Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid With Nivolumab (VIPOR-Nivo) for Diffuse Large B-cell Lymphoma Involving the Central Nervous System

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Suspended

CT.gov ID

NCT05211336

Collaborator

(none)

Enrollment

Location

Arm

74.4

Anticipated Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

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 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

CT, PDG PET, and 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.

Condition or Disease	Intervention/Treatment	Phase
Primary Diffuse Large B-cell Lymphoma of the Central Nervous System (CNS) Aggressive B-cell Lymphoma With Secondary Involvement of the CNS	Drug: Obinutuzumab Drug: Nivolumab Drug: Prednisone Drug: Lenalidomide Drug: Venetoclax Drug: Ibrutinib	Phase 1

Detailed Description

Background:

Primary diffuse large B-cell lymphoma of the CNS (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
CNSL often have copy number alterations or chromosomal rearrangements involving the PD-1 ligands, PD-L1 and PD-L2, making this a rational therapeutic target for CNSL
PD-1 inhibitors have limited monotherapy activity in CNSL, but demonstrate synergy with Bruton s tyrosine kinase (BTK) inhibitors, BCL2 inhibitors, and lenalidomide in pre-clinical models
All agents in the VIPOR combination achieve meaningful CNS penetration and PD-1 inhibitors have known clinical activity for lymphomas involving the CNS

Objective:

-To determine the safety and tolerability of VIPOR-Nivo in participants with PCNSL and SCNSL

Eligibility:

Primary diffuse large B-cell lymphoma of the CNS (PCNSL) or an aggressive 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 (accrual ceiling will be set at 12 to allow for inevaluable participants or screen failures)
Participants will first be treated with a 21-day Window of lenalidomide and nivolumab to identify early signs of clinical activity with the doublet
Participants will then receive VIPOR-Nivo in 21-day cycles for a maximum of 6 cycles

Study Design

Study Type:

Interventional

Anticipated Enrollment :

12 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase 1 Study of Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid With Nivolumab (VIPOR-Nivo) for Diffuse Large B-cell Lymphoma Involving the Central Nervous System

Actual Study Start Date :

Apr 19, 2022

Anticipated Primary Completion Date :

Dec 31, 2027

Anticipated Study Completion Date :

Jun 30, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1: Lenalidomide + nivo window; followed by VIPOR-Nivo Nivolumab on day 1 with lenalidomide (days 1-14) for a 21-day cycle. Following Window, VIPOR-Nivo (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles	Drug: Obinutuzumab Obinutuzumab 1000 mg IV (intravenous) days 1 and 2 for a maximum of 6 cycles every 21 days (each cycle is 21 days) Drug: Nivolumab Nivolumab 360 mg fixed dose IV (intravenous) on day 1 for 1 cycle (21 days); followed by Nivolumab 360 mg IV on day 1 for a maximum of 6 cycles every 21 days (each cycle is 21 days) Drug: Prednisone Prednisone 100 mg PO (by mouth) daily days 1-7 for a maximum of 6 cycles every 21 days (each cycle is 21 days) Drug: Lenalidomide 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) Drug: Venetoclax Venetoclax 800 mg PO (by mouth) on days 1-14 for a maximum of 6 cycles every 21 days (each cycle is 21 days) Drug: Ibrutinib Ibrutinib 560 mg PO (by mouth) daily days 1-14 for a maximum of 6 cycles every 21 days (each cycle is 21 days)

Arm

Intervention/Treatment

Experimental: 1: Lenalidomide + nivo window; followed by VIPOR-Nivo

Nivolumab on day 1 with lenalidomide (days 1-14) for a 21-day cycle. Following Window, VIPOR-Nivo (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles

Drug: Obinutuzumab

Obinutuzumab 1000 mg IV (intravenous) days 1 and 2 for a maximum of 6 cycles every 21 days (each cycle is 21 days)

Drug: Nivolumab

Nivolumab 360 mg fixed dose IV (intravenous) on day 1 for 1 cycle (21 days); followed by Nivolumab 360 mg IV on day 1 for a maximum of 6 cycles every 21 days (each cycle is 21 days)

Drug: Prednisone

Prednisone 100 mg PO (by mouth) daily days 1-7 for a maximum of 6 cycles every 21 days (each cycle is 21 days)

Drug: Lenalidomide

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)

Drug: Venetoclax

Venetoclax 800 mg PO (by mouth) on days 1-14 for a maximum of 6 cycles every 21 days (each cycle is 21 days)

Drug: Ibrutinib

Ibrutinib 560 mg PO (by mouth) daily days 1-14 for a maximum of 6 cycles every 21 days (each cycle is 21 days)

Outcome Measures

Primary Outcome Measures

Absence of toxicity/SAE [After 2 Cycles]
Success is defined as completing at least 2 cycles of VIPOR-Nivo therapy without the need to discontinue treatment due to toxicity. The fraction of participants who achieve a success will be determined and reported along with a 95% confidence interval.

Secondary Outcome Measures

Complete Response [After cycles 3 and 6]
The complete response rate of up to 6 cycles of VIPOR-Nivo in PCNSL and SCNSL will be reported along with a 95% confidence interval.
Progression Free Survival [Up to 10 years post-treatment]
The progression-free survival (PFS) after VIPOR-Nivo in PCNSL and 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.
Overall Response Rate to VIPOR-Nivo [After cycles 3 and 6]
The overall response rate of up to 6 cycles of VIPOR-Nivo in PCNSL and SCNSL will be reported along with a 95% confidence interval.
Overall Survival [Up to 10 years post-treatment]
Overall survival (OS) after VIPOR-Nivo in PCNSL and SCNSL will be determined using a Kaplan-Meier curve. The median will be determined and presented with its associated 95% confidence interval.
Duration of Response [First date that recurrent or progressive disease is objectively documented]
The duration of response after VIPOR-Nivo in PCNSL and 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.
Overall Response Rate to lenalidomide and nivolumab (window) [After 1 cycle]
The overall response rate after 1 cycle of Window therapy will be reported along with a 95% confidence interval.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

INCLUSION CRITERIA:
Participants must have histologically or cytologically confirmed primary diffuse large B- cell lymphoma of the CNS (PCNSL) or an aggressive 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 participants without prior therapy who are considered ineligible for standard frontline therapy
Participants must have the evaluable disease by clinical exam (i.e., palpable lymphadenopathy, measurable skin lesions, etc.) and/or imaging (measurable lymph nodes or masses on CT or MRI and/or evaluable FDG avid lesions on PET)
Participants with second malignancies not requiring active systemic therapy or pre- malignant conditions such as monoclonal B-cell lymphocytosis (MBL) or monoclonal gammopathy of undetermined significance (MGUS).
Participants that are positive for hepatitis B core antibody, 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).
Participants with suspicious radiologic evidence of aspergillosis infection (i.e., Chest CT and/or Brain MRI) are eligible if confirmatory laboratory testing of Beta-D glucan and aspergillus antigen are negative.
Age >=18 years
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) <= 5.0 x institutional ULN unless lymphoma related
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 eGRF in the clinical lab

Laboratory assessments to determine eligibility may be performed at CLIA (or equivalent) certified laboratories outside the 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 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, 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:

Pre-Treatment/During Treatment (Women/Men - Time frame prior to/during dosing):

--All drugs : Women Begins 28 days prior to treatment; Men Begins on day 1

Post-Treatment (Women/Men - Time frame after the last dose):
Venetoclax - Women 90 days; Men 90 days
Ibrutinib - Women 3 months; Men 3 months
Obinutuzumab - Women 18 months; Men 6 months
Revlimid - Women 28 days; Men 28 days
Nivolumab - Women 5 months; Men 5 months
All study participants must be registered into the mandatory Revlimid REMSTM program and be willing and able to comply with the requirements of Revlimid REMSTM.
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)

EXCLUSION CRITERIA:

Participants with plasmablastic lymphoma and B-cell lymphoma, unclassifiable, with features intermediate between 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) BTK inhibitors, (2) BCL2 inhibitors, (3) immunomodulatory imide drugs (IMIDs) (including lenalidomide and pomalidomide).
Participants with autoimmune disease that requires systemic corticosteroids (> 10 mg daily prednisone equivalents) or immunosuppressive medications within 14 days before study drug administration. Inhaled or topical steroids are permitted. NOTE: Steroids for the treatment of other conditions is allowed on study.
Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti CTLA-4 antibody.
Participants who require continuous treatment with a strong 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

HIV-positive participants
Prior allogeneic stem cell (or other organs) transplant within 6 months or any evidence of active graft-versus-host disease prior to the first dose of study drug
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 or an infection requiring systemic antibiotics.
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 NCI/Child Pugh classification
Vaccinated with live, attenuated vaccines within 28 days of first dose of study drug
Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements.