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.

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.

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

Blood ◽

10.1182/blood.v126.23.1344.1344 ◽

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.

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A Phase I Study of CHR-2797, an Orally Active Aminopeptidase Inhibitor in Elderly and/or Treatment Refractory Patients with Acute Myeloid Leukemia or Multiple Myeloma.

Blood ◽

10.1182/blood.v110.11.443.443 ◽

2007 ◽

Vol 110 (11) ◽

pp. 443-443 ◽

Cited By ~ 1

Author(s):

Faith Davies ◽

Gert Ossenkoppele ◽

Pierre Zachee ◽

Richard Noppeney ◽

Alan Burnett ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Phase I ◽

Active Metabolite ◽

Myeloid Leukemia ◽

Single Agent ◽

Once Daily ◽

Grade Iii ◽

Acute Myeloid

Abstract Background. CHR-2797 is a novel, orally bioavailable agent which displays potent, tumor cell-selective, anti-proliferative properties. It is an inhibitor of Zn++-dependent aminopeptidases and generates signs of amino acid deprivation in sensitive cells, decreased protein synthesis and an increase in the level of the pro-apoptotic protein, NOXA. CHR-79888 is an active metabolite of CHR-2797. Methods. This was an open label, single agent, dose escalating phase I salvage study to assess tolerance, MTD/DLT, activity, and pharmacokinetics of CHR-2797 in patients with hematological malignancies. Elderly patients and/or relapsed patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM) were eligible. Patients were treated with escalating once daily doses (60–180 mg) for up to 84 days or until progressive disease (PD). Clinical responses were assessed by monthly bone marrow aspirates in AML/MDS patients and by M-protein levels in MM patients. Results. Sixteen adults (4 women, 12 men) of median age 70 yrs, (range 45–84 yrs) were accrued between May 2006 and Jan 2007: 13 patients with AML, 1 with MDS, and 2 with MM. Thirteen patients finished the dose finding phase of 28 days and 6 patients continued for at least 84 days. CHR-2797 was well tolerated and, except for one patient with grade III ALT elevation, no grade III/IV drug related non-hematological toxicity was observed during the first 28 days of treatment. Two patients on 180 mg developed DLT that was considered drug related: >75 percent reduction in platelet count. CHR-2797 had no influence on hemoglobin or neutrophils in this trial. Overall the most frequently reported adverse events were thrombocytopenia (6.7%), diarrhea (4.5%), dizziness (3.9%), and fatigue (3.9%). Five AML patients died in the first 3 months of the trial or within 4 weeks of discontinuing CHR-2797: 3 due to disease progression and 2 following a MI (not related to drug). Bone marrow studies revealed complete responses (< 5% blasts in bone marrow) in 3/12 AML patients after 1–3 months of therapy (60 and 130mg), one of which was also a cytogenetic response. One of the 2 responding patients on 130 mg was evaluated as a CRp at 3 months; this patient was in remission for 3 months following platelet recovery after the drug was stopped. One further AML patient (60 mg) became completely transfusion independent and remained so for 6 weeks. Good exposure to CHR-2797, including levels of the active metabolite CHR-79888 has been observed on days 1 and 28 with a terminal half life (for 79888) of 8– 11 hours. Conclusions. Oral once daily CHR-2797 in AML/MDS/MM patients with adverse prognostic risk was well tolerated. MTD for maintenance therapy was reached at 180 mg. Single agent CHR-2797 therapy showed encouraging clinical activity (incl. 3/12 CRs) in these elderly and poor risk AML patients who were able to continue therapy for at least 28 days. Because of the favorable results a phase II study with CHR-2797 in advanced AML is currently in progress.

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Phase I study of idarubicin dose escalation for remission induction therapy in acute myeloid leukemia

Leukemia & Lymphoma ◽

10.3109/10428194.2016.1138294 ◽

2016 ◽

Vol 57 (10) ◽

pp. 2268-2274 ◽

Cited By ~ 1

Author(s):

Mark Hong Lee ◽

Sung-Yong Kim

Keyword(s):

Acute Myeloid Leukemia ◽

Phase I ◽

Induction Therapy ◽

Dose Escalation ◽

Myeloid Leukemia ◽

Phase I Study ◽

Remission Induction ◽

Acute Myeloid

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A Phase I Study of Lenalidomide and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v124.21.2318.2318 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2318-2318

Author(s):

Elizabeth A. Griffiths ◽

William Brady ◽

Wei Tan ◽

Carlos E Vigil ◽

James E. Thompson ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Myeloid Leukemia ◽

Research Funding ◽

Phase I Study ◽

Response Rate ◽

Single Agent ◽

Grade 3 ◽

Acute Myeloid ◽

Intermediate Dose

Abstract Background: Relapsed/refractory (r/r) Acute Myeloid Leukemia (AML) remains a therapeutic challenge. Although cytarabine arabinoside (AraC) is the most active drug, constituting the backbone of a majority of r/r regimens, the benchmark response to therapy remains a dismal 17 to 20% (Burnett, Wetzler et al. JCO, 2011.). The immunomodulatory drug lenalidomide (Len), is approved by the Food and Drug Administration for multiple myeloma and myelodysplasia and has demonstrated activity as a single agent in AML at doses as high as 50 mg for 21 days (d) of a 28 d cycle (Blum et al, JCO, 2010.). Based upon this activity profile we developed a phase I study to evaluate the safety and tolerability of Len in combination with AraC in patients with r/r AML. Methods: Eligible patients were older than 18 years(y), had r/r AML with an Eastern Cooperative Oncology Group performance status better than 2 and adequate renal and hepatic function. Patients were excluded for active CNS disease, uncontrolled infections, congestive heart failure, adrenal insufficiency, anti-cancer therapy within 14 d of enrollment, or prior exposure to Len. All enrolled patients had to practice appropriate contraception. Patients received AraC 1.5 g/m2/d over 3 hours on d 1-5 of a 28 day cycle, with a plan for standard 3+3 Len dose escalation. Initial patients received Len 25 mg on d 6-10 (n= 3), subsequent patients received doses between 25 and 10 mg (dose de-escalation) on d 6-26 with 2 d of rest prior to the next cycle. Following induction, patients who had residual AML (>5%) could receive a second identical course of therapy, provided they demonstrated an improvement in blast percentage relative to baseline. Patients who achieved CR received maintenance with Len 10 mg/d continuously. A 12 patient expanded cohort was enrolled at the maximum tolerated dose (MTD) to assess efficacy. Responses were assessed by International Working Group Criteria for AML (Cheson B et al. JCO, 2003.). Patient Characteristics: Fifty-one patients were consented and 45 were treated on study, 32 of these were evaluable for response, all patients were evaluated for toxicity. Approximately half the patients were female (20/45). The median age was 66 y (range 33-82) and median WBC 2.42x109/L (range 0.18-63.15). Four patients (8%) had an antecedent hematological disorder. By European LeukemiaNet criteria 2 patients (4%) had favorable risk disease, 8 (18%) were Int-1, 12(27%) were Int-2 and 11 (24%) were adverse risk; 12(27%) patients were not evaluable by ELN due to lack of karyotype or molecular data from diagnosis. Twelve patients had primary refractory AML. Results: The MTD for Len given on d 6-26 in combination with AraC at 1.5 g/m2/d x 5 d was 10 mg. Dose de-escalation from the starting dose of 25 mg on this schedule was required due to excess toxicity. The most commonly observed non-hematologic drug related adverse events seen on the study (all < grade 2 unless indicated) were nausea, increased liver function tests (>grade 3), rash (grade >3), hypokalemia (> grade 3) and fatigue. At the 25 mg dose level the dose limiting toxicity was rash, while patients enrolled at the 15 mg dose level experienced dose limiting elevation in LFTs, fatigue and bleeding. Five patients achieved a CR (16%), 5 demonstrated CRi (16%) and there were 3 hematological improvements (HI) for an overall response rate (CR+Cri+HI) of 41% (13/32). The median overall survival (OS) (95% confidence interval) for patients treated on study was 5.8 (2.5, 10.6) months and disease free survival was 3.4 (2.3, 6.2) months. Conclusions: Although prior interesting data support the activity of single agent high dose Len in r/r AML, our single institute phase I study of intermediate dose AraC followed by Len was associated with marked skin and other toxicities at the Len 25 mg dose level, precluding dose escalation to the historically more active 50 mg dose. The CR rate in this study was not dissimilar to previously reported responses with single agent or combination AraC based regimens. Issues of dose and schedule for this combination may have had a significant impact on the potential benefit for these two drugs in combination. Nevertheless, the overall low CR rate from this study does not suggest any superiority for this combination in comparison with the historical single agent response rate for intermediate dose AraC in r/r AML. Disclosures Griffiths: Celgene, Incyte and Alexion: Honoraria; Astex Pharmaceuticals: Research Funding. Wang:Incyte: Speakers Bureau; Immunogen: Other. Wetzler:MedPace: Consultancy; Bristol Myers Squibb: Research Funding; Jazz Pharmaceuticals: Consultancy; Sigma Tau: Consultancy; Amgen: Honoraria; Novartis: Honoraria; Teva: Honoraria; Plexus: Consultancy; Celgene: Research Funding.

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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 ◽

10.1182/blood-2019-128472 ◽

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.

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