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 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.

Determination of the Maximum Tolerated Dose of Panobinostat in Combination with Cytarabine and Mitoxantrone As Salvage Therapy for Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 423-423 ◽  
Author(s):  
Richard F. Schlenk ◽  
Jürgen Krauter ◽  
Markus Schaich ◽  
Didier Bouscary ◽  
Hervé Dombret ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Febrile Neutropenia ◽  
Dose Escalation ◽  
Salvage Therapy ◽  
Myeloid Leukemia ◽  
Maximum Tolerated Dose ◽  
Refractory Acute Myeloid Leukemia ◽  
Grade 3 ◽  
Acute Myeloid ◽  
Refractory Aml

Abstract Abstract 423 BACKGROUND: Relapsed/refractory acute myeloid leukemia (AML) is characterized by poor prognosis, with low complete remission (CR) rates after salvage therapy and low overall survival. A major challenge is to improve the CR rate, thereby increasing allogeneic hematopoietic stem cell transplantation (alloHSCT) rates. Panobinostat is a pan-deacetylase inhibitor that increases acetylation of proteins involved in cancer. Preclinical studies in AML demonstrated that panobinostat potentiates the activity of cytarabine (ara-C) and fludarabine and has synergistic activity in combination with doxorubicin in vitro. Single-agent panobinostat has induced CR in patients (pts) with AML. The addition of panobinostat to an active chemotherapeutic regimen in pts with relapsed/refractory AML has the potential to improve therapeutic outcomes in this setting. AIMS: This phase Ib, multicenter, open-label dose-escalation study was designed to determine the maximum tolerated dose (MTD) of panobinostat in combination with a fixed dose of ara-C and mitoxantrone in pts with relapsed/refractory AML. The secondary objectives were to characterize safety and tolerability during the dose-escalation phase and at the MTD and to evaluate anti-leukemic activity. METHODS: Successive cohorts of at least 3 pts with confirmed relapsed or refractory AML were treated with oral panobinostat (starting with 20 mg, escalated in 10-mg steps) thrice weekly on days 1, 3, 5, 8, 10, and 12, in combination with intravenous ara-C (1 g/m2) on days 1–6 and mitoxantrone (5 mg/m2) on days 1–5 of a 28-day cycle. The MTD was determined on the basis of the observed dose-limiting toxicities (DLTs), safety assessment, and tolerability during the first 28 days after starting panobinostat. A DLT was defined as any adverse event (AE) or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications with the following criteria: neutropenia lasting > 28 days after cycle 1 for hematologic DLTs; grade 4 AST/ALT or grade 3 AST/ALT for > 7 days; grade 3/4 bilirubin, vomiting, diarrhea, or any non-hematologic toxicity for non-hematologic DLTs. Safety and tolerability were described as type, duration, frequency, relatedness, and severity of AEs according to CTCAE v3.0. The adaptive Bayesian logistic regression model was used to guide dose escalation with overdose control. RESULTS: Of 5 dose levels, 40 pts (median age, 55 years; range, 19–73 years) were treated at panobinostat dosages of 20 to 60 mg, with 5 pts at 20 mg, 8 at 30 mg, 10 at 40 mg, 11 at 50 mg, and 6 at 60 mg. Of 6 DLTs observed, 1 was at 40 mg (sepsis and tachyarrhythmia), 2 were at 50 mg (vomiting/nausea; diarrhea), and 3 were at 60 mg (neutropenic colitis; 2 hypokalemic events). Frequent AEs of all grades, regardless of causality, included nausea (32 [80%]), diarrhea (31 [78%]), vomiting (26 [65%]), hypokalemia (25 [63%]), thrombocytopenia (24 [60%]), abdominal pain (22 [55%]), decreased appetite, and febrile neutropenia (21 each [53%]). The most frequent grade 3/4 treatment-related AEs were thrombocytopenia (20 [50%]), anemia (9 [23%]), leukopenia, and neutropenia (7 each [18%]). Serious AEs, regardless of causality, were reported in 23 pts, with febrile neutropenia (12 [30%]) being the most common. The MTD was determined to be 50 mg of panobinostat on the basis of observed DLTs and safety and tolerability in cycle 1 of the dose-escalation phase. Clinical responses were observed in 22 pts (55%), including 13 CR, 5 morphological CR, and 4 partial remissions. In pts receiving 40- and 50-mg doses of panobinostat, the preliminary efficacy was promising, with a response in 11 of 21 pts (52%). An alloHSCT was performed in 8 pts after the start of salvage therapy. CONCLUSIONS: The combination of panobinostat, ara-C, and mitoxantrone showed no unexpected toxicities and promising anti-leukemic activity in pts with relapsed/refractory AML. The MTD was determined to be 50 mg of panobinostat; enrollment at this dose is ongoing for the dose-expansion phase to further assess safety, tolerability, and activity. Thrombocytopenia and anemia were the principal treatment-related hematologic AEs. Treatment-related non-hematologic AEs were primarily gastrointestinal toxicities and fatigue. Disclosures: Krauter: Novartis: Consultancy, Honoraria. Winiger:Novartis AG: Employment, Equity Ownership, Honoraria. Squier:Novartis Corporation: Employment. Zahlten:Novartis AG: Employment. Wang:Novartis Corporation: Employment. Ottmann:Novartis Corporation: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding.

A Phase Ib Dose-Finding Study of Oral Panobinostat In Combination with Cytarabine (ara-C) and Mitoxantrone as Salvage Therapy for Refractory or Relapsed Acute Myeloid Leukemia (AML)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3310-3310
Author(s):  
Jürgen Krauter ◽  
Richard F. Schlenk ◽  
Markus Schaich ◽  
Didier Bouscary ◽  
Hervé Dombret ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Single Agent ◽  
Fixed Dose ◽  
Phase Ib ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Abstract 3310 Background: Panobinostat (PAN) is an oral pan-deacetylase inhibitor (pan-DACi) that increases acetylation of a series of proteins such as HSP90, p53, α-tubulin and HIF-1α which are involved in cell cycle regulation, gene transcription, angiogenesis, and tumor cell survival. Preclinical studies demonstrated that PAN potentiates the activity of cytarabine (ara-C) and fludarabine and has synergistic activity in combination with doxorubicin in AML cell lines and patient (pt) blast cells. Clinical activity of single-agent PAN has been demonstrated in a phase I trial, including complete responses in pts with AML. Acute myeloid leukemia (AML) is associated with a poor prognosis, particularly in pts with relapsed or refractory disease. The addition of PAN to a chemotherapeutic regimen that is active in pts with AML who have relapsed or are refractory to prior induction therapy has the potential to improve therapeutic outcomes in this setting. Methods: This phase Ib, multicenter, open-label study is comprised of 3 parts: 1) dose-escalation to determine the maximum tolerated dose (MTD) of PAN in combination with ara-C and mitoxantrone, 2) dose-expansion to assess safety and preliminary activity at the MTD, and 3) optional dose extension to assess safety of single-agent PAN (60 mg thrice weekly) in pts who responded but are not eligible for other therapies. The primary objective is to determine the MTD of PAN in combination with a fixed dose of ara-C and mitoxantrone. The primary endpoint is incidence of dose-limiting toxicities (DLTs) within the first treatment cycle. Secondary and exploratory objectives include assessment of the safety profile of PAN and evaluation of anti-leukemic activity. Adult pts with AML (WHO criteria) who are relapsed or refractory to 1 prior treatment regimen with an ECOG PS ≤2 were eligible for enrollment on the study. PAN was orally administered (20 mg starting dose) thrice weekly on Days (D) 1, 3, 5, 8, 10, and 12, in combination with iv ara-C (1 g/m2) D1–6, and iv mitoxantrone (5 mg/m2) D1–5 of a 28-D cycle (C). Pts can receive a maximum of 3 cycles of combination therapy. Pts who are eligible for the optional dose extension part received single-agent PAN (60 mg thrice weekly). Results: As of July 29, 2010, 23 pts have been enrolled, 5 in cohort 1 (20 mg PAN), 8 in cohort 2 (30 mg PAN), and 10 in cohort 3 (40 mg PAN). Safety and efficacy analyses are based on 18 pts. The median age of the pts was 53.5 years (range 19–72). Prior to treatment, all had received ara-C. One DLT has been observed (sepsis and tachyarrhythmia) in the 40 mg cohort. Adverse events were observed with 16 pts (89%): hematologic adverse events (AEs) were observed in 12 pts (67%): including thrombocytopenia, febrile neutropenia, anemia, leukopenia and neutropenia. Non-hematologic AEs included: general disorders and administration site conditions (16 [89%]), gastrointestinal and metabolism/nutrition disorders (15 [83%] each), infections (12 [67%]), respiratory/thoracic disorders (11 [61%]), vascular and skin/subcutaneous tissue disorders (10 [56%] each) and cardiac disorders (8 [44%]). Most frequent Grade 3/4 adverse events (AEs) observed in all cohorts to date were hematologic, including febrile neutropenia and thrombocytopenia (8 [44%] each), leukopenia (5 [28%]), anemia and neutropenia (4 [22%] each). Grade 3/4 AEs suspected to be study treatment related were mostly related to thrombocytopenia (6 [33%]) and neutropenia (4 [22%]). Serious AEs were observed in all cohorts, with most related to infectious complications (8 [44%]), febrile neutropenia (6 [33%]) pneumonia and fungal pneumonia (2 [11%]). QTcF prolongation of ≥480 ms (but < 500 ms) was observed in 2 pts (11%), but no pt demonstrated QTcF prolongation of > 500 ms. Encouraging clinical efficacy was observed, especially with higher doses of PAN, with 8 responders (partial response [PR] or better) (44%): 3 complete remissions (CR), 2 complete remissions with incomplete blood count recovery (CRi) and 3 partial responses (PR). Conclusions: The MTD of PAN in combination with ara-C and mitoxantrone has not been reached, and the study is ongoing. The current data show that the addition of PAN to ara-C and mitoxantrone is safe with no unexpected toxicities and showing promising activity in refractory or relapsed AML pts. Updated data, including safety and preliminary efficacy data will be presented at the meeting. Disclosures: Krauter: Novartis: Research Funding. Off Label Use: Panobinostat is an investigational agent currently being evaluated for the treatment of hematologic and solid malignancies. Schlenk:Novartis: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Amgen: Research Funding; Cephalon: Research Funding. Winiger:Novartis Pharma AG: Employment. Squier:Novartis: Employment. Bengoudifa:Novartis Pharma AG: Employment. Ottmann:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals A Comparison of Patients with Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome Treated on Versus Off Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2787-2787
Author(s):  
Sarah A. Buckley ◽  
Mary-Elizabeth M. Percival ◽  
Megan Othus ◽  
Anna B. Halpern ◽  
Emily M Huebner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Selection Bias ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Response Rates ◽  
Secondary Leukemia ◽  
Kaplan Meier ◽  
Acute Myeloid

Abstract Introduction: Despite decades of research, acute myeloid leukemia (AML) remains difficult to treat, and clinical trials are recommended as first line therapy by the NCCN. Although many new drugs show promise in early trials, further experience often does not confirm these results. One possible explanation is that patients on trials are not broadly representative. Here, we retrospectively compared characteristics, response, and survival in patients given the same investigational regimens according to whether treatment was given on versus off study. Methods: Patients treated for AML or high-risk MDS at FHCRC/UW between 2008 and 2015 were included. Investigator-initiated protocols for newly diagnosed (ND) and relapsed / refractory (RR) disease were included if ≥15 patients were treated off study. Analyses used Fisher's exact test, Wilcoxon rank sum test, the Kaplan-Meier method, and Cox multivariate models. Results: 165 ND patients received either escalating doses of G-CLAM or idarubicin, cytarabine, and pravastatin while 243 RR patients received G-CLAM, decitabine-primed MEC or G-CLAC. Overall, 216 were treated on study and 192 were treated off study; reasons for the latter were: protocol not open (n=64), high treatment-related mortality score (n=21), poor health / organ function (n=26), physician or patient preference (n=25), lack of insurance (n=6), and not identified (n=50). No significant differences were found in age, gender, cytogenetic risk, or primary vs. secondary leukemia, but those treated on study in dose escalation protocols were more likely to receive higher doses. RR patients treated off study had typically received more salvage regimens. The 86 ND patients treated on study had higher rates of CR/CRi (90% vs. 64%, P<0.001) and CR without MRD (67% vs. 36%, P<0.001) than the 79 treated off study. These associations remained after adjusting for treatment date, age, gender, secondary leukemia, adverse cytogenetics, and regimen type (OR 3.99 [95% CI: 1.60-9.97] and OR 2.93 [1.39-6.17] respectively). In contrast, neither CR/CRi nor CR without MRD rates differed for RR patients treated on (n=130) or off (n=113) protocol: 52% vs. 41%, P=0.07 and 28% vs. 19%, P=0.14. The same applied after adjusting for the above factors as well as duration of first remission and salvage number: OR 1.79 [0.95-3.40] and OR 1.73 [0.80-3.71]. Despite having higher remission rates, ND patients treated on vs. off study had comparable OS, and, among patients achieving remission, RFS (Figure 1a and 1b). After multivariate adjustment, there remained no association with OS (HR 0.87 [0.52-1.47]) or RFS (HR 0.96 [0.53-1.75]). Survival outcomes were also similar regardless of study assignment among RR patients (Figure 1c and 1d), in both univariate and multivariate analysis (OS, HR 0.82 [0.58-1.17]; RFS HR 0.72 [0.39-1.34]). Patients treated on or off dose escalation protocols at the maximum tolerated dose were no more likely to achieve remission or have longer survival, and incorporating subsequent allogeneic transplant as a time-varying covariate did not significantly affect outcomes. Conclusions: The higher response rates in ND patients treated on vs. off study suggests a measure of selection bias unrelated to readily assessable covariates, while the fundamental determinant of response in RR patients and survival in all patients appears to be unfavorable disease features (adverse cytogenetics, number of prior salvages, duration of CR1). Routine reporting of off study data for investigator-initiated studies could provide a clearer picture of regimen response rates and would grant further insight into the effects of selection bias. Figure 1 Kaplan-Meier curves for on and off study patients depicting OS and, among patients achieving remission, RFS. Outcomes are depicted in ND patients (a and b) and in RR patients (c and d). Figure 1. Kaplan-Meier curves for on and off study patients depicting OS and, among patients achieving remission, RFS. Outcomes are depicted in ND patients (a and b) and in RR patients (c and d). Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Shadman:Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Emergent: Research Funding; Acerta: Research Funding.

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 &gt;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 &gt;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.

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.

Safety and Efficacy of Bendamustine and Idarubicin in Combination Therapy for Patients Age ≥50 with Untreated Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome – Results From a Phase I/II Adaptive Design Study.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2622-2622
Author(s):  
Mazyar Shadman ◽  
Jack M. Lionberger ◽  
Raya Mawad ◽  
Ravinder K Sandhu ◽  
Carol Dean ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Posterior Probability ◽  
Performance Status ◽  
Outpatient Setting ◽  
Ecog Performance Status ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Abstract 2622 Background: Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS with 10–19% blasts) are associated with higher mortality in the elderly population. This poor outcome is in part attributed to therapy resistance and therefore, using combinations of agents with different mechanisms of action may improve outcomes. The nitrogen mustard Bendamustine combines unique alkylating characteristics with putative anti-metabolite activity while Idarubicin inhibits DNA and RNA synthesis by intercalation between DNA base pairs. In this single-arm adaptive phase I/II dose-escalation trial, we assessed increasing doses of Bendamustine in combination with a uniform dose of Idarubicin. We used a Bayesian approach to determine whether there was a dose of Bendamustine which, together with Idarubicin can provide a complete response (CR) rate of at least 40%, with minimal (<30%) grade 3–4 extramedullary toxicity in untreated AML or high-risk MDS patients age > 50. Methods: Eligible patients were age 350 with untreated AML or high-risk MDS, had an ECOG performance status <3 and creatinine and bilirubin each less <2.0. Patients received 1 of 3 doses of Bendamustine (45, 60 or 75 mg/m2 daily days 1–5) together with Idarubicin (12 mg/m2 days 1–2). Response was assessed according to the International Working Group (IWG) criteria (Cheson et. al., JCO, 2003) and non-hematologic toxicities according to the NCI CTCAE v.3. After each cohort of 3 patients at a given dose had been evaluated for toxicity and response, Bayesian posterior probabilities based on the data and non-informative prior probabilities were computed. If no Bendamustine dose was associated with a >95% posterior probability of both grade 3–4 extramedullary toxicity <30% (between the 1/6 and 2/6 of the conventional 3+3) and CR rate >40%, the study stopped. Otherwise, the study would continue at the highest dose that met the above criteria until 45 patients had been treated. Treatments were administered in the outpatient setting and patients were admitted to the hospital only if medically indicated. Results: Between October 2010 and May 2012, 39 patients were treated per protocol. The median age was 73 (range, 56–82). Patients had ECOG performance status of 1 (92%), or 2 (7%). AML patients comprised majority of the cases (34/39; 87%). Among AML patients, 35% (12/34) had primary AML, 47% (16/34) had AHD (antecedent hematologic disorders) and 18% (6/34) had secondary AML with a prior history of chemotherapy or radiation. None of the patients had favorable-risk cytogenetic (CG) and 19 (49%) had poor-risk CG including 9 patients (23%) with monosomal karyotype. None of the patients with normal CG had favorable molecular markers. Treatment was given in 1, 2, and 3 cycles in 25 (64%), 7 (18%) and 7(18%) patients, respectively. The number of patients in each cohort and the treatment efficacy and toxicity is reported in the table below. The MTD (maximum tolerated dose) was established at 60 mg/m2 of Bendamustine as two grade 3 toxicities were seen at the dose of 75 mg/m2 (congestive heart failure and mucositis in one patient each). Patients were treated as outpatients but hospitalization was required in 90% of the patients (35/39; 90%). The leading cause of admission was febrile neutropenia (26/35; 74%) followed by fungal infections (4/35; 11%). Conclusion: The combination of Bendamustine (60 mg/m2 (for 5 days) with Idarubicin (12 mg/m2 for 2 days) can be delivered in the outpatient setting and had a <95% posterior probability of >30% toxicity. However, the posterior probability of a CR rate >40% was also <95%, suggesting that continued exploration of new therapeutic combinations is warranted in elderly patients with AML or high-grade MDS. Disclosures: Off Label Use: Bendamustine is indicated for the treatment of CLL and indolent non-Hodgkin's lymphoma. In our study we are using Bendamustine to treat AML.

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.

scholarly journals Preliminary Results from a Phase 1 Study of APVO436, a Novel Anti-CD123 x Anti-CD3 Bispecific Molecule, in Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-12
Author(s):  
Justin M. Watts ◽  
Tara Lin ◽  
Eunice S. Wang ◽  
Alice S. Mims ◽  
Elizabeth H. Cull ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase 1 ◽  
Cytokine Release ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Acute Myeloid

Introduction Immunotherapy offers the promise of a new paradigm for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). CD123, the IL-3 receptor alpha-chain, represents an attractive target for antibody therapies because of its high expression on AML/MDS blasts and leukemic stem cells compared to normal hematopoietic stem and progenitor cells. APVO436, a novel bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecule, depleted CD123+ cells in AML patient samples ex vivo (Godwin et al. ASH 2017), reduced leukemia engraftment in a systemic AML xenograft model (Comeau et al. AACR 2018), and transiently reduced peripheral CD123+ cells in non-human primates with minimal cytokine release and in a dose-dependent fashion (Comeau et al. AACR 2019). These data provide a basis for the clinical application of APVO436 as a treatment in AML and MDS. Here, we report preliminary data from a first-in-human dose-escalation study of APVO436 in patients with R/R AML and high-risk MDS. Study Design/Methods This ongoing Phase 1/1b study (ClinicalTrials.gov: NCT03647800) was initiated to determine the safety, immunogenicity, pharmacokinetics, pharmacodynamics, and clinical activity of APVO436 as a single agent. Major inclusion criteria were: R/R AML with no other standard treatment option available, R/R MDS with &gt; 5% marrow blasts or any peripheral blasts and failure of a hypomethylating agent, ECOG performance status ≤ 2, life expectancy &gt; 2 months, white blood cells ≤ 25,000 cells/mm3, creatinine ≤ 2 x upper limit of normal (ULN), INR and PTT &lt; 1.5 x ULN and alanine aminotransferase &lt; 3 x ULN. Patients were not restricted from treatment due to cytogenetic or mutational status. Intravenous doses of APVO436 were administered weekly for up to six 28-day cycles (24 doses) with the option to continue dosing for up to 36 total cycles (144 doses). Flat and step dosing regimens were escalated using a safety-driven modified 3 + 3 design. Pre-medication with diphenhydramine, acetaminophen, and dexamethasone was administered starting with dose 1 to mitigate infusion related reactions (IRR) and cytokine release syndrome (CRS). First doses and increasing step doses of APVO436 were infused over 20-24 hours followed by an observation period of 24 hours or more. Bone marrow biopsies were performed every other cycle with responses assessed by European Leukemia Net 2017 criteria for AML or International Working Group (IWG) 2006 criteria for MDS. Results The data cut-off for this interim analysis was July 9, 2020. Twenty-eight patients with primary R/R AML (n=19), therapy-related R/R AML (n=3), or high-risk MDS (n=6) have been enrolled and received a cumulative total of 186 doses. The number of doses received per patient ranged from 1 to 43 (mean of 6.4 doses). Most patients discontinued treatment due to progressive disease; however, blast reduction was achieved in 2 patients, with one patient with MDS maintaining a durable response for 11 cycles before progressing. APVO436 was tolerated across all dose regimens in all cohorts tested. The most common adverse events (AEs), regardless of causality, were edema (32%), diarrhea (29%), febrile neutropenia (29%), fever (25%), hypokalemia (25%), IRR (21%), CRS (18%), chills (18%), and fatigue (18%). AEs ≥ Grade 3 occurring in more than one patient were: febrile neutropenia (25%), anemia (18%), hyperglycemia (14%), decreased platelet count (11%), CRS (11%), IRR (7%), and hypertension (7%). After observing a single dose limiting toxicity (DLT) at a flat dose of 9 µg, step dosing was implemented and no DLTs have been observed thereafter. No treatment-related anti-drug antibodies (ADA) were observed. Transient serum cytokine elevations occurred after several reported IRR and CRS events, with IL-6 most consistently elevated. Conclusions Preliminary results indicate that APVO436 is tolerated in patients with R/R AML and MDS at the doses and schedules tested to date, with a manageable safety profile. Dose escalation continues and the results will be updated for this ongoing study. Disclosures Watts: BMS: Membership on an entity's Board of Directors or advisory committees; Aptevo Therapeutics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Lin:Ono Pharmaceutical: Research Funding; Pfizer: Research Funding; Abbvie: Research Funding; Bio-Path Holdings: Research Funding; Astellas Pharma: Research Funding; Aptevo: Research Funding; Celgene: Research Funding; Genetech-Roche: Research Funding; Celyad: Research Funding; Prescient Therapeutics: Research Funding; Seattle Genetics: Research Funding; Mateon Therapeutics: Research Funding; Jazz: Research Funding; Incyte: Research Funding; Gilead Sciences: Research Funding; Trovagene: Research Funding; Tolero Pharmaceuticals: Research Funding. Wang:Abbvie: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; PTC Therapeutics: Consultancy; Stemline: Speakers Bureau; Genentech: Consultancy; Pfizer: Speakers Bureau. Mims:Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Agios: Consultancy; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Abbvie: Membership on an entity's Board of Directors or advisory committees. Cull:Aptevo Therapeutics: Research Funding. Patel:Agios: Consultancy; Celgene: Consultancy, Speakers Bureau; DAVA Pharmaceuticals: Honoraria; France Foundation: Honoraria. Shami:Aptevo Therapeutics: Research Funding. Walter:Aptevo Therapeutics: Research Funding. Cogle:Aptevo Therapeutics: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Chenault:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Macpherson:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Chunyk:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. McMahan:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gross:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Stromatt:Aptevo Therapeutics: Current equity holder in publicly-traded company.

scholarly journals Combination of Sorafenib and 5-Azacytidine in Older Patients with Untreated Acute Myeloid Leukemia with FLT3-ITDmutation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1611-1611 ◽  
Author(s):  
Maro Ohanian ◽  
Guillermo Garcia-Manero ◽  
Elias J. Jabbour ◽  
Naval Daver ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Median Overall Survival ◽  
Cell Transplant ◽  
Overall Response ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Background: The combination of 5-azacytidine (AZA) and sorafenib has been reported to be a safe and effective strategy in patients with relapsed and/or refractory FLT3-ITD mutated acute myeloid leukemia (AML). We hypothesized that combining sorafenib with AZA, may be used effectively in older patients with untreated AML whose leukemic cells harbor the mutation. Methods: Patients were eligible if they had untreated AML with a FLT3-ITD clone detectable by polymerase chain reaction (at least 10% mutation burden), were 60 years of age or older, and had adequate performance status (ECOG ≤ 2) and organ function. The treatment regimen included AZA 75 mg/m2daily for 7 days combined with sorafenib 400 mg twice daily for 28 days. Cycles were repeated approximately every 4 to 5 weeks. Dose adjustments of both agents, and delay of AZA, based on toxicity were allowed. Results: Overall, 23 patients with untreated AML with a median age of 74 yrs (range, 61-86 yrs) were enrolled. They included 14 (61%) patients with normal cytogenetics, 2 (9%) with complex karyotype, 4 (17%) with other miscellaneous abnormalities, and 3 (13%) with insufficient metaphases. Prior to the initiation of treatment, FLT3-ITD was detected in all patients with a median allelic ratio of 0.35 (range, 0.01-0.89). The overall response rate in 22 evaluable patients was (77%) including 7 (32%) with CR, 9 (41%) CRi/CRp, and 1 (5%) PR. Patients have received a median of 3 (range, 1-35) treatment cycles with the median number of cycles to response being 2 (range, 1-5) and the median time to achieve response, 1.9 months (range, 0.7-4.3 months). The median duration of CR/CRp/CRi is 14.5 months (range, 1.2-28.7 months). Two (9%) patients have proceeded to allogeneic stem cell transplant. With a median follow-up of 4.2 months (range, 0.9-61.4), 8 patients remain alive, 7 still in remission (CR/CRP/CRi). The median overall survival for the entire group is 8.8 months, and 9.2 months in the 17 responding patients (Figure 1). Treatment-related grade 3/4 adverse events included: grade 3 diarrhea (n=2), grade 3 pneumonitis (n=3), grade 4 sepsis (n=2), grade 3 infections (n=3). When patients treated with AZA + sorafenib (n=23) were compared to a matched cohort of historical patients older than 60 years who were treated with hypomethylator-based therapy without sorafenib (n=20), overall response rates (including CR, CRp, CRi, and PR) were statistically similar (77% vs.31%, respectively; p=0.6). The median overall survival for the two groups were 8.8 months and 9.4 months (p=0.67), respectively. The remission duration for the responding patients treated with AZA+sorafenib was significantly longer (16 months) than those on other hypomethylator-based regimens without sorafenib (3.8 months)(p=0.008) (Figure 2). Conclusions: The combination of AZA and Sorafenib is effective and well tolerated in older patients with untreated FLT3-ITD mutated AML. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Karyopharm: Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; Ariad: Research Funding. Burger:Roche: Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Portola: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

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