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A Study of Venetoclax in Combination With Low Dose Cytarabine Versus Low Dose Cytarabine Alone in Treatment Naive Patients With Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy

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ClinicalTrials.gov Identifier: NCT03069352
Recruitment Status : Recruiting
First Posted : March 3, 2017
Last Update Posted : July 19, 2018
Sponsor:
Information provided by (Responsible Party):
AbbVie

Brief Summary:

Acute Myeloid Leukaemia (AML) is an aggressive and rare cancer of myeloid cells (a white blood cell responsible for fighting infections). Successful treatment of AML is dependent on what subtype of AML the patient has, and the age of the patient when diagnosed.

Venetoclax is an experimental drug that kills cancer cells by blocking a protein (part of a cell) that allows cancer cells to stay alive. This study is designed to see if adding venetoclax to cytarabine works better than cytarabine on its own.

This is a Phase 3, randomized, double-blind (treatment unknown to patients and doctors), placebo-controlled, multicenter study in patients with AML who are 18 or more years old and have not been treated before. Patients who take part in this study should not be suitable for intensive induction chemotherapy (usual starting treatment). Abbvie is funding this study which will take place at approximately 125 hospitals globally and enrol approximately 210 patients. In this study, 2/3 of patients will receive venetoclax every day with cytarabine and the remaining 1/3 will receive placebo (dummy) tablets with azacitidine.

Patients will continue to have study visits and receive treatment for as long as they are having a clinical benefit. The effect of the treatment on AML will be checked by taking blood, bone marrow, scans, measuring side effects and by completing health questionnaires. Blood and bone marrow tests will be completed to see why some people respond better than others. Additional blood tests will be completed for genetic factors and to see how long the drug remains in the body.


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia (AML) Drug: Placebo Drug: Venetoclax Drug: Cytarabine Phase 3

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 210 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo Controlled Phase 3 Study of Venetoclax Co-Administered With Low Dose Cytarabine Versus Low Dose Cytarabine in Treatment Naïve Patients With Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy
Actual Study Start Date : May 23, 2017
Estimated Primary Completion Date : October 20, 2019
Estimated Study Completion Date : November 25, 2019


Arm Intervention/treatment
Experimental: Venetoclax + Low Dose Cytarabine (LDAC)
Venetoclax 600 mg orally every day (QD) QD on Days 1 - 28 plus LDAC 20 mg/m^2 subcutaneously QD on Days 1 - 10 (28 day cycle)
Drug: Venetoclax
tablet
Other Names:
  • ABT-199
  • Venclexta

Drug: Cytarabine
Subcutaneous
Other Names:
  • Cytosar-U
  • Ara-C
  • Arabinosylcytosine

Placebo Comparator: Placebo + LDAC
Matching Placebo for Venetoclax 600 mg orally QD on Days 1 - 28 plus LDAC 20 mg/m^2 subcutaneous QD on Days 1 - 10 (28 day cycle)
Drug: Placebo
tablet

Drug: Cytarabine
Subcutaneous
Other Names:
  • Cytosar-U
  • Ara-C
  • Arabinosylcytosine




Primary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: Measured up to 2 years after the last participant is enrolled ]
    OS is defined as the number of days from the date of randomization to the date of death.


Secondary Outcome Measures :
  1. Composite Complete Remission Rate [ Time Frame: Up to 2 years after the last participant is randomized ]
    This will be calculated based on the modified International Working Group (IWG) criteria. CR is defined as absolute neutrophil count greater than 10^3/ microliter (mcL), platelets greater than or equal to 10^5/mcL, red cell transfusion independence, bone marrow with less than 5% blasts, absence of circulating blasts and blasts with Auer rods and absence of extramedullary disease. All criteria as CR except for residual neutropenia < 10^3/microliter (mcL) (1,000/mcL) or thrombocytopenia < 10^5/microliter (mcL) (100,000/mcL) and no morphologic evidence of AML. If all criteria for CR are met except for RBC transfusion independence, this also fulfills CRi criteria.

  2. Complete Remission and Complete Remission With Partial Hematologic Recovery (CR + CRh) [ Time Frame: Up to 2 years after the last participant is enrolled ]
    A response of CRh is achieved when the following criteria are met : Bone marrow with <5% blasts; Peripheral blood neutrophil count of >0.5*10^3/microliter (mcL); Peripheral blood platelet count of >0.5*10^5/microliter (mcL); A 1 week (>= 7 days) platelet transfusion-free period to the hematology lab collection.

  3. Composite Complete Remission Rate by Initiation of Cycle 2 [ Time Frame: Up to 6 months after the last participant is randomized ]
    This will be calculated based on the modified International Working Group (IWG) criteria. CR is defined as absolute neutrophil count greater than 10^3/ microliter (mcL), platelets greater than or equal to 10^5/mcL, red cell transfusion independence, bone marrow with less than 5% blasts, absence of circulating blasts and blasts with Auer rods and absence of extramedullary disease. All criteria as CR except for residual neutropenia < 10^3/microliter (mcL) (1,000/mcL) or thrombocytopenia < 10^5/microliter (mcL) (100,000/mcL) and no morphologic evidence of AML. If all criteria for CR are met except for RBC transfusion independence, this also fulfills CRi criteria by initiation of Cycle 2.

  4. Complete Remission Rate [ Time Frame: Up to 2 years after the last participant is enrolled ]
    The proportion of subjects with complete remission (CR) will be calculated based on the modified IWG criteria for AML.

  5. Patient Reported Outcomes [ Time Frame: Up to 2 years after the last participant is enrolled ]
    Exploratory research will be conducted on the subscales and items from the PROMIS and Fatigue SF 7a.

  6. Patient Reported Outcomes [ Time Frame: Up to 2 years after the last participant is enrolled ]
    Additional subscales and items from EORTC QLQ-C30 will be evaluated using a linear mixed effects regression model to test for differences between the two treatment arms.

  7. Patient Reported Outcomes [ Time Frame: Up to 2 years after the last participant is enrolled ]
    Exploratory research will be conducted on the subscales and items from EORTC QLQ-C30.

  8. Patient Reported Outcomes [ Time Frame: Up to 2 years after the last participant is enrolled ]
    Exploratory research will be conducted on the subscales and items from EQ-5D-5L.

  9. Event-free survival (EFS) [ Time Frame: Up to 2 years after the last participant is enrolled ]
    EFS will be defined as the number of days from randomization to the date of progressive disease, relapse from CR to CRi, treatment failure defined as failure to achieve CR, CRi, Partial Remission (PR), or Morphologic Leukemia Free State (MLFS), or death from any cause.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participant must have histological confirmation of Acute Myeloid Leukemia (AML) by World Health Organization criteria, be ineligible for intensive induction chemotherapy and either be:

    1. ≥ 75 years of age OR
    2. ≥ 18 to 74 years of age and fulfill at least one criteria associated with lack of fitness for intensive induction chemotherapy:

    i. Eastern Cooperative Oncology Group (ECOG) Performance status of 2 - 3; ii. Cardiac history of Congestive Heart Failure (CHF) requiring treatment or Ejection Fraction ≤ 50% or chronic stable angina; iii. Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) ≤ 65% or Forced Expiratory Volume in 1 second(FEV1) ≤ 65%; iv. Creatinine clearance ≥ 30 mL/min to < 45 ml/min; v. Moderate hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 × Upper Limit of Normal (ULN); vi. Other comorbidity that the physician judges to be incompatible with conventional intensive chemotherapy which must be reviewed and approved by the study medical monitor before study enrollment.

  • Participant must have an ECOG Performance status:

    1. of 0 to 2 for participants ≥ 75 years of age or
    2. of 0 to 3 for participants between 18 to 74 years of age.
  • Participant must have a projected life expectancy of at least 12 weeks.
  • Participant 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.
  • Participant must have adequate liver function as demonstrated by:

    1. aspartate aminotransferase (AST) ≤ 3.0 × ULN*
    2. alanine aminotransferase (ALT) ≤ 3.0 × ULN*
    3. bilirubin ≤ 1.5 × ULN*

      ° Subjects who are < 75 years of age may have bilirubin of ≤ 3.0 × ULN

    4. Unless considered to be due to leukemic organ involvement.
  • Female participants must be either postmenopausal defined as:

    1. Age > 55 years with no menses for 12 or more months without an alternative medical cause.
    2. Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause AND an FSH level > 40 IU/L; or
    3. Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy); or
    4. A Woman of Childbearing Potential (WOCBP) practicing at least one protocol specified method of birth control starting at Study Day 1 through at least 180 days after the last dose of study drug.
  • Male participants who are sexually active, must agree, from Study Day 1 through at least 180 days after the last dose of study drug, to practice protocol specified methods of contraception. Male subjects must agree to refrain from sperm donation from initial study drug administration through at least 180 days after the last dose of study drug.
  • Females of childbearing potential must have negative results for pregnancy test performed:

    1. At Screening with a serum sample obtained within 14 days prior to the first study drug administration, and
    2. Prior to dosing with urine sample obtained on Cycle 1 Day 1, if it has been > 7 days since obtaining the serum pregnancy test results.
    3. Participants with borderline pregnancy tests at Screening must have a serum pregnancy test ≥ 3 days later to document continued lack of a positive result.
  • Participant must voluntarily sign and date an informed consent form, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.

Exclusion Criteria:

  • Participant has received any prior treatment for AML with the exception of hydroxyurea, allowed through the first cycle of study treatment. Note: Prior treatment for Myelodysplastic Syndrome is allowed except for use of cytarabine.
  • Participant had an antecedent myeloproliferative neoplasm (MPN) including myelofibrosis, essential thrombocytosis, polycythemia vera, or chronic myelogenous leukemia (CML) with or without BCR-ABL 1 translocation and AML with BCR-ABL 1 translocation.
  • Participants that have acute promyelocytic leukemia (APL).
  • Participant has known Central Nervous System (CNS) involvement with AML.
  • Participant has known Human Immunodeficiency Virus (HIV) infection (due to potential drug-drug interactions between antiretroviral medications and venetoclax). HIV testing will be performed at Screening, if required per local guidelines or institutional standards.
  • Participant is known to be positive for hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Inactive hepatitis carrier status or low viral hepatitis titer on antivirals (non-exclusionary medications) are not excluded.
  • Participant has received strong or moderate CYP3A inducers 7 days prior to the initiation of study treatment.

    • Chinese participants are excluded from receiving strong and/or moderate CYP3A inhibitors 7 days prior to the initiation of study treatment through the end of intensive PK collection (24 hours post dose on Cycle 1 Day 10).
  • Participant has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to the initiation of study treatment.
  • Participant has cardiovascular disability status of New York Heart Association Class > 2.

Class 2 is defined as cardiac disease which subjects are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or angina pain.

Class 3 is defined as cardiac disease which subjects are comfortable at rest but less than ordinary activity causes fatigue, palpitation, or dyspnea.

Class 4 is defined as cardiac disease which subjects have an inability to carry on any physical activity without discomfort, symptoms of heart failure at rest, and if any physical activity is undertaken then discomfort increases.

  • Participant has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, any other medical condition or known hypersensitivity to any of the study medications including excipients of LDAC that in the opinion of the investigator would adversely affect his/her participating in this study.
  • Participant has a malabsorption syndrome or other condition that precludes enteral route of administration.
  • Participant exhibits evidence of other clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial or fungal).
  • Participant has a history of other malignancies prior to study entry, with the exception of:

    1. Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast;
    2. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
    3. Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
  • Participant has a white blood cell count > 25 × 109/L. (Note: Hydroxyurea administration or leukapheresis is permitted to meet this criterion).
  • Previous treatment with venetoclax and/or current participation in any other research study with investigational products.

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): NCT03069352


Contacts
Contact: ABBVIE CALL CENTER 847.283.8955 abbvieclinicaltrials@abbvie.com

  Show 111 Study Locations
Sponsors and Collaborators
AbbVie
Investigators
Study Director: AbbVie Inc. AbbVie

Additional Information:
Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT03069352     History of Changes
Other Study ID Numbers: M16-043
2016-003900-30 ( EudraCT Number )
First Posted: March 3, 2017    Key Record Dates
Last Update Posted: July 19, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Analytic Code
Time Frame: Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered.
Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). For more information on the process, or to submit a request, visit the following link.
URL: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by AbbVie:
Acute Myeloid Leukemia
Leukemia
Treatment naïve
Venetoclax
Cytarabine

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Venetoclax
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs