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

2020 ◽  
Vol 4 (9) ◽  
pp. 2032-2043 ◽  
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.

Results of a Phase 1/2a dose–escalation study of FF-10501-01, an IMPDH inhibitor, in patients with acute myeloid leukemia or myelodysplastic syndromes

2020 ◽  
Vol 61 (8) ◽  
pp. 1943-1953 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Naveen Pemmaraju ◽  
Yesid Alvarado ◽  
Kiran Naqvi ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dose Escalation ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Dose Escalation Study ◽  
Acute Myeloid

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

2019 ◽  
Vol 3 (13) ◽  
pp. 1939-1949 ◽  
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.

scholarly journals 445 Trial in progress: A phase 1b/2 study of alrizomadlin (APG-115), alone or combined with 5-azacitidine, in patients with relapsed/refractory acute myeloid leukemia (R/R AML)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A474-A474
Author(s):  
Yifan Zhai ◽  
Tapan Kadia
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Leukemia ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Maximum Tolerated Dose ◽  
Wild Type ◽  
Open Label ◽  
Durable Response ◽  
Link Type ◽  
Acute Myeloid

BackgroundAcute myeloid leukemia (AML) is the most common form of acute leukemia in adults, with an incidence that increases with age and a generally poor prognosis. This aggressive blood and bone-marrow malignancy is characterized by rapid and uncontrolled clonal proliferation of abnormal myeloid progenitor cells. Patients with R/R AML have very few approved effective treatment options, especially in the absence of a targetable mutation. Alrizomadlin is a novel, orally active, potent, small-molecule selective inhibitor that destabilizes the p53-MDM2 complex and activates p53-mediated apoptosis in tumor cells with wild-type TP53 and/or MDM2 amplification. In acute leukemia human wild-type TP53 AML cell lines and xenograft models, alrizomadlin potently inhibited tumor cell growth when administered alone or with concomitant chemotherapy.MethodsThis US open-label study is evaluating the safety and tolerability of alrizomadlin, with or without 5-azacitidine, in adults with histologically confirmed R/R AML and adequate organ function. Eligible candidates will have AML with no known available therapies that are either indicated or expected to confer a durable response. In Part 1 of this trial, the safety and tolerability of alrizomadlin monotherapy are being assessed by evaluating the dose-limiting toxicity rate during the first 4 weeks of treatment, using a standard 3+3 design. The starting once-daily oral dose of alrizomadlin administered on Day 1 to 5 of every 28-day cycle is 100 mg, increasing to 150, 200, and 250 mg in each subsequent cohort. The severity of adverse events is being assessed using NCI CTCAE v5.0. Once the recommended phase 2 dose (RP2D) has been determined, 3 to 6 additional patients will be enrolled in the dose-expansion phase. In Part 2, alrizomadlin will be administered in combination with 5-azacitidine 75 mg/m2/day on Days 1–7 of a 28-day cycles. Alternatively, a 5-days-on, 2-days-off, 2-days-on schedule is allowed if consecutive day infusion is not available. A standard 3+3 design will also be implemented to determine the maximum tolerated dose/RP2D in the dose-escalation phase. Once the RP2D has been determined, there will be an expansion cohort of up to 15 patients. As of July 13, 2021, 2 patients have been enrolled in the alrizomadlin monotherapy dose-escalation phase. The overall estimated enrollment will be 69 study participants. Internal study identifier APG115AU101. ClinicalTrials.gov identifier: NCT04358393.Trial RegistrationClinicalTrials.gov identifier: NCT04358393

scholarly journals Safety and tolerability of lenalidomide maintenance in post-transplant acute myeloid leukemia and high-risk myelodysplastic syndrome

2021 ◽  
Author(s):  
Brian Pham ◽  
Rasmus Hoeg ◽  
Rajeev Krishnan ◽  
Carol Richman ◽  
Joseph Tuscano ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Chronic Gvhd ◽  
Maximum Tolerated Dose ◽  
Cell Transplant ◽  
Dose Escalation Study ◽  
Post Transplant ◽  
Acute Myeloid

AbstractRelapse after allogeneic stem cell transplant in unfavorable-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) portends a poor prognosis. We conducted a single-center phase I dose-escalation study with lenalidomide maintenance in high-risk MDS and AML patients after allogeneic transplantation. Sixteen patients enrolled in a “3 + 3” study design starting at lenalidomide 5 mg daily, increasing in increments of 5 mg up to 15 mg. Lenalidomide was given for 21 days of a 28-day cycle for a total of six cycles. Most common dose-limiting toxicities were lymphopenia, diarrhea, nausea, and neutropenia. Two patients had acute graft-versus-host disease (GVHD), and five patients developed chronic GVHD. The maximum tolerated dose was 10 mg, after dose-limiting toxicities were seen in the 15 mg group. Two dose-limiting toxicities were seen from development of acute GVHD and grade III diarrhea. Limitations of the study include time to initiation at 6 months post transplant, as many high-risk patients will have relapsed within this time frame before starting maintenance lenalidomide. Overall, lenalidomide was well tolerated with minimal GVHD and low rates of relapse rates, warranting further study.

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