scholarly journals A Safety Study of the Addition of Omacetaxine to the Standard-of-Care Induction Regimen of Cytarabine and Idarubicin in Newly-Diagnosed AML Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5218-5218
Author(s):  
Sonia Christian ◽  
Kelley E. Kozma ◽  
Stephanie Barath ◽  
Ardaman Shergill ◽  
Damiano Rondelli ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
De Novo ◽  
Standard Of Care ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Induction Regimen ◽  
Dose Levels

Abstract Background: Omacetaxine mepesuccinate (OM) is a semi-synthetic form of Homoharringtonine (HH), a cephalotaxine alkaloid. OM induces cell apoptosis by inhibiting peptide bond formation during mRNA translation, with rapid loss of short-lived proteins, such as MCL-1, c-MYC, and Cyclin D1 (Lu, J Hematol Oncol. 2014, 7: 2). Notably, cytarabine synergizes with HH in causing apoptosis of leukemia cells in vitro. A phase III RCT in China of 620 patients with de novo AML demonstrated superior CR and 3-yr survival rates upon addition of HH to a standard 2-drug AML induction therapy ('7 + 3'; Jin, Lancet Oncol. 2013, 14:599). Thus, we hypothesized that OM, at an appropriate dose, would similarly enhance the efficacy of a 7 + 3 regimen. OM is FDA-approved for the treatment of TKI-resistant CML. The MTD of 1.25 mg/m2/d SQ for 14 days every 28 days, as determined in a phase I/II CML trial of OM (Quintás-Cardama, Cancer 2007, 109: 248), served as a basis for the dose escalation used in this study. Methods: The primary endpoint of this phase I safety trial was to determine the optimally safe and active dose (OD) of OM when added to a standard 7 + 3 induction regimen, cytarabine and idarubicin. OM was administered SQ q12h d1-7 with cytarabine (100mg/m2 CIV) d1-7 and idarubicin (12mg/m2 IV) d1-3. Four dose levels were tested, starting with OM 0.625 mg/m2 q12h (further dose levels: 1.25, 2.0, 3.0, and 4.2 mg/m2 q12h). All newly diagnosed, untreated de novo or secondary AML patients, aged 18-70y with ECOG PS of 0-3 were eligible for this study. Secondary endpoints included overall response rate (ORR) and overall and event free survival (OS, EFS). Hematologic toxicity (HT) was defined as incomplete hematologic recovery; ANC < 1.0 x 109/L or platelet count < 100 x 109/L present at d49, with the bone marrow documented to be free of leukemic infiltration. Dose escalation was based on the EffTox design (Biometrics 2004, 60:684), a Bayesian adaptive design which considers the trade-off between efficacy and toxicity in determining the OD for Phase II trials. Results: Twenty-two patients, median age 58 (range 25-69) years were enrolled from June 2015 to June 2018. 12 patients (54.5%) had adverse cytogenetics, 6 (27%) intermediate risk, 3 (13.7%) favorable risk and 1 patient's cytogenetic risk was unknown (fibrotic BM). Eight patients demonstrated disease evolution from myelodysplastic syndrome (MDS). Altogether 16 of the 22 patients (73%) were deemed high risk based on cytogenetics or MDS-AML evolution. The EffTox design was implemented until cohort 4 (3 mg/m2 q12h), where 2 of 3 patients experienced a grade 5 non-hematologic toxicity (NHT), resulting in a dose-limiting toxicity (DLT). Since no DLTs were observed in cohort 3, an additional 5 patients were thus enrolled at this dose level to ensure safety. The OD was determined to be the dose level used in cohort 3: OM 2 mg/m2. No HTs were observed in 21 of 22 patients, (one patient not evaluable). The most common non-hematologic treatment emergent adverse events (TEAEs) of any grade were fever (68%), nausea (64%), vomiting (55%), hyperglycemia (41%), diarrhea (41%), mucositis (36%), headache (36%), sinus tachycardia (32%), rash/dermatitis (32%), and abdominal pain (32%). The most prevalent non-hematologic grade 3/4 TEAEs were febrile neutropenia (23%), hypoxia (18%), hyperglycemia (18%), and dyspnea (18%). ORR (CR and CRi) was 45.5%. Median OS was 605 days and EFS was 100 days. Conclusion: In this population with predominantly high-risk AML, the combination of OM with a standard 7 + 3 regimen demonstrates a manageable safety profile with acceptable efficacy. As ~ 25% of patients achieving CR with '7 + 3' do so after a second induction (based on meta-analysis of 6 trials, n = 1980, see Cancer 2010, 116: 5012), the ORR here is comparable to those receiving a single standard of care induction. The results in this high-risk group are therefore promising and warrant further investigation in a phase II trial. At present, we are assessing leukemic blast MCL protein expression in stored pre-treatment samples to determine if this predicts OM efficacy. NCT02440568. Teva has performed a Medical Accuracy Review of this abstract. Figure. Figure. Disclosures Khan: Teva: Speakers Bureau. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

Final Results of a Phase I Study of the Fc Engineered CD19 Antibody XmAb®5574 (MOR00208) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2894-2894 ◽  
Author(s):  
Jennifer A. Woyach ◽  
Farrukh Awan ◽  
Ian W. Flinn ◽  
Rolondo Enoch ◽  
Paul A. Foster ◽  
...  
Keyword(s):  
High Risk ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Phase I ◽  
B Cell ◽  
Dose Level ◽  
Phase I Trial ◽  
Hematologic Toxicity ◽  
B Cell Malignancies ◽  
Dose Levels

Abstract Abstract 2894 Antibody (Ab) therapies such as the CD20 monoclonal abs rituximab and ofatumumab are commonly used in CLL alone and in combination with chemotherapy, however, CD20 density is low on CLL cells, suggesting this may not be the ideal target. CD19, which is ubiquitously expressed on CLL cells and those of other B cell malignancies is a reasonable candidate for ab targeting. XmAb5574 is a novel humanized IgG1 CD19 monoclonal ab with an engineered Fc region to enhance Fc gamma receptor binding affinity. In vitro, this ab demonstrates direct cytotoxicity and antibody dependent cellular phagocytosis similar to rituximab, however, shows enhanced natural killer antibody dependent cellular cytotoxicity compared to other therapeutic abs used in CLL (Awan, FT Blood 2009). We have performed a first in human trial of this ab as a single agent in relapsed or refractory (R/R) CLL, and present the results in this report. This study is a multi-institutional phase I trial of XmAb5574 in patients (pts) with R/R CLL. Eligible pts were those with CLL who had at least 1 prior therapy and required treatment by International Working Group on CLL (IWCLL) 2008 Guidelines (Hallek, M Blood 2008), had Eastern Cooperative Oncology Group Performance Status <3, had platelets ≥50,000/mm3, and had adequate organ function. Primary endpoints were to determine maximal tolerated dose (MTD), describe toxicity, and characterize pharmacokinetics (PK). A secondary endpoint was to explore efficacy. An accelerated titration design was used in which 1 pt was accrued to the first two dose levels provided there were no dose limiting toxicities (DLT) or ≥ grade 2 adverse events (AE), and then a standard 3×3 design was employed from dose level 3 forward. Dose levels included 0.3, 1, 3, 6, 9, and 12 mg/kg with an expansion to a total of 16 pts at the MTD. XmAb5574 was administered as an intravenous infusion on days 1, 4, 8, 15, and 22 of cycle (C) 1, and on days 1, 8, 15, and 22 of C2. Toxicity was assessed using the National Cancer Institute's Common Criteria for Adverse Events v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. Disease response assessment by physical exam was performed on C1D28, C2D28, and 4, 8, and 12 weeks after the end of C2. Radiographic assessment was performed C2D28. 27 pts were enrolled to this phase I trial. The median age of all pts was 66 years (range 40–84). The pts were generally high risk: 14 (52%) had high-risk disease by Rai stage, 8 (30%) had del(11q22.3) and 10 (37%) had del(17p13.1) by FISH, and 24 (89%) had IgVH unmutated disease. The median number of prior therapies was 4 (range 1–14). Toxicity with this agent was modest. Dose escalation continued without dose limiting toxicity (DLT) until the highest dose level, in which one patient experienced grade 4 neutropenia associated with febrile neutropenia which required dose discontinuation. 100% of patients experienced any AE, with the majority of AE being grade 1–2. The most common AEs were infusion reactions in 18 patients (67%), all of which were grade 1 or 2. Treatment-related Grade 3 or 4 AEs occurred in 5 pts (19%), and included neutropenia (n=3), thrombocytopenia (n=2), increased aspartate aminotransferase (AST) (n=1), febrile neutropenia (n=1), and tumor lysis syndrome (n=1). All were on the 12 mg/kg dose level except one pt receiving 1mg/kg who experienced neutropenia. Overall response rate by IWCLL 2008 criteria is 11%, all of which have been partial responses (PR). Using IWCLL 1996 response criteria which does not include CT scan assessment of disease resulted in a PR in 13 pts (42%). Only 2 pts had PD at the 8 week evaluation point. Responses occurred at the 6, 9, and 12 mg/kg dose levels. All objective responses were in pts categorized as CLL as opposed to SLL, and no patients with lymph nodes >5cm responded. PK was best modeled by a two-compartment model. Half-life was 14 days, with clearance 5mL/day/kg that was not dose-dependent. Across the dose range, area under the curve increased in a dose-proportional manner, while maximum concentration increased in a less than proportional manner. A steady-state was reached at or before infusion 9. XmAb5574 shows acceptable toxicity and signs of preliminary efficacy in patients with high-risk, heavily pretreated CLL. These results justify movement into phase II study in CLL as well as other B cell malignancies. Modest toxicity, in particular infectious toxicity, will potentially allow combinations with other active agents in CLL. Disclosures: Enoch: Xencor, Inc.: Employment. Foster:Xencor, Inc: Consultancy.

Clofarabine in Combination with a Standard Remission Induction Regimen (AraC and idarubicin) in Patients with Previously Untreated Intermediate and Bad Risk Acute Myelogenous Leukemia (AML) or High Risk Myelodysplasia (MDS):Phase I Results of An Ongoing Phase I/II Study of the EORTC-LG and GIMEMA(EORTC GIMEMA 06061/AML-14A trial)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2610-2610
Author(s):  
Roelof Willemze ◽  
Petra Muus ◽  
Stijn J.M. Halkes ◽  
Giovanna Meloni ◽  
Stefan Suciu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Adverse Events ◽  
Phase I ◽  
Dose Level ◽  
De Novo ◽  
Hematological Toxicity ◽  
Remission Induction ◽  
Induction Regimen ◽  
Grade Iii

Abstract Abstract 2610 Introduction: Remission induction treatment in previously untreated intermediate/bad risk AML or high risk MDS needs continuous improvement. Clofarabine is a nucleoside analog with proven activity in acute leukemias. The aim of the study was to determine the recommended/maximum tolerated dose (MTD) of Clofarabine when administered with standard remission induction regimen (Ara-C and Idarubicin) in patients suffering from AML/MDS. Methods: This open label, 2-arm, multi-center, phase I trial included adult patients (pts) with previously untreated intermediate/bad risk AML or high risk MDS. All FAB subtypes except M3 and the cytogenetic groups, t(8;21) or inv(16) with WBC<100×109/l, were eligible. Pts with blast crisis of CML or CNS leukemia were excluded. Arm A: 1h infusion Clofarabine (10 mg/m2/d and 15 mg/m2/d) on d2, d4, d6, d8, d10; Ara-C continuous infusion (c.i.): 100 mg/m2/d on d1-d10, Idarubicin (i.v): 10 mg/m2/d, on d1, d3, d5. Arm B: push injection Clofarabine (10 mg/m2/d and 15 mg/m2/d on d2, d4, d6, d8, d10); Ara-C and Idarubicin same regimen as in arm A. A minimum of 3 pts per arm were to be included at each dose level. The next dose level was visited if none of the first 3 patients experienced a Dose Limiting Toxicity (DLT) at a certain dose level. DLT was defined as treatment-related adverse events: non-hematological grade III-IV toxicity (CTCAE 3.0) occurring during 8 weeks (except grade III events resolving to grade < III within 4 weeks) after the start of the remission induction, and/or hematological toxicity defined as bone marrow hypoplasia leading to neutrophil or platelet recovery (ANC > 0.5 × 109/l and platelets >50 × 109/l) later than 8 weeks after start of remission induction. If 1 out of the first 3 pts experienced a DLT, 3 additional pts were added (a maximum of 6 pts per dose level) in order to ensure the safety profile of this dose level. If a second patient experienced a DLT, no further pts were entered at that particular dose level. Dose escalation stopped and additional pts included at the previous lower dose to have a minimum of 6 pts treated at the recommended dose. Results: 25 pts have been entered into this phase I part in 3 participating sites. WHO PS status was 0 (N=16), 1 (N=8) or 2 (N=1). Age range was 25–60 years (median 55 years). 20 pts had de novo AML, 3 pts had secondary AML, 2 pts had de novo MDS (WHO RAEB-2). 7 pts had high cytogenetic risk features. In arm A and in arm B 10 mg/m2/d Clofarabine, and in arm A 15 mg/m2/d Clofarabine 6 pts each have been included. In arm B 15 mg/m2/d Clofarabine 7 pts were included, as one patient was substituted since she received 60% of total dose of Clofarabine and refused further treatment with Clofarabine due to related adverse event. All 25 pts were evaluable for DLT analysis. Overall, 5 pts with DLTs were observed: 1 in Arm A 10mg/m2/d Clofarabine, 3 in Arm A 15 mg/m2/d Clofarabine, 1 in Arm B 15 mg/m2/d Clofarabine. One patient with prolonged hematological toxicity as DLT reported in Arm A 10mg/m2/d Clofarabine. Two deaths in cytopenia/aplasia and one toxic death following sepsis/multiorgan failure have been reported as DLTs in 3 patients in both Arm A and B 15 mg/m2/d Clofarabine. The 5th patient had grade 4 anorexia, diarrhea, infection, prolonged hypoplasia and grade 3 confusion which classified as DLT in Arm A 15 mg/m2/d Clofarabine. In addition, three pts in the 15 mg/m2/d Clofarabine arms needed to be withdrawn from Clofarabine due to adverse events not classified as DLT. Main toxicity was bone marrow toxicity resulting in prolonged aplasia. Out of 25 pts, complete remission (CR) following induction 1/2 has been achieved in 19 pts: in 10/12 pts using 10 mg/m2/d Clofarabine (5 pts each in Arm A and Arm B) and in 9/13 pts using 15 mg/m2/d Clofarabine (4 pts in Arm A and 5 pts in Arm B). In addition CR with incomplete blood count recovery (CRi) following induction 1/2 was observed in 2 pts: 1 in Arm A 10 mg/m2/d Clofarabine and 1 in Arm B 15 mg/m2/d Clofarabine. Conclusion: Infusion of 15 mg/m2/d Clofarabine resulted in a high rate of DLTs (4/13 pts) and early treatment withdrawals (3/13 pts). The infusion of 10 mg/m2/d Clofarabine had an acceptable rate of DLTs (1/12 pts), no early treatment withdrawals occurred, and a high CR/CRi rate (11/12 pts) was observed. Therefore the MTD of Clofarabine in combination with Ara-C and Idarubicin is defined at 10 mg/m2/d and will be the recommended dose for the phase II part of this study. Disclosures: Willemze: Genzyme: member advisory committee clofarabine. Muus:Amgen: Membership on an entity's Board of Directors or advisory committees. de Witte:Novartis: Consultancy, Honoraria, Speakers Bureau.

scholarly journals Dose-Escalation Study of Azacitidine Followed By High-Dose Cytarabine (HiDAC) and Mitoxantrone (Mito) for Remission Induction in High-Risk Acute Myeloid Leukemia (AML)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3777-3777
Author(s):  
Yasmin H Karimi ◽  
Nitin Jain ◽  
Margaret Green ◽  
Lucy A Godley ◽  
Howie Lawrence Weiner ◽  
...  
Keyword(s):  
High Risk ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
De Novo ◽  
Remission Induction ◽  
High Dose ◽  
Hematologic Toxicity ◽  
First Relapse ◽  
De Novo Aml

Abstract Background: High-risk AML including relapsed and/or refractory (R/R) disease remains largely incurable. There is no standard therapy for R/R AML but HiDAC based regimens are commonly employed. We hypothesized that the use of azacitidine (AZA), a DNA methyltransferase inhibitor and epigenetic modulator, followed by HiDAC and Mito would sensitize leukemia cells to chemotherapy. Methods: We performed a phase I dose escalation trial in cohorts of patients (pts) with high risk AML that combined increasing doses of AZA with a fixed dose/schedule of HiDAC/Mito. The primary endpoint of the study was to determine the maximum tolerated dose (MTD) of AZA when given in combination with HiDAC/Mito. AZA was given daily on days 1-5 followed by single doses of HiDAC 3 gm/m2 and Mito 30 mg/m2 on days 6 and 10. Dose reductions were made to 2mg/m2 and 20 mg/m2 for HiDAC and Mito, respectively, for pts >70. Cohorts of 3-6 pts were treated in a dose escalation design to a maximum AZA dose of 75 mg/m2. Dose limiting toxicity (DLT) was defined as any grade 4 or greater non hematologic toxicity, grade 3 non hematologic toxicity lasting >7 days, or persistent bone marrow aplasia in the absence of bone marrow involvement for >56 days. Once a dose level had been declared tolerable, additional pts could be enrolled at that level to provide additional toxicity and efficacy experience while further dose escalation was ongoing. Results: As of July 2015, 46 pts had enrolled. AZA dose levels were 37.5mg/m2 (n=18), 50 mg/m2 (n=16), 75mg/m2 (n=12). Median age = 66 (range, 21-83). R/R AML = 25 (54%), de novo t-MN =10 (22%), de novo AML arising from antecedent myeloid neoplasm = 6 (13%), untreated de novo AML in pts age >60 = 5 (11%). 17 (37%) of pts were in first relapse, 4 (9%) were beyond first relapse, and 4 (9%) were primary refractory. Median number of prior therapies was 1 (range of 0-4 prior therapies). Prior therapies included cytarabine and anthracycline =21 (46%), HiDAC =14 (30%), AZA =9 (20%) and allogeneic stem cell transplant (alloSCT) =9 (20%). Molecular/genetic group profiles by European Leukemia Net (ELN) criteria included adverse =21 (46%), intermediate I =10 (22%), intermediate II =7 (15%), favorable =7 (15%) and unknown in 1 patient. Pts in the favorable ELN group all had R/R AML, AML from antecedent myeloid neoplasm, or age> 60. Myelosuppression was the most common toxicity and universal. Both median and average times to count recovery (defined as ANC >1000, platelet count >100,000, and independent of RBC transfusions) from initiation of AZA (Day 1) was 42 days and from initiation of HiDAC (Day 6) was 37 days. Common toxicities included 38 cases of febrile neutropenia (87%) and pneumonia (20%). This was similar to our prior published retrospective experience with only the HiDAC/Mito regimen; 64% had neutropenic fever and a 20% had pneumonia (Larson S et al, Leuk Lymphoma 2012). There was 1 DLT from reversible acute liver failure at the 37.5mg/m2 dose level in a pt with relapsed t-MN and prior chemoradiotherapy for both breast cancer and mantle cell lymphoma. 30 day and 60 day induction mortality was 2% (1 pt with refractory AML died from sepsis). Pts in the highest AZA dose cohort had similar rates of hematologic and non-hematologic toxicity as well as time to count recovery as lower dose cohorts. 45 pts were evaluable for response: CR =19 (42%), CRi= 7 (16%), ORR (CR/CRi/PR) =27 (60%). Among pts with R/R AML, CR = 8 (32%), CRi = 5 (20%); among pts with untreated de novo AML and age >60, CR = 4 (80%). In first relapse, CR = 7 (41%) with an ORR =11 (65%). Response rates were similar at all 3 AZA dose levels (Table 1). All 7 pts with favorable ELN risk entered CR including 5 with R/R disease. Overall, 18 (40%) pts proceeded to alloSCT after treatment. Conclusions: The AZA/HiDAC/Mito regimen is feasible and tolerable. AZA dose escalation was feasible up to 75 mg/m2/day. It is associated with significant clinical activity with an ORR of 60% and allowed 40% of pts to proceed to alloSCT. The recommended phase II dose is 75 mg/m2 of AZA given daily on days 1-5 followed by 3g/m2 HiDAC and 30mg/m2 Mito on days 6 and 10. A randomized study is required to assess the relative contribution of AZA to HiDAC/Mito for remission induction in high risk AML. Correlative laboratory studies to analyze the effects of AZA on deoxycytidine kinase and related enzymes involved in cytarabine metabolism are ongoing. Table 1. AZA Dose Level # Pts Evaluated CR CRi PR TF DLT 37.5 mg/m2 18 10 2 0 6 1 50 mg/m2 16 5 3 1 7 0 75 mg/m2 11 4 2 0 5 0 Disclosures Off Label Use: Azacitidine (DNA methyltransferase inhibitor) used in combination with high dose cytarabine and mitoxantrone for induction therapy in acute myeloid leukemia. Liu:Pfizer: Consultancy; Pfizer: Consultancy; Astra Zeneca/Medimmune: Consultancy; Astra Zeneca/Medimmune: Consultancy. Thirman:AbbVie: Research Funding; Gilead: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Merck: Research Funding. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

A Phase I Dose-Escalation Trial of Oral Clofarabine for Relapsed/Refractory Non-Hodgkin Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1775-1775
Author(s):  
Jeremy S Abramson ◽  
Tak Takvorian ◽  
Eric D Jacobsen ◽  
Jennifer R Brown ◽  
Jeffrey A. Barnes ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Dose Level ◽  
Dose Escalation ◽  
Median Number ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Non Hodgkin Lymphoma ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 1775 Background: Clofarabine is a second-generation purine analogue currently FDA-approved for intravenous use for relapsed/refractory pediatric ALL. Purine analogues demonstrate significant clinical activity in non-Hodgkin lymphomas (NHL), though clofarabine offers potential pharmacologic advantages over existing agents. Clofarabine is a more efficient substrate for deoxycytidine kinase, more completely inhibits ribonucleotide reductase and DNA polymerase α, and demonstrates improved activity in cells that are non-dividing or have a low proliferation rate. This phase I trial is the first evaluation of an oral formulation of clofarabine in relapsed or refractory non-Hodgkin lymphoma. Patients and Methods: The primary objective was to determine the maximum tolerated dose (MTD) and define dose-limiting toxicities (DLT). Efficacy was a secondary objective. Patients (pts) were eligible if they had relapsed or refractory B-cell or T-cell NHL without prior stem cell transplant. All pts were required to have adequate organ function and performance status ≤2 as well as absence of both CNS involvement and HIV infection. No routine infectious prophylaxis was given. Patients were treated at 4 dose levels (1mg, 2mg, 4mg and ultimately 3mg) with oral clofarabine administered once daily on days 1–21 of a 28 day cycle for up to 6 cycles. Three to 6 pts were treated at each dose level in a traditional 3+3 design. Response assessment occurred after cycles 2 and 6. DLT was assessed during cycle 1 and was defined as Grade 4 neutropenia or thrombocytopenia occurring for ≥5 days, any grade 3–4 non-hematologic toxicity, and grade 2 non-hematologic toxicity that did not recover prior to the subsequent cycle of therapy. Results: Twenty-one pts were enrolled on the dose-escalation phase of the study. The median age was 63 years (range 51–85). The median number of prior regimens was 2 (range 1–7). Histologies included follicular lymphomas (FL; 5 pts), small lymphocytic lymphomas (SLL; 5 pts), diffuse large B-cell lymphomas (DLBCL; 4 pts), marginal zone lymphomas (MZL; 4 pts), mantle cell lymphomas (MCL. 2 pts) and lymphoplasmacytic lymphoma (LPL; 1 pt). Median number of cycles administered was 5.5. No DLTs were observed at the 1mg or 2mg dose levels. Three pts were accrued at 4mg with 1 patient experiencing DLT of persistent grade 3 thrombocytopenia and grade 4 neutropenia. No additional DLTs occurred in the cohort, but the majority of pts required late dose reductions due to grade 3–4 hematologic toxicity. The dose was therefore de-escalated to 3mg and 6 additional pts were accrued. No DLTs were observed at the 3mg dose level with a median of 6 cycles administered (range 5–6); 3mg was declared the recommended phase 2 dose. Grade 3–4 hematologic toxicity included neutropenia (7 pts), thrombocytopenia (4 pts), and anemia (2 pts). Grade 1–2 non-hematologic toxicities were uncommon, and included fatigue, diarrhea, cough, and dizziness. There were no grade 3–4 non-hematologic toxicities. Seventeen pts completed one cycle of therapy and were evaluable for response. Radiographic disease reduction was observed in 11 of 17 pts (65%). The overall response rate (ORR) was 35% (6 of 17), all partial responses (PR). Responders included FL (2 pts), MZL (2 pts), SLL and LPL (1 pt ea.). ORR among low grade histologies (FL, MZL, SLL) was 43% in this phase 1 trial. Seven pts had stable disease, including 5 pts with reduction in tumor size that did not reach threshold for PR. Of the 4 pts with progressive disease, 2 had DLBCL, 1 had MCL and 1 had FL with biopsy following relapse identifying ALK-negative anaplastic large T-cell lymphoma. Of the 4 pts not evaluable for response, 1 pt died of progressive DLBCL during cycle 1 on dose level 1 and was replaced, 1 pt was the DLT pt on the 4mg dose level and was removed due to prolonged cytopenias, and 2 pts withdrew consent (1pt at 4mg, 1pt at 3mg), and were replaced. The 3mg dose level has been expanded in a 10-patient dose-expansion cohort limited to low-grade NHL and MCL. Conclusions: Oral clofarabine demonstrates encouraging tolerability and efficacy in relapsed B-cell NHL, particularly in low-grade histologies, warranting further investigation. Disclosures: Abramson: Genzyme: Consultancy. Off Label Use: Clofarabine is not FDA approved for NHL.

Lenalidomide in Combination with Melphalan and Dexamethasone in Patients with Newly-Diagnosed Light-Chain (AL)-Amyloidosis: a Multicenter Phase I/II Dose Escalation Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 427-427
Author(s):  
Philippe Moreau ◽  
Arnaud Jaccard ◽  
Lotfi Benboubker ◽  
Bruno Royer ◽  
Xavier Leleu ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Treatment Delay ◽  
Phase Iii ◽  
Al Amyloidosis ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Dose Escalation Study

Abstract Abstract 427 Introduction: The combination of melphalan and dexamethasone (M-dex) is widely used in patients with newly diagnosed AL-amyloidosis, with hematologic and organ response rates of 50 and 40%, respectively (Jaccard, New Engl J Med 2007). Lenalidomide has also been evaluated, mainly in the relapse setting, and the initial dose of 25 mg/day was poorly tolerated. However, a 15 mg/day dose regimen was well tolerated and effective, with both hematologic and organ responses (Dispenzieri, Blood 2007 & Sanchorawala, Blood 2007). Combining M-dex with lenalidomide could increase the response rate but the toxicity of this regimen is still unknown. Thus we have initiated a multicenter single-arm open-label phase I/II dose escalation study of lenalidomide administered in combination with M-dex. Patients and methods: The primary endpoint was the incidence of dose limiting toxicities (DLT) during the first cycle of lenalidomide at a given dose level in order to determine the maximum tolerated dose (MTD). In addition to melphalan 0.18mg/kg/day from day 1-4 of each 28 day cycle and dexamethasone 40mg/day from day 1- 4 of each 28 day cycle, patients were successively exposed to escalating doses of lenalidomide (5, 10, 15 and 20 mg once daily on days 1–21 of a 28 day cycle). Nine cycles were planned at each dose level, according to safety and efficacy. DLT was defined using National Cancer Institute common toxicity criteria during the first 4 weeks of treatment (one cycle) as the following: at least grade 2 cardiac arrhythmia, at least grade 3 non hematologic toxicity, grade 4 neutropenia lasting >7 days or any other Grade 4 hematologic toxicity, or treatment delay due to toxicity that occurred during the first cycle. Organ involvement and the response to therapy were evaluated according to the international consensus guidelines (Gertz Am J Hem 2005). Results: From 03/2008 to 01/2009, 27 patients were enrolled. 1 patient withdrew consent after the first month of therapy and was thereafter lost to follow-up. No DLT was observed among the patients treated at 5 (3 patients), 10 (4 patients) and 15 mg lenalidomide/day (13 patients). 2 / 6 patients treated in cohort 4 at the dose of 20 mg lenalidomide/day experienced DLT, grade 4 hematologic toxicity and treatment delay due to toxicity; thus 15 mg lenalidomide/day, in combination with M-dex, was considered as the MTD. With a median follow-up of 12 months (7-17), 20/26 patients (77%) are alive. Six deaths were observed, due to progressive disease in 5 cases (median time from diagnosis 1 month, 1 to 3), or cholangiocarcinoma in 1 case (7 months after the diagnosis of AL-amyloidosis). Hematologic and organ responses were observed in 68 and 50% of the cases, respectively. At the reference date of Aug15th, 2009 none of the responding patients experienced progression, and all were able to receive 9 cycles according to the protocol.Conclusion: The recommended dose of lenalidomide in combination with M-dex in subjects with AL-amyloidosis previously untreated is 15 mg/day (days 1-21 of a 28 day cycle). Response and survival rates compare favourably with those achieved with M-dex alone. A prospective phase III trial comparing M-dex with M-dex lenalidomide should be valuable. Disclosures: Moreau: celgene: Speakers Bureau. Off Label Use: lenalidomide in combination with melphalan and dexamethasone in patients with AL-amyloidosis. Jaccard:celgene: Speakers Bureau. Salles:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Alakl:Celgene: Employment. Harousseau:celgene: Speakers Bureau. Fermand:celgene: Speakers Bureau.

Phase I Study of Triapine® and Cytarabine (ara-C) in Patients with Relapsed or Refractory Acute Leukemias and High-Risk Myelodysplastic Syndrome (MDS).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4925-4925
Author(s):  
Karen W.L. Yee ◽  
Jorge Cortes ◽  
Guillermo Garcia-Manero ◽  
Srdan Verstovsek ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Acute Leukemias ◽  
Elevated Liver Enzymes ◽  
Synergistic Cytotoxicity

Abstract Triapine is a potent inhibitor of ribonucleotide reductase (RNR), which is required for the conversion of ribonucleotides to deoxyribonucleotides. Two phase I trials in patients with hematologic malignancies demonstrated that Triapine could reduce circulating blasts in the majority of patients without significant non-hematologic toxicity (Giles et al. Leuk Res2003;27:1077–1083; Karp et al. Blood2002;100:560a). Preclinical studies have shown that the combination of Triapine and ara-C produces additive or synergistic cytotoxicity against several tumor cell lines, potentially by increasing intracellular ara-CTP levels when Triapine inhibits RNR. Therefore, a phase I study of Triapine in combination with ara-C was conducted in 32 patients with relapsed or refractory acute leukemia and high-risk MDS (1 MDS, 28 AML, 2 Ph+ ALL, and 1 Ph- ALL) in order to determine the tolerability, safety, and maximum tolerated dose (MTD). Triapine® was administered at a dose of 105 mg/m2/d as a 6-hour infusion for 5 consecutive days (D1–5) followed immediately by ara-C [100 (n=4), 200 (n=6), 400 (n=7), or 800 (n=8) mg/m2/d] as an 18-hour infusion for 5 consecutive days (D1–5). Median age was 59 years (range, 15–83 years). Median ECOG status 1 (range, 0–2). Median number of prior therapies was 2 (range 1–9), including prior autologous (n= 2) and allogeneic stem cell transplant (SCT) (n=4). Dose-limiting toxicities (DLTs) were observed at the 800 mg/m2 ara-C dose level (1 patient each with grade 4 mucositis; grade 4 neutropenic colitis, sepsis and death; grade 4 neuropathy; and grade 4 hyperbilirubinemia). Therefore, the study was amended to include an ara-C dose level of 600 mg/m2/d. Seven patients were treated at this dose level without development DLTs. Thirty-one patients received at least 1 course, 2 received 2 courses, and 4 received 3 courses; 1 patient withdrew prior to completion of 1 course of therapy. Of the 31 evaluable patients, 4 (13%) patients (3 AML, 1 Ph+ ALL) achieved a CR (1 at an ara-C dose of 800 mg/m2; 2 at 600 mg/m2; 1 at 200 mg/m2). Two of the responders also achieved a complete cytogenetic remission (including 1 Ph+ ALL). All responses occurred after 1 induction course. One patient went on to receive an allogeneic (SCT) and continues in CR. Duration of responses was 9, 20, 52+, and 73+ weeks. Mean Cmax and AUC achieved for Triapine were 1.13 μg/mL and 251.5 min•μg/mL. The most frequent toxicities included nausea &/or vomiting (66%), elevated liver enzymes (50%; gr. 3 in 22%), fever (47%), diarrhea (41%; gr. 3 in 6%), rash (31%; gr. 3 in 6%), mucositis (28%), hand-foot syndrome (16%; gr. 3 in 3%), and peripheral edema (16%; gr. 3 in 9%). Triapine and cytarabine has activity in patients with relapsed or refractory acute leukemias. The recommended phase II dose is Triapine 105 mg/m2/day for 5 consecutive days (D1–5) followed by ara-C 600 mg/m2/d for 5 consecutive days (D1–5).

Lenalidomide, Bortezomib, and Dexamethasone (Rev/Vel/Dex) as Front-Line Therapy for Patients with Multiple Myeloma (MM): Preliminary Results of a Phase 1/2 Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 187-187 ◽  
Author(s):  
Paul Richardson ◽  
Sundar Jagannath ◽  
Noopur Raje ◽  
Andrzej Jakubowiak ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase 1 ◽  
Single Agent ◽  
Safety Data ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Front Line ◽  
Dose Levels ◽  
Dose Reductions

Abstract Background: Bortezomib (VELCADE®, Vel) as a single agent and lenalidomide (Revlimid®, Rev) plus dexamethasone (Dex) are approved for the treatment of relapsed MM patients (pts) following ≥1 prior therapy. Rev/Vel±Dex is active and well tolerated in relapsed/refractory MM, and Rev/Dex and Vel/Dex have substantial activity in front-line MM. The aims of this phase 1/2 study were to determine the MTD of Rev/Vel/Dex in newly diagnosed MM pts, and to assess safety and efficacy. Methods: Pts received Rev 15–25 mg on d 1–14, Vel 1.0–1.3 mg/m2 on d 1, 4, 8, 11, and Dex 40/20 mg (cycles 1–4/5–8) on d 1, 2, 4, 5, 8, 9, 11, 12, for up to 8 21-d cycles, initially at 4 planned dose levels (Rev/Vel: 15/1.0, 15/1.3, 20/1.3, 25/1.3). Dose escalation proceeded (3-pt cohorts) depending on DLTs (G≥3 non-hematologic toxicity; G4 thrombocytopenia with platelets &lt;10,000/mm3 on &gt;1 occasion despite transfusion support; G4 neutropenia for &gt;5 d and/or resulting in neutropenic fever; inability to receive cycle 2/d 1 dose due to drug-related toxicity). Based on safety data, dose level 4M was added with a reduced Dex starting dose (Rev/Vel 25/1.3, Dex 20 mg in all cycles). Toxicities were graded by NCI CTCAE v3.0. Pts with G&gt;2 peripheral neuropathy (PNY) were excluded. Responses were assessed by modified EBMT and Uniform criteria. Pts with CR/nCR/VGPR/PR could proceed to ASCT after ≥4 cycles. Results: 33 pts (median age 56 yrs, 55% men, 84% IgG MM, 47% with ISS Stage II/III) have been enrolled to date in dose levels 1–4 and 4M, respectively, including 10 pts enrolled at the maximum planned dose (Dose Level 4M). Pts have received a median of 5 cycles; 9 pts have completed all 8 cycles. Two DLTs of G3 hyperglycemia due to high dose Dex were seen in dose level 4. Dose reductions in cycle 2 and beyond have occurred in dose levels 1–4 for Rev in 9 pts, Vel in 7 pts, and Dex in 17 pts, with 3 dose reductions having occurred in dose level 4M. Toxicities to date have been manageable. Only 1 G4 toxicity (thrombocytopenia) has been reported, plus 1 G3 DVT (reversed with LMWH), and no G≥3 PNY has been seen. The response rate across all dose cohorts (CR/nCR+VGPR+PR: subject to confirmation) is currently 89% in 25/28 evaluable pts, including 35% CR/nCR/VGPR. After median follow-up of 3 mos, median DOR, TTP, PFS, and OS have not been reached; all responders except 1 remain in remission, with 2 pts proceeding to ASCT. Conclusions: Rev/Vel/Dex is very active and well tolerated in newly diagnosed MM pts. The maximum planned dose has been reached at Rev 25 mg, Vel 1.3 mg/m2, and Dex 20 mg, with Phase 1 enrollment now complete using the lower dose of Dex. Enrollment to the Phase 2 component is ongoing.

A Multicenter Phase I/II Dose Escalation Study of Lenalidomide in Combination with Melphalan and Dexamethasone in Subjects with Newly-Diagnosed Light-Chain (AL)-Amyloidosis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1732-1732
Author(s):  
Philippe Moreau ◽  
Arnaud Jaccard ◽  
Lotfi Benboubker ◽  
Bruno Royer ◽  
Valerie Coiteux ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Response Rate ◽  
Standard Dose ◽  
High Dose ◽  
Al Amyloidosis ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Open Label ◽  
Dose Escalation Study

Abstract A recent prospective randomized trial comparing standard-dose to high-dose melphalan in patients presenting with newly diagnosed AL-amyloidosis showed that oral melphalan-dexamethasone (M-dex) given monthly could be considered the current standard of care, with a median survival of 56 months (Jaccard, N Engl J Med 2007). The use of a combination of lenalidomide and dexamethasone has also been tested in patients with symptomatic AL-amyloidosis. The initial dose of lenalidomide at 25 mg/day was poorly tolerated. However, a 15 mg/day dose regimen was well tolerated and effective, with both hematologic and organ responses (Dispenzieri, Blood 2007 & Sanchorawala, Blood 2007). Combining M-dex with lenalidomide (M-dex-rev) could increase the response rate but the toxicity of this regimen is still unknown. Thus we have initiated a multicenter single-arm open-label phase I/II dose escalation study of lenalidomide administered in combination with M-dex. The primary endpoint was the incidence of dose limiting toxicities (DLT) during the first cycle of lenalidomide at a given dose level in order to determine the maximum tolerated dose (MTD). In addition to melphalan 0.18mg/kg/day from day 1–4 of each 28 day cycle and dexamethasone 40mg/day from day 1– 4 of each 28 day cycle, 3 cohorts of 3 subjects were successively exposed to escalating doses of lenalidomide (5, 10 and 15mg once daily on days 1–21 of a 28 day cycle). DLT was defined using National Cancer Institute (NCI) common toxicity criteria during the first 4 weeks of treatment (one cycle) as the following: at least grade 2 cardiac arrhythmia, at least grade 3 non hematologic toxicity, grade 4 neutropenia lasting &gt;7 days or any other Grade 4 hematologic toxicity, or treatment delay due to toxicity that occurred during the first cycle. No DLT was observed among the first 3 patients treated at 5, 10 and 15 mg lenalidomide/day. 9 additional subjects will be enrolled at 15 mg/day to better define the safety profile and estimate the hematologic and organ response rate. Final results regarding both toxicity and efficacy will be presented during the meeting.

Clinical Activity of a Novel Multiple Tyrosine Kinase and Aurora Kinase Inhibitor, ENMD-2076, Against Multiple Myeloma: Interim Phase I Trial Results

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1957-1957 ◽  
Author(s):  
Sherif Farag ◽  
Shuhong Zhang ◽  
Attaya Suvannasankha ◽  
Jing Liang ◽  
Robyn O'Bryant ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase I Clinical Trial ◽  
M Protein ◽  
High Dose ◽  
Significant Activity ◽  
Dose Levels ◽  
Asymptomatic Elevation

Abstract Abstract 1957 Background: Despite recent improvements, MM remains incurable, indicating the need for continued investigation of novel agents. ENMD-2076 is a novel, orally active molecule that has been shown to have significant activity against Aurora and multiple receptor tyrosine kinases. Recently, we demonstrated that ENMD-2076 has significant pre-clinical in vitro and in vivo activity against MM cell lines and primary myeloma cells (Wang et al., Br J Haematol, 2010). Furthermore, ENMD-2076 inhibited critical pathways for MM cell survival and proliferation, including PI3K/AKT pathway with downregulation of survivin and XIAP, and Aurora A and B kinases, inducing G2/M cell cycle arrest, angiogenesis, and the FGFR3 pathway. We present the interim results of a phase I clinical trial of ENMD-2076 in patients with relapsed and refractory MM. Methods: An open label, single agent, dose-escalation dose safety and tolerability trial of ENMD-2076 is currently conducted in heavily pre-treated, relapsed and refractory MM patients who have previously failed standard therapy. Using a 3+3 design, dose escalation with ENMD-2076 is currently being studied at the doses: 150, 225, 325, 400 mg PO daily in 28 day cycles. Patients receive 28-day cycles according to safety and tolerability and absence of progression. Pharmacokinetics and pharmacodynamic studies, including effect on phosphorylated histone 3 (pH3) in purified bone marrow MM cells, effect on the PI3K pathway in peripheral blood mononuclear cells (PBMC), and circulating endothelial cell precursors are being investigated. Results: Currently, dose-escalation for the first three dose levels has been completed. Nine patients of median age 54 (range, 48–76) years were treated. There were 5 males and 4 females. The median number of prior regimens was 3 (range, 2–5), with 8 patients having failed high-dose melphalan and autologous stem cell transplantation. The most commonly observed toxicities included grades 1–2 anorexia (n=2), nausea (n=2), diarrhea (n=3), fatigue (n=3), asymptomatic elevation of amylase (n=3) and lipase (n=1), leucopenia (n=1), and heavy proteinuria (n=1). Grades 3 toxicities included hypertension (n=1), asymptomatic elevation of lipase (n=2), and thrombocytopenia (n=1). No dose-limiting toxicity was observed with all toxicities resolving promptly upon interruption or discontinuation of dosing. All patients treated on dose level 1 had progression of disease on treatment, 1 patient in dose level 2 had stabilization of disease, and 2 patients on dose level 3 had stable disease although with 21% and 19% reduction in serum M-protein after the first cycle. Significant increases in pH3 in MM cells were observed in 4 of 5 patients tested in dose levels 2 and 3. p-STAT3 and pGSK-beta were downregulated in PBMC in one patient, who also had a 19% reduction in M-protein. Conclusion: In the ongoing phase I clinical trial, ENMD-2076 appears safe and well –tolerated at the doses tested to date. Additional schedules are under investigation based on tolerability and correlative analyses. ENMD-2076 may hold promise as a treatment for MM and further study is warranted. Disclosures: Farag: EntreMed, Inc: Research Funding. Bray:EntreMed, Inc.: Employment. Sidor:EntreMed, Inc: Employment.

A Phase 1/2 Study of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1068-1068 ◽  
Author(s):  
Anna B. Halpern ◽  
Megan Othus ◽  
Emily M Huebner ◽  
Kaysey F. Orlowski ◽  
Bart L. Scott ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Phase 1 ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3 ◽  
Dose Levels

Abstract Introduction:"7+3" with standard doses of cytarabine and an anthracycline has remained the mainstay of induction chemotherapy for newly diagnosed AML. Since some studies have shown improved outcomes with high-dose cytarabine, cladribine, or escalated doses of anthracyclines, we conducted a phase 1/2 study (NCT02044796) of G-CLAM using escalated doses of mitoxantrone for newly diagnosed AML or high-risk MDS (>10% blasts). Methods: Patients≥18 years were eligible if they had treatment-related mortality (TRM) scores of ≤6.9 (corresponding to a predicted risk of early death with standard induction chemotherapy of ≤6.9%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5 times upper limit of normal). Excluded were patients with uncontrolled infection or concomitant illness with expected survival <1 year. In phase 1, cohorts of 6-12 patients were assigned to 1 of 4 total dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day, days 1-3, compared to 10 mg/m2/day used in standard dose G-CLAM previously established in relapsed/refractory AML). Other drug doses were G-CSF 300 or 480 μg/day (for weight </≥76 kg; days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). In phase 2, patients were treated at the maximum tolerated dose (MTD) of mitoxantrone. A second identical course of G-CLAM was given if complete remission (CR) was not achieved with cycle 1. Up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed if CR or CR with incomplete platelet or blood count recovery (CRp/i) was achieved with 1-2 cycles of induction therapy. Dose-limiting toxicities (DLTs) were: 1) grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7-day delay of the subsequent treatment cycle; 2) grade ≥4 non-hematologic toxicity if recovery to grade ≤2 within 14 days, both excluding febrile neutropenia, infection or constitutional symptoms. Results: Among 33 patients (median age of 57.3 [range: 26-77], median TRM score 2.31 [0.16-5.90]) treated in phase 1, one DLT occurred at dose levels 3 and 4 (respiratory failure in both cases), establishing G-CLAM with mitoxantrone at 18 mg/m2/day as the MTD. Sixty-two patients, including 6 treated in phase 1, received G-CLAM at MTD. Patient characteristics were as follows: median age 58 (21-81) years, median TRM score 2.85 (0.06-6.73), with AML (n=52) or high-risk MDS (n=10). Cytogenetics were favorable in 6, intermediate in 44, and adverse in 12 (MRC criteria); 11 patients had NPM1 and 6 had FLT3 mutations. Fifty-two patients (83.9%, 95% confidence interval: 72.3-92.0%) achieved a CR (n=48 [77.4%: 65.0-87.1%]), or CRp/i (n=4 [6.5%: 1.8-15.7%]) with 1-2 cycles of therapy. Only 3 patients required 2 cycles to best response. Among the 48 CR patients, 43 (89.6%) were negative for measurable residual disease (MRDneg) by flow cytometry. Four patients had morphologic leukemia free state, 1 patient with myeloid sarcoma had a partial remission, 4 had resistant disease, and 1 died from indeterminate cause. One patient died within 28 days of treatment initiation (septic shock). Median times to an absolute neutrophil count ≥500/μL and a platelet count of ≥50,000/μL were 26 and 23 days. Besides infections and neutropenic fever, maculopapular rash, and hypoxia (fluid overload/infection-related) were the most common grade ≥3 adverse events. In addition to the phase 1/2 MTD cohort, there were 15 patients treated in an expansion cohort and 3 eligible patients treated off protocol with mitoxantrone at 18 mg/m2. For these 80 patients combined treated at MTD, the CR and CR/CRp/i rates were 76.3% and 81.2%. After multivariable adjustment, compared to 300 patients treated with 7+3 on the SWOG S0106 trial, G-CLAM with mitoxantrone 18mg/ m2 was associated with an increased probability of CR (odds ratio [OR]= 3.08, p=.02), CR/CRp/i (OR=2.96, p=.03), a trend towards improved MRDnegCR (OR= 3.70, p=.06), and a trend towards improved overall survival ([OS]; hazard ratio=0.34, p=.07). For the entire study cohort, the 6 and 12-month relapse-free survival were 73% (64-83%) and 62% (42-74%) and the 6 and 12-month OS were 89% (82- 96%) and 77% (67-88%). Conclusions: G-CLAM with mitoxantrone up to 18 mg/m2/day is well tolerated and has potent anti-leukemia activity. This regimen may warrant further randomized comparison with 7+3. We also plan to examine the addition of sorafenib to G-CLAM in newly diagnosed AML patients regardless of FLT3 status. Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding. Erba:Ariad: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Novartis: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celator: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Amgen: Consultancy, Research Funding.

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