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A Phase 1 study of intravenous infusions of tigecycline in patients with acute myeloid leukemia.

ABSTRACT: Acute myeloid leukemia (AML) cells meet the higher energy, metabolic, and signaling demands of the cell by increasing mitochondrial biogenesis and mitochondrial protein translation. Blocking mitochondrial protein synthesis through genetic and chemical approaches kills human AML cells at all stages of development in vitro and in vivo. Tigecycline is an antimicrobial that we found inhibits mitochondrial protein synthesis in AML cells. Therefore, we conducted a phase 1 dose-escalation study of tigecycline administered intravenously daily 5 of 7 days for 2 weeks to patients with AML. A total of 27 adult patients with relapsed and refractory AML were enrolled in this study with 42 cycles being administered over seven dose levels (50-350 mg/day). Two patients experienced DLTs related to tigecycline at the 350 mg/day level resulting in a maximal tolerated dose of tigecycline of 300 mg as a once daily infusion. Pharmacokinetic experiments showed that tigecycline had a markedly shorter half-life in these patients than reported for noncancer patients. No significant pharmacodynamic changes or clinical responses were observed. Thus, we have defined the safety of once daily tigecycline in patients with refractory AML. Future studies should focus on schedules of the drug that permit more sustained target inhibition.

SUBMITTER: Reed GA

PROVIDER: S-EPMC5119957 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia.

Project description:A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5'-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib (clinicaltrials.gov Identifier:00827138).

| S-EPMC5394958 | biostudies-literature

A phase 2 study of vorinostat in acute myeloid leukemia.

Project description:BackgroundThis two-stage, multi-institutional, randomized phase 2 trial assessed the toxicity and response rate associated with two treatment schedules of the histone deacetylase inhibitor, vorinostat (suberoylanilide hydroxamic acid; SAHA) in patients with relapsed acute myeloid leukemia and in selected untreated patients with high-risk acute myeloid leukemia.Design and methodsPatients with relapsed or untreated acute myeloid leukemia who were not candidates for chemotherapy entered one of the two treatment arms. In both arms a total dose of 8400 mg of vorinostat was delivered in each 21-day cycle of treatment: in arm A the dose regimen was 400 mg daily whereas in arm B the dose regimen was 200 mg three times daily for 14 days followed by 1 week rest.ResultsData from all 37 patients were used for the analyses. In arm A (n=15), the confirmed complete remission rate was 0% (95% CI, 0% to 23%); this arm was closed at the planned interim analysis. In arm B (n=22), the confirmed complete remission rate was 4.5% (1 response; 95% CI, 0.4% to 24%), with a duration of response exceeding 398 days. The median time to treatment failure in arm A was 42 days (95% CI, 26 to 57); although a minimum of four cycles of treatment were planned, 11 patients (79%) received no more than two cycles. The median time to treatment failure in arm B was 46 days (95% CI, 20 to 71); 13 patients (59%) received no more than two cycles of treatment.ConclusionsVorinostat monotherapy demonstrated minimal activity in this group of patients with acute myeloid leukemia. Therapy was discontinued in many patients before the planned four cycles had been administered, either because of failure of vorinostat to control the leukocyte count or patients' and physicians' preference. Future studies of vorinostat in acute myeloid leukemia should focus on combinations with other drugs with which it might interact pharmacodynamically. ClinicalTrials.gov Identifier: NCT00305773.

| S-EPMC2754953 | biostudies-literature

A phase II study of the EGFR inhibitor gefitinib in patients with acute myeloid leukemia.

Project description:Novel therapies for the treatment of acute myeloid leukemia are required to overcome disease resistance and to provide potentially less toxic therapies for older adults. Prior clinical trials involving patients with non-small cell lung cancer have demonstrated the safety and biologic activity of the administration of EGFR inhibitors in carefully selected patients. The potential efficacy of this approach in patients with acute myeloid leukemia is unknown. The effects of gefitinib on differentiation induction and cell viability in AML cell lines and primary patient AML cells were previously reported and cell viability was inhibited in a clinically achievable range. To determine if EGFR inhibitors would be therapeutically efficacious in advanced AML, we performed a phase II trial in which 18 patients with a median age of 72 (range, 57-84 years) were treated with gefitinib (750mg orally daily). While there were no unexpected toxicities, no patients experienced an objective response, though one had stable disease lasting 16 months. We conclude that in spite of pre-clinical activity and anecdotal cases of response to EGFR inhibitors, routine use of the EGFR inhibitor gefitinib as a single agent for advanced AML is not appropriate.

| S-EPMC4860003 | biostudies-literature

Phase II study of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia.

Project description:PurposeTo determine the efficacy and safety of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia (AML).Patients and methodsA phase II, open-label, multicenter study was conducted with single-agent clofarabine in pediatric patients with refractory or relapsed AML. Clofarabine was administered intravenously over 2 hours at the pediatric maximum-tolerated dose (MTD) of 52 mg/m(2) daily for 5 consecutive days. Cycles were repeated every 2 to 6 weeks. Responses determined by an independent response review panel.ResultsThe 42 patients treated on the study had a median age of 13 years (range, 2 to 22 years) and had received a median number of two (range, one to five) prior regimens. The response rate was 26% and included one complete response without platelet recovery and 10 partial responses. The median duration of response was 20 weeks (range, 2 to >or= 156 weeks). Six of 28 patients who were refractory to the immediately preceding therapy achieved response. Thirteen patients (31%), including seven responders, proceeded to hematopoietic stem-cell transplantation (HSCT) after treatment with clofarabine and survived between 24 to >or= 160 weeks. Five patients (12%) remain alive post-transplantation at >or= 63, >or= 71, >or= 86, >or= 114, and >or= 130 weeks. The most common grade 3 or greater adverse events without regard to causality were febrile neutropenia, catheter-related infection, epistaxis, hypotension, nausea, and fever. Transient elevation of liver enzymes and hypokalemia occurred frequently. Five patients died within 30 days of clofarabine administration secondary to progressive disease, and another five died as a result of an adverse event.ConclusionClofarabine is active in pediatric patients with multiply relapsed or refractory AML. Responses allowed several refractory patients to proceed to HSCT. The toxicity profile was expected in this patient population.

| S-EPMC2744276 | biostudies-literature

Acute myeloid leukemia study

Project description:Acute myeloid leukemia study. Supplementary Table 1: Clinical, morphological, cytogenetic and molecular genetic information on 116 AML patient samples. Supplementary Table 2: Summary of the distribution of clinical and molecular genetic characteristics within the AML sample set. Supplementary Table 3: Fluorescence ratios of the 6,283 well-measured and variably-expressed genes. Supplementary Table 4: Clinical and laboratory characteristics of normal karyotype predominant subtypes I and II. Supplementary Table 5: Supervised analysis of group-specific gene expression signatures. Supplementary Table 6: Gene-expression outcome class predictor. Supplementary Table 7: Multivariate proportional hazards analysis. Keywords: other

2004-04-15 | GSE425 | GEO

Phase I study of AR-42 and decitabine in acute myeloid leukemia.

Project description:This phase I trial sought to determine a biologically safe and effective dose of AR-42, a novel histone deacetylase inhibitor, which would lead to a doubling of miR-29b prior to decitabine administration. Thirteen patients with previously untreated or relapsed/refractory AML were treated at 3 dose levels (DL): AR-42 20 mg qd on d1,3,5 in DL1, 40 mg qd on d1,3,5 in DL2 and 40 mg qd on d1,3,4,5 in DL3. Patients received decitabine 20 mg/m2 on d6-15 of each induction cycle and 20 mg/m2 on d6-10 of each maintenance cycle. One DLT of polymicrobial sepsis and multi-organ failure occurred at DL3. Two patients achieved a CRi and one patient achieved a CR for an ORR of 23.1%. The higher risk features of this patient population and the dosing schedule of AR-42 may have led to the observed clinical response and failure to meet the biologic endpoint.

| S-EPMC7375689 | biostudies-literature

A new peptide vaccine OCV-501: in vitro pharmacology and phase 1 study in patients with acute myeloid leukemia.

Project description:Wilms' tumor 1 (WT1) is a promising target of new immunotherapies for acute myeloid leukemia (AML) as well as for other cancers. OCV-501 is a helper peptide derived from the WT1 protein. OCV-501 induced OCV-501-specific Type 1 T-helper (Th1) responses dose-dependently and stimulated helper activity of the specific Th1 cells in peripheral blood mononuclear cells from healthy donors. OCV-501 also enhanced the increase in WT1-killer peptide-specific cytotoxic T lymphocytes. OCV-501 stimulated the OCV-501-specific Th1 clones in an HLA class-II restricted manner and formed a complex with HLA class-II protein. OCV-501-specific Th1 clones demonstrated significant OCV-501-specific cytolytic activity against OCV-501-pulsed B-lymphoblastoid cell line cells. Based on the pre-clinical results, phase 1 clinical trial was conducted. The result of this trial suggested that the subcutaneous administration of OCV-501 once weekly for 4 weeks at doses of 0.3, 1, and 3 mg in older patients with AML during complete remission was safe and well tolerated. The maximum tolerated dose was considered to be ?3 mg. Of the nine subjects enrolled, neither relapse nor blast cells were observed during the study. Immunological responses were observed in OCV-501-specific delayed-type hypersensitivity test. This trial was registered at http://www.clinicaltrials.gov as NCT 01440920.

| S-EPMC5489634 | biostudies-other

A phase 2 study of belinostat (PXD101) in patients with relapsed or refractory acute myeloid leukemia or patients over the age of 60 with newly diagnosed acute myeloid leukemia: a California Cancer Consortium Study.

Project description:We performed a phase II study of belinostat in patients with acute myeloid leukemia (AML). In this open label phase II study (NCT00357032), patients with relapsed/refractory AML, or newly diagnosed patients with AML over the age of 60, were eligible. Belinostat was administered intravenously (IV) at a dose of 1000 mg/m(2) daily on days 1-5 of a 21-day cycle until progression or unacceptable toxicity. The primary endpoint was complete response (CR) rate, with secondary endpoints of overall response rate (CR + partial response [PR]), time to treatment failure (TTF), overall survival and safety. Twelve eligible patients with AML were enrolled, of whom six had received at least one prior line of therapy. No CR or PR was seen. Four patients had stable disease for at least five cycles. Grade 3 non-hematological toxicities occurred in four patients. Belinostat as monotherapy has minimal single-agent effect in AML on this dosing schedule.

| S-EPMC4143479 | biostudies-literature

Phase 1 study of CWP232291 in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome.

Project description:CWP232291 (CWP291) is a small-molecule inhibitor of Wnt signaling that causes degradation of β-catenin via apoptosis induction through endoplasmic reticulum stress activation. This first-in-human, open-label, dose-escalation study to evaluate the safety, maximum tolerated dose (MTD), and preliminary efficacy of CWP291 enrolled 69 patients with hematologic malignancies (acute myeloid leukemia [AML], n = 64; myelodysplastic syndrome, n = 5) in 15 dose-escalation cohorts of 4 to 334 mg/m2 using a modified 3+3 design and 1 dose-expansion cohort. CWP291 was administered IV daily for 7 days every 21 days. The most common treatment-emergent adverse events (TEAEs) were nausea (n = 44, 64%), vomiting (n = 32, 46%), diarrhea (n = 25, 36%), and infusion-related reactions (n = 20, 29%). Grade ≥3 TEAEs in >3 patients (5%) were pneumonia (n = 8, 12%); hypophosphatemia (n = 6, 8%); leukocytosis, nausea, cellulitis, sepsis, and hypokalemia (n = 5 each, 7% each); and hypertension (n = 4, 6%). Dose-limiting toxicities included nausea (n = 3) and abdominal pain, anaphylactic reaction, myalgia, and rash (n = 1, each); the MTD was defined at 257 mg/m2. CWP232204, the active metabolite of CWP291, showed pharmacokinetic linearity on both days 1 and 7, and a terminal half-life of ∼12 hours. Among 54 response-evaluable AML patients, there was one complete response at a dose of 153 mg/m2 and one partial response at 198 mg/m2; bone marrow blast percentage reduced from a median of 58.3% to 3.5% and 15.0% to 4.2%, respectively. Future studies will explore CWP291, with a mechanism of action aimed at eradication of earlier progenitors via Wnt pathway blockade, as combination therapy. This trial was registered at www.clinicaltrials.gov as #NCT01398462.

| S-EPMC7218422 | biostudies-literature

Selinexor in combination with decitabine in patients with acute myeloid leukemia: results from a phase 1 study.

Project description:Current treatment options for older and relapsed or refractory (R/R) acute myeloid leukemia (AML) patients are limited and represent an unmet need. Based on preclinical studies showing strong anti-leukemic effects in vivo, this phase I dose-escalation study assessed the safety and preliminary clinical activity of the oral exportin-1 inhibitor, selinexor, in combination with the hypomethylating agent, decitabine 20 mg/m2, in adults with R/R AML and in older (age ≥ 60) untreated AML patients. There were no protocol-defined dose limiting toxicities. The recommended phase 2 dose of selinexor was 60 mg (∼35 mg/m2) given twice-weekly. Notable grade ≥3 toxicities included asymptomatic hyponatremia (68%), febrile neutropenia (44%), sepsis (44%), hypophosphatemia (36%), and pneumonia (28%). In 25 patients, the overall response rate was 40%. Modification of selinexor to a flat dose of 60 mg, twice-weekly for two weeks after decitabine, improved tolerability of the regimen and demonstrated preliminary clinical activity in poor-risk patients with AML.

| S-EPMC7552944 | biostudies-literature

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