A Phase I Study of Idarubicin Dose Escalation for Remission Induction Therapy in Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1344-1344
Author(s):  
Mark Lee ◽  
Sung-Yong Kim
Keyword(s):  
Acute Myeloid Leukemia ◽  
Platelet Count ◽  
Phase I ◽  
Dose Level ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Level 1 ◽  
Level 2 ◽  
Acute Myeloid

Abstract The maximum tolerated dose (MTD) of idarubicin has been acknowledged to be 12-15 mg/m2/day for 3 days for acute leukemias. Its MTD should be reevaluated in the treatment of acute myeloid leukemia (AML) in the era of granulocyte colony-stimulating factor and better supportive care. We conducted a phase I study to investigate the safety of escalating doses of idarubicin in combination with cytarabine 100 mg/m2/day for 7 days for previously untreated AML. The starting dose of idarubicin was 12 mg/m2/day for 3 days with dose escalations by 3 mg/m2/day. Cohorts of three patients were treated at each dose level, and the idarubicin dose was escalated up to 18 mg/m2/day until at least two patients among a cohort of three to six patients experienced the dose-limiting toxicities (DLTs) (traditional 3+3 design for phase I clinical trials: J Natl Cancer Inst 2009;101:708). Hematologic DLTs were defined as the time to recovery of neutrophils {absolute neutrophil count (ANC) ≥500/μL} or platelets (platelet count ≥20,000/μL) exceeded 42 days after the start of induction therapy (J Clin Oncol 2004;22:4290). Non-hematologic DLTs were defined as grade 4 or 5 toxicities (Leukemia 1998;12:865). We adopted the NCI CTCAE v3.0 to grade the hematologic and non-hematologic toxicities. Thirteen adult patients were enrolled in the study, but two and two were excluded at level 1 and level 2, respectively, because they received reinduction therapy for resistant disease within 4 weeks after the start of the assigned induction therapy. Consequently, nine patients were evaluable for the phase I study. The median times to recovery of neutrophils (ANC ≥500/μL) after the start of induction therapy at level 1, level 2, and level 3 were day 20 (range, 19-22), day 19 (range, 17-20), and day 25 (range, 21-26), respectively. The median times to recovery of platelet (platelet count ≥20,000/μL) at each level were day 20 (range, 19-23), day 20 (range, 16-34), and day 24 (range, 20-35), respectively. Therefore, grade 4 hematologic toxicities were observed at all 3 levels; however, these hematologic toxicities did not meet the criteria of the hematologic DLTs as defined in this study. There was any instance of grade 4 non-hematologic toxicity at each dose level. No death associated with the induction treatment was observed in this trial. Hematologic and non-hematologic DLTs as defined above were not observed at all 3 dose levels; therefore, idarubicin 18 mg/m2/day for 3 days could be defined as the MTD for this trial. Disclosures No relevant conflicts of interest to declare.

A Phase I Study of Tipifarnib Combined with Conventional Induction and Consolidation Therapy for Previously Untreated Patients with Acute Myeloid Leukemia Age 60 and Over.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 899-899 ◽  
Author(s):  
Joseph M. Brandwein ◽  
Brian F. Leber ◽  
Kang Howson-Jan ◽  
Aaron D. Schimmer ◽  
Andre C. Schuh ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Dose Level ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Grade Iii ◽  
Acute Myeloid

Standard induction therapy for patients over age 60 with acute myeloid leukemia (AML) has produced complete response (CR) rates of around 55%, but most patients eventually relapse. Tipifarnib (R115777, ZarnestraR) has shown activity as a single agent in AML, and is well tolerated in older patients at doses up to 600 mg BID. This agent also has additive/synergistic effects on AML cell lines when combined with daunorubicin (DNR). From 2005–2007, patients age 60 and over with previously untreated AML (de novo or secondary) were enrolled in a Phase I study combining tipifarnib with standard induction therapy. The regimen consisted of cytarabine 100 mg/m2/day continuous IV infusion on days 1–7, DNR 60 mg/m2/day IV push x 3 on days 6–8 and tipifarnib orally twice daily on days 6–15. Tipifarnib was escalated over four doses levels in successive patient cohorts (200, 300, 400 and 600 mg). Patients achieving CR were eligible to received one consolidation using the same regimen. Dose-limiting toxicity (DLT) was defined as Grade III–IV non–hematologic toxicity or hematologic recovery times > 40 days unless due to persistent leukemia. Up to 2/6 DLTs were permitted at each dose level. The following DLT’s were identified during induction: Dose level I: 2/6 (grade III hyperbilirubinemia, grade IV transient respiratory arrest), dose level II: 0/3, dose level III: 0/3 and dose level IV: 2/6 (grade III typhlitis, grade III supraventricular tachycardia). Four additional patients were enrolled at dose level IV, with one DLT (grade III diarrhea). There were no DLTs during consolidation. There were no cases of delayed hematologic recovery. Of 22 evaluable patients, there were 9 CR, 3 MLFS, 2 PR and 8 non-responders. Of 7 patients with adverse risk cytogenetics, there were 3 CR, 1 MLFS and 1 PR. In summary, this regimen was well tolerated and the DLT was not reached, although somewhat more GI toxicity was seen at dose level IV. Because of the inherent toxicity of the underlying regimen and the elderly population, it was decided not to escalate further, and tipifarnib 600 mg BID has been chosen as the recommended dose for further study using this regimen.

scholarly journals Preliminary Analysis Results of a Phase I Study of the FLT3 Inhibitor SKLB1028 in Patients with Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2654-2654
Author(s):  
Ting Liu ◽  
Huanling Zhu ◽  
Xuekun Yao ◽  
Yueying Peng ◽  
Yumei Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Preliminary Analysis ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Study Drug ◽  
Full Analysis ◽  
Acute Myeloid

Background: Mutations of FMS-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia (AML) are associated with poor prognosis. SKLB1028, a novel multikinase inhibitor, has shown exceptional antileukemic activity in mouse xenograft models of FLT3-driven AML. Preclinical data has demonstrated that SKLB1028 has anti-proliferation and pro-apoptosis effects on tumor cells in vitro and in vivo, and prolonged survival in SKLB1028-treated mice has been observed in a dose-dependent manner (Cao et al., Leukemia, 2012). The present study is to assess the safety, tolerability and pharmacokinetics (PK) of SKLB1028 in patients with relapsed/refractory (R/R) FLT3-mutated AML. Here we report the preliminary analysis results of the study. Methods: An open label, 3+3 cohort dose escalation, single arm, phase I study was conducted in adult patients with FLT3-mutated AML who were refractory to or relapsed after ≥ 1 cycle of induction chemotherapy and had an Eastern Cooperative Oncology Group performance status of ≤ 3. Dose cohorts of at least 3 patients received study drug following a sequential dose-escalation design with 20 mg/day as the lowest dose level. For each dose level, patients were firstly given 1 dose of SKLB1028 as an oral capsule followed by 72-hour observation in the single-dose PK period. Then the patients entered the repeated-dose period from day 1, cycle 1, and received oral SKLB1028 once per day in a 28-day cycle. Observations of dose limiting toxicities (DLTs) were recorded through cycle 1. For a specific dose level, if a DLT was observed during the first cycle in 1 patient, 3 additional patients were enrolled at that level. If a second DLT was observed within the same dose cohort, escalation was discontinued, and maximum tolerated dose (MTD) was defined as the immediately lower dose level. Patient who had completed cycle 1 and did not experience a DLT or disease progressionduring cycle 1 could continue receiving SKLB1028, at the discretion of the investigator, until disease progression or intolerable toxicity occurred. The primary endpoints were safety and tolerability. Secondary endpoints included PK and efficacy. Analyses of safety (e.g. DLT and adverse event (AE)) and efficacy parameters (e.g. complete response (CR) and partial response (PR))were performed using descriptive statistics on safety analysis set and full analysis set respectively. PK parameters were estimated using non-compartmental analysis on PK analysis set. Results: Twenty-eight patients with a median age of 50 years (range 19-70 years) were enrolled. The median number of prior regimens was 3.5 (range 1-9). Patients received a median of 2.5 cycles (range 1-15)of therapyin 8 dose cohorts: 20, 40, 80, 120, 160, 200, 250, and 310 mg/day. Three patients discontinued from the study due to AEs. For a subject to be eligible for DLT evaluation, he/she should have received 100% of the planned (28) doses of SKLB1028 in cycle 1, unless the doses were omitted for DLT defining event. Two patients did not complete the first treatment cycle, 1 because of DLT and 1 because of withdrawal of consent. Twenty-seven patients were evaluable for DLT.One patient in the 200 mg cohort experienced DLT (Grade 3 hepatic function abnormal). Among 3 additional patients at this dose level, no DLTs occurred again. The most common treatment-emergent AEs of any grade (regardless of causality) were pyrexia (67.9%), diarrhoea (64.3%), asthenia (53.6%), dizziness (50.0%). There was no death attributed to the use of SKLB1028. The MTD had not been reached. Among the 28 patients treated, only 26 patients were evaluable for efficacy. Two patients were not enlisted due to premature discontinuation of study drug in cycle 1; 1 for DLT and the other for withdrawal of consent. Of 28 patients in the full analysis set, overall response rate (ORR) was 21.4% (6/28) with 1 CR, 5 PR, 20 stable disease and no progressive disease as the best response. One patient achieved CR at the does of 250 mg/day. Of the 5 patients with PR, 1 was in the 160mg cohort, 3 in the 200 mg cohort, and 1 in the 310 mg cohort. The ORR for the 160 mg, 200 mg, 250 mg, and 310 mg cohort of 16 patients was 37.5% (6/16). Conclusions: The results of our preliminary analysis suggested that SKLB1028 is safe, well-tolerated and effective for R/R FLT3-mutated AML patients. Larger studies are needed to more comprehensively assess the safety and efficacy of SKLB1028 in this population. This trial is registered at Clinical Trials.gov, number NCT02859948. Disclosures Yao: CSPC Zhongqi: Employment. Wang:CSPC Zhongqi: Employment. Zhan:CSPC Zhongqi: Employment. Ni:CSPC Zhongqi: Employment. Qiao:CSPC Zhongqi: Employment. Hu:CSPC Zhongqi: Employment.

scholarly journals A phase I study of lenalidomide plus chemotherapy with mitoxantrone, etoposide, and cytarabine for the reinduction of patients with acute myeloid leukemia

2017 ◽  
Vol 93 (2) ◽  
pp. 254-261 ◽  
Author(s):  
Daniel J. DeAngelo ◽  
Andrew M. Brunner ◽  
Lillian Werner ◽  
David Avigan ◽  
Amir T. Fathi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Acute Myeloid

scholarly journals Phase I Study of Alvocidib Followed by 7+3 (Cytarabine + Daunorubicin) in Newly Diagnosed Acute Myeloid Leukemia

2020 ◽  
Vol 27 (1) ◽  
pp. 60-69
Author(s):  
Joshua F. Zeidner ◽  
Daniel J. Lee ◽  
Mark Frattini ◽  
Gil D. Fine ◽  
Judy Costas ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Newly Diagnosed ◽  
Acute Myeloid

Abstract LB-070: Immune monitoring of PNK-007, an allogeneic, off the shelf NK cell in a Phase I study of acute myeloid leukemia

2019 ◽  
Author(s):  
William van der Touw ◽  
Lin Kang ◽  
Julie M. Curtsinger ◽  
Vanessa Voskinarian-Berse ◽  
Bhavani Stout ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Nk Cell ◽  
Immune Monitoring ◽  
Acute Myeloid

scholarly journals A phase I study using bortezomib with weekly idarubicin for treatment of elderly patients with acute myeloid leukemia

2013 ◽  
Vol 37 (11) ◽  
pp. 1502-1508 ◽  
Author(s):  
Dianna S. Howard ◽  
Jane Liesveld ◽  
Gordon L. Phillips ◽  
John Hayslip ◽  
Heidi Weiss ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Acute Myeloid

Sunitinib and Intensive Chemotherapy in Patients with Acute Myeloid Leukemia and Activating FLT3 Mutations: Results of the AMLSG 10-07 Study (ClinicalTrials.gov No. NCT00783653)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1483-1483 ◽  
Author(s):  
Walter Fiedler ◽  
Sabine Kayser ◽  
Maxim Kebenko ◽  
Jürgen Krauter ◽  
Helmut R. Salih ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Single Agent ◽  
Intensive Chemotherapy ◽  
Consolidation Therapy ◽  
Flt3 Mutations ◽  
Level 1 ◽  
Acute Myeloid

Abstract Abstract 1483 Background: Activating FLT3 mutations including internal tandem duplications (FLT3-ITD) and tyrosine-kinase domain mutation (FLT3-TKD) occur in approximately one third of patients with acute myeloid leukemia (AML) and are particularly associated with a poor outcome in case of FLT3-ITD. Sunitinib is a multitargeted FLT3 inhibitor approved for the treatment of advanced/metastatic renal cancer and metastatic/unresectable malignant GIST after failure of imatinib. Sunitinib has been evaluated in refractory AML as single agent treatment resulting in transient blast count reduction and in several cases of partial response in AML with activating FLT3 mutations. Aims: To evaluate the feasibility of a standard induction and consolidation therapy in combination with orally administered sunitinib in elderly AML patients with activating FLT3 mutations. Methods: Patients aged 60 years or higher with AML with activating FLT3 mutations (FLT3-ITD, FLT3-TKD) and fit enough for intensive chemotherapy were eligible. Induction therapy included cytarabine 100 mg/m2 per continuous infusion on days 1–7 and daunorubicin 60 mg/m2 i.v. on days 1–3 (DA). A second course was allowed in responding patients, who did not achieve a complete remission (CR). In patients achieving a CR after induction therapy three consolidation cycles were intended (cytarabine 1 g/m2 i.v. bid, on days 1,3,5). A 3+3 dose escalation/de-escalation scheme was used to define the dose and scheduling of sunitinib. The first cohort of three patients received oral sunitinib continuously starting from day 1 in a dose of 25 mg/day (level 1). Dose escalation to level 2 with sunitinib 37.5 mg/day continuously or dose de-escalation to level −1 with 25 mg day 1 to 7 had been defined in the protocol. After definition of the maximally tolerated dose (MTD) an extension of the cohort at that dose was intended. Results: A total of twenty-two patients were enrolled between January 2009 and March 2011. The median age was 70 years (range 60–78), 13 were female. The type of AML was de novo in 16 pts., s-AMLin one patient and t-AML in 4 pts. Fifteen patients had a FLT3-ITD (68%) and 7 a FLT3-TKD (32%) mutation. A NPM1 mutation was present in 11 patients (50%), 15 patients exhibited a normal karyotype, 3 an intermediate-2 risk karyotype according to ELN guidelines and 2 a complex karyotype and 2 had no evaluable metaphases. In the first cohort 5 patients were treated and two experienced dose-limiting toxicity (DLT), i) prolonged hematological recovery beyond day 35 in a patient achieving a CR and ii) a hand-foot-syndrome grade III. Four of the 5 patients achieved a CR. According to the protocol the following patients received treatment at dose level −1 with sunitinib 25mg days 1 to 7. In this cohort only one DLT occurred, again prolonged hematological recovery. Thus the MTD was defined at dose level −1. Response to induction therapy in all patients was CR in 13 pts. (59%), partial remission in 1 pt. (4.5%), refractory disease in 5 pts. (23%), death in 3 pts. (13.5%). CR rate in AML with FLT3-ITD was 53% (8/15) and 71% (5/7) in those with FLT3-TKD. All 13 patients achieving CR received repetitive cycles of high-dose cytarabine consolidation therapy and 7 proceeded to single agent sunitinib maintenance therapy (median 11 months, range 1–24 months). In these patients relapse occurred in 10, one patient died due to severe colitis during consolidation therapy and two patients are in sustained CR. Two patients not achieving a CR after induction therapy underwent allogeneic stem cell transplantation form matched unrelated donors. Twelve of the 22 patients died leading to a median survival of 18.8 months and a 2 year survival of 36% (95%-CI, 19–70%). Median relapse-free survival was 11 months. Conclusion: Combination of intensive induction and consolidation therapy with oral sunitinib in AML with activating FLT3 mutations is feasible with 25 mg sunitinib given during intensive therapy on days 1 to 7 and continuously during maintenance. Disclosures: Fiedler: Novartis: Consultancy, Research Funding; Pfizer Inc.: Consultancy, Research Funding.

scholarly journals Phase I Study of Clofarabine in Adult Patients with Acute Myeloid Leukemia in Japan

2013 ◽  
Vol 43 (12) ◽  
pp. 1177-1183 ◽  
Author(s):  
T. Suzuki ◽  
T. Yamauchi ◽  
K. Ando ◽  
T. Nagai ◽  
K. Kakihana ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Adult Patients ◽  
Acute Myeloid
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