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

• ClinicalTrials.gov Identifier: NCT05211336
• Recruitment Status: Recruiting
• First Posted: January 27, 2022
• Last Update Posted: March 10, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

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: 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
• 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated 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 (VIPOR) for Diffuse Large B-cell Lymphoma Involving the Central Nervous System
• Actual Study Start Date: April 19, 2022
• Estimated Primary Completion Date: March 31, 2024
• Estimated Study Completion Date: March 31, 2034

Arms and Interventions

Arm

Intervention/treatment

Experimental: 1: VIPOR; VIPOR (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: 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 :

1. Absence of toxicity/SAE [ Time Frame: After 2 Cycles ]
   Success is defined as completing at least 2 cycles of VIPOR 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 :

1. Complete Response [ Time Frame: After cycles 3 and 6 ]
   The complete response rate of up to 6 cycles of VIPOR in PCNSL and SCNSL will be reported along with a 95% confidence interval.
2. Overall Response Rate to VIPOR [ Time Frame: After cycles 3 and 6 ]
   The overall response rate of up to 6 cycles of VIPOR in PCNSL and SCNSL will be reported along with a 95% confidence interval.
3. Overall Survival [ Time Frame: Up to 10 years post-treatment ]
   Overall survival (OS) after VIPOR 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.
4. Progression Free Survival [ Time Frame: Up to 10 years post-treatment ]
   The progression-free survival (PFS) after VIPOR 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.
5. Duration of Response [ Time Frame: First date that recurrent or progressive disease is objectively documented ]
   The duration of response after VIPOR 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

• INCLUSION CRITERIA:
• Participants must have histologically or cytologically confirmed primary diffuse large B-cell lymphoma of the CNS (PCNSL) or non-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 CT or MRI and/or evaluable FDG-avid lesions on 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
• 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 glutamicoxaloacetic 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 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 (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 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 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 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
• 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 NCI/Child Pugh classification)
• Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements.

Contacts and Locations

Contacts

Contact: NCI Medical Oncology Referral Office; (240) 760-6050; ncimo_referrals@nih.gov

Contact: Mark J Roschewski, M.D.; (240) 760-6183; mark.roschewski@nih.gov

Locations

United States, Maryland

National Institutes of Health Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office 888-624-1937

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Mark J Roschewski, M.D.; National Cancer Institute (NCI)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT05211336
• Other Study ID Numbers: 10000516; 000516-C
• First Posted: January 27, 2022
• Last Update Posted: March 10, 2023
• Last Verified: March 7, 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@All large scale genomic sequencing data will be shared with subscribers to dbGaP.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Clinical data available during the study and indefinitely.@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• Access Criteria: Genomic data are made available via dbGaP through requests to the data custodians.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

CNS; PCNSL; SCNSL; Systemic Lymphoma

Additional relevant MeSH terms:

Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin; Prednisone; Lenalidomide; Venetoclax; Obinutuzumab; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antineoplastic Agents, Immunological