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

Phase 1

Active, not recruiting

Conditions: Primary Diffuse Large B-cell Lymphoma of the Central Nervous System (CNS)
Aggressive B-cell Lymphoma With Secondary Involvement of the CNS

Interventions: Drug: Obinutuzumab
Drug: Prednisone
Drug: Lenalidomide
Drug: Venetoclax
Drug: Ibrutinib
Drug: Acetaminophen
Drug: Diphenhydramine
Other: Peg-filgrastim
Diagnostic Test: CT Scan (chest, abdomen, and pelvis)
Diagnostic Test: MRI
Diagnostic Test: 18f-FDG-PET
Diagnostic Test: PET
Diagnostic Test: Lumbar puncture/Ommaya tap
Diagnostic Test: Bone marrow aspiration/biopsy
Combination Product: EKG

Registration Number: NCT05211336

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 14

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
1: VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide)	Obinutuzumab	VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles
1: VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide)	Prednisone	VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles
1: VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide)	Lenalidomide	VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles
1: VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide)	Venetoclax	VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles
1: VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide)	Ibrutinib	VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles
1: VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide)	Acetaminophen	VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles
1: VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide)	Diphenhydramine	VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles
1: VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide)	Peg-filgrastim	VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles
1: VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide)	CT Scan (chest, abdomen, and pelvis)	VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles
1: VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide)	MRI	VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles
1: VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide)	18f-FDG-PET	VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles
1: VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide)	PET	VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles
1: VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide)	Lumbar puncture/Ommaya tap	VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles
1: VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide)	Bone marrow aspiration/biopsy	VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles
1: VIPOR (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide)	EKG	VIPOR (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) in 21-day cycles for up to 6 cycles

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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.
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.