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A Study to Compare the Efficacy and Safety of Obinutuzumab + Venetoclax (GDC-0199) Versus Obinutuzumab + Chlorambucil in Participants With Chronic Lymphocytic Leukemia

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ClinicalTrials.gov Identifier: NCT02242942
Recruitment Status : Active, not recruiting
First Posted : September 17, 2014
Results First Posted : October 1, 2019
Last Update Posted : October 1, 2019
Sponsor:
Collaborators:
AbbVie
German CLL Study Group
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE September 16, 2014
First Posted Date  ICMJE September 17, 2014
Results First Submitted Date  ICMJE August 15, 2019
Results First Posted Date  ICMJE October 1, 2019
Last Update Posted Date October 1, 2019
Actual Study Start Date  ICMJE December 31, 2014
Actual Primary Completion Date August 17, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 10, 2019)
Progression Free Survival (PFS) Based on Investigator Assessment According to IWCLL Criteria [ Time Frame: Baseline until disease progression or death up to approximately 3.75 years ]
PFS was determined according to IWCLL 2008 criteria and defined as the time from randomization to the first occurrence of PD or death from any cause. Disease progression was characterized by at least one of the following: 1) >/= 50% increase in the absolute number of circulating lymphocytes to at least 5*10^9/L, 2) Appearance of new palpable lymph nodes (> 15 mm in longest diameter) or any new extra-nodal lesion; 3) >/= 50% increase in the longest diameter of any previous site of lymphadenopathy; 4) >/= 50% increase in the enlargement of the liver and/or spleen; 5) Transformation to a more aggressive histology.
Original Primary Outcome Measures  ICMJE
 (submitted: September 16, 2014)
Progression-free survival (PFS), defined as the time from randomization to the first occurrence of progression, relapse or death from any cause as assessed by the investigator using IWCLL criteria [ Time Frame: Up to 5 years ]
Change History Complete list of historical versions of study NCT02242942 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 10, 2019)
  • Progression Free Survival (PFS) Based on Institutional Review Committee (IRC)-Assessments According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria [ Time Frame: Baseline until disease progression or death up to approximately 3.75 years ]
    PFS was determined according to IWCLL 2008 criteria and defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause. Disease progression was characterized by at least one of the following: 1) >/= 50% increase in the absolute number of circulating lymphocytes to at least 5*10^9/L, 2) Appearance of new palpable lymph nodes (> 15 mm in longest diameter) or any new extra-nodal lesion; 3) >/= 50% increase in the longest diameter of any previous site of lymphadenopathy; 4) >/= 50% increase in the enlargement of the liver and/or spleen; 5) Transformation to a more aggressive histology.
  • Percentage of Participants With an Overall Response (OR) at Completion of Treatment, as Determined by the Investigator According to IWCLL Criteria [ Time Frame: At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months) ]
    OR was defined as complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) according to IWCLL 2008 criteria. CR requires all of the following: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and computed tomography (CT) scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, bone marrow at least normocellular for age without clonal infiltrate (except for Cri). PR: two of the following features for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L.
  • Percentage of Participants With a Complete Response Rate (CRR) at the Completion of Treatment Assessment as Determined by the Investigator According to IWCLL Criteria [ Time Frame: At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months) ]
    CRR was defined as the rate of a clinical response of CR or CRi according to IWCLL 2008 criteria. CR requires all of the following: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and CT scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, bone marrow at least normocellular for age without clonal infiltrate (except for Cri).
  • Percentage of Participants With Minimal Residual Disease (MRD) Negativity in Peripheral Blood as Measured by Allele-Specific Oligonucleotide Polymerase Chain Reaction (ASO-PCR) at Completion of Treatment [ Time Frame: At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months) ]
    MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in peripheral blood.
  • Percentage of Participants With MRD Negativity in Bone Marrow as Measured by ASO-PCR at Completion of Treatment [ Time Frame: At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months) ]
    MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in bone marrow.
  • Overall Survival (OS) [ Time Frame: Baseline until death, up to approximately 5.75 years ]
    OS was defined as the time between the date of randomization and the date of death due to any cause.
  • Percentage of Participants With MRD Negativity in Peripheral Blood as Measured by ASO-PCR at Completion of Combination Treatment Assessment [ Time Frame: Day 1 Cycle 9 or 3 months after last IV infusion, approximately 9 months ]
    MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in peripheral blood.
  • Percentage of Participants With MRD Negativity in Bone Marrow as Measured by ASO-PCR at Completion of Combination Treatment Assessment [ Time Frame: Day 1 Cycle 9 or 3 months after last IV infusion at approximately 9 months ]
    MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in bone marrow.
  • Percentage of Participants With OR at Completion of Combination Treatment Response Assessment [ Time Frame: Day 1 Cycle 7 or 28 days after last IV infusion, approximately 6 months ]
    OR was defined as CR, CRi or PR according to IWCLL 2008 criteria. CR required all of the following: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L. PR: two of the following features for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L.
  • Duration of Objective Response (DOR) [ Time Frame: Time from the first occurrence of a documented objective response to the time of PD as determined by the investigator or death from any cause, up to approximately 5.75 years ]
    PD was defined as lymphadenopathy, >=50% increase in liver or spleen size, >=50% increase in lymphocyte count, transformation to a more aggressive histology or occurrence of cytopenia.
  • Percentage of Participants By Best Response Achieved (CR, CRi, PR, Stable Disease (SD), or PD) [ Time Frame: Baseline up to the completion of treatment assessment 3 months after treatment completion (up to approximately 15 months) ]
    CR: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and CT scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, bone marrow at least normocellular for age without clonal infiltrate (except for Cri). PR: any two for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L. PD: lymphadenopathy, >=50% increase in liver or spleen size, >=50% increase in lymphocyte count, transformation to a more aggressive histology or occurrence of cytopenia. SD: a non-response and used to characterize participants who did not achieve a CR or a PR, and who have not exhibited PD.
  • Event-Free Survival [ Time Frame: Time between date of randomization and the date of disease progression/relapse on the basis of investigator-assessment, death, or start of a new anti-leukemic therapy, up to 5.75 years ]
  • Time to Next Anti-Leukemic Treatment [ Time Frame: Time between the date of randomization and the date of first intake of new anti-leukemic therapy, up to 5.75 years ]
  • Number of Participants With Adverse Events (AEs) [ Time Frame: Up to approximately 5.75 years ]
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as AEs.
  • Percentage of Participants With CD19 + /CD5+ B Cells or CD14+ Monocytes [ Time Frame: Baseline up to approximately 5.75 years ]
  • Percentage of Participants With Human-Anti-Human Antibodies [ Time Frame: Baseline up to approximately 5.75 years ]
  • Percentage of Participants Recorded as Premature Study Withdrawals [ Time Frame: Up to approximately 5.75 years ]
  • Plasma Concentrations of Venetoclax [ Time Frame: Pre-venetoclax dose (0 hour) and 4 hours post- venetoclax dose on Day 1 Cycle 4 ]
  • Serum Concentrations of Obinutuzumab [ Time Frame: Pre-obinutuzumab infusion (0 hour) and end of obinutuzumab infusion on Day 1 Cycle 4 ]
  • Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) Score [ Time Frame: Baseline up to approximately 5.75 years ]
    The MDASI-CLL is a questionnaire of 25 items related to CLL specific symptoms that a participant may have experienced in the past 24 hours. Participants were asked to rate the severity of 13 symptoms called mean core symptom severity (i.e., pain, fatigue, nausea, disturbed sleep, distressed, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sadness, vomiting, and numbness or tingling), 6 disease-specific symptoms called mean module symptom severity (night sweats, fevers and chills, lymph node swelling, diarrhea, easy bruising or bleeding, and constipation) and 6 mean interference on life questions (i.e., general activity, walking, work, mood, relations with other people, and enjoyment of life) on a scale from 0 to 10 with 0 indicating that the symptom is "not present" or "did not interfere" with the participant's activities and 10 indicating "as bad as you can imagine" or "interfered completely". Scores were averaged (range 0 to 10) for each of three parts.
  • Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQC30) [ Time Frame: Baseline up to approximately 5.75 years ]
    The EORTC QLQ-C30 is a validated and reliable self-report measure consisting of 30 questions incorporated into five functional scales (physical, role, cognitive, emotional, and social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), and a global health status/global quality−of−life scale. The remaining single items (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) assess the additional symptoms experienced by patients with cancer and the perceived financial burden of treatment. The 28 function and symptom items were scored on a 4-point scale that ranged from "not at all" to "very much," and the 2 global health status/global quality-of-life items were scored on a 7-point scale that ranged from "very poor" to "excellent." Raw average scale scores were linearly transformed to range 0-100 with higher scores indicating higher response levels (i.e., higher functioning, higher symptom severity).
  • Change From Baseline in EuroQol 5 Dimension Questionnaire (EQ-5D-3L) [ Time Frame: Baseline up to approximately 5.75 years ]
    The EQ-5D-3L questionnaire is a generic, preference based health utility measure that assesses 5 health states (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and is used to build a composite of the patient's health status. The EQ-5D-3L was employed in this study to calculate health utilities for economic modeling, which ranged 0-1. The EQ-5D-3L also contained a visual analog scale (VAS) to assess the participant's overall health, which ranged from 0-100 with a higher score indicating a worse health status.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 16, 2014)
  • PFS Based on Institutional Review Committee (IRC)-Assessments, Defined as the Time From Randomization to the First Occurrence of Progression or Relapse or Death From any Cause [ Time Frame: Up to 5 years ]
  • Objective response rate ([ORR] defined as rate of a clinical response of complete response [CR], CR with incomplete bone marrow recovery [CRi] or partial response [PR]) as determined by the investigator, according to the IWCLL criteria [ Time Frame: At the completion of treatment assessment, approximately 1 year ]
  • Minimal residual disease (MRD) response rate, as measured by allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) [ Time Frame: At the completion of treatment assessment, approximately 1 year ]
  • ORR at completion of combination treatment response assessment [ Time Frame: Cycle 7 day 1 or 28 days after last IV infusion, approximately 6 months ]
  • MRD response rate, as measured by ASO-PCR at completion of combination treatment response assessment [ Time Frame: Cycle 9 day 1 or 3 months after last IV infusion, approximately 9 months ]
  • Overall Survival [ Time Frame: Time between the date of randomization and the date of death due to any cause, up to approximately 5 years ]
  • Duration of Objective Response [ Time Frame: Time from the first occurrence of a documented objective response to the time of progressive disease as determined by the investigator or death from any cause, up to approximately 5 years ]
  • Best response achieved (CR, CRi, PR, stable disease, or progressive disease) [ Time Frame: Up to and including the assessment at completion of treatment assessment, within 3 months of last day of treatment, approximately 1 year ]
  • Event-Free Survival [ Time Frame: Time between date of randomization and the date of disease progression/relapse on the basis of investigator-assessment, death, or start of a new anti-leukemic therapy, up to 5 years ]
  • Time to Next Anti-Leukemic Treatment [ Time Frame: Time between the date of randomization and the date of first intake of new anti-leukemic therapy, up to 5 years ]
  • Incidence of adverse events assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 [ Time Frame: 28 days after the last dose of GDC-0199 or after 90 days after last dose of obinutuzumab, whichever is longer ]
  • Incidence of severe adverse events [ Time Frame: Up to 5 years ]
  • Incidence of adverse events of special interest [ Time Frame: Up to 2 years after last dose of study drug ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Compare the Efficacy and Safety of Obinutuzumab + Venetoclax (GDC-0199) Versus Obinutuzumab + Chlorambucil in Participants With Chronic Lymphocytic Leukemia
Official Title  ICMJE A Prospective, Open-Label, Multicenter Randomized Phase III Trial to Compare The Efficacy and Safety of A Combined Regimen of Obinutuzumab and Venetoclax (GDC-0199/ABT-199) Versus Obinutuzumab and Chlorambucil in Previously Untreated Patients With CLL and Coexisting Medical Conditions
Brief Summary This open-label, multicenter, randomized Phase III study is designed to compare the efficacy and safety of a combined regimen of obinutuzumab and venetoclax versus obinutuzumab + chlorambucil in participants with chronic lymphocytic leukemia (CLL) and coexisting medical conditions. The anticipated time on study treatment will be approximately one year and the follow-up period will be up to 5 years.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Lymphocytic Leukemia, Chronic
Intervention  ICMJE
  • Drug: Chlorambucil
    Chlorambucil 0.5 milligrams per kilogram (mg/kg) orally at Day 1 and Day 15 at of each 28 day cycle for 12 cycles.
  • Drug: Venetoclax
    Venetoclax, oral tablet: 20 mg daily during Cycle 1, Day 22-28; 50 mg daily during Cycle 2, Day 1-7; 100 mg daily during Cycle 2, Day 8-14; 200 mg daily during Cycle 2, Day 15-21; 400 mg daily during Cycle 2, Day 22-28 and on Day 1-28 for all subsequent cycles until the end of Cycle 12.
    Other Name: ABT-0199, GDC-0199
  • Drug: Obinutuzumab
    Obinutuzumab, IV infusion: 100 mg or 1000 mg, depending on splitting rules, at Cycle 1, Day 1 (if 100 mg was received on Day 1, 900 mg will be administered on Cycle 1, Day 2); 1000 mg at Cycle 1, Day 8 and Day 15; 1000 mg at Day 1 for all subsequent cycles until the end of Cycle 6
    Other Name: GA-101; Gazyva
Study Arms  ICMJE
  • Experimental: Safety Run-in Obinutuzumab + Venetoclax
    Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.
    Interventions:
    • Drug: Venetoclax
    • Drug: Obinutuzumab
  • Experimental: Obinutuzumab + Chlorambucil
    Participants will receive obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles will comprise 28 days.
    Interventions:
    • Drug: Chlorambucil
    • Drug: Obinutuzumab
  • Experimental: Obinutuzumab + Venetoclax
    Participants will receive obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles will comprise 28 days.
    Interventions:
    • Drug: Venetoclax
    • Drug: Obinutuzumab
Publications * Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, Robrecht S, Warburton S, Humphrey K, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Dû K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Boettcher S, Tausch E, Humerickhouse R, Eichhorst B, Wendtner CM, Langerak AW, Kreuzer KA, Ritgen M, Goede V, Stilgenbauer S, Mobasher M, Hallek M. Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. N Engl J Med. 2019 Jun 6;380(23):2225-2236. doi: 10.1056/NEJMoa1815281. Epub 2019 Jun 4.

*   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: September 1, 2016)
445
Original Estimated Enrollment  ICMJE
 (submitted: September 16, 2014)
432
Estimated Study Completion Date  ICMJE September 1, 2020
Actual Primary Completion Date August 17, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Documented previously untreated CLL according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria
  • CLL requiring treatment according to IWCLL criteria
  • Total Cumulative Illness Rating Scale (CIRS score) greater than (>) 6
  • Adequate marrow function independent of growth factor or transfusion support within 2 weeks of screening as per protocol, unless cytopenia is due to marrow involvement of CLL
  • Adequate liver function
  • Life expectancy > 6 months
  • Agreement to use highly effective contraceptive methods per protocol

Exclusion Criteria:

  • Transformation of CLL to aggressive Non-Hodgkin's lymphoma (Richter's transformation or pro-lymphocytic leukemia)
  • Known central nervous system involvement
  • Participants with a history of confirmed progressive multifocal leukoencephalopathy (PML)
  • An individual organ/ system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the treatment regimen of this trial with the exception of eyes, ears, nose, throat organ system
  • Participants with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
  • Inadequate renal function
  • History of prior malignancy, except for conditions as listed in the protocol if participants have recovered from the acute side effects incurred as a result of previous therapy
  • Use of investigational agents or concurrent anti-cancer treatment within the last 4 weeks of registration
  • Participants with active bacterial, viral, or fungal infection requiring systemic treatment within the last two months prior to registration
  • History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
  • Hypersensitivity to chlorambucil, obinutuzumab, or venetoclax or to any of the excipients
  • Pregnant women and nursing mothers
  • Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive hepatitis B surface antigen [HBsAg] serology) or positive test result for hepatitis C (hepatitis C virus [HCV] antibody serology testing)
  • Participants with known infection with human immunodeficiency virus (HIV) or human T-cell leukemia virus-1 (HTLV-1)
  • Requires the use of warfarin, marcumar, or phenprocoumon
  • Received agents known to be strong and moderate Cytochrome P450 3A inhibitors or inducers within 7 days prior to the first dose of study drug
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (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 Argentina,   Australia,   Austria,   Brazil,   Bulgaria,   Canada,   Croatia,   Denmark,   Estonia,   France,   Germany,   Italy,   Mexico,   New Zealand,   Poland,   Romania,   Russian Federation,   Spain,   Switzerland,   United Kingdom,   United States
Removed Location Countries Egypt
 
Administrative Information
NCT Number  ICMJE NCT02242942
Other Study ID Numbers  ICMJE BO25323
2014-001810-24 ( EudraCT Number )
CLL14
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE
  • AbbVie
  • German CLL Study Group
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date September 2019

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