Safety and Efficacy of Venetoclax in Combination With Azacitidine and HA Regimen in the Treatment of AML in the Elderly

The Second Affiliated Hospital of Kunming Medical University

This is a prospective phase II, single-arm clinical study that plans to enroll 45 patients aged 60 years or older with primary AML diagnosed after April 1, 2023.The purpose of this trial is to evaluate the efficacy of Venetoclax in combination with azacitidine and HA regimens in elderly patients aged >60 years with primary acute myeloid leukemia and to provide evidence for optimal selection of clinical treatment regimens.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Procedure: Venetoclax in Combination With Azacitidine and HA Regimen

Detailed Description

Patients diagnosed with primary AML according to morphology, immunophenotyping and medical history and meeting the exclusion criteria for enrollment: induction therapy with Venetoclax combined with azacitidine and HA regimen, after induction therapy up to CR, CRi, MLFS, according to ELN prognostic stratification and NCCN and Chinese guidelines for the treatment of adult AML (non-acute promyelocytic leukemia), according to patient risk stratification and treatment For patients with allogeneic hematopoietic stem cell transplantation due to various reasons (financial, physical, and other reasons), the patient will be recommended for transplantation. Patients who are not considered for allogeneic HSCT due to various reasons (financial, physical, donor constraints, etc.) will continue to receive two courses of intensive treatment with Venetoclax combined with a medium-dose Ara-c regimen and three courses of reduced-dose chemotherapy for consolidation. Patients completing intensive consolidation therapy enter maintenance treatment with Venetoclax in combination with azacitidine, danazol and thalidomide. Patients who do not achieve CR, CRi and MLFS with 1 course of induction therapy will be re-induced with the original regimen if they achieve PR. Patients who did not achieve PR on the first induction treatment and did not achieve CR, CRi, and MLFS after two induction treatments were dropped from the group and given salvage therapy. Patients with persistent positive MRD or recurrence during treatment were withdrawn from the group and given salvage therapy.

• Study Type: Interventional
• Enrollment (Estimated): 45
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: yaxian tan; Phone Number: 18208821198; Email: 353964619@qq.com

Study Locations

• China
  • Yunnan
    • Kunming, Yunnan, China
      • Recruiting
      • The Second Affiliated Hospital of Kunming Medical University.
      • Contact: DanQi Deng, Dr; Phone Number: 087165351281; Email: kycyjszx@public.km.yn.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. patients with acute myeloid leukemia other than APL who meet the World Health Organization diagnostic criteria (WHO 2016 criteria);
2. those with AML not otherwise classified under the World Health Organization AML classification except for acute myeloproliferative disorder with myelofibrosis and myeloid sarcoma.
3. Age > 60 years, male or female.
4. Have a score of 0-2 on the Eastern Cooperative Oncology Group Physical Status Scale (ECOG-PS).
5. pass the requirements of the following laboratory test indicators (performed within 7 days prior to treatment): 1) Aspartate aminotransferase (ALT), alanine aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 x upper limit of normal (ULN), serum bilirubin ≤ 2 x ULN; serum cardiac enzymes < 2.0 x ULN; serum creatinine ≤ 2.0 x ULN; 2) Cardiac ejection fraction within normal values as determined by cardiac ultrasound (ECHO).
6. Informed consent had to be signed before all specific study procedures were started, and the informed consent was signed by the patient himself/herself or his/her immediate family members; in view of the patient's condition, if the signature of the patient himself/herself was not conducive to the treatment of his/her condition, the informed consent was signed by his/her legal guardian or the patient's immediate family members.

Exclusion Criteria:

1、Treated patients (is defined as having received induction chemotherapy in the past, regardless of the efficacy).

2, Concurrent malignant tumors of other organs (those requiring treatment). 3, Patients participating in the trial must use contraception during the trial treatment and within 3 years after completion of treatment.

4, Significantly abnormal liver and kidney function beyond the enrollment criteria.

5. Active heart disease, defined as one or more of the following:

1. History of uncontrolled or symptomatic angina;
2. Myocardial infarction less than 6 months from study entry;
3. A history of arrhythmia requiring medication or clinically significant symptoms;
4. Uncontrolled or symptomatic congestive heart failure (> NYHA class 2);
5. Ejection fraction below the lower limit of the normal range. 6. severe infectious diseases (untreated tuberculosis, pulmonary aspergillosis).

7) Those deemed unsuitable for enrollment by the investigator

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: Venetoclax in Combination With Azacitidine and HA Regimen; Details for: Venetoclax 200mg d1-10 Azacitidine 100mg/d (or 50-75mg/m2/d), d2-7 Hautriacontin 2mg/m2/d, d3-7 Cytarabine 100mg/m2/d, d3-8 (infusion 24h)

Procedure: Venetoclax in Combination With Azacitidine and HA Regimen; Patients diagnosed with primary AML based on morphology, immunophenotyping, and history and meeting the inclusion exclusion criteria were induced with Venetoclax in combination with Azacitidine and HA regimen. Details for: Venetoclax 200mg d1-10 Azacitidine 100mg/d (or 50-75mg/m2/d), d2-7 Hautriacontin 2mg/m2/d, d3-7 Cytarabine 100mg/m2/d, d3-8 (infusion 24h)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	which evaluates the efficacy of patient induction therapy, including complete remission (CR), complete remission with incomplete blood count recovery (CRi), and morphologic leukemia-free state (MLFS)	up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Minimal residual disease (MRD)	MRD percentage	up to 12 months
overall survival (OS)	Overall Survival (OS) is used to evaluate all patients enrolled in a clinical trial, from the date of enrollment until death from any cause or the date of last follow-up for surviving patients.	up to 12 months
relapse-free survival (RFS)	Relapse-Free Survival (RFS) is only used to evaluate patients who achieve complete remission (CR) through reinduction therapy. RFS is defined as the time from achievement of CR until death from any cause, relapse, or the date of last follow-up.	up to 12 months
30-day mortality rate	The 30-day mortality rate is used to evaluate all patients enrolled in a clinical trial, and is defined as the percentage of patients who die within 30 days of starting chemotherapy.	Within 30 days after starting the medication
adverse drug reactions	Adverse drug reactions during chemotherapy and follow-up	up to 12 months

Collaborators and Investigators

• Sponsor: ZePing Zhou
• Collaborators: Guizhou Provincial People's Hospital; Second Xiangya Hospital of Central South University; Tianjin People's Hospital; Taian City Central Hospital; Handan Central Hospital; Western War Zone General Hospital
• Investigators: Study Chair: ZePing Zhou, The Second Affiliated Hospital of Kunming Medical University

Publications and helpful links

General Publications

• Dohner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015 Sep 17;373(12):1136-52. doi: 10.1056/NEJMra1406184. No abstract available.
• Wei AH, Strickland SA Jr, Hou JZ, Fiedler W, Lin TL, Walter RB, Enjeti A, Tiong IS, Savona M, Lee S, Chyla B, Popovic R, Salem AH, Agarwal S, Xu T, Fakouhi KM, Humerickhouse R, Hong WJ, Hayslip J, Roboz GJ. Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study. J Clin Oncol. 2019 May 20;37(15):1277-1284. doi: 10.1200/JCO.18.01600. Epub 2019 Mar 20.
• DiNardo CD, Lachowiez CA, Takahashi K, Loghavi S, Xiao L, Kadia T, Daver N, Adeoti M, Short NJ, Sasaki K, Wang S, Borthakur G, Issa G, Maiti A, Alvarado Y, Pemmaraju N, Montalban Bravo G, Masarova L, Yilmaz M, Jain N, Andreeff M, Jabbour E, Garcia-Manero G, Kornblau S, Ravandi F, Konopleva MY, Kantarjian HM. Venetoclax Combined With FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed or Refractory Acute Myeloid Leukemia. J Clin Oncol. 2021 Sep 1;39(25):2768-2778. doi: 10.1200/JCO.20.03736. Epub 2021 May 27.
• DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, Konopleva M, Dohner H, Letai A, Fenaux P, Koller E, Havelange V, Leber B, Esteve J, Wang J, Pejsa V, Hajek R, Porkka K, Illes A, Lavie D, Lemoli RM, Yamamoto K, Yoon SS, Jang JH, Yeh SP, Turgut M, Hong WJ, Zhou Y, Potluri J, Pratz KW. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020 Aug 13;383(7):617-629. doi: 10.1056/NEJMoa2012971.
• Del Poeta G, Venditti A, Del Principe MI, Maurillo L, Buccisano F, Tamburini A, Cox MC, Franchi A, Bruno A, Mazzone C, Panetta P, Suppo G, Masi M, Amadori S. Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML). Blood. 2003 Mar 15;101(6):2125-31. doi: 10.1182/blood-2002-06-1714. Epub 2002 Nov 7.
• Mei M, Aldoss I, Marcucci G, Pullarkat V. Hypomethylating agents in combination with venetoclax for acute myeloid leukemia: Update on clinical trial data and practical considerations for use. Am J Hematol. 2019 Mar;94(3):358-362. doi: 10.1002/ajh.25369. Epub 2018 Dec 13.
• DiNardo CD, Maiti A, Rausch CR, Pemmaraju N, Naqvi K, Daver NG, Kadia TM, Borthakur G, Ohanian M, Alvarado Y, Issa GC, Montalban-Bravo G, Short NJ, Yilmaz M, Bose P, Jabbour EJ, Takahashi K, Burger JA, Garcia-Manero G, Jain N, Kornblau SM, Thompson PA, Estrov Z, Masarova L, Sasaki K, Verstovsek S, Ferrajoli A, Weirda WG, Wang SA, Konoplev S, Chen Z, Pierce SA, Ning J, Qiao W, Ravandi F, Andreeff M, Welch JS, Kantarjian HM, Konopleva MY. 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. Lancet Haematol. 2020 Oct;7(10):e724-e736. doi: 10.1016/S2352-3026(20)30210-6. Epub 2020 Sep 5.
• Wei H, Wang Y, Gale RP, Lin D, Zhou C, Liu B, Qiu S, Gu R, Li Y, Zhao X, Wei S, Gong B, Liu K, Gong X, Liu Y, Zhang G, Song Z, Wang Y, Li W, Mi Y, Wang J. Randomized Trial of Intermediate-dose Cytarabine in Induction and Consolidation Therapy in Adults with Acute Myeloid Leukemia. Clin Cancer Res. 2020 Jul 1;26(13):3154-3161. doi: 10.1158/1078-0432.CCR-19-3433. Epub 2020 Feb 6.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2023
• Primary Completion (Estimated): April 1, 2024
• Study Completion (Estimated): April 1, 2024

Study Registration Dates

• First Submitted: July 10, 2023
• First Submitted That Met QC Criteria: July 10, 2023
• First Posted (Actual): July 18, 2023

Study Record Updates

• Last Update Posted (Actual): July 18, 2023
• Last Update Submitted That Met QC Criteria: July 10, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Venetoclax; Azacitidine
• Other Study ID Numbers: SHEN-PJ-KE-2023-157

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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