Study to determine safety, efficacy and tolerability of Venetoclax in combination with Fludarabine, Citarabine and Idarubicin to achieve "the absence of disease" in newly diagnosed Acute Myeloid Leukemia not classified as low risk that is there is an intermediate risk or high that the disease recurs

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

26 Oct 2018 → ongoing

Decision date (initial)

2024-08-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AbbVie Srl · A.I.L. Associazione Italiana contro le leucemie · Fondazione GIMEMA Franco Mandelli onlus

External identifiers

EU CT number

2023-510517-26-00

EudraCT number

2018-000392-33

WHO UTN

U0000-0000-0000

ClinicalTrials.gov

NCT03455504

ISRCTN

ISRCTN00000000

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacodynamic, Efficacy, Pharmacokinetic, Safety

The primary objectives of the study are:
- To determine efficacy of Venetoclax added in combination with chemotherapy in obtaining Complete remission (CR + CRi + CRp) in new onset, non ELN Low risk AML (safety run-in, part1, and part2).

Co-primary objectives:
- Determine safety of combination of Venetoclax and FLAI scheme (safety run-in)
- Determine best dose of the tested compound in combination (part 1)

Secondary objectives 7

1. Establish survival of the treatment population (run-in, part1, and part 2) in term of: 1) Overall Survival as the time between diagnosis and death or last follow-up 2)Disease Free Survival as the time between complete remission and relapse or death for any cause or last follow-up visit
2. Define treatment safety and incidence of adverse events (run-in, part1, and part 2)
3. Define the number of patient that will have a transplant (run-in, part1, and part2)
4. Determine the pharmacokinetic parameters of the tested compound in combination with chemotherapy (run-in and part 1)
5. Determine the pharmacodynamics parameters of the tested compound in combination with chemotherapy (run-in and part 1)
6. Determine safety and effectiveness of long term maintenance with venetoclax (run-in, part1 and part 2)
7. Describe the role of MRD determination with specific fusion genes or specific gene mutation (run-in, part 1 and part 2)

Conditions and MedDRA coding

Acute Myeloid Leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Patients with newly diagnosed non-m3 acute myeloid leukemia documented / confirmed according to WHO 2017 diagnostic criteria
2. The haematological pathology must be classified as intermediate or high risk according to the ELN criteria
3. Patients between the ages of 18 and 65
4. ECOG Performance Status = 2
5. Patients with life expectancy> 12 weeks
6. Patients may have Acute Myeloid Leukemia arising after previous treatment or other antecedent pathology
7. Adequate hepatic function as established by the following criteria: 1) Total serum bilirubin = 2 above the normal limit, if not considered for Gilbert's syndrome or a hepatic infiltration of leukemia 2) Alanine aminotransferase (ALT) =2.5 higher at the normal limit (or below the limit of normality of the reference laboratory, in the case of hepatic leukemia infiltration) 3) Aspartate aminotransferase (AST) =2.5 higher than the normal limit (or = 5 higher than the normal limit of the reference case, in case of hepatic infiltration of leukemia) 4) Adequate pancreatic function as established by the following criterion: serum lipase and amylase =2 higher than the normal limit
8. Adequate renal function, principle based on: serum creatinine in the reference laboratory or creatinine clearance (based on the Cockcroft Gault formula) = 50 ml / min for patients in whom, according to the Inve
9. All non-haematological adverse events should be resolved to = 2 NCI-CTCAE, prior to initiation of therapy.
10. Patients should be considered suitable by the Investigator to receive the chemotherapy combination.
11. The chemotherapy combination should not be considered toxic without waiting for a benefit for the patient
12. For women of child-bearing potential, a negative pregnancy test must be documented within 72 hours prior to the first study drug administration
13. All patients should be willing to use effective contraception during the treatment period and for the next 100 days after the last dose of Venetoclax. Women must be postmenopausal (= 1 year of amenorrhea), surgically sterile, or have to consent to the use of 2 contraceptive methods with at least one method with a failure rate = 1% per year (eg hormonal devices, contraceptives combined oral, partners with vasectomies) and as a second, preferably a contraceptive barrier method. Oral or injectable contraceptive instruments can not be used as the only method. Male patients must be surgically sterile to consent to use an acceptable method of contraception
14. Ability to understand and availability to sign informed consent.
15. The subject must voluntarily sign and date informed consent, approved by an Independent Ethics Committee (IEC) / Institutional Review Board (IRB), prior to the start of any screening or study-specific procedure

Exclusion criteria 19

1. Patients with low risk AML according ELN criteria
2. Patients with current clinical evidence of CNS leukemia.
3. Patients with myeloproliferative syndromes assessed by bone marrow biopsy
4. AML supervening after antecedent myelodysplastic syndromes of more than 6 months duration
5. Any patient with an history of neoplastic disease with the exception of: a. patients with non-melanoma skin cancer or stage I cancer who do not received systemic chemotherapy or radiation whom cancer where completely removed from at least 1 year a.b. patients who are alive, in complete remission and with no evidence of the neoplasia from at least 5 years
6. Patients receiving any other investigational or commercial agents or therapies administered with the intention to treat their malignancy with the exception of Hydroxyurea (HU) or 6-Mercaptopurine (6MP) in patients who need to continue this agent to maintain WBC count =10,000/mm3. HU and 6MP must be discontinued at the time of initiation of study medications.
7. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study including but not limited at: unstable angina, symptomatic or otherwise uncontrolled arrhythmia requiring medication (does not include stable, lone atrial fibrillation), QTcF = 480 msecs based on the average of 3 screening ECG’s, uncontrolled hypertension, symptomatic congestive heart failure (NYHA III, IV), ejection fraction <40, serious uncontrolled cardiac arrhythmia, cerebrovascular accidents = 6 months before study treatment start, any active (acute or chronic) or uncontrolled infection/disorders that impair the ability to evaluate the patient or for the patient to complete the study.
8. Patients who are on anti-microbial agents with therapeutic intent for the following conditions: Fungal infection with visceral involvement, other than mucosal candidiasis, with = 2 weeks of appropriate systemic antifungal therapy, Bacterial infection with positive blood cultures in the 7 days prior to dosing or with= 5 days of appropriate therapeutic antibiotic therapy, Neutropenic fever considered infection-related within 72h prior to dosing, Infection considered by the investigator to be clinically uncontrolled or at unacceptable risk to the patient upon induction of neutropenia
9. Patients with nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by this study treatment, such as, severe diabetes mellitus that is not controlled with medical management.
10. Patients with evidence of electrolyte imbalance such as hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia (corrected for serum albumin level), hypomagnesemia, and hypomagnesemia of Grade = 2, as per NCICTCAE, version 5 which cannot be corrected prior to study initiation.
11. Patients with creatinine clearance <40ml/min (crokoft-grault calculation will be consider reliable for patients <65 years and with no history of renal diseases)
12. Patients who must receive strong CYP3A4 inducers or moderate/strong CYP3A4 inhibitors while on study except for antifungal prophylaxis.
13. HIV-positive patients receiving combination anti-retroviral therapy.
14. Patients who refuse to potentially receive blood products and/or have a hypersensitivity to blood products.
15. Patients with a history of active or chronic infectious hepatitis unless serology demonstrates clearance of infection.
16. Patients who have a history of liver cirrhosis by radiologic, clinical or laboratory data, or biopsy despite normal liver function tests.
17. Patients who have had prior BCL-2 antagonists.
18. Pregnant or breast feeding patients.
19. Patients with reproductive potential not willing to use effective methods of contraception.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary end point is % of CR (CR + CRi + CRp) after course 1 or course 2 if course 2 is administered

Secondary endpoints 7

1. Incidence time and nature of any adverse event.
2. Severe effect related to treatment safety is defined as an adverse event occurring within the first cycle, judged to be related to treatment and meeting any of the following criteria: 1) Grade 3 non- hematological toxicity lasting more than 7 days 2) Grade 4 non- hematological toxicity.
3. DLT as any grade 4 non-infective and non-hematologic adverse event that for the experience of the investigator cannot be due to FLAI chemotherapy alone and any grade 5 adverse event
4. Incidence, severity, seriousness and treatment-causality of Treatment Emergent Signs and Symptoms.
5. Frequency of clinically significant abnormalities in physical examination, safety laboratory tests, vital signs and 12-Lead ECG
6. TLS occurred during or after protocol or transplant procedures for up to 1 years.
7. Description of patient-reported QoL over time

Investigational products

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

Test 3

Auxiliary 3

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

Centro Dati GIMEMA

Public contact point

Organisation

Fondazione Gimema Franco Mandelli Onlus

Contact name

Centro Dati GIMEMA

Third parties 2

Locations

1 EU/EEA country · 25 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 9 files

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

Application history

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