with MaHR, median survival was not reached as of >1 year of follow-up by Kaplan-Meier analysis (95% CI 2.4 to not reached) versus 3.5 months (95% CI 2.2–3.9) in patients without MaHR (Figure). Median time to disease progression was 2.2 months (95% CI 1.5–2.9). Grade 3/4 laboratory hematologic toxicities included thrombocytopenia (43/44 patients), anemia (36/44), neutropenia (36/44), and leukopenia (29/44), with most of the thrombocytopenia and neutropenia toxicities occurring in earlier cycles and attenuating in later cycles. The most common (≥5%) grade 3/4 nonhematologic AEs were hypercalcemia and bone pain (4/44 each), followed by confusional state (3/44). The most common reasons for discontinuation were progressive disease (21 patients) and death (14 patients); 2 patients discontinued due to AEs. One patient discontinued due to transfer for stem cell transplantation (7 cycles received on study over 6.7 months). Nineteen deaths occurred on study and 19 during follow-up; disease progression was the most common cause (25/38). One death was deemed related to the study drug (sepsis). Conclusions Among heavily pretreated patients with CML-BP who had failed prior TKI therapy, omacetaxine demonstrated limited activity, although 13% of patients had hematologic improvement, 2 patients had responses with duration longer than one year. Most grade 3/4 events were hematologic; grade 3/4 nonhematologic AEs were less common. Support: Teva Pharmaceutical Industries Ltd. Disclosures: Off Label Use: Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine has shown clinical activity in 2 studies of chronic myeloid leukemia (CML), one in patients with a history of the T315I Bcr-Abl mutation and the other in patients failing at least 2 tyrosine kinase inhibitors. Cortes:Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Chemgenex (Teva): Consultancy, Research Funding; Deciphera: Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Wetzler:BMS: Research Funding; Teva: Membership on an entity9s Board of Directors or advisory committees. Baccarani:Teva: Research Funding. Douer:Teva: Consultancy. Craig:Teva: Consultancy. Kantarjian:ChemGenex (Teva): Research Funding. Akard:Celgene: Research Funding, Speakers Bureau; Millenium: Speakers Bureau; Eisai: Speakers Bureau; Pfizer: Research Funding; Merck: Research Funding; Ariad: Research Funding; Teva: Research Funding; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

Albert Padwa - One of the best experts on this subject based on the ideXlab platform.

  • an approach to the Cephalotaxine ring skeleton using an ammonium ylide stevens 1 2 rearrangement
    Tetrahedron Letters, 1998
    Co-Authors: Scott L. Beall, Albert Padwa
    Abstract:

    Abstract Ammonium ylides derived from the Cu(II)-catalyzed decomposition of α-diazo carbonyls tethered to tertiary amines underwent a benzylic Stevens [1, 2]-rearrangement to give tetrahydroisoquinolines or benzazepines containing fused five-membered rings, a feature found in the cephalotaxus and lycorane alkaloids.

  • An Approach to the Cephalotaxine Ring Skeleton Using an Ammonium Ylide/Stevens [1,2]-Rearrangement
    1998
    Co-Authors: Scott L. Beall, Albert Padwa
    Abstract:

    Abstract: Ammonium ylides derived from the Cu(lI)-catalyzed decomposition fct-diazo carbonyls tethered to tertiary amines underwent a benzylic Stevens [1,2J-rearrangement to give tetrahydroisoquinolines or benzazepines containing fused five-membered rings, a feature found in the cephalotaxus and lycorane alkaloids. © 1998 Elsevier Science Ltd. All rights reserved. The tandem ammonium ylide generation/rearrangement sequence represents an effective method for the preparation of nitrogen-containing heterocycles. 1 A typical example involves the ring expansion reaction of a spirocyclic ammonium ylide such as 3 which has been nicely exploited for the synthesis of a number of alkaloids. Thus, the key step in West and Naidu's enantioselective synthesis of (-)-epilupinine 2 involved the ammonium ylide-Stevens [1,2]-rearrangement of the (L)-proline derivative 1which furnished the advanced intermediate 4 in 84 % yield and with 76 % ee. Starting from a related (L)-proline derivative 2 (R=vinyl), Clark and Hodgson synthesized the CE ring system 5 in their approach to the Mazamine A ring skeleton via an ammonium ylide-[2,3]-sigmatropic rearrange-ment (Scheme 1).3'

Meir Wetzler - One of the best experts on this subject based on the ideXlab platform.

  • subcutaneous omacetaxine mepesuccinate in patients with chronic phase chronic myeloid leukemia previously treated with 2 or more tyrosine kinase inhibitors including imatinib
    Clinical Lymphoma Myeloma & Leukemia, 2013
    Co-Authors: Jorge E. Cortes, Luke P Akard, Franck E Nicolini, Meir Wetzler, Jeffrey H Lipton, Nisha Nanda, Annie Claude Benichou, Adam R Craig, Janis Leonoudakis, Jean H Khoury
    Abstract:

    Abstract Introduction Omacetaxine mepesuccinate (omacetaxine) is a first-in-class Cephalotaxine that has demonstrated efficacy in CML. In this analysis we evaluated omacetaxine in CML patients with resistance or intolerance to 2 or more tyrosine kinase inhibitors (TKIs). Patients and Methods Data were pooled from 2 phase II trials of subcutaneous omacetaxine, administered at 1.25 mg/m 2 twice daily for 14 consecutive days every 28 days until response, then for 7 days every 28 days as maintenance. Patients with resistance or intolerance to imatinib and at least 1 other approved TKI (dasatinib and/or nilotinib) were included; results for patients in chronic phase (CP) are reported here. Major cytogenetic response (MCyR) was the primary end point. Results Eighty-one patients with CML-CP (median age, 59 years; range, 26-83 years) were included in the analysis. All patients previously received imatinib, 69 (85%) previously received dasatinib, and 48 (59%) previously received nilotinib. Median omacetaxine exposure was 7.5 months (range, 0.03-38.6 months), with 13 patients ongoing. MCyR was reported in 16 patients (20%; one-sided 95% lower confidence limit, 12.8%), including 8 complete responses; median duration was 17.7 months (95% confidence interval, 4.1 months – not reached). Fifty-six patients (69%) achieved and/or maintained hematologic response for at least 8 weeks; median duration was 12.2 months (range, 8.4-26.2 months). Median failure-free and overall survival were 9.6 months and 34 months, respectively. Toxicity was mainly hematologic: the most common grade 3/4 adverse events were thrombocytopenia (67%), neutropenia (47%), and anemia (37%). Conclusion Omacetaxine produced clinically meaningful responses with acceptable tolerability in patients with CML-CP previously treated with 2 or more TKIs.

  • predictive factors associated with achievement of major cytogenetic response mcyr to omacetaxine mepesuccinate among patients with chronic phase chronic myeloid leukemia cml cp
    Journal of Clinical Oncology, 2013
    Co-Authors: Meir Wetzler, Hanna Jean Khoury, Hagop M. Kantarjian, Adam Craig, Luke P Akard, Franck E Nicolini, Jeffrey H Lipton, Michele Baccarani, Jorge E. Cortes
    Abstract:

    7088 Background: Omacetaxine mepesuccinate (OMA), a first-in-class Cephalotaxine, is a protein synthesis inhibitor not dependent on Bcr-Abl signaling. OMA has shown clinical activity in CML patient...

  • post hoc analysis of sustained efficacy tolerability of 12 cycles of omacetaxine mepesuccinate in chronic myeloid leukemia cml
    Journal of Clinical Oncology, 2013
    Co-Authors: Delphine Rea, Hanna Jean Khoury, Hagop M. Kantarjian, Luke P Akard, Franck E Nicolini, Meir Wetzler, Jeffrey H Lipton, Mauricette Michallet, Agnes Guercibresler, Charles Chuah
    Abstract:

    7066 Background: Subcutaneous omacetaxine mepesuccinate (OMA), a first-in-class Cephalotaxine, inhibits protein synthesis independent of Bcr-Abl signaling. It showed clinical activity in 2 phase II, open-label CML trials, 1 in patients with a T315I Bcr-Abl mutation failing imatinib, and 1 in patients failing ≥2 tyrosine kinase inhibitors (TKIs). Methods: This post hoc analysis pooled patients with chronic phase (CP) or accelerated phase (AP) from the 2 trials. 28-day cycles of OMA 1.25 mg/m2BID were given ≤14 days for induction, ≤7 days as maintenance with dose delay/change as needed. Primary endpoints were major cytogenetic response (MCyR) for CP and complete hematologic response (CHR) for AP. Adverse events (AEs) were assessed. Results: Of 108 CP and 51 AP patients from the 2 trials, 31 (29%) CP and 7 (14%) AP patients received ≥12 cycles (Table). At baseline in the ≥12-cycle groups, most CP (median age 59 y) and AP patients (median age 67 y) had received hydroxyurea (17/31, 4/7) and ≥2 TKIs (22/31, 5/7...

  • phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors
    American Journal of Hematology, 2013
    Co-Authors: Jorge E. Cortes, Meir Wetzler, Annie Claude Benichou, Raghunadharao Digumarti, Adam R Craig, Purvish M Parikh, J H Lipton, Andreas Hochhaus, F E Nicolini, Hagop M. Kantarjian
    Abstract:

    Omacetaxine mepesuccinate (omacetaxine) is a first-in-class Cephalotaxine with a unique mode of action, independent of BCR-ABL, that has shown promising activity in patients with chronic myeloid leukemia (CML). This multicenter, noncomparative, open-label phase 2 study evaluated the efficacy and safety of subcutaneous omacetaxine in CML patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs); results in patients in chronic phase are reported here. Patients received subcutaneous omacetaxine 1.25 mg/m2 twice daily days 1–14 every 28 days until hematologic response (up to a maximum of six cycles), then days 1–7 every 28 days as maintenance. Primary endpoints were rates of hematologic response lasting >8 weeks and major cytogenetic response (MCyR). Forty-six patients were enrolled: all had received imatinib, 83% had received dasatinib, and 57% nilotinib. A median 4.5 cycles of omacetaxine were administered (range, 1–36). Hematologic response was achieved or maintained in 31 patients (67%); median response duration was 7.0 months. Ten patients (22%) achieved MCyR, including 2 (4%) complete cytogenetic responses. Median progression-free survival was 7.0 months [95% confidence interval (CI), 5.9–8.9 months], and overall survival was 30.1 months (95% CI, 20.3 months—not reached). Grade 3/4 hematologic toxicity included thrombocytopenia (54%), neutropenia (48%), and anemia (33%). Nonhematologic adverse events were predominantly grade 1/2 and included diarrhea (44%), nausea (30%), fatigue (24%), pyrexia (20%), headache (20%), and asthenia (20%). Subcutaneous omacetaxine may offer clinical benefit to patients with chronic-phase CML with resistance or intolerance to multiple TKI therapies. Am. J. Hematol. 88:350–354, 2013. © 2013 Wiley Periodicals, Inc.

  • long term follow up of ongoing patients in 2 studies of omacetaxine mepesuccinate for chronic myeloid leukemia
    Blood, 2012
    Co-Authors: Hagop M. Kantarjian, Adam Craig, Luke P Akard, Franck E Nicolini, Meir Wetzler, Jeffrey H Lipton, Michele Baccarani, Laurence Legros, Krzysztof Warzocha, Jorge E. Cortes
    Abstract:

    Abstract 2787 Background Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is an investigational, first-in-class Cephalotaxine, a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine reduces levels of multiple oncoproteins, including Bcr-Abl, and induces apoptosis in leukemic stem cells. It has shown clinical activity and adequate tolerability in two phase 2, open-label studies of chronic myeloid leukemia (CML), the first in patients with a history of the T315I Bcr-Abl mutation (enrolled September 2006 through March 2010) and the second in patients with resistance or intolerance to ≥2 approved tyrosine kinase inhibitors (TKIs; enrolled March 2007 through June 2009). This ad hoc analysis presents the efficacy and safety results of patients in the phase 2 studies who remained on omacetaxine as of March 31, 2012. Methods Efficacy and safety data were pooled from patients with CML chronic phase (CML-CP) and CML accelerated phase (CML-AP) who received omacetaxine in either of the phase 2 studies and had not discontinued omacetaxine as of March 31, 2012. Omacetaxine 1.25 mg/m 2 was given subcutaneously twice daily up to 14 consecutive days per 28-day cycle for induction and at the same dosage for up to 7 days/cycle as maintenance. Results Of the 203 patients enrolled in the 2 studies (108 CML-CP, 51 CML-AP, and 44 CML blast phase), 9 CML-CP patients (median 35 cycles [range 26–53]) and 2 CML-AP patients (median 20.5 cycles [range 19–22]) continue to receive omacetaxine. Median age of ongoing CML-CP patients at baseline was 61 years (range 45–73); 7 were male. Median age of ongoing CML-AP patients was 58 years (range 48–67); all were male. For CML-CP patients, the median number of dosing days was 137 (range 68–342) over a median of 35 cycles (range 26–53); the 2 CML-AP patients had 189 and 277 dosing days during 19 and 22 cycles, respectively. Other baseline clinical characteristics are presented in the Table. Seven of the CML-CP patients achieved MCyR, including 6 complete responses. One CML-CP patient achieved a minimal cytogenetic response and 1 had no response. No CML-AP patient achieved MCyR. Time to onset of MCyR for the CML-CP patients were Six CML-CP patients were in CHR at baseline and 3 achieved CHR within 3 months. One CML-AP patient achieved CHR at All patients had at least 1 AE and 1 serious AE. The most common AEs were anemia (11/11), thrombocytopenia (9/11), neutropenia (6/11), nausea (7/11), diarrhea or fatigue (5/11 each), and headache (4/11). Grade 3/4 AEs occurred in 10 (91%) patients. The most common were hematologic: thrombocytopenia (79% \(79\) CML-CP, 100% \(22\) CML-AP), anemia (67% \(49\) CML-CP, 100% \(22\) CML-AP), and neutropenia (56% \(59\) CML-CP, 0% \(02\) CML-AP). Leukopenia and pancytopenia were reported in 1 patient each in the CML-AP group. Blast crisis, which was deemed treatment-related, was reported in 1 patient in the CML-AP group; this patient was discontinued. No deaths were reported. Conclusions A subset of heavily pretreated patients with CP or AP CML who participated in phase 2 studies of omacetaxine were able to continue omacetaxine for up to 53 cycles and experience durable major cytogenetic and hematologic responses. Grade 3/4 AEs were primarily hematologic and consistent with the known safety profile of omacetaxine. Disclosures: Kantarjian: ChemGenex (Teva): Research Funding. Off Label Use: Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine has shown clinical activity in 2 studies of chronic myeloid leukemia (CML), one in patients with a history of the T315I Bcr-Abl mutation and the other in patients failing at least 2 tyrosine kinase inhibitors. Baccarani: Teva: Research Funding. Nicolini: BMS: Research Funding, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Teva: Speakers Bureau. Wetzler: Teva: Membership on an entity9s Board of Directors or advisory committees; BMS: Research Funding. Akard: Merck: Research Funding; Pfizer: Research Funding; Eisai: Speakers Bureau; Millenium: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Ariad: Research Funding; Teva: Research Funding. Legros: Celgene: Speakers Bureau; BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Craig: Teva: Consultancy. Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Chemgenex (Teva): Consultancy, Research Funding; Deciphera: Research Funding.

Luke P Akard - One of the best experts on this subject based on the ideXlab platform.

  • subcutaneous omacetaxine mepesuccinate in patients with chronic phase chronic myeloid leukemia previously treated with 2 or more tyrosine kinase inhibitors including imatinib
    Clinical Lymphoma Myeloma & Leukemia, 2013
    Co-Authors: Jorge E. Cortes, Luke P Akard, Franck E Nicolini, Meir Wetzler, Jeffrey H Lipton, Nisha Nanda, Annie Claude Benichou, Adam R Craig, Janis Leonoudakis, Jean H Khoury
    Abstract:

    Abstract Introduction Omacetaxine mepesuccinate (omacetaxine) is a first-in-class Cephalotaxine that has demonstrated efficacy in CML. In this analysis we evaluated omacetaxine in CML patients with resistance or intolerance to 2 or more tyrosine kinase inhibitors (TKIs). Patients and Methods Data were pooled from 2 phase II trials of subcutaneous omacetaxine, administered at 1.25 mg/m 2 twice daily for 14 consecutive days every 28 days until response, then for 7 days every 28 days as maintenance. Patients with resistance or intolerance to imatinib and at least 1 other approved TKI (dasatinib and/or nilotinib) were included; results for patients in chronic phase (CP) are reported here. Major cytogenetic response (MCyR) was the primary end point. Results Eighty-one patients with CML-CP (median age, 59 years; range, 26-83 years) were included in the analysis. All patients previously received imatinib, 69 (85%) previously received dasatinib, and 48 (59%) previously received nilotinib. Median omacetaxine exposure was 7.5 months (range, 0.03-38.6 months), with 13 patients ongoing. MCyR was reported in 16 patients (20%; one-sided 95% lower confidence limit, 12.8%), including 8 complete responses; median duration was 17.7 months (95% confidence interval, 4.1 months – not reached). Fifty-six patients (69%) achieved and/or maintained hematologic response for at least 8 weeks; median duration was 12.2 months (range, 8.4-26.2 months). Median failure-free and overall survival were 9.6 months and 34 months, respectively. Toxicity was mainly hematologic: the most common grade 3/4 adverse events were thrombocytopenia (67%), neutropenia (47%), and anemia (37%). Conclusion Omacetaxine produced clinically meaningful responses with acceptable tolerability in patients with CML-CP previously treated with 2 or more TKIs.

  • predictive factors associated with achievement of major cytogenetic response mcyr to omacetaxine mepesuccinate among patients with chronic phase chronic myeloid leukemia cml cp
    Journal of Clinical Oncology, 2013
    Co-Authors: Meir Wetzler, Hanna Jean Khoury, Hagop M. Kantarjian, Adam Craig, Luke P Akard, Franck E Nicolini, Jeffrey H Lipton, Michele Baccarani, Jorge E. Cortes
    Abstract:

    7088 Background: Omacetaxine mepesuccinate (OMA), a first-in-class Cephalotaxine, is a protein synthesis inhibitor not dependent on Bcr-Abl signaling. OMA has shown clinical activity in CML patient...

  • post hoc analysis of sustained efficacy tolerability of 12 cycles of omacetaxine mepesuccinate in chronic myeloid leukemia cml
    Journal of Clinical Oncology, 2013
    Co-Authors: Delphine Rea, Hanna Jean Khoury, Hagop M. Kantarjian, Luke P Akard, Franck E Nicolini, Meir Wetzler, Jeffrey H Lipton, Mauricette Michallet, Agnes Guercibresler, Charles Chuah
    Abstract:

    7066 Background: Subcutaneous omacetaxine mepesuccinate (OMA), a first-in-class Cephalotaxine, inhibits protein synthesis independent of Bcr-Abl signaling. It showed clinical activity in 2 phase II, open-label CML trials, 1 in patients with a T315I Bcr-Abl mutation failing imatinib, and 1 in patients failing ≥2 tyrosine kinase inhibitors (TKIs). Methods: This post hoc analysis pooled patients with chronic phase (CP) or accelerated phase (AP) from the 2 trials. 28-day cycles of OMA 1.25 mg/m2BID were given ≤14 days for induction, ≤7 days as maintenance with dose delay/change as needed. Primary endpoints were major cytogenetic response (MCyR) for CP and complete hematologic response (CHR) for AP. Adverse events (AEs) were assessed. Results: Of 108 CP and 51 AP patients from the 2 trials, 31 (29%) CP and 7 (14%) AP patients received ≥12 cycles (Table). At baseline in the ≥12-cycle groups, most CP (median age 59 y) and AP patients (median age 67 y) had received hydroxyurea (17/31, 4/7) and ≥2 TKIs (22/31, 5/7...

  • long term follow up of ongoing patients in 2 studies of omacetaxine mepesuccinate for chronic myeloid leukemia
    Blood, 2012
    Co-Authors: Hagop M. Kantarjian, Adam Craig, Luke P Akard, Franck E Nicolini, Meir Wetzler, Jeffrey H Lipton, Michele Baccarani, Laurence Legros, Krzysztof Warzocha, Jorge E. Cortes
    Abstract:

    Abstract 2787 Background Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is an investigational, first-in-class Cephalotaxine, a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine reduces levels of multiple oncoproteins, including Bcr-Abl, and induces apoptosis in leukemic stem cells. It has shown clinical activity and adequate tolerability in two phase 2, open-label studies of chronic myeloid leukemia (CML), the first in patients with a history of the T315I Bcr-Abl mutation (enrolled September 2006 through March 2010) and the second in patients with resistance or intolerance to ≥2 approved tyrosine kinase inhibitors (TKIs; enrolled March 2007 through June 2009). This ad hoc analysis presents the efficacy and safety results of patients in the phase 2 studies who remained on omacetaxine as of March 31, 2012. Methods Efficacy and safety data were pooled from patients with CML chronic phase (CML-CP) and CML accelerated phase (CML-AP) who received omacetaxine in either of the phase 2 studies and had not discontinued omacetaxine as of March 31, 2012. Omacetaxine 1.25 mg/m 2 was given subcutaneously twice daily up to 14 consecutive days per 28-day cycle for induction and at the same dosage for up to 7 days/cycle as maintenance. Results Of the 203 patients enrolled in the 2 studies (108 CML-CP, 51 CML-AP, and 44 CML blast phase), 9 CML-CP patients (median 35 cycles [range 26–53]) and 2 CML-AP patients (median 20.5 cycles [range 19–22]) continue to receive omacetaxine. Median age of ongoing CML-CP patients at baseline was 61 years (range 45–73); 7 were male. Median age of ongoing CML-AP patients was 58 years (range 48–67); all were male. For CML-CP patients, the median number of dosing days was 137 (range 68–342) over a median of 35 cycles (range 26–53); the 2 CML-AP patients had 189 and 277 dosing days during 19 and 22 cycles, respectively. Other baseline clinical characteristics are presented in the Table. Seven of the CML-CP patients achieved MCyR, including 6 complete responses. One CML-CP patient achieved a minimal cytogenetic response and 1 had no response. No CML-AP patient achieved MCyR. Time to onset of MCyR for the CML-CP patients were Six CML-CP patients were in CHR at baseline and 3 achieved CHR within 3 months. One CML-AP patient achieved CHR at All patients had at least 1 AE and 1 serious AE. The most common AEs were anemia (11/11), thrombocytopenia (9/11), neutropenia (6/11), nausea (7/11), diarrhea or fatigue (5/11 each), and headache (4/11). Grade 3/4 AEs occurred in 10 (91%) patients. The most common were hematologic: thrombocytopenia (79% \(79\) CML-CP, 100% \(22\) CML-AP), anemia (67% \(49\) CML-CP, 100% \(22\) CML-AP), and neutropenia (56% \(59\) CML-CP, 0% \(02\) CML-AP). Leukopenia and pancytopenia were reported in 1 patient each in the CML-AP group. Blast crisis, which was deemed treatment-related, was reported in 1 patient in the CML-AP group; this patient was discontinued. No deaths were reported. Conclusions A subset of heavily pretreated patients with CP or AP CML who participated in phase 2 studies of omacetaxine were able to continue omacetaxine for up to 53 cycles and experience durable major cytogenetic and hematologic responses. Grade 3/4 AEs were primarily hematologic and consistent with the known safety profile of omacetaxine. Disclosures: Kantarjian: ChemGenex (Teva): Research Funding. Off Label Use: Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine has shown clinical activity in 2 studies of chronic myeloid leukemia (CML), one in patients with a history of the T315I Bcr-Abl mutation and the other in patients failing at least 2 tyrosine kinase inhibitors. Baccarani: Teva: Research Funding. Nicolini: BMS: Research Funding, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Teva: Speakers Bureau. Wetzler: Teva: Membership on an entity9s Board of Directors or advisory committees; BMS: Research Funding. Akard: Merck: Research Funding; Pfizer: Research Funding; Eisai: Speakers Bureau; Millenium: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Ariad: Research Funding; Teva: Research Funding. Legros: Celgene: Speakers Bureau; BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Craig: Teva: Consultancy. Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Chemgenex (Teva): Consultancy, Research Funding; Deciphera: Research Funding.

  • blast phase chronic myeloid leukemia a pooled analysis of subcutaneous omacetaxine mepesuccinate in treatment resistant patients
    Blood, 2012
    Co-Authors: Jean H Khoury, Jorge E. Cortes, Hagop M. Kantarjian, Adam Craig, Meir Wetzler, Jeffrey H Lipton, Michele Baccarani, Dan Douer, Luke P Akard
    Abstract:

    Abstract 3753 Background Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is a first-in-class Cephalotaxine. Omacetaxine is a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine reduces levels of multiple oncoproteins, including Bcr-Abl, and induces apoptosis in leukemic stem cells. Omacetaxine has shown clinical activity and adequate tolerability in two phase 2, open-label, international, multicenter studies in patients with chronic myeloid leukemia (CML): the first in patients with history of T315I mutation who had failed prior imatinib and the second in patients with resistance or intolerance to ≥2 tyrosine kinase inhibitors (TKIs). This is a pooled analysis of the efficacy and safety data of omacetaxine in patients with CML in the blast phase (BP). Methods Data from patients with CML-BP were included from two phase 2 studies. All patients received omacetaxine 1.25 mg/m2 subcutaneously twice daily for up to 14 consecutive days every 28 days for induction and the same dosage for up to 7 days every 28 days as maintenance. The number of consecutive days of dosing could be adjusted, as clinically indicated. Recombinant growth factor support was allowed in the event of febrile neutropenia. The primary outcome measures were major hematologic response (MaHR) and major cytogenetic response (MCyR). MaHR was defined as complete hematologic response (CHR) lasting ≥4 weeks, no evidence of leukemia, or return to chronic phase. MCyR included confirmed or unconfirmed complete or partial response. Secondary endpoints included duration of response, time to disease progression, overall survival and safety. Results Forty-four patients with CML-BP (median age 53.5 years [range, 19–68]) received treatment with omacetaxine. Forty-two patients (96%) had ECOG status ≤2. All but 1 patient had prior treatment with imatinib; 5 (11%) patients received imatinib only, 20 (45%) received 2 approved TKIs (imatinib, dasatinib, or nilotinib), and 19 (43%) were treated with all 3 approved TKIs. Most common non-TKI agents included hydroxyurea in 18/44 (41%), anthracyclines and related agents in 17 (39%), cytarabine in 14 (32%), and interferons in 11 (25%). Mutation analysis was not performed per protocol; however, point mutations were detected in 23 patients, and 17 (74%) of these had the T315I mutation. No mutations were identified in 7 patients and 14 were not assessed for mutations. The median number of cycles of omacetaxine administered was 2 (range 1–12) with a median duration of exposure of 1.5 months (range 0–13.8). Four patients (9%) had a MaHR (3 with CHR and 1 returned to chronic phase); additional 2 patients had hematologic improvement as a best response. No patient achieved MCyR; 3 patients (7%) achieved a minimal cytogenetic response. Median duration of MaHR was 1.7 months (range 1.7–4.9 months). Median survival was 3.5 months (95% CI 2.2–4.5); in 4 patients with MaHR, median survival was not reached as of >1 year of follow-up by Kaplan-Meier analysis (95% CI 2.4 to not reached) versus 3.5 months (95% CI 2.2–3.9) in patients without MaHR (Figure). Median time to disease progression was 2.2 months (95% CI 1.5–2.9). Grade 3/4 laboratory hematologic toxicities included thrombocytopenia (43/44 patients), anemia (36/44), neutropenia (36/44), and leukopenia (29/44), with most of the thrombocytopenia and neutropenia toxicities occurring in earlier cycles and attenuating in later cycles. The most common (≥5%) grade 3/4 nonhematologic AEs were hypercalcemia and bone pain (4/44 each), followed by confusional state (3/44). The most common reasons for discontinuation were progressive disease (21 patients) and death (14 patients); 2 patients discontinued due to AEs. One patient discontinued due to transfer for stem cell transplantation (7 cycles received on study over 6.7 months). Nineteen deaths occurred on study and 19 during follow-up; disease progression was the most common cause (25/38). One death was deemed related to the study drug (sepsis). Conclusions Among heavily pretreated patients with CML-BP who had failed prior TKI therapy, omacetaxine demonstrated limited activity, although 13% of patients had hematologic improvement, 2 patients had responses with duration longer than one year. Most grade 3/4 events were hematologic; grade 3/4 nonhematologic AEs were less common. Support: Teva Pharmaceutical Industries Ltd. Disclosures: Off Label Use: Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine has shown clinical activity in 2 studies of chronic myeloid leukemia (CML), one in patients with a history of the T315I Bcr-Abl mutation and the other in patients failing at least 2 tyrosine kinase inhibitors. Cortes:Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Chemgenex (Teva): Consultancy, Research Funding; Deciphera: Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Wetzler:BMS: Research Funding; Teva: Membership on an entity9s Board of Directors or advisory committees. Baccarani:Teva: Research Funding. Douer:Teva: Consultancy. Craig:Teva: Consultancy. Kantarjian:ChemGenex (Teva): Research Funding. Akard:Celgene: Research Funding, Speakers Bureau; Millenium: Speakers Bureau; Eisai: Speakers Bureau; Pfizer: Research Funding; Merck: Research Funding; Ariad: Research Funding; Teva: Research Funding; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.