Study of Venetoclax in Combination With Azacytidine in AML Patients Selected Using Ex Vivo Drug Sensitivity Screening

NCT ID: NCT04267081

Last Updated: 2024-09-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 104 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-02-12
• Study Completion Date: 2024-02-28

Brief Summary

This is a multi center two-stage, two-arm, open label phase II study of venetoclax in combination with azacytidine in acute myeloid leukemia patients selected for therapy with ex vivo venetoclax sensitivity screening. This study will characterize the usability of ex vivo drug sensitivity testing for patient selection for selecting the responsive patients for venetoclax therapy. The exploratory study will aim to find novel combinations for overcoming resistance as well as finding/validating biomarkers for both sensitivity and resistance.

Conditions

Acute Myeloid Leukemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm 1 (de novo AML)

This arm will recruit the patients with de novo AML unfit for conventional chemotherapy. In validation cohort all the participants will receive azacytidine-venetoclax. In study cohort the patients with ex vivo resistance to venetoclax will be excluded from the study therapy.

All patients in validation and study cohorts (ARM1 and ARM2) will receive azacytidine and venetoclax. The purpose for the validation cohort is to validate the specificity and sensitivity of the ex vivo drug testing. Patients exhibiting ex vivo sensitivity and receiving azacytidine-venetoclax in validation cohort are analyzed also for study cohort.

Group Type: EXPERIMENTAL

Venetoclax

Intervention Type: DRUG

Ex vivo venetoclax sensitivity testing is used for patient selection.

Arm 2 (relapsed, refractory or secondary AML)

This arm will recruit the patients with relapsed, refractory or secondary AML. In validation cohort all the participants will receive azacytidine-venetoclax. In study cohort the patients with ex vivo resistance to venetoclax will be excluded from the study therapy.

All patients in validation and study cohorts (ARM1 and ARM2) will receive azacytidine and venetoclax. The purpose for the validation cohort is to validate the specificity and sensitivity of the ex vivo drug testing. Patients exhibiting ex vivo sensitivity and receiving azacytidine-venetoclax in validation cohort are analyzed also for study cohort.

Group Type: EXPERIMENTAL

Venetoclax

Intervention Type: DRUG

Ex vivo venetoclax sensitivity testing is used for patient selection.

Interventions

Venetoclax

Ex vivo venetoclax sensitivity testing is used for patient selection.

Intervention Type: DRUG

Other Intervention Names

Ex vivo drug sensitivity testing

Eligibility Criteria

Inclusion Criteria

1. Written informed consent

2. Patients who present with one of the following (except acute promyelocytic leukemia):

• De novo or secondary AML patients who are non-fit for standard induction therapy (see below)
• Relapsed or refractory AML patients following at least 1 line of prior therapies (see below)

3. Ex vivo sensitivity testing performed to assess venetoclax sensitivity

1. Validation cohort: All participants are treated with venetoclax+azacitidine irrespective of the ex vivo screening results.

2. Study cohort: Only the participants exhibiting ex vivo sensitivity to venetoclax are included to study therapy.

4. Participant must have ECOG Performance status ≤ 2 for participants ≥ 75 years of age OR ≤ 3 for participants ≥ 18 to 74 years of age

5. Leukocyte count < 25 x10E9/l. Hydroxyurea use is permitted to meet this criterion.

6. Participant must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined by the Cockcroft Gault formula.

7. Participant must have adequate liver function as demonstrated by

1. alanine aminotransferase (ALT) ≤ 4.0 × ULN

2. bilirubin ≤ 1.5 × ULN

Participant must be:

≥ 70 years of age OR ≥ 18 to 69 years of age and ineligible for intensive chemotherapy meeting at least one of the criteria following:

• Clinically significant comorbidities, reflected at least 1 of:

• Left ventricular ejection fraction (LVEF) < 50%.
• Lung diffusion capacity for carbon monoxide (DLCO) ≤ 65% of expected.
• Forced expiratory volume in 1 second (FEV1) ≤ 65% of expected.
• Chronic stable angina or congestive heart failure controlled with medication.
• Alanine aminotransferase (ALT) 3.0-4.0 × ULN
• Other contraindication(s) to anthracycline therapy (must be documented)
• Adverse risk karyotype associated with poor outcome with standard chemotherapy
• Patient's refusal from intensive chemotherapy

Participant must be ≥ 55 years of age with non-CBF AML relapse OR ≥ 18 of age and meeting at least one of the criteria following:

• Not candidate for intensive chemotherapy (see the criteria 8.)
• The duration of remission < 12 months.
• Relapse after allogeneic transplantation.
• 2nd (or higher) relapse.

4. Participant has known CNS involvement with AML (note: CSF or radiological investigations are not required without clinical suspicion)

5. Participant with known HIV infection or active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection that is not controlled with anti-viral medication.

6. Participant has cardiovascular disability status of New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which participants are comfortable at rest but ordinary physical activity results in palpitations, fatigue, dyspnea, or anginal pain.

7. Evidence of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participation in this study (including but not limited to):

1. Participant has a chronic respiratory disease that requires continuous oxygen use

2. Systemic uncontrolled infection requiring therapy (viral, bacterial or fungal)

3. Malabsorption syndrome or other condition that precludes enteral route of administration.

4. Uncontrolled GVHD.

8. Participant has a history of other malignancies prior to study entry, with the exception of previous malignancy treated with curative intent.

Exclusion Criteria

1. Participant has acute promyelocytic leukemia (APL)

2. The leukemic cell content (blast percentage) in bone marrow/peripheral blood (depending which is used for drug sensitivity testing) is ≤ 10 %

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Helsinki University Central Hospital

OTHER

Sponsor Role: lead

Responsible Party

Mika Kontro

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

HelsinkiUCH

Helsinki, Uusimaa, Finland

Countries

Finland

References

Kytola S, Vanttinen I, Ruokoranta T, Partanen A, Holopainen A, Saad J, Kuusisto MEL, Koskela S, Raty R, Itala-Remes M, Vastrik I, Suvela M, Parsons A, Porkka K, Wennerberg K, Heckman CA, Jalkanen T, Huttunen T, Ettala P, Rimpilainen J, Siitonen T, Pyorala M, Kuusanmaki H, Kontro M. Ex vivo venetoclax sensitivity predicts clinical response in acute myeloid leukemia in the prospective VenEx trial. Blood. 2025 Jan 23;145(4):409-421. doi: 10.1182/blood.2024024968.

Reference Type: DERIVED

PMID: 39357056 (View on PubMed)

Kuusanmaki H, Kytola S, Vanttinen I, Ruokoranta T, Ranta A, Huuhtanen J, Suvela M, Parsons A, Holopainen A, Partanen A, Kuusisto MEL, Koskela S, Raty R, Itala-Remes M, Vastrik I, Dufva O, Siitonen S, Porkka K, Wennerberg K, Heckman CA, Ettala P, Pyorala M, Rimpilainen J, Siitonen T, Kontro M. Ex vivo venetoclax sensitivity testing predicts treatment response in acute myeloid leukemia. Haematologica. 2023 Jul 1;108(7):1768-1781. doi: 10.3324/haematol.2022.281692.

Reference Type: DERIVED

PMID: 36519325 (View on PubMed)

Other Identifiers

FLG-V001

Identifier Type: -

Identifier Source: org_study_id