Primary Diffuse Large B-cell Lymphoma of the Central Nervous System (CNS), Aggressive B-cell Lymphoma With Secondary Involvement of the CNS
Conditions
Keywords
CNS, PCNSL, SCNSL, Systemic Lymphoma
Brief summary
Background: People with primary diffuse large B-cell lymphoma of the central nervous system (CNS) and aggressive B-cell lymphomas with secondary CNS involvement have a poor prognosis. Researchers want to learn if a combination of drugs can help. Objective: To learn if it is safe to give people with these cancers Nivolumab (VIPOR-Nivo). Eligibility: People aged 18 and older with B-cell lymphoma in the CNS that does not respond to treatment, response to treatment does not last long, or there is no standard treatment. Design: Participants will be screened with: Health history Physical exam Blood, urine, and heart tests Computed tomography (CT), fludeoxyglucose F18 (FDG) positron emission tomography (PET), and magnetic resonance imaging (MRI) scans. Participants will lie in scanners that take pictures of the body. For some scans, a contrast or chemical agent will be injected into a vein. Lumbar puncture or Ommaya tap. Participants will have a small needle inserted into their lower back or scalp to obtain fluid. Possible tumor biopsy. Participants will have a needle inserted into a tumor to take a sample. Participants will get the study drugs in 21-day cycles. They may have up to 6 treatment cycles. They will take some drugs by infusion into a vein and some drugs by mouth. Participants will get counseling at least every 28 days on the risks of lenalidomide. Participants will have visits throughout the study. Visits may include repeats of the screening tests. They may also include: Bone marrow biopsy. Participants will have a needle inserted into their hipbone to remove marrow. Saliva samples and cheek swabs Participants will have periodic follow-up visits for about 10 years.
Detailed description
Background: * Primary diffuse large B-cell lymphoma of the central nervous system (CNS) primary central nervous system lymphoma (PCNSL) and aggressive B-cell lymphomas with secondary CNS involvement (SCNSL) have a poor prognosis * Most CNS lymphomas (CNSL) exhibit molecular biology features of activated B cell diffuse large B-cell lymphoma (ABC DLBCL) * We developed VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide \[Revlimid (Registered Trademark)\]) treatment in systemic lymphomas as a platform most effective for ABC DLBCL * All agents in the VIPOR combination achieve meaningful CNS penetration and clinical activity for lymphomas involving the CNS Objective: -To determine the safety and tolerability of VIPOR in participants with PCNSL and SCNSL Eligibility: * Primary diffuse large B-cell lymphoma of the CNS (PCNSL) or non-germinal center B-cell (non-GCB) diffuse large B-cell lymphoma with secondary involvement of the CNS (SCNSL) * Relapsed/refractory after prior therapy or ineligible for standard frontline therapy * Age \>= 18 years * No pregnant women * Adequate organ function Study Design: * A safety study of 10 evaluable participants with PCNSL or SCNSL treated with VIPOR (the original study protocol enrolled 4 participants to Cohort 1, Arm 1 consisting of VIPOR plus nivolumab which is now closed). * Participants will receive VIPOR in 21-day cycles for a maximum of 6 cycles to collect data on safety and efficacy. * Accrual ceiling will be set at 16 participants to allow for a few inevaluable participants or screen failures.
Interventions
DRUGObinutuzumab
Obinutuzumab 1000 mg IV (intravenous) days 1 and 2 for a maximum of 6 cycles every 21 days (each cycle is 21 days)
DRUGPrednisone
Prednisone 100 mg PO (by mouth) daily days 1-7 for a maximum of 6 cycles every 21 days (each cycle is 21 days)
DRUGLenalidomide
Lenalidomide 10 or 15 mg PO (by mouth) on days 1-14 for 1 cycle (21 days); followed by Lenalidomide 10 or 15 mg PO daily days 1-14 for a maximum of 6 cycles every 21 days (each cycle is 21 days)
DRUGVenetoclax
Venetoclax 800 mg PO (by mouth) on days 1-14 for a maximum of 6 cycles every 21 days (each cycle is 21 days)
DRUGIbrutinib
Ibrutinib 560 mg PO (by mouth) daily days 1-14 for a maximum of 6 cycles every 21 days (each cycle is 21 days)
DRUGAcetaminophen
650 mg by mouth (PO) daily on days 1 and 2 approximately 30-60 minutes prior to Obinutuzumab infusion.
DRUGDiphenhydramine
50mg by mouth (PO) daily on days 1 and 2 approximately 30-60 minutes prior to Obinutuzumab infusion.
OTHERPeg-filgrastim
6 mg subcutaneous once on day 8 only.
DIAGNOSTIC_TESTCT Scan (chest, abdomen, and pelvis)
To assess sites of disease.
DIAGNOSTIC_TESTMRI
If clinically indicated.
DIAGNOSTIC_TEST18f-FDG-PET
If clinically indicated.
DIAGNOSTIC_TESTPET
If clinically indicated.
DIAGNOSTIC_TESTLumbar puncture/Ommaya tap
If clinically indicated.
DIAGNOSTIC_TESTBone marrow aspiration/biopsy
If clinically indicated.
COMBINATION_PRODUCTEKG
To determine eligibility.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: * Participants must have histologically or cytologically confirmed primary diffuse large B-cell lymphoma of the central nervous system (CNS) primary central nervous system lymphoma (PCNSL) or non-germinal center B-cell-like (GCB) diffuse large B-cell lymphoma with secondary involvement of the CNS (SCNSL). NOTE: Participants with B-cell lymphomas that were previously indolent but now involve the CNS (i.e., transformed from previous follicular lymphoma, chronic lymphocytic leukemia, marginal zone lymphoma, and mantle cell lymphoma) are eligible. * Participants must have a disease that is relapsed or refractory after initial systemic treatment or be considered ineligible for standard frontline therapy with high-dose methotrexate due to one of the following criteria: * Age\>= 70 years * Estimated glomerular filtration rate \< 60 ml/min/1.73m\^2 * Presence of ascites or pleural effusion * Participants must have evaluable disease by clinical exam (i.e., palpable lymphadenopathy, measurable skin lesions, etc.) and/or imaging (measurable lymph nodes or masses on computed tomography (CT) or magnetic resonance imaging (MRI) and/or evaluable fluorodeoxyglucose (FDG)-avid lesions on positron emission tomography (PET). * Participants with second malignancies not requiring active systemic therapy or premalignant conditions such as monoclonal B-cell lymphocytosis (MBL) or monoclonal gammopathy of undetermined significance (MGUS) are eligible. * Participants that are positive for hepatitis B core antibody (HBcAb), hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative hepatitis B and/or C viral load by polymerase chain reaction (PCR). * Age \>=18 years * Eastern Cooperative Oncology Group (ECOG) performance status \<=2. NOTE: In participants with neurologic deficits caused by CNS lymphoma any ECOG status is acceptable to be eligible. * Participants must have adequate organ and marrow function as defined below: * absolute neutrophil count \>= 1000 cells/mcL (1 X 10\^9/L) * platelet count \>= 50,000 cells/mcL (50 X 10\^9/L) * hemoglobin \> 8.0 g/dL (transfusions permitted) * total bilirubin \<= 1.5 X upper limit of normal (ULN) (unless Gilbert's syndrome or disease infiltration of the liver is present) * Aspartate Aminotransferase or serum glutamic oxaloacetic transaminase/ Alanine Aminotransferase or serum glutamic pyruvic transaminase AST(SGOT)/ALT(SGPT) \<= 3.0 X institutional ULN for those without lymphoma involvement OR \<= 5.0 X institutional ULN for those with lymphoma involvement * Serum Creatinine OR creatinine clearance (Cr Cl) \<= 1.5 mg/dL OR \> 40 ml/min/1.73m\^2 NOTE: Cr Cl will be calculated with the use of the 24-hour creatinine clearance or estimated glomerular filtration rate (eGRF) in the clinical lab Laboratory assessments to determine eligibility may be performed at Clinical Laboratory Improvement Amendments (CLIA) (or equivalent) certified laboratories outside the National Institutes of Health (NIH) and results forwarded to the study team for review and management. Given that the methodologies utilized are similar across all laboratories, no significant variability is expected and there is no anticipation that study data will be affected. However, as different laboratories use slightly different kinds of equipment, each laboratory must determine/validate its own reference ranges. Therefore, on this protocol, normal ranges from each lab will be used in reference to terms such as upper limit of normal (ULN), except in cases where absolute values are appropriate and are specified as such * Prothrombin time (PT) and activated partial thromboplastin time (aPTT) must be \< 1.5 x the ULN; except if, the aPTT is prolonged because of a positive Lupus Anticoagulant. * Male and female participants must agree to use certain methods of birth control. A highly effective method of birth control for female participants is defined as a method that has a low failure rate (i.e., less than 1% per year) when used consistently and correctly and includes implants, injectables, birth control pills with two hormones, some intrauterine devices (IUDs). Male participant cannot use highly effective methods and are required to use barrier. The specific guidelines are as follows: * Women: Females of childbearing potential (FOCBP), defined as a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months), must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking Revlimid (R), as well as for the duration after the last dose of study drug as listed below. * Men: Men must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures to prevent pregnancy of their partner and should also agree to not donate sperm while taking the study treatment and for the durations as listed below. * Contraception Requirements * Time frame/Study Drug/Women/Men * Pre-Treatment/During Treatment: Time frame prior to/during dosing: * All drugs: Begins 28 days prior to treatment/Begins on day 1 * Post-Treatment: Time frame after the last dose: * Venetoclax: 90 days/90 days * Ibrutinib: 3 months/3 months * Obinutuzumab: 18 months/6 months * Revlimid (R): 28 days/28 days * All study participants must be registered into the mandatory Revlimid Risk Evaluation and Mitigation Strategy (REMS)(TM) program and be willing and able to comply with the requirements of Revlimid REMS(TM). * Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through designated time points after study drugs discontinuation (as required for women contraception in the table above)
Exclusion criteria
* Participants with plasmablastic lymphoma and B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma are not eligible. * Chemotherapy (excluding corticosteroids), radiation therapy, and/or monoclonal antibody \<=7 days prior to first administration of study treatment. Rationale for a short 7-day window is that participants with relapsed CNS lymphomas often have existing neurologic conditions that mandate urgent therapy. * Previous treatment with more than one of the following classes of medications: (1) Bruton's tyrosine kinase (BTK) inhibitors, (2) B-cell lymphoma 2 (Bcl-2) inhibitors, (3) immunomodulatory imide drugs (IMIDs) (including lenalidomide and pomalidomide). * Participants who require continuous treatment with a strong cytochrome P450 family 3, subfamily A (CYP3A) inhibitor/inducer (i.e., with the exception of any medication to be specifically studied in this protocol). --NOTE: A comprehensive list of inhibitors, inducers, and substrates may be found at: https://drug-interactions.medicine.iu.edu/MainTable.aspx * Human immunodeficiency virus (HIV)-positive participants * Pregnant women- a pregnancy test (urine or serum) with a sensitivity of 25 mIU/mL must be done at screening. * Participants with second malignancies requiring active systemic therapy are excluded. * Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification * History of any ventricular arrhythmia * Unable to swallow capsules, or disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, or symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction. * Uncontrolled ongoing or active infection * Concomitant use of warfarin or other vitamin K antagonists * Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia. * Currently active, clinically significant hepatic impairment (\>= moderate hepatic impairment according to the National Cancer Institute (NCI)/Child Pugh classification) * Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Who Completed at Least 2 Cycles of VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) Therapy Without Stopping Due to Toxicity | After 2 Cycles (each cycle is 21 days) | The proportion of participants who complete at least 2 cycles of VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) therapy without stopping due to toxicity will be determined and reported along with a 95% confidence interval. Success is defined as completing at least 2 cycles of VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) therapy without the need to discontinue treatment due to toxicity (i.e., serious adverse event). A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response (CR) | After cycles 3 and 6 | Complete response is disappearance of all detectable evidence of disease and disease-related symptoms measured by the Lugano criteria. The complete response rate of up to 6 cycles of VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) in primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) will be reported along with a 95% confidence interval. |
| Proportion of Participants Overall Response Rate (Complete Response + Partial Response) to VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) | After cycles 3 and 6 | The overall response rate of up to 6 cycles of VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) in primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) will be reported along with a 95% confidence interval. Complete response (CR) + Partial response (PR) was measured by the Lugano criteria. Complete response is disappearance of all detectable evidence of disease and disease-related symptoms. Partial response is a ≥50% decrease in the sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. |
| Progression Free Survival (PFS) | Up to 2.6 years | Progression-free survival (PFS) is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, death, or 10 years post-treatment, whichever occurs first. The progression-free survival (PFS) after VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) in primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) will be estimated using progression or death without progression as events, using a Kaplan-Meier curve. The median will be determined and presented with its associated 95% confidence interval. Progression was measured by the Lugano criteria and is appearance of any new nodal lesion ≥1.6 cm in greatest tumor dimension or ≥1.1 cm in short axis during or after the end of therapy, even if other lesions are decreasing in size. |
| Duration of Response (DOR) | From date of first response until the date of recurrent or progressive disease is objectively documented, up to a max 2.6 years | The duration of response after VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) in primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) will be determined starting at the date a response is identified and will be estimated using a Kaplan-Meier curve along with a median DOR, and its associated 95% confidence interval. The duration of response (DOR) is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, death, or, in the absence of progressive disease (PD), date of last assessment. CR is disappearance of all detectable evidence of disease and disease-related symptoms. PR is a ≥50% decrease in the sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. Progression is appearance of any new nodal lesion. |
| Overall Survival (OS) | Up to 2.6 years | Overall survival (OS) is defined as the duration of time from the date of study enrollment until time of death from any cause, or 10 years post-treatment whichever occurs first. Overall survival (OS) after VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) in primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) will be determined using a Kaplan-Meier curve. The median will be determined and presented with its associated 95% confidence interval. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). | Adverse events were monitored/assessed from the date of first dose of any study drug, through 30 days after the last dose of any study drug after the last dose of any study drug. Participants were followed for a maximum duration of 2.6 years. | Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lenalidomide+Nivolumab Followed by Venetoclax, Ibrutinib,Prednisone, Obinutuzumab, Lenalidomide-Nivo Cohort 1, Arm 1: Participants with primary diffuse large B-cell lymphoma of the central nervous system (CNS) primary central nervous system lymphoma (PCNSL) or secondary CNS lymphoma (SCNSL).
Experimental - Nivolumab on Day 1 with lenalidomide (days 1-14) for a 21-day cycle. Following Window, VIPOR-Nivo (venetoclax, ibrutinib, prednisone, Obinutuzumab, lenalidomide, and nivolumab) in 21-day cycles for up to 6 cycles. | 4 |
| Cohort 1, Arm 2: Experimental- VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) Participants with primary diffuse large B-cell lymphoma of the central nervous system (CNS) primary central nervous system lymphoma (PCNSL) or secondary CNS lymphoma (SCNSL). VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) in 21-day cycles for up to 6 cycles. | 10 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death due to myocardial infarction | 0 | 1 |
| Overall Study | Death due to unknown cause | 0 | 1 |
| Overall Study | Progressive disease | 0 | 4 |
| Overall Study | Unacceptable adverse event - autoimmune hepatitis | 1 | 0 |
| Overall Study | Worsening kidney function and quality of response | 0 | 1 |
Baseline characteristics
| Characteristic | Lenalidomide+Nivolumab Followed by Venetoclax, Ibrutinib,Prednisone, Obinutuzumab, Lenalidomide-Nivo | Total | Cohort 1, Arm 2: Experimental- VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 7 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 7 Participants | 5 Participants |
| Age, Continuous | 67.5 years STANDARD_DEVIATION 16.66 | 64.5 years STANDARD_DEVIATION 13.14 | 63.3 years STANDARD_DEVIATION 12.3 |
| Disease Category (Primary/Secondary Central Nervous System Lymphoma) Primary | 3 Participants | 9 Participants | 6 Participants |
| Disease Category (Primary/Secondary Central Nervous System Lymphoma) Secondary | 1 Participants | 5 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 6 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 7 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 10 Participants | 6 Participants |
| Region of Enrollment United States | 4 participants | 14 participants | 10 participants |
| Sex: Female, Male Female | 0 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Male | 4 Participants | 9 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 4 | 6 / 10 |
| other Total, other adverse events | 4 / 4 | 9 / 10 |
| serious Total, serious adverse events | 3 / 4 | 6 / 10 |
Outcome results
Primary
Proportion of Participants Who Completed at Least 2 Cycles of VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) Therapy Without Stopping Due to Toxicity
The proportion of participants who complete at least 2 cycles of VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) therapy without stopping due to toxicity will be determined and reported along with a 95% confidence interval. Success is defined as completing at least 2 cycles of VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) therapy without the need to discontinue treatment due to toxicity (i.e., serious adverse event). A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time frame: After 2 Cycles (each cycle is 21 days)
Population: 9/10 participants were analyzed in Cohort 1, Arm 2 because 1 participant progressed before 2 cycles and was unevaluable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide+Nivolumab Followed by Venetoclax, Ibrutinib,Prednisone, Obinutuzumab, Lenalidomide-Nivo | Proportion of Participants Who Completed at Least 2 Cycles of VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) Therapy Without Stopping Due to Toxicity | 0.75 proportion of participants |
| Cohort 1, Arm 2: Experimental- VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) | Proportion of Participants Who Completed at Least 2 Cycles of VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) Therapy Without Stopping Due to Toxicity | 1.0 proportion of participants |
Secondary
Complete Response (CR)
Complete response is disappearance of all detectable evidence of disease and disease-related symptoms measured by the Lugano criteria. The complete response rate of up to 6 cycles of VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) in primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) will be reported along with a 95% confidence interval.
Time frame: After cycles 3 and 6
Population: 3/4 participants are analyzed in Arm 1 and 7/10 are analyzed in Arm 2 after cycle 3 because 1 patient in Arm 1 and 3 patients in Arm 2 did not complete 3 cycles of treatment and stopped earlier.~3/4 participants are analyzed in Arm 1 and 3/10 are analyzed in Arm 2 after cycle 6 because 1 patient in Arm 1 and 7 patients in Arm 2 did not complete 6 cycles of treatment and stopped earlier.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lenalidomide+Nivolumab Followed by Venetoclax, Ibrutinib,Prednisone, Obinutuzumab, Lenalidomide-Nivo | Complete Response (CR) | After cycle 3 | 0.33 proportion of participants |
| Lenalidomide+Nivolumab Followed by Venetoclax, Ibrutinib,Prednisone, Obinutuzumab, Lenalidomide-Nivo | Complete Response (CR) | After cycle 6 | 0.67 proportion of participants |
| Cohort 1, Arm 2: Experimental- VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) | Complete Response (CR) | After cycle 3 | 0 proportion of participants |
| Cohort 1, Arm 2: Experimental- VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) | Complete Response (CR) | After cycle 6 | 0.67 proportion of participants |
Secondary
Duration of Response (DOR)
The duration of response after VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) in primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) will be determined starting at the date a response is identified and will be estimated using a Kaplan-Meier curve along with a median DOR, and its associated 95% confidence interval. The duration of response (DOR) is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, death, or, in the absence of progressive disease (PD), date of last assessment. CR is disappearance of all detectable evidence of disease and disease-related symptoms. PR is a ≥50% decrease in the sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. Progression is appearance of any new nodal lesion.
Time frame: From date of first response until the date of recurrent or progressive disease is objectively documented, up to a max 2.6 years
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Lenalidomide+Nivolumab Followed by Venetoclax, Ibrutinib,Prednisone, Obinutuzumab, Lenalidomide-Nivo | Duration of Response (DOR) | Complete Response | 21.9 Months |
| Lenalidomide+Nivolumab Followed by Venetoclax, Ibrutinib,Prednisone, Obinutuzumab, Lenalidomide-Nivo | Duration of Response (DOR) | Partial Response | 4.9 Months |
| Cohort 1, Arm 2: Experimental- VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) | Duration of Response (DOR) | Complete Response | 7.2 Months |
| Cohort 1, Arm 2: Experimental- VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) | Duration of Response (DOR) | Partial Response | 4.8 Months |
Secondary
Overall Survival (OS)
Overall survival (OS) is defined as the duration of time from the date of study enrollment until time of death from any cause, or 10 years post-treatment whichever occurs first. Overall survival (OS) after VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) in primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) will be determined using a Kaplan-Meier curve. The median will be determined and presented with its associated 95% confidence interval.
Time frame: Up to 2.6 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide+Nivolumab Followed by Venetoclax, Ibrutinib,Prednisone, Obinutuzumab, Lenalidomide-Nivo | Overall Survival (OS) | 23.4 Months |
| Cohort 1, Arm 2: Experimental- VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) | Overall Survival (OS) | 10.4 Months |
Secondary
Progression Free Survival (PFS)
Progression-free survival (PFS) is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, death, or 10 years post-treatment, whichever occurs first. The progression-free survival (PFS) after VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) in primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) will be estimated using progression or death without progression as events, using a Kaplan-Meier curve. The median will be determined and presented with its associated 95% confidence interval. Progression was measured by the Lugano criteria and is appearance of any new nodal lesion ≥1.6 cm in greatest tumor dimension or ≥1.1 cm in short axis during or after the end of therapy, even if other lesions are decreasing in size.
Time frame: Up to 2.6 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide+Nivolumab Followed by Venetoclax, Ibrutinib,Prednisone, Obinutuzumab, Lenalidomide-Nivo | Progression Free Survival (PFS) | 8.4 Months |
| Cohort 1, Arm 2: Experimental- VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) | Progression Free Survival (PFS) | 3.0 Months |
Secondary
Proportion of Participants Overall Response Rate (Complete Response + Partial Response) to VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide)
The overall response rate of up to 6 cycles of VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) in primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) will be reported along with a 95% confidence interval. Complete response (CR) + Partial response (PR) was measured by the Lugano criteria. Complete response is disappearance of all detectable evidence of disease and disease-related symptoms. Partial response is a ≥50% decrease in the sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses.
Time frame: After cycles 3 and 6
Population: 3/4 participants are analyzed in Arm 1 and 7/10 are analyzed in Arm 2 after cycle 3 because 1 patient in Arm 1 and 3 patients in Arm 2 did not complete 3 cycles of treatment and stopped earlier.~3/4 participants are analyzed in Arm 1 and 3/10 are analyzed in Arm 2 after cycle 6 because 1 patient in Arm 1 and 7 patients in Arm 2 did not complete 6 cycles of treatment and stopped earlier.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lenalidomide+Nivolumab Followed by Venetoclax, Ibrutinib,Prednisone, Obinutuzumab, Lenalidomide-Nivo | Proportion of Participants Overall Response Rate (Complete Response + Partial Response) to VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) | After cycle 3 | 1.0 proportion of participants |
| Lenalidomide+Nivolumab Followed by Venetoclax, Ibrutinib,Prednisone, Obinutuzumab, Lenalidomide-Nivo | Proportion of Participants Overall Response Rate (Complete Response + Partial Response) to VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) | After cycle 6 | 1.0 proportion of participants |
| Cohort 1, Arm 2: Experimental- VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) | Proportion of Participants Overall Response Rate (Complete Response + Partial Response) to VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) | After cycle 3 | 0.71 proportion of participants |
| Cohort 1, Arm 2: Experimental- VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) | Proportion of Participants Overall Response Rate (Complete Response + Partial Response) to VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) | After cycle 6 | 1.0 proportion of participants |
Other Pre-specified
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).
Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time frame: Adverse events were monitored/assessed from the date of first dose of any study drug, through 30 days after the last dose of any study drug after the last dose of any study drug. Participants were followed for a maximum duration of 2.6 years.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lenalidomide+Nivolumab Followed by Venetoclax, Ibrutinib,Prednisone, Obinutuzumab, Lenalidomide-Nivo | Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). | 4 Participants |
| Cohort 1, Arm 2: Experimental- VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide) | Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). | 9 Participants |