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.

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/II Dose Escalation Trial of ONCOHIST® (Recombinant Human Histone H1.3) in Patients with Relapsed or Refractory Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 918-918 ◽  
Author(s):  
Michael Zeppezauer ◽  
Grazina Formicka-Zeppezauer ◽  
Peter Gross ◽  
Hans Joernvall ◽  
Joerg Schubert ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Side Effects ◽  
Phase I ◽  
Dose Level ◽  
Myeloid Leukemia ◽  
Study Drug ◽  
Acute Myelogenous ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract Background: Histone H1.3 suppresses tumor growth of leukemic cells in vitro, ex vivo and in animal models. To evaluate toxicity and efficacy of ONCOHIST, recombinant human histone H1.3 (rhH1.3) in patients suffering from acute myelogenous leukemia, we initiated a phase-I/II dose escalation study. Methods: This was an open-label unicentric phase I/II study. Nine patients suffering from relapsed or refractory acute myeloid leukemia (median age: 69 years, range 49 to 83 years) with a life expectancy of at least one month who were unable or unwilling to receive curative chemotherapy without major organ dysfunction were eligible for the trial. Exclusion criteria were presence of HIV, HBV, or HBC infection, heparin treatment during the 2 weeks before enrolment, and medical conditions known to potentially interfere with rhH1.3 treatment such as rheumatoid arthritis or SLE, as well as circulating anti-histone H1.3 antibodies. One treatment course consisted of 9 applications in 3 weeks. 3 patients were treated at each dose level. Starting dose level was 245 mg/m2 and in the absence of dose-limiting toxicities, the dose was increased to the next higher dose level (392 and 628 mg/m2 rhH1.3) in the third week of the treatment course. Primary endpoints of the study was the definition of the maximal tolerated dose and dose-limiting toxicities of the study drug. Results: To date, 9 patients have been treated and all patients are evaluable for toxicity and efficacy. No side-effects were observed except for one atrial fibrillation under infusion of rhH1.3, which was considered not to be related to the study drug. All patients completed one course of therapy (9 applications), and one responding patient received a second course without side effects. No dose-limiting toxicities were observed and the maximal tolerated dose has not been reached at 628 mg/m2. With respect to efficacy, the formal criteria of response were not met in any of the 9 patients. However, two patients had a temporary increase of their platelet counts while on therapy, and in one patient platelet counts raised from 22 000/mm3 to 100 000/mm3, remaining stable for 3 months. Two patients achieved a reduction of blasts upon treatment. Conclusion: rhH1.3 is well tolerated at the doses treated so far. While the achieved serum levels are still below the growth-inhibiting concentrations in vitro, first clinical effects have been observed. Additional patients and higher dose levels are needed to delineate the efficacy and toxicity profile of rhH1.3 for the treatment of acute myelogenous leukemias.

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 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

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

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

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

Sign in / Sign up

Export Citation Format

Share Document