Mantle Cell Lymphoma (MCL)
Conditions
Keywords
MCL, Venetoclax, ABT-199, Ibrutinib, Imbruvica
Brief summary
Mantle Cell Lymphoma (MCL) is a form of Non-Hodgkin Lymphoma (NHL - cancer of the lymphatic system in blood) where cells from outer edge of the lymph nodes, called mantle zone become cancerous. In Japan, MCL accounts for about 3% of all NHL cases. Symptoms of MCL may include enlarged lymph nodes, stomach pain, fever, night sweats, and weight loss. Currently, MCL is not curable with standard therapies. The purpose of this study is to evaluate the safety, efficacy, and effect of venetoclax in combination with ibrutinib on best overall response of complete response in participants with relapsed (return of disease) or refractory (not responding to treatment) (R/R) MCL. Venetoclax is an investigational drug being developed for the treatment of MCL. Ibrutinib is a drug approved for the treatment of MCL. Participants will receive venetoclax (increasing doses) and ibrutinib (fixed dose) for approximately 104 weeks, followed by ibrutinib alone. Adult participants with R/R MCL will be enrolled. Around 12 participants will be enrolled in Japan. Participants will receive oral venetoclax tablet and oral ibrutinib capsule for 104 weeks. After 104 weeks, participants will receive ibrutinib once daily until their disease progresses, or they cannot tolerate the medication, or until they do not want to participate in the study. There may be a higher treatment burden for participants in this study compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, bone marrow biopsies, checking for side effects, and completing questionnaires.
Interventions
DRUGIbrutinib
Capsule; Oral
DRUGVenetoclax
Tablet; Oral
Sponsors
AbbVie
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pathologically confirmed Mantle Cell Lymphoma (MCL) (tumor tissue) by local testing. * At least 1 measurable site of disease on cross-sectional imaging that is \>= 2.0 centimeters (cm) in the longest diameter and measurable in 2 perpendicular dimensions per Computed Tomography (CT). * At least 1, but no more than 5, prior treatment regimens for MCL including at least 1 prior rituximab/anti-CD20 containing regimen. * Failure to achieve at least partial response (PR) with, or documented disease progression after, the most recent treatment regimen.
Exclusion criteria
* Prior therapy with ibrutinib or other Bruton Tyrosine Kinase (BTK) inhibitors. * History of other malignancies, except: * Malignancy treated with curative intent and with no known active disease present for \>= 3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician. * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. * Adequately treated carcinoma in situ without evidence of disease. * History or current evidence of central nervous system lymphoma. * Treatment with any of the following within 7 days prior to the first dose of study drug: * Moderate or strong cytochrome P450 3A (CYP3A) inhibitors. * Moderate or strong CYP3A inducers. * Anticancer therapy, including chemotherapy, radiotherapy, small molecule, and investigational agents, and/or monoclonal antibody \<=21 days prior to the first dose of study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Best Overall Response of Complete Response (CR), as Assessed by the Independent Review Committee (IRC) | Week 13 | Complete response rate (CRR), defined as the percentage of participants achieving a best overall response of complete response (CR) per the Revised Criteria for Response Assessment for Malignant Lymphoma following the Lugano classification (Cheson 2014), assessed by an Independent Review Committee (IRC). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Best Overall Response of CR or PR, as Assessed by the IRC | Median follow-up time of 48 months (range: 2.3 to 50.7) | Overall Response Rate (ORR), defined as the percentage of participants with a best overall response of CR or PR, per the Revised Criteria for Response Assessment for Malignant Lymphoma, assessed by an Independent Review Committee (IRC). |
| Percentage of Participants Achieving Best Overall Response of CR as Assessed by the Investigator | Median follow-up time of 48 months (range: 2.3 to 50.7) | Best overall response of CR is defined as the percentage of participants achieving a best overall response of CR for the venetoclax and ibrutinib combination, as assessed by the investigator per the Revised Criteria for Response Assessment for Malignant Lymphoma . |
| Percentage of Participants Achieving Best Overall Response of CR or PR, as Assessed by the Investigator | Median follow-up time of 48 months (range: 2.3 to 50.7) | Best overall response of CR or PR will be evaluated using ORR. The ORR is defined as the percentage of participants with a best overall response of CR or PR, according to the Revised Criteria for Response Assessment for Malignant Lymphoma, as assessed by the investigator. |
| Duration of Response (DOR) for Participants Who Achieved a Best Overall Response of CR or PR, as Assessed by the Investigator | Median follow-up time of 48 months (range: 2.3 to 50.7) | DOR is defined as the time from the first occurrence of response (CR or PR) to disease progression or death, whichever occurs first, according to the Revised Criteria for Response Assessment for Malignant Lymphoma, as assessed by the investigator. |
| DOR for Participants Who Achieved a Best Overall Response of CR or PR, as Assessed by the IRC | Median follow-up time of 48 months (range: 2.3 to 50.7) | DOR is defined as the time from the first occurrence of response (CR or PR) to disease progression or death, whichever occurs first, according to the Revised Criteria for Response Assessment for Malignant Lymphoma, as assessed by the IRC. |
| Undetectable Minimal Residual Disease (uMRD) in Peripheral Blood in Participants Who Achieve a Best Overall Response of CR as Assessed by the Investigator and the IRC | Median follow-up time of 48 months (range: 2.3 to 50.7) | MRD rate is defined as the percentage of participants with uMRD who achieve a best overall response of CR, according to the Revised Criteria for Response Assessment for Malignant Lymphoma, as assessed by the investigator. |
| uMRD in Bone Marrow Participants Who Achieve a Best Overall Response of CR as Assessed by the Investigator and the IRC. | Median follow-up time of 48 months (range: 2.3 to 50.7) | MRD rate is defined as the percentage of participants with uMRD who achieve a best overall response of CR, according to the Revised Criteria for Response Assessment for Malignant Lymphoma, as assessed by investigator and the IRC. |
| Progression-Free Survival (PFS) | Median follow-up time of 48 months (range: 2.3 to 50.7) | PFS is defined as the time from the date of the first dose of study drug (venetoclax or ibrutinib) to the date of investigator-assessed disease progression, using the Revised Response Criteria for Response Assessment for Malignant Lymphoma, or death from any cause, whichever occurs first. |
| Overall Survival (OS) | Median follow-up time of 48 months (range: 2.3 to 50.7) | OS is defined as the time from the date of the first dose of the study drug (venetoclax or ibrutinib) to death from any cause. |
Countries
Japan
Contacts
STUDY_DIRECTORABBVIE INC.
AbbVie
Participant flow
Recruitment details
A total of 13 participants were enrolled across 8 sites in Japan. The study was not considered terminated because, after venetoclax plus ibrutinib combination therapy was approved in Japan for relapsed/refractory mantle cell lymphoma, the remaining participants transitioned to commercially available drug supply or other available treatment options. As specified in the protocol, the study was therefore considered discontinued rather than terminated.
Pre-assignment details
The Full Analysis Set (FAS) included all participants who received at least one dose of study drug and was used for all efficacy analyses (except for those based on IRC assessment), safety, and baseline analyses (N=13). The Per-protocol (PP) population excluded participants with non-evaluable disease at baseline (based on IRC assessment). PP population was used for IRC-assessed endpoints (N=12).
Participants by arm
| Arm | Count |
|---|---|
| Ibrutinib + Venetoclax Participants received Ibrutinib 560 mg QD + Venetoclax starting at 20 mg QD, gradually ramped up over 5 weeks to a target dose of 400 mg QD. Ibrutinib 560 mg QD + Venetoclax 400 mg QD was continued for up to 104 weeks, followed by Ibrutinib monotherapy. | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Ibrutinib + Venetoclax |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 11 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Age, Continuous | 69.8 Years STANDARD_DEVIATION 5.97 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 13 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment Japan | 13 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 5 / 13 |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 7 / 13 |
Outcome results
Primary
Percentage of Participants Achieving Best Overall Response of Complete Response (CR), as Assessed by the Independent Review Committee (IRC)
Complete response rate (CRR), defined as the percentage of participants achieving a best overall response of complete response (CR) per the Revised Criteria for Response Assessment for Malignant Lymphoma following the Lugano classification (Cheson 2014), assessed by an Independent Review Committee (IRC).
Time frame: Week 13
Population: Per-Protocol Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Venetoclax | Percentage of Participants Achieving Best Overall Response of Complete Response (CR), as Assessed by the Independent Review Committee (IRC) | 83.3 percentage of participants |
p-value: <0.001Exact Binomial Distribution
Secondary
DOR for Participants Who Achieved a Best Overall Response of CR or PR, as Assessed by the IRC
DOR is defined as the time from the first occurrence of response (CR or PR) to disease progression or death, whichever occurs first, according to the Revised Criteria for Response Assessment for Malignant Lymphoma, as assessed by the IRC.
Time frame: Week 104
Secondary
Duration of Response (DOR) for Participants Who Achieved a Best Overall Response of CR or PR, as Assessed by the Investigator
DOR is defined as the time from the first occurrence of response (CR or PR) to disease progression or death, whichever occurs first, according to the Revised Criteria for Response Assessment for Malignant Lymphoma, as assessed by the investigator.
Time frame: Week 104
Secondary
Overall Survival (OS)
OS is defined as the time from the date of the first dose of the study drug (venetoclax or ibrutinib) to death from any cause.
Time frame: Week 104
Secondary
Percentage of Participants Achieving Best Overall Response of CR as Assessed by the Investigator
Best overall response of CR is defined as the percentage of participants achieving a best overall response of CR for the venetoclax and ibrutinib combination, as assessed by the investigator per the Revised Criteria for Response Assessment for Malignant Lymphoma .
Time frame: Week 104
Secondary
Percentage of Participants Achieving Best Overall Response of CR or PR, as Assessed by the Investigator
Best overall response of CR or PR will be evaluated using ORR. The ORR is defined as the percentage of participants with a best overall response of CR or PR, according to the Revised Criteria for Response Assessment for Malignant Lymphoma, as assessed by the investigator.
Time frame: Week 104
Secondary
Percentage of Participants Achieving Best Overall Response of CR or PR, as Assessed by the IRC
Overall Response Rate (ORR), defined as the percentage of participants with a best overall response of CR or PR, per the Revised Criteria for Response Assessment for Malignant Lymphoma, assessed by an Independent Review Committee (IRC).
Time frame: Week 104
Secondary
Progression-Free Survival (PFS)
PFS is defined as the time from the date of the first dose of study drug (venetoclax or ibrutinib) to the date of investigator-assessed disease progression, using the Revised Response Criteria for Response Assessment for Malignant Lymphoma, or death from any cause, whichever occurs first.
Time frame: Week 104
Secondary
uMRD in Participants Who Achieve a Best Overall Response of CR as Assessed by IRC.
MRD rate is defined as the percentage of participants with uMRD who achieve a best overall response of CR, according to the Revised Criteria for Response Assessment for Malignant Lymphoma, as assessed by the IRC.
Time frame: Week 104
Secondary
Undetectable Minimal Residual Disease (uMRD) in Participants Who Achieve a Best Overall Response of CR as Assessed by the Investigator.
MRD rate is defined as the percentage of participants with uMRD who achieve a best overall response of CR, according to the Revised Criteria for Response Assessment for Malignant Lymphoma, as assessed by the investigator.
Time frame: Week 104