Study aimed at evaluating the efficacy of the combination of the two drugs, Venetoclax and Azacitidine, on the treatment of patients suffering from Acute Myeloid Leukemia with NPM1 mutation.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Gimema Franco Mandelli Onlus

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

1 Mar 2022 → ongoing

Decision date (initial)

2024-07-04

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Fondazione GIMEMA Franco Mandelli onlus · AbbVie Srl

External identifiers

EU CT number

2023-510432-36-00

EudraCT number

2021-002361-17

ClinicalTrials.gov

NCT04867928

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

The primary objective of the trial is to determine the efficacy of venetoclax and azacitidine in preventing morphological relapse in adult NPM1mut AML patients who experience molecular relapse/progression during chemotherapy treatment or subsequent follow-up monitoring.

Secondary objectives 8

1. To evaluate the rate of MRD-negativity achieved with venetoclax-azacitidine
2. To evaluate the number of patients who proceed to allogeneic stem cell transplant (alloSCT)
3. To evaluate the number of patients who proceed to alloSCT in MRD-negativity
4. To evaluate Overall Survival (OS)
5. To evaluate Progression-Free Survival (PFS)
6. To evaluate Molecular Disease-Free Survival (MDFS)
7. To evaluate Molecular progression-free survival (MPFS)
8. To evaluate safety and toxicity of venetoclax-azacitidine in the experimental setting

Conditions and MedDRA coding

Acute Myeloid Leukemia with NPM1 mutation

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Subject must be greater than or equal to 18 years of age
2. Subject must have received previous diagnosis of NPM1mut AML with or without concomitant FLT3-TKD or FLT3-ITD
3. At screening, subject must have confirmed NPM1 type A, B, or D mutant transcripts
4. Subject must be eligible for alloSCT, according to transplant center policy
5. Subject must have undergone at least two cycles of conventional anthracycline- and cytarabine based chemotherapy, achieving first CR (CR1)
6. Subject must be in morphological CR1 with bone marrow detectable minimal residual disease (MRD) positivity, defined as qRT-PCR NPM1 transcript = 0.01/100 ABL1 copies and confirmed in two consecutive determinations performed at 2 to 4 weeks’ distance: a. Molecular progression is defined in patients with molecular persistence at low copy number as an increase of MRD copy number = 1 log10 between 2 positive samples. b. Molecular relapse is defined in patients previously tested MRD negative as an increase in MRD copy number = 1 log10 between 2 positive samples
7. Subject must have a projected life expectancy of at least 12 weeks.
8. Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status < 2
9. Subject must have adequate renal and hepatic function per local laboratory reference range as follows: - Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0X ULN - Bilirubin =1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of nonhepatic origin) - Subject must have adequate renal function as demonstrated by a creatinine clearance = 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours’urine collection.
10. Female subjects of childbearing potential must have negative results for pregnancy test at screening
11. Female and male patients who are fertile must agree to use an effective form of contraception with their sexual partners from screening through 3 months after the end of treatment.
12. Signed written informed consent according to ICH/EU/GCP and national local laws.

Exclusion criteria 13

1. Subject has acute promyelocytic leukemia (APL)
2. Subject has known active CNS involvement with AML
3. Subject has received previous treatment with venetoclax and/or hypomethylating agents
4. Subject has undergone alloSCT for AML
5. Subject has more than 5% of bone marrow blast cells at screening bone marrow aspirate
6. Subject is known to be positive for HIV
7. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: a. Uncontrolled and/or active systemic infection (viral, bacterial or fungal) b. Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate.
8. Cardiac history of CHF requiring treatment or Ejection Fraction = 50% or chronic stable angina;
9. DLCO = 65% or FEV1 = 65%;
10. Creatinine clearance < 30 ml/min
11. Subject has a cardiovascular disability status of New York Heart Association Class > 2 a. Class 2 is i. defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity ii. results in fatigue, palpitations, dyspnea, or anginal pain
12. Patients who are pregnant or breast feeding and adults of reproductive potential not employing an effective method of birth control (women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of induction therapy). Post-menopausal women must be amenorrhoic for at least 12 months to be considered of non-child bearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drugs.
13. Patients unwilling or unable to comply with the protocol

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Percentage of patients who do not experience overt relapse at 6 months or within stem cell transplant

Secondary endpoints 10

1. MRD negativity rate at 3 and 6 months and at transplant
2. Percentage of patients undergoing alloSCT in CR
3. Percentage of patients undergoing alloSCT in MRD negativity
4. Disease Progression rate at 3, 6 and 12 months and at transplant
5. Molecular Disease Progression at 3, 6 and 12 months and at transplant
6. Overall Survival (OS), defined as the number of days between the first study drug administration and death from any cause or lost to follow up.
7. Progression-Free Survival (PFS), defined as the number of days between the first study drug administration and any event including disease progression or death.
8. Molecular Disease-Free Survival (MDFS), defined as the number of days between the data of response (MRD negativity) and molecular disease progression or death.
9. Molecular progression-free survival (MPFS), defined as the number of days between the first study drug administration and molecular disease progression or death.
10. Safety and toxicity of venetoclax-azacitidine in the experimental setting

Investigational products

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

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Gimema Franco Mandelli Onlus

Sponsor organisation

Fondazione Gimema Franco Mandelli Onlus

Address

Via Casilina 5

City

Rome

Postcode

00182

Country

Italy

Scientific contact point

Organisation

Fondazione Gimema Franco Mandelli Onlus

Contact name

GIMEMA Centro Dati

Public contact point

Organisation

Fondazione Gimema Franco Mandelli Onlus

Contact name

GIMEMA Centro Dati

Third parties 2

Locations

1 EU/EEA country · 29 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 4 files

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

Application history

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