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A Study to Evaluate the Efficacy of Venetoclax in Relapsed/Refractory Participants With Chronic Lymphocytic Leukemia (CLL) Including Those With 17p Deletion or TP53 Mutation or Those Who Have Received a Prior B-cell Receptor Inhibitor (VENICE I)

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02756611
Recruitment Status : Active, not recruiting
First Posted : April 29, 2016
Results First Posted : May 4, 2020
Last Update Posted : May 4, 2020
Sponsor:
Information provided by (Responsible Party):
AbbVie

Tracking Information
First Submitted Date  ICMJE April 26, 2016
First Posted Date  ICMJE April 29, 2016
Results First Submitted Date  ICMJE March 30, 2020
Results First Posted Date  ICMJE May 4, 2020
Last Update Posted Date May 4, 2020
Actual Study Start Date  ICMJE June 22, 2016
Actual Primary Completion Date April 10, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 30, 2020)
Complete Remission Rate in Participants Not Previously Treated With BCRi Therapy [ Time Frame: From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months. ]
Complete remission rate is defined as the percentage of participants achieving a complete remission (CR) or complete remission with incomplete marrow recovery (CRi) as their best response assessed by the investigator based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria. CR required all of the following:
  • Peripheral blood lymphocytes <4000/μL
  • Absence of lymphadenopathy by physical examination and computed tomography scan
  • No hepatomegaly or splenomegaly by physical examination
  • Absence of disease or constitutional symptoms (unexplained fevers >38°C, drenching night sweats, >10% weight loss in last 6 months)
  • Blood counts above the following:
    • Neutrophils >1500/μL
    • Platelets >100,000/μL
    • Hemoglobin >110 g/L
  • Bone marrow at least normocellular for age, <30% lymphocytes
CRi was defined as participants with CR who had persistent cytopenia unrelated to CLL but related to drug toxicity.
Original Primary Outcome Measures  ICMJE
 (submitted: April 27, 2016)
Complete Remission Rate (CR + CRi) as assessed by the investigator [ Time Frame: When all participants have completed Week 48 disease assessment, or after all enrolled participants have discontinued venetoclax, whichever is earlier. ]
The proportion of participants achieving a CR or CRi as their best response (per the investigator assessment) based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 30, 2020)
  • Complete Remission Rate in Participants Previously Treated With BCRi Therapy [ Time Frame: From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months. ]
    Complete remission rate is defined as the percentage of participants achieving a complete remission (CR) or complete remission with incomplete marrow recovery (CRi) as their best response assessed by the investigator based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria. CR required all of the following:
    • Peripheral blood lymphocytes <4000/μL
    • Absence of lymphadenopathy by physical examination and computed tomography scan
    • No hepatomegaly or splenomegaly by physical examination
    • Absence of disease or constitutional symptoms (unexplained fevers >38°C, drenching night sweats, >10% weight loss in last 6 months)
    • Blood counts above the following:
      • Neutrophils >1500/μL
      • Platelets >100,000/μL
      • Hemoglobin >110 g/L
    • Bone marrow at least normocellular for age, <30% lymphocytes
    CRi was defined as participants with CR who had persistent cytopenia unrelated to CLL but related to drug toxicity.
  • Overall Response Rate (ORR) [ Time Frame: From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months. ]
    Overall response rate was defined as the percentage of participants with an overall best response of CR, CRi, nodular partial remission (nPR), or confirmed partial remission (PR) based on the 2008 Modified IWCLL NCI-WG criteria as assessed by investigator. CR and CRi are defined above. nPR is defined as participants with CR but for whom bone marrow nodules could be identified histologically. For PR at least 2 of the following must be met:
    • ≥ 50% decrease in peripheral blood lymphocyte count from the pretreatment baseline value
    • ≥ 50% reduction in lymphadenopathy
    • ≥ 50% reduction in the size of the liver and/or spleen (if abnormal prior to therapy) and at least one of the following criteria must be met:
    • Neutrophils > 1,500/μL or ≥ 50% improvement over baseline
    • Platelets > 100,000/μL or ≥ 50% improvement over baseline
    • Hemoglobin > 11.0 g/dL or ≥ 50% improvement over baseline without transfusions or exogenous growth factors.
    PR must be confirmed at least 7 weeks later.
  • Duration of Overall Response (DoR) [ Time Frame: From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months. ]
    Duration of response is defined as the time from the date of first response (CR, CRi, nPR, or PR) to the earliest date that progressive disease (PD) is objectively documented (radiographic or clinical) or death. Duration of response was analyzed by Kaplan-Meier (K-M) methodology. If a participant was still responding their data was censored at the date of the last available disease assessment prior to the data cutoff date.
  • Time to Progression (TTP) [ Time Frame: From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months. ]
    Time to progression is defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical). Participants who did not experience disease progression were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline disease assessments were censored at the first dose date plus 1 day. Time to progression was estimated using Kaplan-Meier methodology.
  • Progression-Free Survival (PFS) [ Time Frame: From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months. ]
    Progression-free survival (PFS) was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical) or death. Participants who did not experience disease progression or death were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline tumor assessment or clinical assessment for progression, were censored at the date of first dose plus 1 day. Progression-free survival was analyzed by Kaplan-Meier methodology.
  • Overall Survival (OS) [ Time Frame: From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months. ]
    Overall survival (time to death) will be defined as the number of days from the first dose date of venetoclax to the date of death. If a participant had not died their data were censored at the date when they were last known to be alive prior to the cutoff date. Overall survival was analyzed using Kaplan-Meier methodology.
  • Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) [ Time Frame: Up to Week 108 ]
    The FACT-Leu is a 44-item, leukemia-specific questionnaire designed to assess patient health-related quality of life (HRQoL) and leukemia-specific symptoms.
  • Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-F) [ Time Frame: Up to Week 108 ]
    The FACIT-F questionnaire measures fatigue and its effect on functioning and daily activities. The FACIT-F has 13 items answered on a 5-point rating scale based on a 7-day recall period.
  • EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) [ Time Frame: Up to Week 108 ]
    Five items in the EQ-5D-5L questionnaire (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) are rated on 5 levels of severity.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 27, 2016)
  • Overall Response Rate (ORR) [ Time Frame: Measured up to 2 years after the last subject has enrolled in the study. ]
    ORR assessed as the proportion of participants with an overall response (CR + CRi + Nodular Partial Remission [nPR] + Partial Remission [PR]) based on the IWCLL NCI-WG criteria.
  • Duration of Overall Response (DoR) [ Time Frame: Measured up to 2 years after the last subject has enrolled in the study. ]
    DoR is defined as the number of days from the date of first response (CR, CRi, nPR, or PR) to the earliest recurrence or progressive disease.
  • Time to Progression (TTP) [ Time Frame: Measured up to 2 years after the last subject has enrolled in the study. ]
    TTP is defined as the number of days from the date of first dose or enrollment if not dosed to the date of earliest disease progression.
  • Progression-Free Survival (PFS) [ Time Frame: Measured up to 2 years after the last subject has enrolled into the study. ]
    PFS is defined as the number of days from the date of first dose to the date of earliest disease progression or death.
  • Overall Survival (OS) [ Time Frame: Measured up to 2 years after the last subject has enrolled into the study. ]
    OS is defined as number of days from the date of first dose to the date of death for all dosed subjects.
  • CR Rate (CR + CRi) [ Time Frame: When all participants have completed Week 48 disease assessment, or after all enrolled participants have discontinued venetoclax, whichever is earlier. ]
    CR + CRi in previously treated B-Cell receptor inhibitor (BCRi) subjects assessed based on the 2008 Modified IWCLL NCI-WG criteria.
  • Rate of Minimal Residual Disease (MRD) [ Time Frame: When all participants have completed Week 48 disease assessment, or after all enrolled participants have discontinued venetoclax, whichever is earlier. ]
    The rate is defined as the proportion of participants who had MRD negativity status.
Current Other Pre-specified Outcome Measures
 (submitted: April 30, 2020)
Minimal Residual Disease (MRD) Negativity Rate [ Time Frame: From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months. ]
The MRD negativity rate is defined as the percentage of participants who had MRD negative status with less than one CLL cell per 10,000 leukocytes (< 10⁻⁴) in peripheral blood and bone marrow. MRD was evaluated using next-generation sequencing. Per protocol, peripheral blood MRD assessments were to be collected from all participants at Week 24 and Week 48 and at the time the bone marrow assessment for confirmation of CR/CRi, and bone marrow (BM) MRD assessments were to be collected for participants undergoing a bone marrow procedure for confirmation of CR/CRi. Participants with no blood or BM MRD assessments were included in the calculation of MRD negativity rate as not having MRD negative status.
Original Other Pre-specified Outcome Measures
 (submitted: April 27, 2016)
  • Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) [ Time Frame: Up to Week 108 ]
    The FACT-Leu is a 44-item, leukemia-specific questionnaire designed to assess patient health-related quality of life (HRQoL) and leukemia-specific symptoms.
  • Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-F) [ Time Frame: Up to Week 108 ]
    The FACIT-F questionnaire measures fatigue and its effect on functioning and daily activities. The FACIT-F has 13 items answered on a 5-point rating scale based on a 7-day recall period.
  • EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) [ Time Frame: Up to Week 108 ]
    Five items in the EQ-5D-5L questionnaire (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) are rated on 5 levels of severity.
 
Descriptive Information
Brief Title  ICMJE A Study to Evaluate the Efficacy of Venetoclax in Relapsed/Refractory Participants With Chronic Lymphocytic Leukemia (CLL) Including Those With 17p Deletion or TP53 Mutation or Those Who Have Received a Prior B-cell Receptor Inhibitor
Official Title  ICMJE Open-Label, Single Arm, Phase 3b, Multi-Center Study Evaluating the Efficacy of Venetoclax (ABT 199) in Relapsed/Refractory Subjects With Chronic Lymphocytic Leukemia (CLL)
Brief Summary The purpose of this study is to evaluate the efficacy of venetoclax monotherapy in participants with relapsed/refractory CLL including those with the 17p deletion or TP53 mutation OR those who have received prior treatment with a B-cell receptor inhibitor.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Chronic Lymphocytic Leukemia
Intervention  ICMJE Drug: Venetoclax
Tablets for oral administration
Other Names:
  • ABT-199
  • VENCLEXTA®
Study Arms  ICMJE Experimental: Venetoclax

Venetoclax will be administered orally once daily (QD) beginning with a dose-titration phase. The initial venetoclax dose is 20 mg QD. After 1 week of treatment at 20 mg QD, the dose will be escalated to 50 mg QD followed by subsequent increases, each after 1 week, to 100 mg QD, 200 mg QD and the maximum dose of 400 mg QD. Participants may continue to receive venetoclax for up to 2 years provided they continue to tolerate the drug, have no evidence of disease progression (based on investigator's assessment), do not have unacceptable toxicity, and do not meet any of the criteria for discontinuation.

In countries where venetoclax is not commercially available, participants who continue to derive benefit after 2 years of treatment may be able to extend their treatment for up to 2 additional years, determined on a case by case basis.

Intervention: Drug: Venetoclax
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: December 10, 2019)
258
Original Estimated Enrollment  ICMJE
 (submitted: April 27, 2016)
250
Estimated Study Completion Date  ICMJE April 3, 2022
Actual Primary Completion Date April 10, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Participant has Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to 2
  • Participant has relapsed/refractory disease (received at least 1 prior therapy)
  • Participant has diagnosis of CLL that meets published 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute Working Group (IWCLL NCI-WG) Guidelines and:

    • has an indication for treatment according to the 2008 Modified IWCLL NCI-WG criteria
    • has clinically measurable disease (lymphocytosis greater than 5 × 10^9/L and/or palpable and measurable nodes by physical exam and/or organomegaly assessed by physical exam)
  • In addition, participants:

    • with or without 17p deletion or TP53 mutation, assessed by a local laboratory in bone marrow or peripheral blood AND/OR
    • may have been previously treated with a prior B-cell receptor inhibitor
  • Participant must have adequate bone marrow function, coagulation profile, renal, and hepatic function, per laboratory reference range at Screening

Exclusion Criteria:

  • Participant has developed Richter's transformation or Prolymphocytic leukemia
  • Participant has previously received venetoclax
  • History of active malignancies other than CLL within the past 2 years prior to first dose of venetoclax, with the exception of:

    • adequately treated in situ carcinoma of the cervix uteri
    • adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin
    • previous malignancy confined and surgically resected (or treated with other modalities) with curative intent
  • Participant has active and uncontrolled autoimmune cytopenias (for 2 weeks prior to Screening), including autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura despite low dose corticosteroids
  • Participant has undergone an allogeneic stem cell transplant
  • Treatment with any of the following within five half-lives or 14 days (if half-life unknown) as applicable prior to the first dose of venetoclax, or clinically significant adverse effect(s)/toxicity(s) of the previous therapy have not resolved to < National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 Grade 2:

    • Any anti-cancer therapy including chemotherapy, or radiotherapy;
    • Investigational therapy, including targeted small molecule agents
  • Participant is human immunodeficiency virus (HIV) positive
  • Participant has known allergy to both xanthine oxidase inhibitors and rasburicase
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Belgium,   Canada,   Denmark,   Finland,   France,   Germany,   Greece,   Ireland,   Israel,   Italy,   Netherlands,   Norway,   Portugal,   Puerto Rico,   Spain,   Sweden,   Switzerland,   Turkey,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02756611
Other Study ID Numbers  ICMJE M15-550
2015-003667-11 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
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
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: 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
Responsible Party AbbVie
Study Sponsor  ICMJE AbbVie
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: AbbVie Inc. AbbVie
PRS Account AbbVie
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP