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Primary Diffuse Large B-Cell Lymphoma of the Central Nervous SystemPhase 1NCT04609046

Testing the Addition of Lenalidomide and Nivolumab to the Usual Treatment for Primary CNS Lymphoma

A Phase 1 study testing Bone Marrow Aspiration and Biopsy, Computed Tomography and Echocardiography Test in people with Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System, run by National Cancer Institute (NCI) at 56 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record

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Trial summary

This phase I trial tests the safety, side effects, best dose and effectiveness of lenalidomide when added to nivolumab and the usual drugs (rituximab and methotrexate) in patients with primary central nervous system (CNS) lymphoma. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Bone Marrow Aspiration and Biopsy, Computed Tomography and Echocardiography Test
Could I receive a placebo?
No, everyone receives an active treatment
How many people
47 participants
Where
56 sitesUnited States
Study dates
24 May 2021to 1 Aug 2027
Phase
Phase 1

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Histologically proven primary CNS diffuse large b-cell lymphoma confirmed by one of the following:
  • Brain biopsy or resection
  • Cerebrospinal fluid
  • Vitreous fluid
  • No prior organ transplantation to exclude post-transplant lymphoproliferative disorders
  • No prior chemotherapy or radiation therapy for lymphoma
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  • No prior allogeneic stem cell transplantation
  • Use of systemic corticosteroids (dexamethasone up to 24 mg/day or equivalent) for disease control or improvement of performance status to be tapered as fast as clinically safe after initiation of therapy is permissible
  • Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown and an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, female of childbearing potential (FCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) =< 7 days prior to registration
  • Age >= 18 years
  • Karnofsky performance scale (KPS) >= 40 (>= 50 for patients older than 60 unless related to lymphoma on investigator's opinion)
  • Absolute neutrophil count (ANC) >= 1,500/mm^3
  • Platelet count >= 100,000/mm^3
  • Calculated (calc.) creatinine clearance >= 50 mL/min by Cockcroft-Gault formula
  • Total Bilirubin =< 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
  • No evidence of non-Hodgkin's lymphoma (NHL) outside CNS
  • No prior history of NHL
  • No history of autoimmune disorder. Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as Systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease. Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
  • Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event)
  • Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (except short course of systemic corticosteroids for disease control or improvement of performance status) or other immunosuppressive medications within 14 days prior to registration. Inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
  • Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study
  • No prior or concurrent malignancies with exception of surgically cured carcinoma in situ (CIS) of the uterus, carcinoma of the skin without evidence of disease for >= 5 years
  • No concurrent malignancy requiring active therapy
  • No untreated hepatitis C virus (HCV) infection with detectable HCV viral load
  • No untreated chronic hepatitis B virus (HBV) infection with detectable HBV viral load
  • No untreated human immunodeficiency virus (HIV) infection or with detectable viral load or with CD4+T-cell count of less than 500/mm^3
  • No history of HIV infection and evidence of Epstein Barr virus (EBV)-related primary central nervous system lymphoma (PCNSL)
  • Inability to tolerate anticoagulation with acetylsalicylic acid, warfarin, or direct oral anticoagulants
  • No other investigational agent
  • No history of severe hypersensitivity reaction to any monoclonal antibody
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to or other agents used in study
  • Sulfonamide drugs, trimethoprim, salicylates, nonsteroidal anti-inflammatory drugs, penicillin, vitamin C, ciprofloxacin, and proton pump inhibitors should be held at least 48 hours prior to methotrexate administration

Who cannot join

None listed.

Trial locations and contacts

56 sites in 1 country.

56 sites in 1 country

United States56 sites

  • Hickman Cancer Center

    Adrian, Michigan, 49221

  • UI Health Care Mission Cancer and Blood - Ankeny Clinic

    Ankeny, Iowa, 50023

  • LSU Health Baton Rouge-North Clinic

    Baton Rouge, Louisiana, 70805

  • Our Lady of the Lake Physician Group

    Baton Rouge, Louisiana, 70808

  • Saint Anthony Regional Hospital

    Carroll, Iowa, 51401

  • UNC Lineberger Comprehensive Cancer Center

    Chapel Hill, North Carolina, 27599

  • Medical University of South Carolina

    Charleston, South Carolina, 29425

  • Siteman Cancer Center at Saint Peters Hospital

    City of Saint Peters, Missouri, 63376

  • UI Health Care Mission Cancer and Blood - West Des Moines Clinic

    Clive, Iowa, 50325

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43210

  • UM Sylvester Comprehensive Cancer Center at Coral Gables

    Coral Gables, Florida, 33146

  • Siteman Cancer Center at West County Hospital

    Creve Coeur, Missouri, 63141

  • UT Southwestern/Simmons Cancer Center-Dallas

    Dallas, Texas, 75390

  • UM Sylvester Comprehensive Cancer Center at Deerfield Beach

    Deerfield Beach, Florida, 33442

  • Iowa Methodist Medical Center

    Des Moines, Iowa, 50309

  • UI Health Care Mission Cancer and Blood - Des Moines Clinic

    Des Moines, Iowa, 50309

  • Broadlawns Medical Center

    Des Moines, Iowa, 50314

  • Mercy Medical Center - Des Moines

    Des Moines, Iowa, 50314

  • UI Health Care Mission Cancer and Blood - Laurel Clinic

    Des Moines, Iowa, 50314

  • Iowa Lutheran Hospital

    Des Moines, Iowa, 50316

  • UM Sylvester Comprehensive Cancer Center at Doral

    Doral, Florida, 33166

  • Marshfield Medical Center-EC Cancer Center

    Eau Claire, Wisconsin, 54701

  • UI Healthcare Mission Cancer and Blood - Fort Dodge

    Fort Dodge, Iowa, 50501

  • University of Iowa/Holden Comprehensive Cancer Center

    Iowa City, Iowa, 52242

  • Gundersen Lutheran Medical Center

    La Crosse, Wisconsin, 54601

  • Northwell Health/Center for Advanced Medicine

    Lake Success, New York, 11042

  • Cedars-Sinai Medical Center

    Los Angeles, California, 90048

  • North Shore University Hospital

    Manhasset, New York, 11030

  • Marshfield Medical Center-Marshfield

    Marshfield, Wisconsin, 54449

  • University of Miami Miller School of Medicine-Sylvester Cancer Center

    Miami, Florida, 33136

  • UM Sylvester Comprehensive Cancer Center at Kendall

    Miami, Florida, 33176

  • Marshfield Medical Center - Minocqua

    Minocqua, Wisconsin, 54548

  • Toledo Clinic Cancer Centers-Monroe

    Monroe, Michigan, 48162

  • West Virginia University Healthcare

    Morgantown, West Virginia, 26506

  • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

    New York, New York, 10032

  • NYP/Weill Cornell Medical Center

    New York, New York, 10065

  • University of Miami Sylvester Comprehensive Cancer Center at Sole Mia

    North Miami, Florida, 33181

  • University of Oklahoma Health Sciences Center

    Oklahoma City, Oklahoma, 73104

  • UM Sylvester Comprehensive Cancer Center at Plantation

    Plantation, Florida, 33324

  • MaineHealth Maine Medical Center - Portland

    Portland, Maine, 04102

  • Rhode Island Hospital

    Providence, Rhode Island, 02903

  • Marshfield Medical Center-Rice Lake

    Rice Lake, Wisconsin, 54868

  • Huntsman Cancer Institute/University of Utah

    Salt Lake City, Utah, 84112

  • UCSF Medical Center-Parnassus

    San Francisco, California, 94143

  • MaineHealth Maine Medical Center- Scarborough

    Scarborough, Maine, 04074

  • MaineHealth Cancer Care and IV Therapy - South Portland

    South Portland, Maine, 04106

  • Washington University School of Medicine

    St Louis, Missouri, 63110

  • Siteman Cancer Center-South County

    St Louis, Missouri, 63129

  • Siteman Cancer Center at Christian Hospital

    St Louis, Missouri, 63136

  • Marshfield Medical Center-River Region at Stevens Point

    Stevens Point, Wisconsin, 54482

  • Overlook Hospital

    Summit, New Jersey, 07902

  • State University of New York Upstate Medical University

    Syracuse, New York, 13210

  • Toledo Clinic Cancer Centers-Toledo

    Toledo, Ohio, 43623

  • UI Health Care Mission Cancer and Blood - Waukee Clinic

    Waukee, Iowa, 50263

  • Methodist West Hospital

    West Des Moines, Iowa, 50266-7700

  • Marshfield Medical Center - Weston

    Weston, Wisconsin, 54476

Other trials in United States

About this study

Official title: Phase I Trial of Methotrexate, Rituximab, Lenalidomide, and Nivolumab (Nivo-MR2) Induction Followed by Lenalidomide and Nivolumab Maintenance in Primary CNS Lymphoma

This phase I trial tests the safety, side effects, best dose and effectiveness of lenalidomide when added to nivolumab and the usual drugs (rituximab and methotrexate) in patients with primary central nervous system (CNS) lymphoma. Lenalidomide may stop or slow primary CNS lymphoma by blocking the growth of new blood vessels necessary for tumor growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Methotrexate is frequently combined with other chemotherapy agents to improve response. This study may help increase the understanding of lenalidomide and nivolumab use in primary CNS lymphoma treatment. In addition, it may help researchers see whether the control of CNS lymphoma can be extended by using these study drugs as maintenance (prolonged therapy) after control is achieved with the initial chemotherapy regimen (induction).

Read the detailed description

PRIMARY OBJECTIVES:

  1. Determine the maximum tolerated dose (MTD) of lenalidomide when given in combination with high dose-methotrexate (HD-MTX) and rituximab, with or without nivolumab, as induction treatment of primary CNS lymphoma.

II. Determine the proportion of patients who are able to stay on maintenance therapy with lenalidomide and/or nivolumab for 6 months after induction treatment of primary CNS lymphoma.

SECONDARY OBJECTIVES:

  1. To evaluate the overall response rate (ORR) of the combination of methotrexate, rituximab, lenalidomide, nivolumab.

II. To evaluate the effect of the treatment regimen and lenalidomide / nivolumab maintenance on progression free survival (PFS).

III. To evaluate the effect of the treatment regimen and lenalidomide / nivolumab maintenance on overall survival (OS).

EXPLORATORY OBJECTIVES:

  1. To analyze tumor tissue and cerebrospinal fluid (CSF) for gene expression profiles, and to correlate these profiles with treatment outcomes.

II. To determine whether CSF proteome and metabolome are predictors of outcomes (prognostic marker).

III. To assess response to therapy and minimal residual disease via MRI-based metrics and minimal residual disease of blood and CSF.

IV. To evaluate the relationship between neurocognitive deficits and tumor and brain volumetrics, as assessed by magnetic resonance imaging (MRI) and tumor metabolism.

OUTLINE: This is a dose-escalation study of lenalidomide.

INDUCTION: Patients receive rituximab intravenously (IV) on day 1, methotrexate IV over 2 hours or orally (PO) on day 2, lenalidomide PO daily on days 5-9, and nivolumab IV over 30 minutes on day 14. (In dose level IV that includes nivolumab, the doses of rituximab for cycles 2-6 may be given on the same day as nivolumab for the previous cycle). Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve complete response, partial response, or stable disease proceed to maintenance therapy.

MAINTENANCE: Within 6 weeks after the last dose of lenalidomide in induction therapy, patients receive lenalidomide PO daily on days 1-21, and nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Patients also undergo magnetic resonance imaging (MRI) throughout the trial, computed tomography (CT) and positron emission tomography (PET)/CT during screening, and lumbar puncture at the end of the 6th cycle of induction, and after 6 months of maintenance. Patients may also undergo bone marrow aspirate and biopsy, testicular ultrasound and/or echocardiogram (ECHO) during screening.

After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for up to 2 years.

Being tested
Bone Marrow Aspiration and Biopsy, Computed Tomography, Echocardiography Test, Lenalidomide, Lumbar Puncture

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Bone Marrow Aspiration and BiopsyProcedure or surgery

    Undergo bone marrow aspirate and biopsy

  • Computed TomographyProcedure or surgery

    Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography

    Undergo CT and PET/CT

  • Echocardiography TestProcedure or surgery

    Also called EC, Echocardiography

    Undergo ECHO

  • LenalidomideDrug

    Also called CC 5013, CC-5013, CC5013, CDC 501

    Given PO

  • Lumbar PunctureProcedure or surgery

    Also called LP, Spinal Tap

    Undergo lumbar puncture

  • Magnetic Resonance ImagingProcedure or surgery

    Also called Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan

    Undergo MRI

  • MethotrexateDrug

    Also called Abitrexate, Alpha-Methopterin, Amethopterin, Brimexate

    Given IV or PO

  • NivolumabBiological

    Also called ABP 206, BCD-263, BMS 936558, BMS-936558

    Given IV

  • Positron Emission TomographyProcedure or surgery

    Also called Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure)

    Undergo PET/CT

  • RituximabBiological

    Also called ABP 798, ABP-798, ABP798, BI 695500

    Given IV

  • Ultrasound ImagingProcedure or surgery

    Also called 2-Dimensional Grayscale Ultrasound Imaging, 2-Dimensional Ultrasound Imaging, 2D-US, Ultrasonography

    Undergo testicular ultrasound

Study groups in NCT04609046
Study groupRoleWhat they receive
Treatment (rituximab, methotrexate, lenalidomide, nivolumab)ExperimentalINDUCTION: Patients receive rituximab IV on day 1, methotrexate IV over 2 hours or PO on day 2, lenalidomide PO daily on days 5-9, and nivolumab IV over 30 minutes on day 14. (In dose level IV that includes nivolumab, the doses of rituximab for cycles 2-6 may be given on the same day as nivolumab for the previous cycle). Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve complete response, partial response, or stable disease proceed to maintenance therapy. MAINTENANCE: Within 6 weeks after the last dose of lenalidomide in induction therapy, patients receive lenalidomide PO daily on days 1-21, and nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI, CT, PET/CT, lumbar puncture, bone marrow aspirate and biopsy, testicular ultrasound and ECHO. (See Detailed Description)
Receives: Procedure: Bone Marrow Aspiration and Biopsy; Procedure: Computed Tomography; Procedure: Echocardiography Test; Drug: Lenalidomide; Procedure: Lumbar Puncture; Procedure: Magnetic Resonance Imaging; Drug: Methotrexate; Biological: Nivolumab; Procedure: Positron Emission Tomography; Biological: Rituximab; Procedure: Ultrasound Imaging

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum tolerated dose

    Defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients). The number and severity of all adverse events will be tabulated and summarized in this patient population both overall and by dose level according to the Common Terminology Criteria for Adverse Events (CTCAE) Cancer Therapy Evaluation Program version 5.0 criteria. The grade 3+ adverse events will also be described and summarized in a similar fashion. This will provide an indication of the level of tolerance for this treatment combination in this patient group.

    Measured: During the first 14-day cycle of treatment

  2. Proportion of evaluable patients who are able to stay on maintenance therapy

    The proportion of evaluable patients who meet the criteria for maintenance feasibility, along with the 95% exact binomial confidence interval, will be provided.

    Measured: Up to 6 months

Secondary outcomes (4)

  1. Overall response

    Will be estimated by the number of patients with the objective status of complete response, unconfirmed complete response, or partial response divided by the total number of evaluable patients. The overall response rate with an exact binomial 95% confidence interval will be provided and will be analyzed at the end of induction therapy and again after all therapy (induction and maintenance).

    Measured: Up to 5 years

  2. Progression free survival (PFS)

    The distribution of progression-free survival will be estimated using the method of Kaplan-Meier (Kaplan-Meier, 1958). PFS time from start of maintenance therapy will also be reported in a similar fashion as the PFS time starting from induction therapy.

    Measured: Time from start of induction treatment to progression or death due to any cause

  3. Overall Survival (OS)

    The distribution of overall survival will be estimated using the method of Kaplan-Meier (Kaplan-Meier, 1958). OS time from start of maintenance therapy will also be reported in a similar fashion as the OS time starting from induction therapy.

    Measured: Time from start of induction treatment to death due to any cause

  4. Incidence of adverse events

    Toxicity will be measured by the CTCAE version 5.0. The maximum grade, frequency, and severity for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration and analyzed descriptively.

    Measured: Up to 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Oct 2020
  2. Study start24 May 2021
  3. Primary completion1 Aug 2027 (estimated)
  4. Study completion1 Aug 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
47 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04609046
Sponsor's protocol ID
NCI-2020-08331
Other IDs
NCI-2020-08331, A051901, A051901, U10CA180821
Status last verified
Oct 2026
First submitted
29 Oct 2020
Last updated
19 Oct 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

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