scholarly journals Phase I Study of Ixazomib in Addition to Chemotherapy for the Treatment of Acute Myeloid Leukemia in Older Adults

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4059-4059
Author(s):  
Philip C. Amrein ◽  
Eyal C. Attar ◽  
Traci M. Blonquist ◽  
Andrew M. Brunner ◽  
Gabriela S. Hobbs ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Dose Escalation ◽  
Proteasome Inhibitor ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Remission Rate ◽  
Secondary Aml ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Introduction: Treatment of acute myeloid leukemia (AML) has remained largely unchanged for several decades despite the emergence of new agents. Long-term survival for patients aged >60 years is less than 10% (median survival 10.5 months). Targeting the proteasome in treating AML is attractive, since leukemia stem cells have demonstrated sensitivity to proteasome inhibition, perhaps through down regulation of nuclear NF-KB (Guzman, Blood 2001). Preclinical studies in leukemia cell lines revealed synergistic cytotoxicity when bortezomib, a proteasome inhibitor, was combined with the standard agents daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate, although neurotoxicity was noted among treated patients, 12% grade 3 sensory (Attar, …, Amrein, et al. Clin Cancer Res 2008, Attar, … Amrein, J Clin Oncol 2012). The next generation proteasome inhibitor, ixazomib, which is less frequently associated with neurotoxicity, was therefore selected for combination with conventional chemotherapy in this phase I trial. The primary objective was to determine the maximum tolerated dose (MTD) in the combination, initially in induction, and then in combination with consolidation in a subsequent portion of the overall study. We report here the results of the induction portion of the study, which has been completed. Methods: Adults >60 years of age with newly diagnosed AML were screened for eligibility. Patients with secondary AML were eligible, including those with prior hypomethylating agent therapy for myelodysplastic syndromes (MDS). We excluded those with promyelocytic leukemia. The induction treatment consisted of the following: cytarabine 100 mg/m2/day by continuous IV infusion, Days 1-7; daunorubicin 60 mg/m2/day IV, Days 1, 2, 3; ixazomib orally at the cohort dose, Days 2, 5, 9, and 12 A standard 3 + 3 patient cohort dose escalation design was used to determine whether the dose of ixazomib could be safely escalated in 3 cohorts (1.5 mg/day, 2.3 mg/day, 3.0 mg/day), initially in induction and subsequently in consolidation. The dose of 3.0 mg/day was the maximum planned for this study. The determined MTD of ixazomib in the first portion of the trial would be used during induction in the second portion, which seeks to test dose escalation of ixazomib during consolidation. Secondary objectives included rate of complete remission and disease-free survival. Results: Fourteen patients have been analyzed for toxicity and activity during the induction portion of the study. There were 4 (28%) patients with either secondary AML or treatment related AML, 9 (64%) were male, and the median age was 67 years (range 62-80 years). There have been no grade 5 toxicities due to study drug. Three patients died early due to leukemia, 2 of which were replaced for assessment of the MTD. Nearly all the grade 3 and 4 toxicities were hematologic (Table). There was 1 DLT (grade 3 thrombocytopenia) indicated at the highest dose level. There has been no neurotoxicity with ixazomib to date. Among the 14 patients, there have been 10 complete remissions (CR's) and 1 CRi for a remission rate of 79%. Conclusions: The highest dose level planned for this portion of the trial, 3.0 mg of ixazomib, was reached with 1 DLT and is the recommended dose for induction in the next portion of this study, which will seek to determine a safe ixazomib dose in combination with conventional consolidation therapy. That no neurotoxicity was encountered was reassuring, and the remission rate in this older adult population is favorable. Table. Table. Disclosures Amrein: Takeda: Research Funding. Attar:Agios: Employment, Equity Ownership. Brunner:Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Fathi:Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria; Agios: Honoraria, Research Funding; Jazz: Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

scholarly journals Phase I Study of Ixazomib with Conventional Chemotherapy in the Treatment of Acute Myeloid Leukemia in Older Adults

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Philip C. Amrein ◽  
Eyal C. Attar ◽  
Geoffrey Fell ◽  
Traci M. Blonquist ◽  
Andrew M. Brunner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Remission Rate ◽  
Conventional Chemotherapy ◽  
Advisory Committees ◽  
Secondary Aml ◽  
Grade 3 ◽  
Acute Myeloid

Introduction: Outcomes for acute myeloid leukemia (AML) among older patients has remained largely unchanged for decades. Long-term survival for patients aged >60 years is poor (median survival 10.5 months). Targeting the proteasome in AML is attractive, since leukemia stem cells have demonstrated sensitivity to proteasome inhibition in preclinical models, perhaps through down regulation of nuclear NF-KB (Guzman, Blood 2001). AML cell lines are susceptible to synergistic cytotoxicity when bortezomib, a proteasome inhibitor, is combined with daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate, although grade 2 sensory neurotoxicity was noted in approximately 12% of treated patients. A newer generation proteasome inhibitor, ixazomib, is less frequently associated with neurotoxicity, and, therefore, was selected for combination with conventional chemotherapy in this phase I trial. The primary objective of this study was to determine the maximum tolerated dose (MTD) of ixazomib in combination with conventional induction and consolidation chemotherapy for AML. Herein are the initial results of this trial. Methods: Adults >60 years of age with newly diagnosed AML were screened for eligibility. Patients with secondary AML were eligible, including those with prior hypomethylating agent therapy for myelodysplastic syndromes (MDS). We excluded those with promyelocytic leukemia. There were 2 phases in this study. In the first phase (A), the induction treatment consisted of the following: cytarabine 100 mg/m2/day by continuous IV infusion, Days 1-7; daunorubicin 60 mg/m2/day IV, Days 1, 2, 3, and ixazomib was provided orally at the cohort dose, Days 2, 5, 9, and 12. Consolidaton or transplant was at the discretion of the treating physician in phase A. In the second phase (B), induction was the same as that with the determined MTD of ixazomib. All patients were to be treated with the following consolidation: cytarabine at 2 g/m2/day, days 1-5 with ixazomib on days 2, 5, 9, and 12 at the cohort dose for consolidation. A standard 3 + 3 patient cohort dose escalation design was used to determine whether the dose of ixazomib could be safely escalated in 3 cohorts (1.5 mg/day, 2.3 mg/day, 3.0 mg/day), initially in induction (phase A) and subsequently in consolidation (phase B). The determined MTD of ixazomib in the first portion (A) of the trial was used during induction in the second portion (B), which sought to determine the MTD for ixazomib during consolidation. Secondary objectives included rate of complete remission, disease-free survival, and overall survival (OS). Results: Thirty-six patients have been enrolled on study, and 28 have completed dose levels A-1 through A-3 and B1 through B-2. Full information on cohort B-3 has not yet been obtained, hence, this report covers the experience with the initial 28 patients, cohorts A-1 through B-2. There were 12 (43%) patients among the 28 with secondary AML, either with prior hematologic malignancy or therapy-related AML. Nineteen patients (68%) were male, and the median age was 68 years (range 61-80 years). There have been no grade 5 toxicities due to study drug. Three patients died early due to leukemia, 2 of which were replaced for assessment of the MTD. Nearly all the grade 3 and 4 toxicities were hematologic (Table). There was 1 DLT (grade 4 platelet count decrease extending beyond Day 42). There has been no grade 3 or 4 neurotoxicity with ixazomib to date. Among the 28 patients in the first 5 cohorts, 22 achieved complete remissions (CR) and 2 achieved CRi, for a composite remission rate (CCR) of 86%. Among the 12 patients with secondary AML 8 achieved CR and 2 achieved CRi, for a CCR of 83%. The median OS for the 28 patients has not been reached (graph). The 18-month OS estimate was 65% [90% CI, 50-85%]. Conclusions: The highest dose level (3 mg) of ixazomib planned for induction in this trial has been reached safely. For consolidation there have been no serious safety issues in the first 2 cohorts with a dose up to 2.3 mg, apart from 1 DLT in the form of delayed platelet count recovery. The recommended phase 2 dose of ixazomib for induction is 3 mg. Accrual to cohort B-3 is ongoing. Notably, to date, no grade 3 or 4 neurotoxicity has been encountered. The remission rate in this older adult population with the addition of ixazomib to standard chemotherapy appears favorable. Figure Disclosures Amrein: Amgen: Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Research Funding. Attar:Aprea Therapeutics: Current Employment. Brunner:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Hobbs:Constellation: Honoraria, Research Funding; Novartis: Honoraria; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding; Jazz: Honoraria; Celgene/BMS: Honoraria. Neuberg:Celgene: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding. Fathi:Blueprint: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Novartis: Consultancy; Kura Oncology: Consultancy; Trillium: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Pfizer: Consultancy; Newlink Genetics: Consultancy; Forty Seven: Consultancy; Trovagene: Consultancy; Kite: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Amphivena: Consultancy; PTC Therapeutics: Consultancy; Agios: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz: Consultancy. OffLabel Disclosure: Ixazomib is FDA approved for multiple myeloma. We are using it in this trial for acute myeloid leukemia.

Early Results Of a Phase I/II Trial Of Midostaurin (PKC412) and 5-Azacytidine (5-AZA) For Patients (Pts) With Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3949-3949
Author(s):  
Paolo Strati ◽  
Hagop M Kantarjian ◽  
Aziz Nazha ◽  
Gautam Borthakur ◽  
Naval G. Daver ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Background Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) affect primarily elderly pts. Their treatment with aggressive chemotherapy is frequently challenging. Moreover, pts with FLT3 mutations have very poor prognosis. We hypothesized that the combination of midostaurin, a FLT3 inhibitor, and 5-AZA, a hypomethylating agent, may be an effective and safe regimen. Methods Both untreated (8) and previously treated (36) pts with AML or MDS were eligible for this study, regardless of FLT3 mutation and prior exposure to FLT3 inhibitors. Pts received 5-AZA 75 mg/mq subcutaneously or intravenously on day 1-7 and midostaurin 25 mg bid (in cohort 1 of phase I) or 50 mg bid (in cohort 2 of Phase I and in Phase II) orally on day 8-21 during the first cycle and continuously thereafter, for 12 cycles of 28 days duration. Cytogenetic risk was defined according to MRC criteria. Differences between categorical variables were compared by the chi2 test. CR duration (CRD) was calculated from the time of CR achievement until relapse and estimated by the Kaplan-Meier method and compared by the log-rank test. Results Fourty-four pts were enrolled, 13 included in Phase I and 31 in Phase II. Baseline pts’ characteristics are shown in the Table. Thirty-eight pts (86%) received 50 mg bid of midostaurin, and 6 (14%; Phase I) received 25 mg bid. The median number of administered cycles was 2 (1-9). Grade 3-4 hematological toxicities consisted of 95% neutropenia, 64% anemia and 93% thrombocytopenia. Grade 3-4 non-hematological toxicities consisted of 45% infections, 23% hypokalemia, 16% hyponatremia, 7% reduction in ejection fraction, 7% hyperuricemia, 4% hyperglycemia, 4% nausea/vomiting, 4% QTc prolongation, 4% hyperbilirubinemia, and 4% elevated AST. Eleven pts (25%) achieved a CR, 9 with incomplete platelet recovery (20%), after a median time of 13 (10-16) weeks from treatment start. Five (11%) of these pts relapsed after achieving CR. Two pts (5%) received an allogeneic stem cell transplant while on study, one in CR and one primary refractory (after a blast count drop from 27 to 7%), and they are both still in CR and alive. Among 26 pts with FLT3 ITD and no D835 mutation, 9 (35%) achieved CR/CRp. Six of 18 (33%) pts not previously exposed to FLT3 inhibitors responded. There was no significant correlation of dose with response (24% with 50 mg bid vs 33% with 25 mg bid, p=0.63). After a median follow-up of 15 (3-72) weeks, 20 pts (64%) died, 3 (7%) while on study (2 died of sepsis, 1 of unknown causes with progressive disease). The median CRD was 16 (9-23) months. Factors significantly associated with a longer CRD were male sex (p=0.04), age older than 65 years (0.03) and use of 50 mg bid of midostaurin (p=0.02). Conclusions The combination of midostaurin and 5-AZA is safe and well tolerated. Its efficacy is most noticeable among pts with FLT3 mutations. A longer response duration is observed using midostaurin at 50 mg bid dose and in elderly male pts. Disclosures: Ravandi: CELGENE: Honoraria; NOVARTIS: Honoraria. Cortes:ARIAD: Consultancy, Research Funding; ASTELLAS: Research Funding; AMBIT: Research Funding; AROG: Research Funding; NOVARTIS: Research Funding.

Determination of the Maximum Tolerated Dose of Panobinostat in Combination with a 5-Day Schedule of Azacitidine in High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia: Planned Interim Analysis of a Phase Ib/II Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1529-1529 ◽  
Author(s):  
Peter T. Tan ◽  
Kate Reed ◽  
Patricia A. Walker ◽  
Sharon Avery ◽  
Sushrut S. Patil ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Maximum Tolerated Dose ◽  
Patient Choice ◽  
Phase Ib ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Abstract 1529 Background: The management options for patients with high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who are not eligible for intensive chemotherapy remain limited. The combination of hypomethylating agent and deacetylase inhibitor (DACi) has been shown to be synergistic, both in terms of leukaemia cell killing and gene reactivation in vitro. Aim: To investigate the safety, tolerability and preliminary efficacy of combining the oral pan-DACi panobinostat (LBH589) with azacitidine in previously untreated MDS or AML, not fit for standard induction therapy. Methods: Phase Ib/II multi-center open label dose-escalation and expansion study. Inclusion criteria: untreated IPSS intermediate-2 or high risk MDS, or AML (marrow blasts ≥20%), not eligible for standard induction therapy. Patients received azacitidine 75 mg/m2 SC on days 1–5 of each 28-day cycle with 10, 20, 30 or 40mg panobinostat orally 3 days per week (M/W/F) for 7 doses per cycle commencing on day 5. The safety and tolerability of the combination was assessed. Results: This preliminary analysis includes 26 patients (M 17, F 9), median age 69 years (36–81). 18 AML patients had intermediate (11/18) or poor cytogenetic risk (7/18); 8 MDS patients with intermediate-2 (7/8) or high risk (1/8) IPSS. Patients were enrolled into panobinostat dose-escalation cohorts of 10mg (4 patients), 20mg (7), 30mg (6) or 40mg (6); and expansion study 30mg (3). All grade non-hematologic adverse events regardless of relatedness to study treatment (>10%) were: subcutaneous injection site redness or pain (57%), fatigue (48%), nausea (30%), anorexia (22%), diarrhoea (22%), dyspnoea (13%), fever (13%), hyperbilirubinemia (13%), hyperglycaemia (13%), hyponatremia (13%), leg oedema (13%) and light headedness (13%). There were no unexpected adverse events or drug reactions. The principal dose-limiting toxicity (DLT) was fatigue, as haematological toxicity was not considered dose-limiting. In the dose-escalation phase, the grade 3/4 DLTs were: panobinostat 10mg cohort (0/4 DLT), panobinostat 20mg cohort (1/7 DLT; grade 3 fatigue), panobinostat 30mg cohort (1/6 DLT; grade 3 fatigue), panobinostat 40mg (4/6 DLTs; all grade 3: fatigue (1), syncope (1), hyponatremia (1) and somnolence/reduced level of consciousness (1)). Therefore, in combination with the 5-day schedule of azacitidine, the maximum tolerated dose (MTD) of panobinostat was defined at 30mg; this dose level has been selected for expanded accrual. At present 10/26 patients (38%) remain on combination study therapy. The panobinostat dose has been reduced by one dose level in 5/26 patients (19%) due to fatigue; 3 patients from panobinostat 40mg cohort. In 16 patients taken off study, the most common cause was disease progression (9), infection (2), atrial fibrillation treated with panobinostat interacting medication (2), patient choice (2) and fatigue (1). The median number of treatment cycles initiated was 4 (1–16). Preliminary efficacy in 18 AML patients, 3 achieved PR, 7 SD, 7 PD and 1 death unrelated to disease or therapy. In 8 MDS patients, 2 achieved CR, 3 PR, 2 SD, and 1 not evaluable (withdrawal due to patient choice). After a median follow-up of 276 days, the median OS is 239 days (22–472). Conclusion: In previously untreated MDS/AML, panobinostat and azacitidine is well tolerated and preliminary assessments demonstrate clinical activity. The MTD was determined to be 30mg of panobinostat in combination with a 5-day azacitidine schedule of 75mg/m2 daily. Further evaluation of this combination with panobinostat 30mg dose is ongoing in the dose-expansion phase of the study. Disclosures: Mollee: Celgene: Membership on an entity's Board of Directors or advisory committees. Gervasio:Novartis: Employment. Winiger:Novartis AG: Employee, Employment, Equity Ownership, Honoraria. Hönemann:Celgene Pty Ltd: Employment. Wei:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Spencer:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

scholarly journals Myelodysplastic Syndrome with Excess Blasts and Secondary Acute Myeloid Leukemia: Same Disease with Different Blast Count

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2692-2692
Author(s):  
Xueyan Chen ◽  
Megan Othus ◽  
Brent L Wood ◽  
Roland B. Walter ◽  
Pamela S. Becker ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Mutational Analysis ◽  
World Health ◽  
Secondary Aml ◽  
Data Safety ◽  
Monitoring Committee ◽  
Mutational Hotspots ◽  
Acute Myeloid

Introduction: The World Health Organization (WHO) diagnoses acute myeloid leukemia (AML) if ≥20% myeloid blasts are present in peripheral blood or bone marrow. Consequently a patient with even 19% blasts is often ineligible for an "AML study". A less arbitrary means to define "AML" and myelodysplastic syndromes ("MDS") emphasizes biologic features. Here, focusing on patients with WHO-defined MDS with excess (5-19%) blasts (MDS-EB) or AML with myelodysplasia-related changes (AML-MRC) or therapy-related (t-AML) (WHO defined secondary AML), we compared morphologic blast percentage (MBP) with the frequency of mutations in genes belonging to different functional groups, and with the variant allele frequency (VAF) for individually mutated genes. Methods: 328 adults with WHO-defined AML (de novo and secondary; n=149) or MDS (n=179) and with mutational analysis by next-generation sequencing (NGS) performed at the University of Washington Hematopathology Laboratory between 2015-2017 were included. Of these, 86 had MDS-EB and 49 had secondary AML. Mutational analysis was performed using a customized, amplicon-based assay, TruSeq Custom Amplicon (Illumina, San Diego, CA). Custom oligonucleotide probes targeted specific mutational hotspots in ASXL1, CBL, CEBPA, CSF3R, EZH2, FBXW7, FGFR1, FLT3, GATA1, GATA2, HRAS, IDH1, IDH2, JAK2, KIT, KMT2A, KRAS, MAP2K1, MPL, NOTCH1, NPM1, NRAS, PDGFRA, PHF6, PTEN, RB1, RUNX1, SF3B1, SRSF2, STAG2, STAT3, TET2, TP53, U2AF1, WT1, and ZRSR2. VAF ≥5% was required to identify point mutations. Spearman's correlation coefficient was used to examine the relation between VAF of individually mutated genes and MBP. The Mann Whitney test served to compare the distribution of VAF in AML (≥20% blasts) vs. MDS (<20% blasts), before and after exclusion of subgroups as described below. Fisher's exact test was used to compare incidence of mutations. Results: 96% of cases had ≥one mutation in the 36 genes tested using NGS. Considering all 328 patients, mutations in tumor suppressor and cohesin complex genes were similarly frequent in MDS and AML, whereas spliceosomal genes, in particular SF3B1 and SRSF2, were more frequently mutated in MDS than in AML (46% vs. 26%, p<0.001). Mutations in epigenetic modifiers were more common in AML than MDS (54% vs. 42%, p= 0.035) as were transcription factor mutations (52% vs. 28%, p<0.001). However comparisons limited to MDS-EB vs. AML-MRC/t-AML, indicated the differences observed when comparing all MDS and all AML were less apparent, both statistically and more perhaps importantly with respect to observed frequencies. For example, spliceosomal gene mutations were found in 35% in MDS-EB and 27% in AML-MRC/t-AML (p=0.34) vs. 46% and 26% in all MDS and all AML. NPM1 mutations were detected in only 8% of AML-MRC/t-AML vs. 3% in MDS-EB but 29% for all AML. Results were analogous with FLT3 ITD, FLT3 TKD, and JAK2 mutations. Examining 20 individually mutated genes detected in ≥ 10 patients only with SRSF2 (p=0.04), did distribution of VAF differ statistically according to whether blast percentage was <20% versus ≥20%. Conclusions: The similar prevalence of mutations in different functional categories in MDS-EB and AML-MRC/t-AML suggests these entities are two manifestations of the same disease. We believe it appropriate to combine these WHO entities allowing patients in each to be eligible for both AML and MDS trials. Disclosures Othus: Glycomimetics: Other: Data Safety and Monitoring Committee; Celgene: Other: Data Safety and Monitoring Committee. Walter:Amgen: Consultancy; Boston Biomedical: Consultancy; Agios: Consultancy; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Amphivena Therapeutics: Consultancy, Equity Ownership; Boehringer Ingelheim: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding. Becker:Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; The France Foundation: Honoraria.

Limited Phase I Trial of Sequential High Dose Cytarabine and Clofarabine (HiDAC→CLOF) in Relapsed or Refractory Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4565-4565
Author(s):  
Bayard L. Powell ◽  
James Lovato ◽  
Claire Kimbrough ◽  
Susan Lyerly ◽  
Sonya Galloway-Daniels ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Phase I Trial ◽  
Phase Ii Trial ◽  
Skin Toxicity ◽  
High Dose ◽  
High Dose Cytarabine ◽  
Grade 3 ◽  
Acute Myeloid

Abstract High dose cytarabine (HiDAC) is the most effective single agent for the treatment of acute myeloid leukemia (AML); clofarabine (CLOF) is also an active agent in AML. Preclinical data suggest synergy between cytarabine and clofarabine. We conducted a two step limited phase I trial of sequential HiDAC (2g/m2 over 3 hours) followed by CLOF (30 or 40 mg/m2 infused over 2 hours), each given daily for 5 days, in adults with AML in first or second relapse or refractory to initial induction chemotherapy. Patients with persistent leukemia on day 12–14 received a second course of HiDAC→CLOF; phase I toxicity evaluation was based on cycle 1 data only. Nine patients (6 men and 3 women) were treated. The median age was 55.5 years (range 29.2 – 68.1). All had relapsed AML; two had prior autologous stem cell transplant. The initial cohort of 3 patients received clofarabine 30 mg/m2 with one dose limiting toxicity (DLT); an additional 3 patients were treated in cohort 1. The second cohort was treated with CLOF 40 mg/m2, the target dose for a planned phase II trial of HiDAC→CLOF. Hematologic toxicities and infections were not considered DLT. In the first cohort (30 mg/m2; n = 6) there was 1 DLT - grade 4 skin rash in a patient who subsequently died on day 17 with sepsis-related multi-organ failure; 3 patients had reversible grade 3 elevations in AST/ALT, 1 had grade 3 skin toxicity. In cohort 2 (40 mg/m2 ; n = 3) there was no DLT; 1 patient had grade 3 AST/ALT; 2 had grade 3 skin. Three of nine patients received a second course of induction HiDACCLOF. Two of six patients in cohort 1 achieved complete remission (CR), 1/3 patients in cohort 2 achieved CRi(CRp). Two of three CR/CRi patients received one course and one received two courses of HiDAC→CLOF induction. Conclusion: HiDAC→CLOF was associated with transient elevation in AST/ALT (4/9) and skin rash (3/9; primarily extensive palmar/plantar); skin toxicity appeared especially prominent in patients with palmar/plantar toxicity during prior therapy with HiDAC. Toxicities (other than skin) were comparable to other salvage regimens for relapsed and refractory AML. This combination is active in relapsed AML with 3/9 CR/CRp. A phase II trial of HiDAC→CLOF is underway; prophylactic intravenous hydrocortisone has been incorporated in an attempt to decrease skin toxicity.

Update of a Phase I Study of Sorafenib in Patients with Refractory/Relapsed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 893-893 ◽  
Author(s):  
John Delmonte ◽  
Hagop M. Kantarjian ◽  
Michael Andreeff ◽  
Stefan Faderl ◽  
John J. Wright ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Maximal Response ◽  
Daily Dose ◽  
Grade 3 ◽  
Acute Myeloid

The critical importance of the Ras, VEGF, and FLT3 pathways in the pathogenesis of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) has been well established. FLT3 abnormalities, internal tandem duplication (ITD) and point mutations, occur in about 30% of pts with AML and the FLT3-ITD mutation independently confers poor prognosis. Sorafenib is an oral multikinase inhibitor targeting the above pathways and is highly potent against FLT3-ITD mutants (IC50 1–3 nM) (ASH abstract, 2006). We are conducting a phase I trial to evaluate the safety and efficacy of two different schedules of sorafenib. To date, 21 patients (pts) with refractory/relapsed AML (n=20) and high risk MDS (n=1) have been enrolled. Pts were randomized to sorafenib for 5 days per week for 21 days (arm A; n=11) or for 14 days every 21 days (arm B; n=10). In both arms the starting dose level (DL) is 200 mg twice daily. Successive dose levels are 600, 800, and 1200 mg daily in a standard 3+3 design. Peripheral blood (PB) and bone marrow (BM) samples were obtained for evaluation of FLT3 status and phosphorylated and total FLT3 and ERK expression. Median age is 62 years (range, 33–82), number of prior therapies 2 (range, 1–5), time from diagnosis to sorafenib treatment 9 months (range, 2–46), and median duration on study was 1.2 months (range, 0.1–3.4). Twenty pts are evaluable. 9/20 (45%) pts received ≤ 1 cycle of sorafenib because of disease progression (n=6), self-discontinuation (n=2), or no benefit (n=1), of whom 5 (56%) were FLT3-ITD negative, 3 (33%) were FLT3-ITD positive, and 1 (11%) was not tested. In contrast, 11/20 (55%) pts received > 1 cycle of sorafenib, of whom 8 (73%) were FLT3-ITD positive and 3 (27%) were FLT3-ITD negative; reasons for discontinuation were disease progression (n=5), self-discontinuation (n=2), stem cell transplant (n=2), or no benefit (n=2). Sorafenib has been well tolerated with 1 pt achieving a DLT of grade 3 hyperbilirubinemia at the 800 mg daily dose in arm B, but the MTD has not been reached; this cohort has been expanded. The only other grade 3 toxicity has been pleural effusion at the 600 mg daily dose in arm A, not considered a DLT because it occurred during cycle 2. A ≥ 50% reduction in PB or BM blasts was obtained in 11/20 (55%) pts. 9/11 (82%) pts harbored the FLT3-ITD mutation and had a median duration of response of 42 days (range, 15–87). In these 9 pts, the median PB absolute blast count at baseline and after maximal response to sorafenib was 10.3 (range, 0.2–18.7) and 0 (range, 0–1)(p=0.008). Median BM blast percentage at baseline and after maximal response to sorafenib was 72% (range, 14–96) and 42% (range, 12–58) (p=0.002), with 1 pt achieving a morphologic complete remission in the BM. Serial determinations of phosphorylation status following sorafenib (at 0, 2, 24,120 hours) in pts with the FLT3-ITD mutation demonstrated inhibition of phospho-FLT3 in 3/3 and phospho-ERK in 5/5 pts. In conclusion, sorafenib administration is safe in AML and appears to preferentially target the FLT3-ITD mutation. This study continues to accrue pts to define the MTD and it will be followed by combination studies of standard chemotherapy with sorafenib, with an emphasis on targeting pts with AML expressing the FLT3-ITD mutation.

Targeted Intravenous Busulfan and Fludarabine Allogeneic Transplantation Conditioning in Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2290-2290
Author(s):  
Joseph A. Pidala ◽  
Jongphil Kim ◽  
Claudio Anasetti ◽  
Melissa Alsina ◽  
Ernesto Ayala ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Large Series ◽  
Myelogenous Leukemia ◽  
Secondary Aml ◽  
Relapsed Disease ◽  
Acute Myeloid

Abstract Abstract 2290 Poster Board II-267 Reduced and intermediate intensity conditioning with allogeneic hematopoietic cell transplantation (HCT) offers promise to effectively control hematologic malignancies, while limiting treatment related toxicity and mortality (TRM). We aimed to examine the efficacy of IV targeted Busulfan and Fludarabine (IV-Bu/Flu) in a large series of adults with exclusively acute myelogenous leukemia (AML). One hundred adults (median age 48) with AML (CR1 49, CR2 25, REL1 8, REL2 1, PIF 16, untreated 1) were treated with Busulfan 130-145 mg/m2/day for four days with pharmacokinetic targeting on the final two days to achieve an area under the curve (AUC) of 5300 (+/-10%) μmol*min/L/day and Fludarabine 40mg/m2/day for 4 days, followed by transplantation of G-CSF mobilized peripheral blood stem cells (PBSC) (N=98) or unstimulated bone marrow (BM) (N=2) from allogeneic donors (MRD 38, MUD 38, MMUD 24). Acute GVHD prophylaxis consisted of tacrolimus/methotrexate (N = 77), tacrolimus/mycophenolate mofetil (N = 22), or tacrolimus/sirolimus (N = 1). Median time to neutrophil and platelet engraftment was 16 and 12 days, respectively. Non-relapse mortality was 3% at 100 days, and 15% by 1 year. The cumulative incidence of relapse was 41%. Overall survival (OS) was 59% (95% CI: 48.1 – 67.5) at 1 year, and 42% (95% CI: 30.8-53.3) at 4 years. OS at 4 years for primary AML in CR1, secondary AML in CR1, CR2, and PIF were 52.9%, 40.1%, 41.2%, and 57.5% respectively; none with relapsed disease survived to 4 years (log-rank p = 0.0014). Progression-free survival (PFS) was 53% (95% CI: 42.8 – 62.2) at 1 year, and 32.3% (95% CI: 21.8 – 43.2) at 4 years. PFS at 4 years for primary AML in CR1, secondary AML in CR1, CR2, and PIF were 44.1%, 33.4%, 33.9%, and 33.1%, respectively, while none with relapsed disease at transplant reached this endpoint (p = 0.0264). On multivariable modeling, remission status at HCT (relapsed disease HR 14.85 (95% CI: 2.12 - 104.2), p = 0.007), moderate/severe cGVHD (HR 0.281, 95% CI: 0.10 - 0.76; p = 0.013), and day 90 bone marrow (BM) chimerism ≥ 90% (HR 0.245, 95% CI: 0.08 - 0.79; p = 0.018) predicted overall survival, and day 90 BM chimerism ≥ 90% (HR of 0.18 (95% CI: 0.08 - 0.45), p = 0.0002) predicted PFS. The following were not significantly related with OS or PFS: age, cytogenetics, donor relation, number of induction cycles, aGVHD prophylaxis regimen, maximum aGVHD grade, WBC at diagnosis, time in first CR, or % BM blasts prior to transplant. Day 90 BM chimerism and cGVHD were significantly related with relapse. Maximum grade of aGVHD predicted non-relapse mortality. These data support the low TRM and efficacy of IV-Bu/Flu in a large series of exclusively AML patients, and demonstrate the impact of day 90 bone marrow chimerism as an important prognostic factor. Further efforts to mitigate relapse risk after HCT are warranted, particularly in those with advanced disease at time of transplant. Disclosures: Off Label Use: IV busulfan and fludarabine for the treatment of acute myeloid leukemia. Alsina:Ortho Biotech: Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau. Field:PDL BioPharma: Research Funding. Fernandez:Otsuka: Honoraria.

Phase I Study of Lenalidomide in Acute Leukemia: Remissions in Post-Allogeneic Relapse of Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 841-841 ◽  
Author(s):  
Jason C. Chandler ◽  
Rebecca B. Klisovic ◽  
Mitch A. Phelps ◽  
Alison Walker ◽  
Ramiro Garzon ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Leukemia ◽  
Phase I ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Allogeneic Transplantation ◽  
Initial Therapy ◽  
Trisomy 13 ◽  
Acute Myeloid

Abstract Abstract 841 Lenalidomide is effective in myeloma and low-risk myelodysplastic syndromes (MDS), especially MDS with the 5q- cytogenetic abnormality, and may also have activity in acute leukemia. We designed a phase I dose escalation trial of lenalidomide in adults with relapsed or refractory acute leukemia to determine the maximum tolerable dose (MTD) and dose limiting toxicity (DLT), as well as to provide preliminary efficacy data in this setting. 35 adults with acute leukemia were enrolled: 31 with acute myeloid leukemia (AML) and 4 with acute lymphoblastic leukemia (ALL). Patients had a median age of 63 years (range, 22-79) and had received a median of 2 prior therapies (range, 1-4). 8 patients had relapsed after transplantation (7-allogeneic, 1-autologous). Patients were treated orally with lenalidomide on days 1-21 of 28 day cycles at the following dose levels: 25mg/day (N=4), 35mg/day (N=9), 50mg/day (N=19, including the expansion at the MTD), and 75mg/day (N=3). Patients were eligible to receive additional cycles of treatment beyond cycle 1 in the absence of disease progression defined as 25% increase in blasts relative to pretreatment. The median number of cycles received was 1 (range, 1-7). DLTs were assessed during cycle 1 of therapy. DLTs were sudden death (N=1, autopsy ruled out pulmonary embolism), rash (N=1), line-associated thrombosis (N=1), and fatigue (N=3). Grade 3 fatigue occurred in two patients at 75mg/day; 50mg/day was thus declared the recommended phase 2 dose and 10 additional patients were treated at this dose. The major toxicities associated with treatment were drug and disease associated myelosuppression and infection, as expected; these did not constitute DLT. In spite of concerns that higher dose lenalidomide would be associated with increased risk of thromboembolism, this toxicity was infrequent, even during multiple cycles of therapy. Two events occurred; both were line associated, and neither was life-threatening. Detailed pharmacokinetic results for the dose escalation cohorts in the trial are listed in the table below. Maximum plasma lenalidomide concentrations and area under the concentration-time curve (AUC) increased proportionally with dose. Drug clearance was independent of dose and correlated with calculated creatinine clearance. Of 31 patients with AML there were 5 complete responses (CR) (by IWG criteria for AML; Cheson, JCO 2003). 3/3 with cytogenetically abnormal AML achieved cytogenetic CR (cCR) as well. Achievement of CR was delayed beyond 2 months from initiation of therapy in each case. The duration of CR was 2.4-8.8 months, with two responders still in CR at 2.4+ and 4.7+ months, respectively. At 25mg, a 74 year old with AML in 2nd relapse with widespread leukemia cutis but no blood/marrow involvement had resolution of disease after 2 cycles. At 35mg, a 69 year old with AML and trisomy 13 achieved cCR after 2 cycles. At 50mg, there were three CRs, including two patients who received lenalidomide as initial therapy for relapsed AML following allogeneic stem cell transplant. In both of these cases, lenalidomide therapy was associated with the onset of skin rash requiring temporary discontinuation of drug; CR was achieved after 2 to 3 cycles of therapy and was preceded by cytogenetic remission before count recovery occurred. A third CR at the 50mg level occurred in a 70 year old with AML who had lenalidomide discontinued after 2 cycles due to no apparent response. Subsequently, CR was achieved 1 month later with no intervening therapy. In conclusion, single agent lenalidomide induced CR in 16% (5/31) of relapsed/ refractory AML patients. None of the responders had 5q-. The DLT was fatigue; the MTD was 50mg daily for days 1-21. Achievement of CR without donor leucocyte infusion in 2/4 patients who received lenalidomide as initial therapy for AML relapse following allogeneic transplantation suggests a possible allogeneic immunomodulatory effect. We are now developing a CTEP-sponsored study of lenalidomide as maintenance following allogeneic transplantation for AML. The promising single agent efficacy reported here supports further study of lenalidomide in combination with other agents in high risk AML. Disclosures: Blum: Celgene: Research Funding.

Phase I Study of Clofarabine (JC0707) in Adult Japanese Patients with Acute Myeloid Leukemia (AML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4295-4295
Author(s):  
Takahiro Yamauchi ◽  
Tatsuya Suzuki ◽  
Kiyoshi Ando ◽  
Tadashi Nagai ◽  
Kazuhiko Kakihana ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Myeloid Leukemia ◽  
The United States ◽  
World Health ◽  
Plasma Samples ◽  
Newly Diagnosed ◽  
The Us ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Abstract 4295 Background and Purpose: Although cytarabine plus anthracycline (7+3 or 7+5) regimens are commonly used for induction therapy in patients (pts) with acute myeloid leukemia (AML) and there have been improvements in the treatment of AML in younger adults, there is no standard of care in pts with relapsed or refractory (R/R) AML. Treatment options for older pts and those with R/R disease remain limited. Clofarabine (JC0707) is a purine nucleoside analog approved in the United States (US) and European Union for the treatment of pediatric pts with R/R acute lymphocytic leukemia (ALL). In a phase II study from the US, single-agent clofarabine showed activity and acceptable toxicity in pts ≥ 60 years with untreated AML and adverse prognostic factors (Kantarjian, J Clin Oncol 2010;28:549–55). The purpose of this phase I open-label, multi-center study is to assess the safety, tolerability, and pharmacokinetics of clofarabine monotherapy in elderly Japanese pts with newly diagnosed AML for whom standard induction chemotherapy is unlikely to be of benefit or Japanese adult pts with R/R AML. Method: Adult pts (20–74 years) with R/R AML according to World Health Organization (WHO) criteria and elderly pts (60–74 years) with newly diagnosed AML were eligible to participate. Additional inclusion criteria included Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and no prior hematopoietic stem cell transplant. The study utilized a standard 3 + 3 dose escalation method; 3 pts enrolled in each dosing cohort, 3 additional pts were added to cohorts where dose-limiting toxicities (DLTs) were observed. The maximum tolerated dose (MTD) was defined as the dose level below that for which 2 DLTs were observed. Based on prior clinical trials in the US, pts were to be treated with clofarabine 20 mg/m2/day (IV over 1 hr), 30 mg/m2/day, or 40 mg/m2/day for one 5 day cycle in cohorts 1, 2 and 3, respectively. Pts with evidence of hematologic response after one cycle could receive up to a maximum of 3 cycles. The primary endpoints of this study were MTD, safety, and pharmacokinetic (PK) parameters. Result: Until June 2011, 14 pts were enrolled and treated in this trial: cohort 1 (n=3), cohort 2 (n=6), and cohort 3 (n=5). Bioanalytical determination of clofarabine concentrations in plasma samples showed an increased concentration with increased dosage. No DLTs were noted in cohort 1 (20 mg/m2). Among the first 3 pts in cohort 2 (30 mg/m2), only 1 patient experienced DLT (reversible, grade 4 elevated ALT). Additionally, 2 pts in cohort 3 (40 mg/m2) experienced DLTs (grade 3 elevated ALT [n=1]; grade 3 elevated amylase [n=1]). Thus, the MTD was determined to be 30 mg/m2. Preliminary safety and efficacy data are available for 9 of these pts and presented herein. Overall, the most common all cause, non-hematologic toxicities were nausea and headache (89% each), rash and elevated ALT and AST (78% each), malaise (56%), pneumonia and hypokalemia (44% each), and elevated bilirubin and vomiting (33% each). Grade 3 or 4 toxicities were primarily hematologic and infectious occurring in 89% and 67% of patients, respectively. Only one patient developed a treatment-related serious adverse event (SAE) (herpes zoster). There were no AE related deaths and no patients discontinued therapy as a result of an AE. Two patients achieved complete remission (CR) and 2 patients achieved CR without platelet recovery (CRp), for an overall response rate (ORR) of 44% (Table 1). Additionally, plasma samples were obtained from all patients for PK evaluation; plasma concentration data from all 14 patients will be presented. Conclusion: Clofarabine monotherapy was well tolerated at doses up to 30mg/m2 and showed preliminary evidence of activity with 44% ORR in elderly newly diagnosed AML or adult Japanese pts with R/R AML, warranting further investigations. Disclosures: Off Label Use: Clofarabine (JC0707) is an investigational agent in Japan; this abstract assesses its use in adult AML patients. Ewesuedo:Sanofi Oncology: Employment. Tabata:Genzyme (a Sanofi company): Employment.

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