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 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.

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.

Low-Dose Clofarabine Has Significant Activity in High-Risk Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia Post-MDS (sAML) After Azacitidine (AZA) Failure: Interim Results of the GFM Clo08 Dose Escalating Phase I/II Study (NCT0106325)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 609-609 ◽  
Author(s):  
Thorsten Braun ◽  
Emmanuel Raffoux ◽  
Thomas Prebet ◽  
Sabine Brechignac ◽  
Aspasia Stamatoullas ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Dose Escalation ◽  
Low Dose ◽  
De Novo ◽  
Early Death ◽  
Hematological Toxicity ◽  
Significant Activity ◽  
Number Of Patients ◽  
Dose Escalating

Abstract Abstract 609 Background: Clofarabine (CLO) alone has shown antileukemic activity in MDS and AML, including sAML, at doses ranging from 15 to 40 mg/m2, although with significant myelosuppression and toxicity. Patients with high-risk MDS or sAML who failed AZA have a median OS of only 5 months (Prébet, JCO, online), and no established drug therapy is available for such patients. In this Phase I/II dose escalating study (NCT0106325), we explored safety and activity of CLO at lower dosing levels (DLs), in such patients. Methods: A standard IV, D1-5 and an extended D1, 3, 5, 8 and 10, administration schedules were studied in parallel, using a standard 3+3 design. Three DLs (CLO 5, 7.5 and 10 mg/m2, daily) were planned. Dose limiting toxicities (DLTs) were defined as any grade >3 non-hematological toxicity, excluding bleeding, infections or febrile neutropenia, or as any delayed cytopenias past D56, defined here as blood counts less than 50% of baseline counts. Responses were evaluated according to IWG 2006 MDS criteria or AML IWG criteria after courses 1 and 2, administered within 56 days. Patients in CR/PR after course 1 could receive up to 7 maintenance courses with only 3 daily infusions at same dosing. Patients in CR/PR or with stable disease after course 2 could receive up to 6 maintenance courses. If DLTs after course 1 were observed in less than 1 of 3 or 2 of 6 patients, dose escalation was permitted. If 2 or more DLTs were observed after course 1, exploration of lower intermediate DLs was planned. Patients with de novo MDS or sAML who failed at least 6 courses of AZA were eligible, if not candidates to intensive chemotherapy. Exclusion criteria included renal dysfunction (MDRD<50 ml/mn), bilirubin>1.5 ULN, liver function tests >2.5 ULN, ECOG score >2, and uncontrolled infection. Patients: Between November 2009 and July 2011, 19 Patients (10F, 9M) were enrolled, at DL1 (5 mg/m2, N=9) and DL2 (7.5 mg/m2, N=10), Median age was 72 years (62-90), WHO diagnosis were: RAEB 1 (N=1), RAEB 2 (N=8), sAML (N=10), including 7 patients with <30% marrow blasts). Cytogenetics was normal in 4 (3 RAEB, 1 AML), complex or with abn chr. 7 in 11 (8 sAML, 3 RAEB), and inv3, +8, 5q and 11q, del9q in 4 patients. Median duration of MDS phase, before entry, was 20 months (9-161). Responses to prior treatment with AZA included 6 CR, 2 marrow CR (mCR) and 4 stable with HI-E, 6 failures and 1 stable w/o HI, after a median number of AZA cycles of 10 (6-34), 11 (6-26) and 6 (6-8) respectively. Eleven patients had only received AZA and eight AZA and 1 to 3 other treatment lines, excluding growth factors. Results: (Table 1) All patients were evaluable for DLTs and response after one cycle. In the D1-5 cohort: one DL1 patient was classified as failure and non-hematological DLT (due to likely unrelated sudden death on D55, before evaluation), and one DL2 patient with mCR as DLT, due to prolonged thrombocytopenia beyond D56. One sAML patient was classified as failure due to early death linked to sepsis, but not as DLT per protocol. In the D1-10 cohort, no DLT was observed after cycle 1. Fifteen patients were eligible for an identical second course, as 2 patients had early death and 2 CR/PR. Twelve patients received a second course, with only 1/8 evaluable for response after course 2, improving response. This patient with mCR obtained durable HI-E and P after course 2. No significant liver or renal toxicity was observed in both cohorts. Seven patients were hospitalized after first course for fever or bleeding (3/9 in DL1/5mg/m2 and 4/10 in DL2/7.5mg/m2 cohorts). Overall, 6 of the 19 patients (32%) had a response after a single course including 2CR/PR and 4 of the 6 responses were seen at the 7.5 mg/m2 dose level. Conclusion: In this dose escalating study in MDS or sAML patients who had failed azacitidine, low-dose clofarabine had significant activity and was administered as an outpatient therapy in most, although hospitalization due to myelosuppression was frequent, even at this low dosing. The extended alternate day (D1-10) schedule may be better tolerated and at least as efficient as the standard D1-5 schedule, although a larger number of patients is required to conclude. Dose escalation in the trial is continuing. Disclosures: Off Label Use: low dose Clofarabine in MDS after AZA failure. Vey:GENZYME: Honoraria. Dombret:GENZYME: Honoraria. Fenaux:GENZYME: Honoraria. Gardin:GENZYME: Honoraria, Research Funding.

Phase I Study of Rituximab, Lenalidomide, and Ibrutinib in Previously Untreated Follicular Lymphoma (Alliance 051103)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 471-471 ◽  
Author(s):  
Chaitra S. Ujjani ◽  
Sin-Ho Jung ◽  
Brandelyn Pitcher ◽  
Peter Martin ◽  
Steven I. Park ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Phase I ◽  
Follicular Lymphoma ◽  
Atrial Flutter ◽  
Median Time ◽  
Dose Level ◽  
Research Funding ◽  
Phase I Study ◽  
Grade 3

Abstract Background Chemoimmunotherapy for advanced stage follicular lymphoma (FL) is associated with acute and long-term toxicity; targeted therapy may improve efficacy and tolerability in this incurable, multiply-relapsing disease. The Alliance for Clinical Trials in Oncology previously demonstrated the efficacy of lenalidomide (20 mg D1-21/28) and rituximab (R2) in untreated FL patients (pts): ORR 93%, CR 72%, 2-yr PFS 89% (Martin P, et al. ASCO 2014), which supported the ongoing phase III RELEVANCE study of R2 vs. R-chemo. Attempts at improving R2 include incorporation of other agents. The BTK inhibitor, ibrutinib (I), demonstrated an ORR of 30-55% (Bartlett N et al. ASH 2014, Fowler N et al. ASH 2012) in relapsed/refractory FL. Based on these data, the Alliance designed a multicenter phase I study of this triplet as a front-line regimen for FL. Methods Pts with previously untreated, grade 1-3a FL, Stage III, IV, or bulky stage II disease, performance status < 2, and adequate organ function were eligible. Pts received R 375 mg/m2 on Cycle 1 D 1, 8, 15, 22 and at week 13, 21, 29, and 37 for 8 doses, lenalidomide (L) as per cohort dose on D1-21/28 for 18 months, and I as per cohort dose on D1-28/28 until progression or unacceptable toxicity. Dose escalation used a 3+3 design from a starting level of L 15 mg and I 420 mg (DL0) to DL2 (L 20 mg, I 560 mg). Pts received allopurinol 300 mg daily for tumor lysis prophylaxis. The primary endpoint was the recommended phase II doses (RP2D) of L and I for combination with R in previously untreated FL. The secondary endpoints were toxicity, pharmacokinetics, and preliminary efficacy. Once the MTD was determined, there was a 10-patient expansion cohort. Due to the known incidence of rash with L, grade 3 rash that resolved to < grade 2 in 10 days with supportive care including systemic corticosteroids was prospectively not included as a DLT. The incidence of grade 3/4 rash with R2 and ibrutinib are 8% and 3%, respectively. Results Twenty-two pts were enrolled between June 2013 - May 2015: DL0 (n=3), DL1 (n=3), DL2 (n=16). Median age was 53.5 years (range 36-81); 68% were male, 73% had grade 1/2 disease, 77% had Stage IV disease. By FLIPI, 18% were low risk, 55% were intermediate risk, and 27% were high risk. There were no dose limiting toxicities reported at any dose level. Dose level 2 (L 20 mg, I 560 mg) was found to be the RP2D. Grade 3/4 hematologic toxicities included neutropenia 18.2%, thrombocytopenia 4.5%, and anemia 4.5%. There were no grade 4 non-hematologic toxicities. Rash occurred in 73% of pts (grade 1/2: 41%, grade 3: 32%), typically during C1-4. Grade 3 rash was noted at every dose level: DL 0 (n=1), DL1 (n=1), DL2 (n=6); 4 pts were on allopurinol at time of grade 3 rash. Several pts successfully continued therapy with discontinuation of allopurinol and/or reduction in treatment dose. Other notable grade 3 non-hematologic adverse events included atrial flutter/chest pain (n=1), diarrhea (n=1), and febrile neutropenia (n=1). Other grade 1/2 non-hematologic adverse events included diarrhea 41%, fatigue 36%, nausea 27%, and AST/ALT elevation 18%. Elevenpts required dose reduction, 8 due to rash. The ORR for all pts was 91% (CR/CRu 63%). Seven pts with bone marrow involvement did not undergo a confirmatory bone marrow biopsy to rule out residual disease after achieving a negative PET/CT. The ORR at DL2 was 94% (CR/CRu 63%). Median time to response was 5.6 months (range 1.9-18.4), and median time on treatment was 12.6 months (range 3.4-23.4). At the time of this report, 3 pts have progressed (DL1 (n=1), DL 2 (n=2)). At median follow-up time of 12 months, the 12-month PFS for all pts was 84% (95% CI: 57-94%). The 12-month PFS for the DL2 cohort was 86% (95% CI: 54% - 96%). Twelve pts discontinued therapy: progression (n=2), adverse events [grade 3 rash (n=2), grade 3 atrial flutter (n=1), grade 3 diarrhea (n=1)], patient decision (n=3), new diagnosis of carcinoma (n=2), depression (n=1). Conclusion Although protocol-defined DLT was not observed, the combination of rituximab, lenalidomide, and ibrutinib in previously untreated follicular lymphoma was associated with a significant incidence of rash, which may have been related to allopurinol, the individual study drugs, or drug interactions. Preliminary ORR data of the regimen were comparable to prior reports of the R2 regimen in this population. Efficacy of the combination, including CR rate, may be affected by the reduction in dose intensity. Disclosures Ujjani: Genentech: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide and ibrutinib have activity in follicular lymphoma but are not approved.. Martin:Janssen: Consultancy, Honoraria; Acerta: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bayer: Consultancy. Park:Teva: Research Funding; Seattle Genetics: Research Funding; Janssen: Other: travel. Blum:cephalon: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy. Czuczman:Celgene: Employment; Morphosys: Consultancy; Boehringer-Ingelheim: Other: ad board; Immunogen: Other: ad board. Davids:Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy. Leonard:Weill Cornell Medical College: Employment; Genentech: Consultancy; Medimmune: Consultancy; AstraZeneca: Consultancy; Spectrum: Consultancy; Boehringer Ingelheim: Consultancy; Vertex: Consultancy; ProNAI: Consultancy; Biotest: Consultancy; Seattle Genetics: Consultancy; Pfizer: Consultancy; Mirati Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy. Cheson:Roche/Genentech: Consultancy, Research Funding; Teva: Research Funding; AstraZeneca: Consultancy; Ascenta: Research Funding; Spectrum: Consultancy; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Astellas: Consultancy; MedImmune: Research Funding; Pharmacyclics: Consultancy, Research Funding.

scholarly journals Pracinostat in Combination with Azacitidine Produces a High Rate and Rapid Onset of Disease Remission in Patients with Previously Untreated Acute Myeloid Leukemia (AML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 947-947 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Ehab Atallah ◽  
Olatoyosi Odenike ◽  
Bruno C Medeiros ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Adverse Events ◽  
Board Of Directors ◽  
Null Hypothesis ◽  
Research Funding ◽  
Progressive Disease ◽  
De Novo ◽  
Phase Ii Study ◽  
Advisory Committees

Abstract Background: Pracinostat is a potent oral inhibitor of histone deacetylases (HDAC’s), selective for class I, II and IV isoforms. In-vitro cytotoxicity assays in AML cell lines revealed an IC50 of <0.1µM, and the combination with azacitidine was synergistic (CI=0.44). A Phase I study of single agent pracinostat showed activity in AML and a pilot Phase II study of pracinostat in combination with azacitidine in higher risk MDS demonstrated a complete response (CR)/CR with incomplete blood count recovery (CRi) rate of 89% (Proc ASH:3821, 2012). We report initial results from a Phase II study of pracinostat with azacitidine in previously untreated, elderly AML. Methods: Eligibility includes previously untreated AML (≥ 20% bone marrow blasts), age ≥65 years, deemed inappropriate for intensive induction therapy, with intermediate or high risk cytogenetics based on SWOG criteria. De-novo, treatment-related, or AML evolved from an antecedent hematologic disorder (AHD) are allowed. Pracinostat is administered orally (60 mg) 3 days a week (e.g., Monday, Wednesday, Friday) for 3 weeks followed by a 1 week break. Azacitidine is administered subcutaneously or intravenously (75 mg/m2) day 1-7 or day 1-5 and 8-9 of each 28-day cycle. The primary endpoint is CR+CRi+ morphologic leukemia free state (MLFS) according to IWG criteria. Response assessments occur at the end of cycle 1 or 2 followed by every other cycle or when clinically indicated. A Simon 2-stage statistical design is utilized with the following assumptions: null=0.10, alternate=0.25, α=0.10, power=0.90. Transition from stage 1 to 2 requires ≥ 3/27 response events; the null hypothesis will be rejected if ≥ 7 response events are observed in the total planned sample of 40 patients. Results: As of August 01, 2014, 21 patients have been enrolled from 12 study sites and are evaluable for safety; 14 are evaluable for efficacy (Table 1), and 7 are ‘too early’ for response assessment. Baseline disease characteristics include: median age 77 (range 69-84); 16 de novo AML, 4 evolved from AHD, 1 treatment related; 11 intermediate-risk, 8 high-risk cytogenetics, and 2 are pending; baseline bone marrow blast counts ranged from 22% to 89%. The primary endpoint of CR +CRi+MLFS was observed in 8 of 14 evaluable patients (57%), the majority after 1 or 2 cycles. No responders have progressed. The most common treatment emergent adverse events (TEAE) were neutropenia/neutropenic fever (n=15), thrombocytopenia (n=12), nausea (n=10), fatigue (n=8), and anemia (n=7). Serious adverse events include febrile neutropenia (n=6) and pulmonary infiltrate/pneumonia (n=2). Three patients discontinued study therapy due to a TEAE, including one each with cellulitis, bacteremia, and subdural hematoma after a fall. There have been 3 deaths on study: 1 bacteremia, 1 subdural hematoma, and 1 progressive disease. Abstract 947. Table 1 Patient Number Days on Study Baseline BM Blast % 1st On-Study BM Blast % Subsequent On-Study BM Blast % Best Response on Study 2 172+ 22 1 (C2) --- CR 3 165+ 24 4 (C1) 0 (C4) CRi 5 162+ 27 9 (C1) 1 (C4) CRi 6 156+ 81 9 (C1) 0 (C4) CRi 7 148+ 78 44 (C1) 17 (C3), 0 (C5) CR 8 114+ 89 4 (C1) --- CR 10 86+ 45 3 (C1) --- CRi 12 81+ 41 2 (C2) --- CRi 4 90 22 43 (C2) Off due to SAE SD 11 56 37 60 (C2) --- PD 15 28 70 --- Patient Withdrew 17 28 60 --- PD 1 26 70 --- Off due to AE 9 26 38 --- Off due to AE +=Patients continue on study; C=cycle; SD=Stable Disease; PD=Progressive Disease Conclusions: The study has achieved the primary goal of rejecting the null hypothesis. The CR+CRi +MLFS response rate estimate of 57% is high compared to historical results with hypomethylating agents alone in this population, and the responses occur rapidly, most within the first 2 cycles. The combination appears tolerable with no unexpected toxicities. Recruitment continues to the final planned sample size of 40 to further define the tolerability and efficacy of the regimen, including remission duration. Updated data will be presented at the meeting. Disclosures Garcia-Manero: MEI Pharma, Inc.: Consultancy. Off Label Use: Azacitidine is not approved for use in acute myelogenous leukemia.. Odenike:Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Suneisis Pharmaceuticals : Honoraria, Membership on an entity's Board of Directors or advisory committees. Medeiros:MEI Pharma, Inc: Research Funding. Cortes:Celgene: Research Funding. Esquibel:MEI Pharma, Inc.: Employment. Cha:MEI Pharma, Inc.: Employment. Khaled:Sequenom: Research Funding.

Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies.

1993 ◽  
Vol 11 (3) ◽  
pp. 499-506 ◽  
Author(s):  
J Weber ◽  
J C Yang ◽  
S L Topalian ◽  
D R Parkinson ◽  
D S Schwartzentruber ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Interleukin 6 ◽  
Phase Ii Trials ◽  
Organ Toxicity ◽  
Advanced Malignancies ◽  
Major Organ ◽  
Dose Levels ◽  
Grade Iii

PURPOSE Based on preclinical evidence in murine models that interleukin-6 (IL-6) mediates regression of metastatic tumors, we performed a phase I study of recombinant human IL-6 in patients with refractory advanced malignancies to determine its pharmacokinetics, toxicities, and possible immunologic and antitumor effects. PATIENTS AND METHODS Recombinant IL-6 was administered as a single subcutaneous dose daily for 7 days, with 7 days off therapy followed by another 7 days of IL-6. Doses were escalated in cohorts of three patients starting at 3 micrograms/kg/d, provided that toxicity at the preceding dose level was not dose-limiting. Dose-limiting toxicity was defined as grade III or IV major organ toxicity that did not resolve to grade II or less in 24 hours after stopping IL-6, using the National Cancer Institute Common Toxicity Criteria. Patients were treated with 3, 10, and 30 micrograms/kg/d IL-6 subcutaneously. RESULTS Three patients each were treated at the 3- and 10-micrograms dose levels. Two of five patients treated with 30 micrograms/kg/d IL-6 subcutaneously had grade III major organ toxicity that required IL-6 therapy to be discontinued. All patients experienced fever, chills, and minor fatigue. Significant increases in C-reactive protein (CRP), fibrinogen, platelet counts, and lymphocyte IL-2 receptor levels were seen in patients at the 10- and 30-micrograms/kg dose levels. Decreases in albumin and hemoglobin were observed, particularly at the 30-micrograms/kg dose level. The half-life (T1/2 beta) was 4.2 hours, with a peak IL-6 level at 5 hours. No antitumor responses were seen. CONCLUSION A safely tolerated dose of daily subcutaneous IL-6 is 10 micrograms/kg, with hepatotoxicity and cardiac arrhythmia being the dose-limiting toxicities at 30 micrograms/kg. Phase II trials of IL-6 administered subcutaneously daily for at least 7 days for two cycles with an intervening week of rest are recommended for phase II trials. However, patients with extensive replacement of liver by tumor and abnormal liver functions should receive IL-6 therapy with caution.

Characteristics of De Novo Acute Leukemia Patients with Glycosylphosphatidylinositol (GPI) Protein-Negative Population of Leukemic Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4462-4462
Author(s):  
Hideyoshi Noji ◽  
Tsutomu Shichishima ◽  
Masatoshi Okamoto ◽  
Kazuhiko Ikeda ◽  
Akiko Nakamura ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
De Novo ◽  
Bone Marrow Failure ◽  
Flow Cytometric Analysis ◽  
Leukemic Cells ◽  
Remission Induction ◽  
Color Flow ◽  
Flow Cytometric ◽  
Number Of Patients

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is considered to be an acquired stem cell disorder affecting all hematopoietic lineages, which lack GPI-anchored membrane proteins, such as CD59, because of abnormalities in the phosphatidylinositol glycan-class A (PIG-A) gene. Also, PNH is one disorder of bone marrow failure syndromes, including aplastic anemia and myelodysplastic syndrome, which are considered as pre-leukemic states. In this study, to know some characteristics of patients with de novo acute leukemia, we investigated expression of CD59 in leukemic cells from 25 patients (female: male=8: 17; mean age ± standard deviation, 57.8 ± 19.5 years) with de novo acute leukemia by single-color flow cytometric analysis. In addition, the PIG-A gene from CD59− leukemic cells sorted by FACS Vantage in 3 patients with acute leukemia was examined by sequence analysis. All the patients had no past history of PNH. Based on the French-American-British criteria, the diagnosis and subtypes of acute leukemia were determined. The number of patients with subtypes M1, M2, M3, M4, M5, and M7 was 1, 14, 2, 4, 2, and 2, respectively. Two of the patients were classified into acute myeloid leukemia with trilineage myelodysplasia from morphological findings in bone marrow. Chromosomal analyses presented abnormal karyotypes in 14 of 25 patients. Flow cytometric analyses showed that leukemic cells from 16 of 25 patients (64%) had negative populations of CD59 expression and the proportion of the populations was 63.3 ± 25.7%, suggesting the possibility that CD59− leukemic cells from patients with de novo acute leukemia might be derived from PNH clones. In fact, the PIG-A gene analyses showed that monoclonal or oligoclonal PIG-A mutations in coding region were found in leukemic cells from 3 patients with CD59− leukemic cells and all of the clones with the PIG-A mutations were minor. Then, various clinical parameters, including rate of complete remission for remission-induction chemotherapy, peripheral blood, bone marrow blood, and laboratory findings, and results of chromosomal analyses were statistically compared between 2 groups of patients with (n=16) and without (n=9) CD59− leukemic cells. The reticulocyte counts (10.5 ± 13.0 x 104/μl) and proportions of bone marrow erythroblasts (17.5 ± 13.9%) in patients with only CD59+ leukemic cells were significantly higher than those (2.5 ± 1.7 x 104/μl, p&lt;0.05; and 5.6 ± 6.2%, p&lt;0.01, respectively) in patients with CD59− leukemic cells. The proportions of bone marrow blasts (69.3 ± 21.1%) in patients with CD59− leukemic cells were significantly higher than those (45.5 ± 19.3%, p&lt;0.02) in patients with only CD59+ leukemic cells. In conclusion, our findings indicate that leukemic cells derived from PNH clones may be common in de novo acute leukemia patients, suggesting that bone marrow failure may have already occurred in localized bone marrow even in de novo acute leukemia.

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).

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