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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04267081
Recruitment Status : Recruiting
First Posted : February 12, 2020
Last Update Posted : February 17, 2020
Sponsor:
Information provided by (Responsible Party):
Mika Kontro, Helsinki University Central Hospital

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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Venetoclax Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a multicenter two-stage, two-arm, open label phase II study.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Two-stage, Two-arm, Open-Label Phase II Study of Venetoclax in Combination With Azacytidine in Acute Myeloid Leukemia Patients Selected Using Ex Vivo Drug Sensitivity Screening
Actual Study Start Date : February 12, 2020
Estimated Primary Completion Date : February 1, 2024
Estimated Study Completion Date : February 1, 2024


Arm Intervention/treatment
Experimental: 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.

Drug: Venetoclax
Ex vivo venetoclax sensitivity testing is used for patient selection.
Other Name: Ex vivo drug sensitivity testing

Experimental: 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.

Drug: Venetoclax
Ex vivo venetoclax sensitivity testing is used for patient selection.
Other Name: Ex vivo drug sensitivity testing




Primary Outcome Measures :
  1. Complete remission (CR)/complete remission rate with incomplete hematologic recovery (CRi) rate in study cohort after three cycles. [ Time Frame: The bone marrow is examined at the end of Cycle 3. Each cycle is 28 days. ]

Secondary Outcome Measures :
  1. 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. [ Time Frame: Through study completion, an average of 3 years ]
  2. 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. [ Time Frame: Through study completion, an average of 3 years ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  8. Specific inclusion criteria for participants non-fit for standard chemotherapy

    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
  9. Specific inclusion criteria for relapsed patients

    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.
  10. Specific inclusion criteria for refractory patients The patients who fail to achieve a complete or partial remission after induction chemotherapy (two cycles of chemotherapy containing cytarabine or clofarabine, in compilation with topoisomerase II inhibitor (e.g. anthracycline or mitoxantrone)

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 %
  3. ECOG >3 (see also inclusion criteria 4)
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04267081


Locations
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Finland
HelsinkiUCH Recruiting
Helsinki, Uusimaa, Finland, 00029
Contact: Mika Kontro, MD,PhD    +358504287052    mika.kontro@helsinki.fi   
Sponsors and Collaborators
Helsinki University Central Hospital

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Responsible Party: Mika Kontro, Principal Investigator, Helsinki University Central Hospital
ClinicalTrials.gov Identifier: NCT04267081    
Other Study ID Numbers: FLG-V001
First Posted: February 12, 2020    Key Record Dates
Last Update Posted: February 17, 2020
Last Verified: February 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Mika Kontro, Helsinki University Central Hospital:
AML
Venetoclax
Azacytidine
Drug Sensitivity Screening
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Hypersensitivity
Neoplasms by Histologic Type
Neoplasms
Immune System Diseases
Azacitidine
Venetoclax
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors