scholarly journals First-In-Man Study of CPX-351: A Liposomal Carrier Containing Cytarabine and Daunorubicin in a Fixed 5:1 Molar Ratio for the Treatment of Relapsed and Refractory Acute Myeloid Leukemia

2011 ◽  
Vol 29 (8) ◽  
pp. 979-985 ◽  
Author(s):  
Eric J. Feldman ◽  
Jeffrey E. Lancet ◽  
Jonathan E. Kolitz ◽  
Ellen K. Ritchie ◽  
Gail J. Roboz ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Adverse Events ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Hypertensive Crisis ◽  
Maximum Tolerated Dose ◽  
Molar Ratio ◽  
Phase Ii Trials ◽  
Platelet Recovery ◽  
Acute Myeloid

Purpose This phase I dose-escalation trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of CPX-351. Patients and Methods CPX-351 induction was administered on days 1, 3, and 5 by 90-minute infusion to 48 relapsed or refractory patients with acute myeloid leukemia (AML) or high-risk myelodysplasia. Doses started at 3 units/m2 with dose doublings in single-patient cohorts until a pharmacodynamic effect (treatment-related adverse events or reduction in bone marrow cellularity or blast count) was observed, followed by 33% escalations in three patient cohorts until dose-limiting toxicity (DLT) occurred. Results The maximum-tolerated dose was 101 units/m2. DLTs consisted of hypertensive crisis, congestive heart failure, and prolonged cytopenias. Adverse events were consistent with cytarabine and daunorubicin treatment. Response occurred at doses as low as 32 units/m2. Of 43 patients with AML, nine had complete response (CR) and one had CR with incomplete platelet recovery; of patients with acute lymphoblastic leukemia, one of three had CR. Eight CRs were achieved among the 31 patients with prior cytarabine and daunorubicin treatment. CR in AML occurred in five of 26 patients age ≥ 60 years and in five of 17 patients younger than age 60 years. Median half-life was 31.1 hours (cytarabine) and 21.9 hours (daunorubicin), with both drugs and their metabolites detectable > 7 days after the last dose. The targeted 5:1 molar ratio was maintained at all dose levels for up to 24 hours. Conclusion The recommended dose of CPX-351 for phase II study is 101 units/m2. Further exploration of efficacy and safety is ongoing in phase II trials in newly diagnosed and first-relapse patients with AML.

scholarly journals Eprenetapopt Plus Azacitidine in TP53-Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Phase II Study by the Groupe Francophone des Myélodysplasies (GFM)

2021 ◽  
pp. JCO.20.02342
Author(s):  
Thomas Cluzeau ◽  
Marie Sebert ◽  
Ramy Rahmé ◽  
Stefania Cuzzubbo ◽  
Jacqueline Lehmann-Che ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Adverse Events ◽  
Phase Ii ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Phase Ii Study ◽  
International Prognostic Scoring System ◽  
High Risk Population ◽  
Very High ◽  
Acute Myeloid

PURPOSE TP53-mutated ( TP53m) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) have very poor outcome irrespective of the treatment received, including 40% responses (20% complete remission [CR]) with azacitidine (AZA) alone, short response duration, and a median overall survival (OS) of approximately 6 months. Eprenetapopt (APR-246), a novel first-in-class drug, leads to p53 protein reconformation and reactivates its proapoptotic and cell-cycle arrest functions. PATIENTS AND METHODS This phase II study assessed the safety and efficacy of eprenetapopt in combination with AZA in untreated high or very high International Prognostic Scoring System-R TP53m MDS and AML patients. RESULTS Fifty-two TP53m patients (34 MDS, 18 AML [including seven with more than 30% blasts]) were enrolled. In MDS, we observed an overall response rate (ORR) of 62%, including 47% CR, with a median duration of response at 10.4 months. In AML, the ORR was 33% including 17% CR (27% and 0% CR in AML with less than and more than 30% marrow blasts, respectively). Seventy-three percent of responders achieved TP53 next-generation sequencing negativity (ie, variant allele frequency < 5%). The main treatment-related adverse events were febrile neutropenia (36%) and neurologic adverse events (40%), the latter correlating with a lower glomerular filtration rate at treatment onset ( P < .01) and higher age ( P = .05), and resolving with temporary drug interruption without recurrence after adequate eprenetapopt dose reduction. With a median follow-up of 9.7 months, median OS was 12.1 months in MDS, and 13.9 and 3.0 months in AML with less than and more than 30% marrow blasts, respectively. CONCLUSION In this very high-risk population of TP53m MDS and AML patients, eprenetapopt combined with AZA was safe and showed potentially higher ORR and CR rate, and longer OS than reported with AZA alone.

scholarly journals Phase II Study of Clofarabine in Pediatric Patients With Refractory or Relapsed Acute Myeloid Leukemia

2009 ◽  
Vol 27 (26) ◽  
pp. 4392-4397 ◽  
Author(s):  
Sima Jeha ◽  
Bassem Razzouk ◽  
Michael Rytting ◽  
Susan Rheingold ◽  
Edythe Albano ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Pediatric Patients ◽  
Single Agent ◽  
Open Label ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Relapsed Acute Myeloid Leukemia ◽  
Acute Myeloid

Purpose To determine the efficacy and safety of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia (AML). Patients and Methods A 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/m2 daily for 5 consecutive days. Cycles were repeated every 2 to 6 weeks. Responses determined by an independent response review panel. Results The 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 ≥ 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 ≥ 160 weeks. Five patients (12%) remain alive post-transplantation at ≥ 63, ≥ 71, ≥ 86, ≥ 114, and ≥ 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. Conclusion Clofarabine 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.

Phase II Study of Clofarabine Monotherapy in Previously Untreated Older Adults With Acute Myeloid Leukemia and Unfavorable Prognostic Factors

2010 ◽  
Vol 28 (4) ◽  
pp. 549-555 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Harry P. Erba ◽  
David Claxton ◽  
Martha Arellano ◽  
Roger M. Lyons ◽  
...  
Keyword(s):  
Older Adults ◽  
Acute Myeloid Leukemia ◽  
Prognostic Factors ◽  
Prognostic Factor ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Phase Ii Study ◽  
Platelet Recovery ◽  
Unfavorable Prognostic Factor ◽  
Acute Myeloid

PurposeThis phase II study assessed clofarabine monotherapy in older adults (≥ 60 years of age) with untreated acute myeloid leukemia (AML) and at least one unfavorable baseline prognostic factor.Patients and MethodsClofarabine was administered intravenously for 5 days at 30 mg/m2/d during induction and 20 mg/m2/d during reinduction/consolidation (six cycles maximum). The primary end point was overall remission rate (ORR; ie, complete remission [CR] plus CR with incomplete platelet recovery [CRp]).ResultsIn 112 evaluable patients who were treated (median age, 71 years; range, 60 to 88 years), the ORR was 46% (38% CR, 8% CRp). ORR by unfavorable prognostic factor was 39% for patients ≥ 70 years of age; 32% for Eastern Cooperative Oncology Group (ECOG) performance status 2; 51% for antecedent hematologic disorder; 54% for intermediate karyotype; 42% for unfavorable karyotype; and 48%, 51%, and 38% for one, two, and three risk factors, respectively. The median disease-free survival was 37 weeks (95% CI, 26 to 56 weeks). Median duration of remission was 56 weeks (95% CI, 33 to not estimable). The estimated median overall survival was 41 weeks (95% CI, 28 to 53 weeks) for all patients, 59 weeks for patients with CR/CRp, and 72 weeks for patients with CR. The 30-day all-cause mortality was 9.8%. The most common non-laboratory drug-related toxicities (≥ 20% patients) were nausea, febrile neutropenia, vomiting, diarrhea, rash, and fatigue.ConclusionClofarabine is an active agent with acceptable toxicity in patients age 60 years or older with untreated AML who have at least one unfavorable prognostic factor. ORR did not seem affected by the presence of multiple unfavorable prognostic factors.

Phase I/II Clinical Study of Tosedostat, an Inhibitor of Aminopeptidases, in Patients With Acute Myeloid Leukemia and Myelodysplasia

2010 ◽  
Vol 28 (28) ◽  
pp. 4333-4338 ◽  
Author(s):  
Bob Löwenberg ◽  
Gareth Morgan ◽  
Gert J. Ossenkoppele ◽  
Alan K. Burnett ◽  
Pierre Zachée ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Platelet Count ◽  
Phase I ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Hematologic Malignancies ◽  
Maximum Tolerated Dose ◽  
Antileukemic Activity ◽  
Once Daily ◽  
Acute Myeloid

Purpose To identify the maximum-tolerated dose (MTD) and to evaluate the antileukemic activity of tosedostat (formerly CHR-2797), an orally bioavailable aminopeptidase inhibitor. Patients and Methods In phase I, the MTD of once daily oral doses of tosedostat in hematologic malignancies was defined. In phase II, the therapeutic activity of the maximum-acceptable dose (MAD) of tosedostat was evaluated in elderly and/or relapsing patients with acute myeloid leukemia (AML) or myelodysplastic syndrome. Results In phase I, 16 patients were treated in four cohorts with tosedostat (60 mg to 180 mg) for 28 days. Three patients reported dose-limiting toxicities: two with reversible thrombocytopenia (> 75% reduction in platelet count) at 180 mg (MTD) and one with a Common Toxicity Criteria (CTC) grade 3 ALT elevation at 130 mg (MAD). In phase II, 41 patients were treated with 130 mg tosedostat. In phases I and II, the most common severe (CTC grades 3 to 5) adverse event was a reduction in the platelet count. Of the 51 AML patients in this study, seven reached complete marrow response (< 5% marrow blasts), with three achieving complete remission, and a further seven patients reaching a partial marrow response (between 5% and 15% marrow blasts). The overall response rate was therefore 27%. All responders were age > 60 years, and 79% had either relapsed or refractory AML. Conclusion This phase I/II study demonstrates that oral once daily dosing with 130 mg tosedostat is well tolerated and has significant antileukemic activity. The favorable risk-benefit profile suggests that further clinical trials are warranted.

scholarly journals Phase 1 study of the MDM2 antagonist RO6839921 in patients with acute myeloid leukemia

2020 ◽  
Vol 38 (5) ◽  
pp. 1430-1441
Author(s):  
Geoffrey L. Uy ◽  
Sarit Assouline ◽  
Anne-Marie Young ◽  
Steven Blotner ◽  
Brian Higgins ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Active Principle ◽  
Wild Type ◽  
Antileukemic Activity ◽  
Platelet Recovery ◽  
Mdm2 Antagonist ◽  
Acute Myeloid

Abstract In acute myeloid leukemia (AML), TP53 mutations and dysregulation of wild-type p53 is common and supports an MDM2 antagonist as a therapy. RO6839921 is an inactive pegylated prodrug of the oral MDM2 antagonist idasanutlin (active principle [AP]) that allows for IV administration. This phase 1 monotherapy study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with AML. Primary objectives identified dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary objectives assessed pharmacokinetic, pharmacodynamic, and antileukemic activity. A total of 26 patients received 120–300 mg AP of idasanutlin. The MTD was 200 mg, with DLTs at 250 (2/8 patients) and 300 mg (2/5). Treatment–related adverse events in >20% of patients were diarrhea, nausea, vomiting, decreased appetite, and fatigue. Six deaths (23.1%) occurred, all unrelated to treatment. Pharmacokinetics showed rapid and near-complete conversion of the prodrug to AP and dose-proportional exposure across doses. Variability ranged from 30%–47% (22%–54% for idasanutlin). TP53 was 21 (87.5%) wild-type and 3 mutant (12.5%). The composite response rate (complete remission [CR], CR with incomplete hematologic recovery/morphological leukemia-free state [CRi/MLFS], or CR without platelet recovery [CRp]) was 7.7%. Antileukemic activity (CR, CRi/MLFS, partial response, hematologic improvement/stable disease) was observed in 11 patients (disease control rate, 42%): 10/11 were TP53 wild-type; 1 had no sample. p53 activation was demonstrated by MIC-1 induction and was associated with AP exposure. There was not sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development of RO6839921. NCT02098967.

scholarly journals Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial

2021 ◽  
Author(s):  
Michael Heuser ◽  
B. Douglas Smith ◽  
Walter Fiedler ◽  
Mikkael A. Sekeres ◽  
Pau Montesinos ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase Ii ◽  
Clinical Benefit ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
De Novo ◽  
Secondary Acute Myeloid Leukemia ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

AbstractThis analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325–0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395–1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151–0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days’ therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038.

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