Alvocidib (CDK9 Inhibitor)
Alvocidib is an investigational, intravenously administered, small molecule cyclin-dependent kinase 9 (CDK9) inhibitor.1
Mechanism of Action
Alvocidib is a potent inhibitor of CDK9.2 The primary function of CDK9 is to activate transcription elongation by phosphorylating the C-terminal domain of RNA polymerase II.3 By inhibiting CDK9, alvocidib downregulates the transcription of target genes, including the myeloid cell leukemia-1 (MCL-1) gene.1 In MCL-1—dependent acute myeloid leukemia (AML), downregulation of MCL-1 protein expression can trigger apoptosis of leukemic blasts.4
Alvocidib has shown clinical activity in multiple types of solid tumors and hematologic malignancies.2 Tolero’s initial focus is the development of alvocidib in MCL-1–dependent AML.
Proof of concept was shown in a multicenter, randomized, phase 2 clinical trial, in which alvocidib in combination with cytarabine and mitoxantrone (ACM) was compared to the standard-of-care cytarabine/daunorubicin (7+3) regimen in newly diagnosed, intermediate- and high-risk AML patients. ACM showed a significant improvement in the complete remission (CR) rate compared to 7+3.5
Phase 2: Alvocidib biomarker-driven trial in relapsed/refractory AML
A phase 2, biomarker-driven, clinical trial (Zella 201) is currently being conducted to compare ACM with cytarabine and mitoxantrone in patients with MCL-1–dependent, relapsed or refractory AML.
This study includes an exploratory arm in adult patients with newly diagnosed high-risk AML and exploratory arms with varying levels of MCL-1 dependency.
Key Inclusion Criteria
- ≥18 and ≤65 years of age
- ECOG PS ≤2
- Pathologically confirmed
diagnosisof AML by World Health Organization criteria, excluding acute promyelocytic leukemia, with a bonemarrow of >5% blasts based on histology or flow cytometry
- In first relapse (within 24 months of CR) or have failed induction therapy (no CR or CRi after treatment with an intensive regimen [eg, anthracycline/cytarabine ± etoposide, gemtuzumab ozogamicin, or cladribine]), or have newly diagnosed high-risk AML
Induction therapy may involve 1 or 2 cycles of the same regimen. Efficacy assessment of induction therapy must be >21 days from the start of the previous induction cycle
- MCL-1 dependency of ≥40% or 30%–<40% (Arm A), 15%–<30% (Arm B), or 0%–<15% (Arm C) as evaluated in bone marrow
- Not received more than 2 cycles of induction therapy for AML, any previous treatment with alvocidib or any other cyclin-dependent kinase (CDK) inhibitor, a hematopoietic stem cell transplant within the previous 2 months, or >360 mg/m2 equivalent of daunorubicin
- Cytarabine and mitoxantrone must be an acceptable treatment option
See ClinicalTrials.gov (NCT02520011) for comprehensive eligibility criteria.
For sites in the US/Canada, and Europe that
*Patients randomized to CM who exhibit progressive disease or no response after a single cycle of CM, or who have
†High-risk AML is characterized by treatment-related AML, secondary AML defined as AML from preexisting myelodysplastic syndromes or myeloproliferative neoplasms, or adverse-risk cytogenetics according to 2017 European LeukemiaNet Guidelines.
Phase 1: Alvocidib and cytarabine/daunorubicin (7+3) in patients with newly diagnosed AML
A phase 1 trial (Zella 101) is currently being conducted to evaluate the maximum tolerated dose, safety, and clinical activity of alvocidib and cytarabine/daunorubicin (7+3) in patients with newly diagnosed, intermediate- and high-risk AML.
Primary outcome measures:
- Maximum tolerated dose
- Dose-limiting toxicities
Secondary outcome measures:
- Antileukemic activity of alvocidib plus 7+3
- Correlation between benefit from alvocidib and sequential 7+3 therapy and evaluation of MCL-1 dependency and other potential biomarkers
- Recommended phase 2 dose of alvocidib in combination with 7+3
Key Inclusion Criteria
- ≥18 and ≤65 years of age
- ECOG PS ≤2
- Pathologically confirmed diagnosis of AML by World Health Organization criteria, excluding acute promyelocytic leukemia and core binding factor AML, with ≥20% bone marrow blasts based on histology or flow cytometry
- Newly diagnosed and previously untreated AML
- Not received >100 mg/m2 equivalent of daunorubicin
See ClinicalTrials.gov (NCT03298984) for comprehensive eligibility criteria.
For sites in the US that are actively recruiting, visit ClinicalTrials.gov (NCT03298984).
IV=intravenous; MCL-1=myeloid cell leukemia 1; ECOG PS=Eastern Cooperative Oncology Group Performance Status.
Phase 1b/2: Alvocidib plus decitabine in patients with MDS
A phase 1b/2 trial is currently being conducted to evaluate the maximum tolerated dose, safety, and clinical activity of alvocidib administered in sequence after decitabine in patients with MDS.
Primary outcome measures
- Phase 1b: Incidence of dose-limiting toxicities and treatment-emergent adverse events
- Phase 2: Objective response rate at 3 months using revised International Working Group criteria6
Secondary outcome measures
- Phase 1b: Complete response rate (CRR) at 3 months
- Phase 1b and 2: Decitabine treatment effect on BH3 profiling results in peripheral blood to find the correlation between the CRR and BH3 profiling by flow cytometry with an emphasis on MCL-1 dependence
Key inclusion criteria
- Age ≥18 years
- ECOG PS ≤2
- Phase 1b: Patients with previously untreated MDS and patients who received fewer than 6 cycles of previous hypomethylating agents
- Phase 2: Untreated patients with de novo or secondary MDS
- Suspected (eg, persistent unexplained cytopenia, circulating peripheral blasts, etc) MDS and undergoing diagnostic work-up with planned bone marrow assessments, or diagnosed with de novo or therapy-related MDS within 6 months of enrollment (per the 2016 World Health Organization guidelines) and undergoing clinical evaluation and planned bone marrow assessments to confirm MDS or to evaluate disease status
See ClinicalTrials.gov (NCT03593915) for comprehensive eligibility criteria.
For sites in the US, visit ClinicalTrials.gov (NCT03593915).
MDS=myelodysplastic syndromes; IV=intravenous; BH3=B cell leukemia/lymphoma-2 homology domain 3; MCL-1=myeloid cell leukemia 1; ECOG PS=Eastern Cooperative Oncology Group Performance Status.
Alvocidib is an investigational, intravenously administered, small molecule cyclin-dependent kinase 9 (CDK9) inhibitor not yet approved by the US FDA or any other health authorities.
- Yeh YY, Chen R, Hessler J, et al. Up-regulation of CDK9 kinase activity and Mcl-1 stability contributes to the acquired resistance to cyclin-dependent kinase inhibitors in leukemia. Oncotarget. 2015;6(5):2667-2679.
- Morales F, Giordano A. Overview of CDK9 as a target in cancer research. Cell Cycle. 2016;15(4):519-527.
- Ocana A, Pandiella A. Targeting oncogenic vulnerabilities in triple negative breast cancer: biological bases and ongoing clinical studies. Oncotarget. 2017;8(13):22218-22234.
- Thomas D, Powell JA, Vergez F, et al. Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. Blood. 2013;122(5):738-748.
- Zeidner JF, Foster MC, Blackford AL, et al. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015;100(9):1172-1179.
- Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108(2):419-425.