Phase 1/2 study to assess the safety, efficacy, and pharmacokinetics of barasertib (AZD1152) in patients with advanced acute myeloid leukemia

AbstractThe primary objective of this 2-part phase 1/2 study was to determine the maximum-tolerated dose (MTD) of the potent and selective Aurora B kinase inhibitor barasertib (AZD1152) in patients with newly diagnosed or relapsed acute myeloid leukemia (AML). Part A determined the MTD of barasertib administered as a continuous 7-day infusion every 21 days. In part B, the efficacy of barasertib was evaluated at the MTD. In part A, 32 patients were treated with barasertib 50 mg (n = 3), 100 mg (n = 3), 200 mg (n = 3), 400 mg (n = 4), 800 mg (n = 7), 1200 mg (n = 6), and 1600 mg (n = 6). Dose-limiting toxicities (stomatitis/mucosal inflammation events) were reported in the 800 mg (n = 1), 1200 mg (n = 1), and 1600 mg (n = 2) groups. The MTD was defined as 1200 mg. In part B, 32 patients received barasertib 1200 mg. In each part of the study, 8 of 32 patients had a hematologic response according to Cheson AML criteria. The most commonly reported grade ≥ 3 events were febrile neutropenia (n = 24) and stomatitis/mucosal inflammation (n = 16). We concluded that the MTD of barasertib is 1200 mg in patients with relapsed or newly diagnosed AML. Toxicity was manageable and barasertib treatment resulted in an overall hematologic response rate of 25%. This study is registered at www.ClinicalTrials.gov as NCT00497991.

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Randomized phase 1 study of sequential (“primed”) vs. concurrent decitabine in combination with cladribine, cytarabine, G-CSF, and mitoxantrone (CLAG-M) in adults with newly diagnosed or relapsed/refractory acute myeloid leukemia (AML) or other high-grade myeloid neoplasm

Leukemia & Lymphoma ◽

10.1080/10428194.2020.1728754 ◽

2020 ◽

Vol 61 (7) ◽

pp. 1728-1731

Author(s):

Raffaele Palmieri ◽

Sarah A. Buckley ◽

Megan Othus ◽

Anna B. Halpern ◽

Mary-Elizabeth M. Percival ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Phase 1 ◽

High Grade ◽

Newly Diagnosed ◽

Phase 1 Study ◽

Myeloid Neoplasm ◽

Refractory Acute Myeloid Leukemia ◽

Acute Myeloid

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Gemtuzumab ozogamicin in acute myeloid leukemia: a remarkable saga about an active drug

Blood ◽

10.1182/blood-2013-03-490482 ◽

2013 ◽

Vol 121 (24) ◽

pp. 4838-4841 ◽

Cited By ~ 100

Author(s):

Jacob M. Rowe ◽

Bob Löwenberg

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Phase 1 ◽

Randomized Study ◽

Gemtuzumab Ozogamicin ◽

New Drugs ◽

Phase 2 ◽

Newly Diagnosed ◽

Phase 3 ◽

Acute Myeloid

Abstract Despite living in an era of unprecedented progress in the understanding of the genetic and molecular biology of acute myeloid leukemia (AML), this has not translated into significant advances in therapy. Never before have so many potential targets been studied. Yet most have not advanced beyond the phase 1 and, occasionally, phase 2 studies. The few ongoing phase 3 studies seem unlikely to have more than a marginal benefit, if at all. Thus, it is not surprising that in past few decades almost no new drugs for AML have received regulatory approval. In 2000, gemtuzumab ozogamicin (GO) was granted accelerated approval by the US Food and Drug Administration based on promising phase 2 data in relapsed older adults with AML. GO held promise as a new agent that also could be efficacious in newly diagnosed AML with acceptable toxicity. Several phase 3 studies were designed to test GO in this setting. The results of a randomized study by the Southwest Oncology Group led in 2010 to the voluntary withdrawal of this agent when improved efficacy could not be demonstrated and toxicity appeared excessive. Since then, 4 randomized studies have been completed that, in aggregate, strongly support the efficacy of this agent in newly diagnosed AML with acceptable toxicity. There is a very plausible explanation for this discrepancy, making a compelling case for reapproval of GO in AML.

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A phase 1 study of AMG 900, an orally administered pan-aurora kinase inhibitor, in adult patients with acute myeloid leukemia

American Journal of Hematology ◽

10.1002/ajh.24736 ◽

2017 ◽

Vol 92 (7) ◽

pp. 660-667 ◽

Cited By ~ 9

Author(s):

Hagop M. Kantarjian ◽

Michael W. Schuster ◽

Nitin Jain ◽

Anjali Advani ◽

Elias Jabbour ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Phase 1 ◽

Aurora Kinase ◽

Adult Patients ◽

Aurora Kinase Inhibitor ◽

Phase 1 Study ◽

Acute Myeloid

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A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease

Blood ◽

10.1182/blood-2004-05-1846 ◽

2005 ◽

Vol 105 (3) ◽

pp. 986-993 ◽

Cited By ~ 356

Author(s):

Walter Fiedler ◽

Hubert Serve ◽

Hartmut Döhner ◽

Michael Schwittay ◽

Oliver G. Ottmann ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Growth Factor ◽

Dose Level ◽

Short Duration ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Phase 1 ◽

Phase 1 Study ◽

Ki 67 ◽

Acute Myeloid

AbstractFifteen patients with refractory AML were treated in a phase 1 study with SU11248, an oral kinase inhibitor of fms-like tyrosine kinase 3 (Flt3), Kit, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) receptors. Separate cohorts of patients received SU11248 for 4-week cycles followed by either a 2- or a 1-week rest period. At the starting dose level of 50 mg (n = 13), no dose-limiting toxicities were observed. The most frequent grade 2 toxicities were edema, fatigue, and oral ulcerations. Two fatal bleedings possibly related to the disease, one from a concomitant lung cancer and one cerebral bleeding, were observed. At the 75 mg dose level (n = 2), one case each of grade 4 fatigue, hypertension, and cardiac failure was observed, and this dose level was abandoned. All patients with FLT3 mutations (n = 4) had morphologic or partial responses compared with 2 of 10 evaluable patients with wild-type FLT3. Responses, although longer in patients with mutated FLT3, were of short duration. Reductions of cellularity and numbers of Ki-67+, phospho-Kit+, phospho–kinase domain–containing receptor–positive (phospho-KDR+), phospho–signal transducer and activator of transcription 5–positive (phospho-STAT5+), and phospho-Akt+ cells were detected in bone marrow histology analysis. In summary, monotherapy with SU11248 induced partial remissions of short duration in acute myeloid leukemia (AML) patients. Further evaluation of this compound, for example in combination with chemotherapy, is warranted.

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Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis

Blood Advances ◽

10.1182/bloodadvances.2017011080 ◽

2018 ◽

Vol 2 (4) ◽

pp. 444-453 ◽

Cited By ~ 56

Author(s):

Richard M. Stone ◽

Paul W. Manley ◽

Richard A. Larson ◽

Renaud Capdeville

Keyword(s):

Acute Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Systemic Mastocytosis ◽

Angiogenesis Inhibitor ◽

European Medicines Agency ◽

Newly Diagnosed ◽

Standard Chemotherapy ◽

Acute Myeloid

Abstract Midostaurin was a prototype kinase inhibitor, originally developed as a protein kinase C inhibitor and subsequently as an angiogenesis inhibitor, based on its inhibition of vascular endothelial growth factor receptor. Despite promising preclinical data, early clinical trials in multiple diseases showed only modest efficacy. In 1996, the relatively frequent occurrence of fms-like tyrosine kinase 3 (FLT3) activating mutations in acute myeloid leukemia (AML) was first recognized. Several years later, midostaurin was discovered to be a potent inhibitor of the FLT3 tyrosine kinase and to have activity against mutant forms of KIT proto-oncogene receptor tyrosine kinase, which drive advanced systemic mastocytosis (SM). Through a series of collaborations between industry and academia, midostaurin in combination with standard chemotherapy was evaluated in the Cancer and Leukemia Group B 10603/RATIFY study, a large, phase 3, randomized, placebo-controlled trial in patients with newly diagnosed FLT3-mutated AML. This was the first study to show significant improvements in overall survival and event-free survival with the addition of a targeted therapy to standard chemotherapy in this population. Around the same time, durable responses were also observed in other trials of midostaurin in patients with advanced SM. Collectively, these clinical data led to the approval of midostaurin by the US Food and Drug Administration and the European Medicines Agency for both newly diagnosed FLT3-mutated AML and advanced SM.

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

Blood Advances ◽

10.1182/bloodadvances.2019000757 ◽

2020 ◽

Vol 4 (9) ◽

pp. 2032-2043 ◽

Cited By ~ 3

Author(s):

Je-Hwan Lee ◽

Stefan Faderl ◽

John M. Pagel ◽

Chul Won Jung ◽

Sung-Soo Yoon ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Dose Escalation ◽

Myeloid Leukemia ◽

Phase 1 ◽

Complete Response ◽

Maximum Tolerated Dose ◽

Open Label ◽

Dose Escalation Study ◽

Acute Myeloid

Abstract 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.

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Ivosidenib (IVO; AG-120) in IDH1-Mutant Newly-Diagnosed Acute Myeloid Leukemia (ND AML): Updated Results from a Phase 1 Study

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2019.07.094 ◽

2019 ◽

Vol 19 ◽

pp. S220 ◽

Cited By ~ 1

Author(s):

Courtney D. DiNardo ◽

Gail J. Roboz ◽

Eytan M. Stein ◽

Stéphane de Botton ◽

Alice S. Mims ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Phase 1 ◽

Newly Diagnosed ◽

Phase 1 Study ◽

Acute Myeloid

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Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia

Blood Advances ◽

10.1182/bloodadvances.2019030916 ◽

2019 ◽

Vol 3 (13) ◽

pp. 1939-1949 ◽

Cited By ~ 13

Author(s):

Harry P. Erba ◽

Pamela S. Becker ◽

Paul J. Shami ◽

Michael R. Grunwald ◽

Donna L. Flesher ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Target Genes ◽

Phase 1 ◽

Maximum Tolerated Dose ◽

Clinical Activity ◽

Open Label ◽

Refractory Acute Myeloid Leukemia ◽

Higher Doses ◽

Acute Myeloid

AbstractThis open-label, phase 1 study evaluated the safety, pharmacokinetics, and maximum tolerated dose of AMG 232, an investigational oral, selective mouse double minute 2 homolog inhibitor in relapsed/refractory acute myeloid leukemia (AML). AMG 232 was administered orally once daily for 7 days every 2 weeks (7 on/off) at 60, 120, 240, 360, 480, or 960 mg as monotherapy (arm 1) or at 60 mg with trametinib 2 mg (arm 2). Dose-limiting toxicities (DLTs), adverse events (AEs), pharmacokinetics, clinical and pharmacodynamic response, and expression of p53 target genes were assessed. All 36 patients received AMG 232. No DLTs occurred in arm 1, and 360 mg was the highest test dose; dose escalation was halted due to gastrointestinal AEs at higher doses. One of ten patients in arm 2 had a DLT (grade 3 fatigue); 60 mg was the highest dose tested with trametinib. Common treatment-related AEs (any grade) included nausea (58%), diarrhea (56%), vomiting (33%), and decreased appetite (25%). AMG 232 exhibited linear pharmacokinetics unaffected by coadministration with trametinib. Serum macrophage inhibitor cytokine-1 and bone marrow expression of BAX, PUMA, P21, and MDM2 increased during treatment. Of 30 evaluable patients, 1 achieved complete remission, 4 had morphologic leukemia-free state, and 1 had partial remission. Four of 13 (31%) TP53-wild-type patients and 0 of 3 (0%) TP53-mutant patients were responders. AMG 232 was associated with gastrointestinal AEs at higher doses but had acceptable pharmacokinetics, on-target effects, and promising clinical activity warranting further investigation in patients with relapsed/refractory AML. This trial was registered at www.clinicaltrials.gov as #NCT02016729.

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