Phase I Study of Alvocidib Followed by 7+3 (Cytarabine + Daunorubicin) in Newly Diagnosed Acute Myeloid Leukemia

Zeidner, Joshua F.; Lee, Daniel J; Frattini, Mark G.; Fine, Gil D.; Costas, Judy; Kolibaba, Kathryn S.; Anthony, Stephen P.; Bearss, David J.; Smith, B. Douglas

doi:10.1158/1078-0432.ccr-20-2649

Cited by 21 publications

(30 citation statements)

References 44 publications

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“…These have demonstrated preclinical activity in AML, which has been primarily attributed to the depletion of MCL-1 protein with subsequent apoptosis. Several clinical trials with CDK9 inhibitors like alvocidib (NCT03298984, NCT03441555, NCT01349972), dinaciclib (NCT03484520), CYC065 (NCT04017546) and AZD4573 (NCT03263637) have been underway to evaluate their effectiveness in combination with other therapeutics [ 99 , 100 , 101 ].…”

Section: In the Grip Of Apoptosis—the Desired Future After Venetoclaxmentioning

confidence: 99%

Targeting Apoptosis in AML: Where Do We Stand?

Krawiec

Strzałka²,

Czemerska³

et al. 2022

Cancers

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More than 97% of patients with acute myeloid leukemia (AML) demonstrate genetic mutations leading to excessive proliferation combined with the evasion of regulated cell death (RCD). The most prominent and well-defined form of RCD is apoptosis, which serves as a defense mechanism against the emergence of cancer cells. Apoptosis is regulated in part by the BCL-2 family of pro- and anti-apoptotic proteins, whose balance can significantly determine cell survival. Apoptosis evasion plays a key role in tumorigenesis and drug resistance, and thus in the development and progression of AML. Research on the structural and biochemical aspects of apoptosis proteins and their regulators offers promise for new classes of targeted therapies and strategies for therapeutic intervention. This review provides a comprehensive overview of current AML treatment options related to the mechanism of apoptosis, particularly its mitochondrial pathway, and other promising concepts such as neddylation. It pays particular attention to clinically-relevant aspects of current and future AML treatment approaches, highlighting the molecular basis of individual therapies.

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Section: In the Grip Of Apoptosis—the Desired Future After Venetoclaxmentioning

confidence: 99%

Targeting Apoptosis in AML: Where Do We Stand?

Krawiec

Strzałka²,

Czemerska³

et al. 2022

Cancers

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“…A + 7 + 3 was administered to newly diagnosed, treatment‐naïve patients (cohort F1). The dose of each component was fixed according to the recommended dose identified by the phase I study in the United States 11 . Patients received alvocidib plus cytarabine 100 mg/m 2 /d by continuous i.v.…”

Section: Methodsmentioning

confidence: 99%

“…In a phase II clinical trial in patients with newly diagnosed AML, the regimen of alvocidib, cytarabine, and mitoxantrone (ACM) demonstrated a significant improvement in CR rate compared with the standard‐of‐care cytarabine + daunorubicin (7 + 3) regimen 10 . In the recently published phase I study of alvocidib followed by 7 + 3 in newly diagnosed AML, 69% (22/32) of patients achieved CR and 89% (8/9) of CR patients had no measurable residual disease 11 . In a prospective biomarker analysis of an open‐label, phase II clinical study of alvocidib given as timed sequential therapy prior to cytarabine and mitoxantrone (i.e., the ACM regimen) for adults with R/R MCL‐1‐dependent AML (defined as MCL‐1 dependence ≥30%), the overall composite CR rate was 56% (22/39 patients) 12 …”

Section: Introductionmentioning

confidence: 99%

Phase I study of alvocidib plus cytarabine/mitoxantrone or cytarabine/daunorubicin for acute myeloid leukemia in Japan

et al. 2022

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Therapeutic improvements are needed for patients with acute myeloid leukemia (AML), particularly those who have relapsed or who have treatment‐refractory (R/R) AML or newly diagnosed patients with poor prognostic factors. Alvocidib (DSP‐2033), a potent cyclin‐dependent kinase 9 inhibitor, has previously demonstrated promising clinical activity for the treatment of AML. In this multicenter, open‐label, uncontrolled, 3 + 3 phase I study, we investigated the safety and tolerability of alvocidib administered in combination with either cytarabine and mitoxantrone (ACM) for R/R AML or cytarabine/daunorubicin (A + 7 + 3) for newly diagnosed AML. Alvocidib was administered to all patients as a 30‐min intravenous (i.v.) bolus (30 mg/m2/d), followed by a continuous i.v. infusion over 4 h on days 1–3 (60 mg/m2/d). A total of 10 patients were enrolled: six received ACM (at two dose levels of cytarabine and mitoxantrone) and four received A + 7 + 3. Alvocidib was tolerated and no dose‐limiting toxicities were observed. All patients experienced adverse events, of which diarrhea was the most frequent (100%); hematologic events were also common. Alvocidib concentration peaked at the end of dosing (4.5 h after start of administration), plasma accumulation after repeated dosing was minimal and urinary excretion was negligible. The rate of complete remission/complete remission with incomplete hematologic recovery was 66.7% with the ACM regimen in R/R AML, including four complete remission (median duration 13.6 months), and 75% (three complete remission) with the A + 7 + 3 regimen. Further development of alvocidib in hematologic malignancies is warranted. The trial is registered with http://clinicaltrials.gov, NCT03563560.

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“…They are mainly used for combined endocrine therapy for HR+/HER2 54 advanced or metastatic breast cancer in premenopausal/perimenopausal and postmenopausal women. 100 Alvocidib, as well as dinaciclib, seliciclib, SNS‐032, and RGB‐286638 are CDK9 targeted inhibitors, and are mainly used for the treatment of leukemia for reversing the progression of cytarabine resistance 101 , 102 (Figure 4 ).…”

Section: Kinase Groupsmentioning

confidence: 99%

Role of protein phosphorylation in cell signaling, disease, and the intervention therapy

Pang

Wang

Qin

et al. 2022

MedComm

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Protein phosphorylation is an important post‐transcriptional modification involving an extremely wide range of intracellular signaling transduction pathways, making it an important therapeutic target for disease intervention. At present, numerous drugs targeting protein phosphorylation have been developed for the treatment of various diseases including malignant tumors, neurological diseases, infectious diseases, and immune diseases. In this review article, we analyzed 303 small‐molecule protein phosphorylation kinase inhibitors (PKIs) registered and participated in clinical research obtained in a database named Protein Kinase Inhibitor Database (PKIDB), including 68 drugs approved by the Food and Drug Administration of the United States. Based on previous classifications of kinases, we divided these human protein phosphorylation kinases into eight groups and nearly 50 families, and delineated their main regulatory pathways, upstream and downstream targets. These groups include: protein kinase A, G, and C (AGC) and receptor guanylate cyclase (RGC) group, calmodulin‐dependent protein kinase (CaMK) group, CMGC [Cyclin‐dependent kinases (CDKs), Mitogen‐activated protein kinases (MAPKs), Glycogen synthase kinases (GSKs), and C dc2‐like kinases (CLKs)] group, sterile (STE)‐MAPKs group, tyrosine kinases (TK) group, tyrosine kinase‐like (TKL) group, atypical group, and other groups. Different groups and families of inhibitors stimulate or inhibit others, forming an intricate molecular signaling regulatory network. This review takes newly developed new PKIs as breakthrough point, aiming to clarify the regulatory network and relationship of each pathway, as well as their roles in disease intervention, and provide a direction for future drug development.

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Phase I Study of Alvocidib Followed by 7+3 (Cytarabine + Daunorubicin) in Newly Diagnosed Acute Myeloid Leukemia

Cited by 21 publications

References 44 publications

Targeting Apoptosis in AML: Where Do We Stand?

Targeting Apoptosis in AML: Where Do We Stand?

Phase I study of alvocidib plus cytarabine/mitoxantrone or cytarabine/daunorubicin for acute myeloid leukemia in Japan

Role of protein phosphorylation in cell signaling, disease, and the intervention therapy

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