A Phase 2 Study of Venetoclax in Combination With Low-dose HHT, G-CSF, and AZA as First-line Treatment for Newly Diagnosed Elderly AML Patients Unfit for Intensive Chemotherapy

Acute myeloid leukemia (AML) is a group of heterogeneous malignancies derived from hematopoietic precursors. Patients older than 65 years can hardly benefit from standard intensive chemotherapy while having a poor toxicity tolerance, leading to a dismal prognosis. Currently, there is no satisfactory treatment modality for this high-risk patient population, which is an unmet clinical need.

Venetoclax (ABT-199/GDC-0199, VEN) is a highly selective, oral B-cell lymphoma 2 (BCL-2) inhibitor that has shown activity in BCL-2- dependent leukemia and lymphoma cell lines, and has recently exerted encouraging therapeutic effect with manageable toxicity profile in the field of treatment of AML. Promising results have emerged in the combination of venetoclax and hypomethylating agents (HMA), decitabine or azacitidin (AZA), producing complete remission (CR) plus CR with incomplete hematologic recovery (CRi) rates of 74% and 66.7%, respectively, in previously untreated elderly AML patients.

Homoharringtonine (HHT) is an alkaloid and has been used in Chinese patients with acute and chronic myeloid leukemia for more than 30 years. The add of HHT to the combination of cytarabin and aclarubicin or daunorubicin has been proved to improve CR rate and prognosis of AML patients. Moreover, HHT combined with low-dose cytarabine and granulocyte colony-stimulating factor (G-CSF) has achieved durable efficacy in AML patients, either in the first-line or salvage setting. Interestingly, HHT has potent synergistic effects with VEN through reducing the expression of BCL-XL and MCL-1 in BCL-2 related pathways as previouly reported.

This study aims at investigating the combination of HHT, VEN, AZA and G-CSF (HVAG) in the treatment of newly diagnosed elderly AML patients who are ineligible for intensive chemotherapy.

Study Overview

• Status: Not yet recruiting
• Conditions: Leukemia, Myeloid, Acute
• Intervention / Treatment: Drug: The combination of HHT, venetoclax, AZA, G-CSF

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participant must have confirmation of Acute Myeloid Leukemia (AML) by World Health Organization (WHO) criteria, previously untreated and unfit for intensive chemotherapy
• Participant must be >= 60 years of age.
• Participant must have a projected life expectancy of at least 12 weeks.
• Participant must have adequate renal function as demonstrated by a creatinine >= 30 mL/min;determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula

• Participant must have adequate liver function as demonstrated by:

  1. aspartate aminotransferase (AST) <= 3.0 x ULN*
  2. alanine aminotransferase (ALT) <= 3.0 x ULN*
  3. bilirubin <= 1.5 x ULN* * Unless considered to be due to leukemic organ involvement i. Subjects who are < 75 years of age may have a bilirubin of <= 3.0 x ULN

Exclusion Criteria:

• Participant has history of myeloproliferative neoplasm (MPN) including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia (CML) with or without BCR-ABL1 translocation and AML with BCR-ABL1 translocation
• Participant has acute promyelocytic leukemia
• Participant has known active central nervous system (CNS) involvement with AML
• Participant is known to be positive for hepatitis B or C infection
• Participant has received anticancer therapies including chemotherapy, radiotherapy or other investigational therapy, including targeted small molecule agents within 5 half-lives prior to first dose of study drug
• Participant has received biologic agents (e.g. monoclonal antibodies) for anti-neoplastic intent within 30 days prior to first dose of study drug

• Participant has received the following within 7 days prior to the first dose of the study drug:

  1. Steroid therapy for anti-neoplastic intent;
  2. Strong and Moderate CYP3A inhibitors (see Appendix A for examples)
  3. Strong and Moderate CYP3A inducers (see Appendix A for examples)
• Participant exhibits evidence of other clinically significant uncontrolled systemic infection requiring therapy
• Participant has a serious cardiovascular, pulmonary or renal disability

• Participant has a history of other malignancies within 2 years prior to study entry, with the exception of:

  1. Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast;
  2. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
  3. Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent; requires discussion with TA MD.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HVAG regimen	Drug: The combination of HHT, venetoclax, AZA, G-CSF; HVAG regimen in a 28-day cycle HHT: d1-d7 1mg/m2; VEN: d1 100mg, d2 200mg, d3-d28 400mg; AZA: d1-d7 75mg/m2; G-CSF: d1-d7 300mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of complete remission (CR)	including Complete Remission with incomplete Platelet recovery (CRp) and Complete Remission with incomplete hematologic recovery (CRi)	Up to 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival (EFS)	EFS is defined as the time from the date of randomization until the date of documented relapse or discontinuation of the treatment, or initiation of other anti-leukemic treatment or death from any cause, whichever occurs first	Up to 36months
Relapse-free survival	Relapse-free survival (RFS) will be measured from time of CR to either leukemia relapse or death, whichever comes first. Leukemia relapse will be defined as bone marrow (BM) blasts 5% or higher (not attributable to regenerating BM), any circulating blasts (not attributable to regenerating BM or growth factors), or any extra-medullary blast foci as per Revised International Working Group (R-IWG) criteria.	36 months
Overall survival(OS)		Up to 36 months
Safety and tolerability assessed by incidence and severity of adverse events	All grade ≥ 3 toxicities according to CTCAE (Common Terminology Criteria for Adverse Events) version 5 will be tabulated	36 months

Collaborators and Investigators

• Sponsor: Shanghai Jiao Tong University School of Medicine

Study record dates

Study Major Dates

• Study Start (Anticipated): March 1, 2021
• Primary Completion (Anticipated): March 1, 2024
• Study Completion (Anticipated): March 1, 2024

Study Registration Dates

• First Submitted: March 28, 2021
• First Submitted That Met QC Criteria: March 28, 2021
• First Posted (Actual): April 1, 2021

Study Record Updates

• Last Update Posted (Actual): April 1, 2021
• Last Update Submitted That Met QC Criteria: March 28, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: AML; combination therapy; venetoclax
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Antineoplastic Agents; Venetoclax
• Other Study ID Numbers: YangSHEN

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No