Preemptive treatment with venetoclax plus azacitidine in patients diagnosed with acute myeloid leukemia (AML) with persistence or reappearance of measurable residual disease (MRD) after frontline chemotherapy and high-level MRD prior to allogeneic hematopoietic cell transplantation (alloHCT)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Grupo Cooperativo De Estudio Y Tratamiento De Las Leucemias Agudas Y Mielodisplasias

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Dec 2024 → ongoing

Decision date (initial)

2024-08-14

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To determine Ven/Aza treatment activity in MRD clearance in patients diagnosed with acute myeloid leukemia (AML) with persistent MRD or MRD reappearance after frontline chemotherapy, or prior to alloHCT.

Secondary objectives 2

1. To assess the activity of Ven/Aza treatment in disease control in patients diagnosed with AML with persistent MRD or MRD reappearance after frontline chemotherapy or prior to allo-HCT.
2. To assess the safety of Ven/Aza treatment in disease control in patients diagnosed with AML with persistent MRD or MRD reappearance after frontline chemotherapy and prior to allo-HCT.

Conditions and MedDRA coding

Patients diagnosed with acute myeloid leukemia (AML) with persistent measurable residual disease (MRD) or MRD reappearance after frontline chemotherapy, or prior to allogeneic hematopoietic cell transplantation (alloHCT). Patients will be recruited in two independent cohorts depending on the pre-established time point for the intervention and ELN risk subtype: - Cohort 1: Patients diagnosed with a favorable European LeukemiaNet (ELN) subtype AML, not intended for alloHCT in first complete remission (CR1), but who present an MRD failure by after frontline intensive chemotherapy, as defined in the 2021 update on MRD guidelines elaborated by the European LeukemiaNet MRD Working Party (Heuser et al. 2021): ○ In patients with persistent low-level MRD (<2%) after consolidation chemotherapy, an increase of MRD ≥1log10 between 2 positive samples ○ Confirmed MRD conversion of MRD negativity to MRD positivity AML during subsequent follow-up (up to 3 years after chemotherapy completion). - Cohort 2: Patients diagnosed with a non-favorable ELN AML subtype, intended to undergo alloHCT, in first complete morphological remission but harboring detectable MRD at time of alloHCT (>0.1%).

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. A patient will be eligible for study participation if he/she meets the following criteria within 30 days prior to the first day of therapy (bone marrow biopsy can be performed 30 days prior to the first day of therapy). Historical records are permitted per investigator discretion.
2. Patients must have confirmation of with acute myeloid leukemia (AML) with persistent measurable residual disease (MRD) or MRD reappearance after frontline intensive chemotherapy (including at least one cycle of cytarabine and anthracycline), and prior to allogeneic hematopoietic cell transplantation (allo-HCT). a. In patients with NPM1 mutation, qRT-PCR of NPM1 will be the method used to establish a molecular failure, defined as failure to achieve molecular response after consolidation therapy (NPM1mut/ABL1·100 > 0.01) or MRD reappearance after molecular response. All cases of molecular failure must be confirmed with a second MRD assessment in 2 to 4 weeks. b. In patients with core-binding factor AML, qRT-BCR of RUNX1-RUNX1T1 and CBFb-MYH11 transcripts will be used. Patients failing to achieve a major MRD reduction after consolidation therapy (i.e., RUNX1-RUNX1T1/ABL1·100>0.1 or CBFb-MYH11/ABL1·100>0.1), a log increase in MRD between two positive samples or confirmed MRD CETLAM-LMA-AC-2024-01- Protocol Version - 1.0 17JUL2023 Page 14/103 VERDI reappearance after molecular response will be considered as molecular failures and could be included in the trial. c. In the remaining cases, an appropriate leukemia-associated immunophenotype (LAIP) measured by multiparameter flow cytometry will be used for MRD surveillance. A cutoff of 0.1% will be used to define MRD positivity.
3. Age ≥18 years.
4. Without clinical signs of active central nervous system disease.
5. Patients must have an Eastern Cooperative Oncology Group (ECOG) Performance status of ≤2 or Karnosky performance status (KPS) equivalent (Appendix
6. Patients must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula.
7. Patients must have adequate liver function as demonstrated by: a. aspartate aminotransferase (AST) ≤ 3.0 × upper limit normal (ULN) b. alanine aminotransferase (ALT) ≤ 3.0 × ULN c. bilirubin ≤ 1.5 × ULN, unless due to Gilbert's syndrome
8. Non-sterile male patients must use contraceptive methods with partner(s) prior to beginning study drug administration and continuing up to 3 months after the last dose of study drug. Male patients must agree to refrain from sperm donation from initial study drug administration until 3 months after the last dose of study drug.
9. WOCBP (Appendix 7) must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting therapy; 2) throughout the entire duration of treatment; 3) during dose interruptions; and 4) for at least 6 months after discontinuation of therapy (last dose of study drug).
10. Patients must voluntarily sign and date an informed consent, approved by an Institutional Review Board (IRB), prior to the initiation of any research directed screening procedures.

Exclusion criteria 11

1. Patient has received other prior rescue treatment for MRD.
2. Patient is known to be positive for Human immunodeficiency virus (HIV). infection with the exception of those with an undetectable viral load under correct virological control throughout the study
3. Patient is known to be positive for hepatitis B (HBV) or C (HCV) infection with the exception of those with an undetectable viral load. CETLAM-LMA-AC-2024-01- Protocol Version - 1.0 17JUL2023 Page 15/103 VERDI Note: Hepatitis B or C testing is not required and patients with serologic evidence of prior vaccination to HBV (i.e., HBsAg-, anti-HBs+ and anti-HBc-) may participate.
4. El paciente tiene afectación activa conocida del sistema nervioso central (SNC) por leucemia mieloide aguda.
5. Patient has received within 7 days prior to the first dose of study drug: steroid therapy ≥ 20 mg/day (prednisone or equivalent) for antineoplastic intent; strong and moderate CYP3A inhibitors; strong and moderate CYP3A inducers.
6. Patient has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to the initiation of study treatment.
7. Patient has any history of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participating in this study including, but not limited to: a. New York Heart Association heart failure > class 2. b. Renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemia.
8. Patient has a malabsorption syndrome or other condition that precludes the enteral route of administration.
9. Patient exhibits evidence of uncontrolled systemic infection requiring therapy (viral, bacterial or fungal).
10. Patient has a history of other malignancies within the prior year to study entry, except for: a. Adequately treated in situ carcinoma of the breast or cervix uteri. b. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin. c. Prostate cancer with no plans for therapy of any kind. d. Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
11. Pregnant and breastfeeding females.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Rate of MRD conversion after 2 to 4 courses of Ven/Aza treatment.

Secondary endpoints 2

1. Duration of MRD response: The length of time from the first obtention of MRD clearance until MRD progression.
2. Relapse risk after intervention: The length of time from the intervention for AML until confirmed hematological relapse.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Grupo Cooperativo De Estudio Y Tratamiento De Las Leucemias Agudas Y Mielodisplasias

Sponsor organisation

Grupo Cooperativo De Estudio Y Tratamiento De Las Leucemias Agudas Y Mielodisplasias

Address

Calle De San Antonio Maria Claret 167 Bj

City

Barcelona

Postcode

08025

Country

Spain

Scientific contact point

Organisation

Grupo Cooperativo De Estudio Y Tratamiento De Las Leucemias Agudas Y Mielodisplasias

Contact name

CETLAM Technical Secretariat

Public contact point

Organisation

Grupo Cooperativo De Estudio Y Tratamiento De Las Leucemias Agudas Y Mielodisplasias

Contact name

MFAR Clinical Research

Locations

1 EU/EEA country · 14 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications