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IIa trial of volasertib combined with decitabine in patients with acute myeloid leukemia (AML) ineligible for intensive therapy
Abstracts 226
227
Phase I/IIa trial of volasertib combined with decitabine in patients with acute myeloid leukemia (AML) ineligible for intensive therapy
Integrated Genomic Profiling, Therapy Response And Survival in Adult Acute Myelogenous Leukemia
1
2
Brian Parkin,1 Peter Ouillette,1 Mehmet Yildiz,1 Kamlai Saiya-Cork,1 Kerby Shedden,2 Sami N. Malek1
Jorge E. Cortes, Nikolai Podoltsev, Sushmita Rajeswari,3 Zhenchao Guo,3 Tillmann Taube,4 Geoffrey L. Uy5
Oncology; 2Department of Statistics, University of Michigan,
1
Ann Arbor, MI
The University of Texas MD Anderson Cancer Center, Houston,
1
Department of Internal Medicine, Division of Hematology and
Texas, USA; 2Department of Internal Medicine, Hematology Section, Yale University School of Medicine, New Haven, Connecticut, USA; 3
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA; 4Boehringer Ingelheim Pharma GmbH & Co. KG, Germany; 5
Division of Oncology, Washington University School of Medicine, St.
Louis, Missouri, USA
Context: Volasertib is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. In a randomized, Phase II trial comparing low-dose cytarabine (LDAC) with or without volasertib in patients with previously untreated AML ineligible for intensive therapy, volasertib plus LDAC increased remission rate, improved survival, and had a clinically manageable safety profile (Döhner. Blood 2014). This trial investigates volasertib plus decitabine in patients with AML ineligible for standard intensive therapy. Decitabine has demonstrated clinical activity in AML, but response is limited and the prognosis remains poor, suggesting an urgent need for novel therapies. Objectives: Phase I: to investigate the maximum tolerated dose (MTD), safety, and pharmacokinetics of volasertib combined with decitabine. Randomized, Phase IIa: to investigate the efficacy and safety of volasertib plus decitabine versus decitabine. Study Design and Patients: Phase I, dose-escalation (3+3 design) study followed by a randomized, Phase IIa study (NCT02003573; EudraCT 2013001752-36; Study 1230.30). Eligible patients are aged 65 years with newly diagnosed or relapsed/refractory AML or high-risk myelodysplastic syndrome (Phase I), or previously untreated AML (Phase IIa), ineligible for standard intensive therapy. Phase I: approximately 36 patients will be enrolled to determine the MTD (3e6 patients per cohort), followed by an extension cohort to evaluate safety of the MTD or highest planned dose to determine the recommended Phase II dose (RP2D). Phase IIa: approximately 100 patients will be randomized 1:1 to volasertib plus decitabine, or decitabine alone, stratified by AML type (de novo vs secondary). Interventions: Phase I: increasing doses of intravenous volasertib (300e350e400 mg; 1-hr infusion Days 1 and 15, Q4W) plus intravenous decitabine (20 mg/m2/day; 1-hr infusion Days 1e5, Q4W). Phase IIa: volasertib RP2D plus decitabine, or decitabine alone. Patients receive repeated cycles until disease progression. Main Outcome Measures: Primary endpoints: incidence of doselimiting toxicities (Phase I); response rate (Phase IIa). Secondary endpoints in Phase IIa include overall survival, event-free and relapse-free survival. Other endpoints, including safety and pharmacokinetics, will be analyzed.
Context and Objectives: Recurrent gene mutations, chromosomal translocations, acquired genomic copy number aberrations (aCNA) and copy-neutral loss-of-heterozygosity (cnLOH) underlie the genomic pathogenesis of acute myelogenous leukemia (AML). Genomic lesion types from all of these categories have been variously associated with AML patient outcome. However, the patterns of co-occurrence of such lesions are only now beginning to be defined, and we seek to further delineate the relative influence of different types of genomic alterations on clinical outcomes in AML. Methods: In this study, we performed SNP 6.0 array-based genomic profiling of aCNA/cnLOH along with sequence analysis of 13 recurrently mutated genes (NPM1, FLT3, CEBPA, IDH1, IDH2, NRAS, KRAS, TP53, RUNX1, ASXL1, TET2, DNMT3A, and BCORL1) on purified leukemic blast DNA from 156 prospectively enrolled non-FAB-M3 AML patients across the clinical spectrum of de novo, secondary, and therapy-related AML. Results: At the time of analysis, median follow-up time was 57.4 months and 119 (76%) patients had died. The cohort comprised 66% de novo AML, 22% secondary AML, and 12% therapy-related AML. We identified positive and negative associations of gene mutations, specific aCNA/cnLOH or total aCNA/cnLOH counts with different AML types as well as the associations of specific mutations with overall genomic complexity or genomic stability. Furthermore, NPM1, RUNX1, ASXL1 and TP53 mutations, elevated SNP-Abased genomic complexity, and specific recurrent aCNAs predicted the type of response to one or two cycles of full-intensity induction chemotherapy. Finally, the results of comprehensive multivariate analyses including age- and cytogenetics-based risk categories demonstrated a strong, independent increase in the hazard of death with TP53 mutations (HR 4.08 [95% CI 1.56-10.7], p<0.01) or aCNA/cnLOH load 3 (HR 1.92 [95% CI 1.01-3.68], p¼0.04). Conclusion: Integrated genomic profiling of a clinically relevant adult AML population reveals the interplay between gene mutations, recurrent aCNAs, and SNP-A-based genomic complexity and identifies among them the genomic characteristics most associated with types of response to intensive induction therapies and with shortened overall survival.
Clinical Lymphoma, Myeloma & Leukemia June 2015
- S193
227
Phase I/IIa trial of volasertib combined with decitabine in patients with acute myeloid leukemia (AML) ineligible for intensive therapy
Integrated Genomic Profiling, Therapy Response And Survival in Adult Acute Myelogenous Leukemia
1
2
Brian Parkin,1 Peter Ouillette,1 Mehmet Yildiz,1 Kamlai Saiya-Cork,1 Kerby Shedden,2 Sami N. Malek1
Jorge E. Cortes, Nikolai Podoltsev, Sushmita Rajeswari,3 Zhenchao Guo,3 Tillmann Taube,4 Geoffrey L. Uy5
Oncology; 2Department of Statistics, University of Michigan,
1
Ann Arbor, MI
The University of Texas MD Anderson Cancer Center, Houston,
1
Department of Internal Medicine, Division of Hematology and
Texas, USA; 2Department of Internal Medicine, Hematology Section, Yale University School of Medicine, New Haven, Connecticut, USA; 3
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA; 4Boehringer Ingelheim Pharma GmbH & Co. KG, Germany; 5
Division of Oncology, Washington University School of Medicine, St.
Louis, Missouri, USA
Context: Volasertib is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. In a randomized, Phase II trial comparing low-dose cytarabine (LDAC) with or without volasertib in patients with previously untreated AML ineligible for intensive therapy, volasertib plus LDAC increased remission rate, improved survival, and had a clinically manageable safety profile (Döhner. Blood 2014). This trial investigates volasertib plus decitabine in patients with AML ineligible for standard intensive therapy. Decitabine has demonstrated clinical activity in AML, but response is limited and the prognosis remains poor, suggesting an urgent need for novel therapies. Objectives: Phase I: to investigate the maximum tolerated dose (MTD), safety, and pharmacokinetics of volasertib combined with decitabine. Randomized, Phase IIa: to investigate the efficacy and safety of volasertib plus decitabine versus decitabine. Study Design and Patients: Phase I, dose-escalation (3+3 design) study followed by a randomized, Phase IIa study (NCT02003573; EudraCT 2013001752-36; Study 1230.30). Eligible patients are aged 65 years with newly diagnosed or relapsed/refractory AML or high-risk myelodysplastic syndrome (Phase I), or previously untreated AML (Phase IIa), ineligible for standard intensive therapy. Phase I: approximately 36 patients will be enrolled to determine the MTD (3e6 patients per cohort), followed by an extension cohort to evaluate safety of the MTD or highest planned dose to determine the recommended Phase II dose (RP2D). Phase IIa: approximately 100 patients will be randomized 1:1 to volasertib plus decitabine, or decitabine alone, stratified by AML type (de novo vs secondary). Interventions: Phase I: increasing doses of intravenous volasertib (300e350e400 mg; 1-hr infusion Days 1 and 15, Q4W) plus intravenous decitabine (20 mg/m2/day; 1-hr infusion Days 1e5, Q4W). Phase IIa: volasertib RP2D plus decitabine, or decitabine alone. Patients receive repeated cycles until disease progression. Main Outcome Measures: Primary endpoints: incidence of doselimiting toxicities (Phase I); response rate (Phase IIa). Secondary endpoints in Phase IIa include overall survival, event-free and relapse-free survival. Other endpoints, including safety and pharmacokinetics, will be analyzed.
Context and Objectives: Recurrent gene mutations, chromosomal translocations, acquired genomic copy number aberrations (aCNA) and copy-neutral loss-of-heterozygosity (cnLOH) underlie the genomic pathogenesis of acute myelogenous leukemia (AML). Genomic lesion types from all of these categories have been variously associated with AML patient outcome. However, the patterns of co-occurrence of such lesions are only now beginning to be defined, and we seek to further delineate the relative influence of different types of genomic alterations on clinical outcomes in AML. Methods: In this study, we performed SNP 6.0 array-based genomic profiling of aCNA/cnLOH along with sequence analysis of 13 recurrently mutated genes (NPM1, FLT3, CEBPA, IDH1, IDH2, NRAS, KRAS, TP53, RUNX1, ASXL1, TET2, DNMT3A, and BCORL1) on purified leukemic blast DNA from 156 prospectively enrolled non-FAB-M3 AML patients across the clinical spectrum of de novo, secondary, and therapy-related AML. Results: At the time of analysis, median follow-up time was 57.4 months and 119 (76%) patients had died. The cohort comprised 66% de novo AML, 22% secondary AML, and 12% therapy-related AML. We identified positive and negative associations of gene mutations, specific aCNA/cnLOH or total aCNA/cnLOH counts with different AML types as well as the associations of specific mutations with overall genomic complexity or genomic stability. Furthermore, NPM1, RUNX1, ASXL1 and TP53 mutations, elevated SNP-Abased genomic complexity, and specific recurrent aCNAs predicted the type of response to one or two cycles of full-intensity induction chemotherapy. Finally, the results of comprehensive multivariate analyses including age- and cytogenetics-based risk categories demonstrated a strong, independent increase in the hazard of death with TP53 mutations (HR 4.08 [95% CI 1.56-10.7], p<0.01) or aCNA/cnLOH load 3 (HR 1.92 [95% CI 1.01-3.68], p¼0.04). Conclusion: Integrated genomic profiling of a clinically relevant adult AML population reveals the interplay between gene mutations, recurrent aCNAs, and SNP-A-based genomic complexity and identifies among them the genomic characteristics most associated with types of response to intensive induction therapies and with shortened overall survival.
Clinical Lymphoma, Myeloma & Leukemia June 2015
- S193