Clinical trial NCT05949762: Safety and Efficacy of Venetoclax in Combination With Azacitidine and HA Regimen in the Treatment of AML in the Elderly
Official title: The Second Affiliated Hospital of Kunming Medical University
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia
Lead sponsor: The Second Affiliated Hospital of Kunming Medical University
Sponsor class: OTHER
Collaborators: name: Handan Central Hospital
name: Taian City Central Hospital
name: Tianjin People's Hospital
name: Guizhou Provincial People's Hospital
name: Second Xiangya Hospital of Central South University
name: Western War Zone General Hospital
First posted: 2023-07-18
Enrollment: 45
Sex: FEMALE
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall response rate (ORR)
timeFrame: up to 12 months
Secondary outcomes:
measure: Minimal residual disease (MRD)
timeFrame: up to 12 months
measure: overall survival (OS)
timeFrame: up to 12 months
measure: relapse-free survival (RFS)
timeFrame: up to 12 months
measure: 30-day mortality rate
timeFrame: Within 30 days after starting the medication
measure: adverse drug reactions
timeFrame: up to 12 months
Other outcomes:
Locations:
city: Kunming
country: China
facility: The Second Affiliated Hospital of Kunming Medical University.
state: Yunnan
Study officials:
affiliation: The Second Affiliated Hospital of Kunming Medical University
name: ZePing Zhou
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.