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

NCT04267081 | Completed Phase 2

• 1 other identifier: FLG-V001
• Study Type: interventional
• Target: 104
• Locations: 1 country
• Sites: 1

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

Keywords

AML; Venetoclax; Azacytidine; Drug Sensitivity Screening

Outcome Measures

Primary Outcomes (1)

• Complete remission (CR)/complete remission rate with incomplete hematologic recovery (CRi) rate in study cohort after three cycles.

  The bone marrow is examined at the end of Cycle 3. Each cycle is 28 days.

Secondary Outcomes (2)

• The correlation of ex vivo venetoclax sensitivity and specific responses: Overall Survival (OS), Duration of Response (DOR), Event-free Survival (EFS) and Minimal Residual Disease (MRD) status.

  Through study completion, an average of 3 years

• The correlation of venetoclax blood concentrations to specific responses: Overall Survival (OS), Duration of Response (DOR), Event-free Survival (EFS) and Minimal Residual Disease (MRD) status.

  Through study completion, an average of 3 years

Study Arms (2)

Arm 1 (de novo AML)

EXPERIMENTAL

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.

Drug: Venetoclax

Arm 2 (relapsed, refractory or secondary AML)

EXPERIMENTAL

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.

Drug: Venetoclax

Interventions

Venetoclax DRUG

Ex vivo venetoclax sensitivity testing is used for patient selection.

Also known as: Ex vivo drug sensitivity testing

Arm 1 (de novo AML); Arm 2 (relapsed, refractory or secondary AML)

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent
• 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)
• Ex vivo sensitivity testing performed to assess venetoclax sensitivity
• Validation cohort: All participants are treated with venetoclax+azacitidine irrespective of the ex vivo screening results.
• Study cohort: Only the participants exhibiting ex vivo sensitivity to venetoclax are included to study therapy.
• Participant must have ECOG Performance status ≤ 2 for participants ≥ 75 years of age OR ≤ 3 for participants ≥ 18 to 74 years of age
• Leukocyte count \< 25 x10E9/l. Hydroxyurea use is permitted to meet this criterion.
• Participant must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined by the Cockcroft Gault formula.
• Participant must have adequate liver function as demonstrated by
• alanine aminotransferase (ALT) ≤ 4.0 × ULN
• 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:

You may not qualify if:

• Participant has acute promyelocytic leukemia (APL)
• The leukemic cell content (blast percentage) in bone marrow/peripheral blood (depending which is used for drug sensitivity testing) is ≤ 10 %
• Participant has known CNS involvement with AML (note: CSF or radiological investigations are not required without clinical suspicion)
• 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.
• 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.
• 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):
• Participant has a chronic respiratory disease that requires continuous oxygen use
• Systemic uncontrolled infection requiring therapy (viral, bacterial or fungal)
• Malabsorption syndrome or other condition that precludes enteral route of administration.
• Uncontrolled GVHD.
• Participant has a history of other malignancies prior to study entry, with the exception of previous malignancy treated with curative intent.

Sponsors & Collaborators

• Helsinki University Central Hospital: lead

Study Sites (1)

HelsinkiUCH

Helsinki, Uusimaa, 00029, Finland

Location

Related Publications (2)

• 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.

  PMID: 39357056 DERIVED

• 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.

  PMID: 36519325 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: This is a multicenter two-stage, two-arm, open label phase II study.

Study Record Dates

• First Submitted: February 7, 2020
• First Posted: February 12, 2020
• Study Start: February 12, 2020
• Primary Completion: February 28, 2024
• Study Completion: February 28, 2024
• Last Updated: September 4, 2024

Record last verified: 2024-09

Locations

FI (1)