Nivolumab and Lenalidomide in Treating Patients With Relapsed or Refractory Non-Hodgkin or Hodgkin Lymphoma
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ClinicalTrials.gov Identifier: NCT03015896 |
Recruitment Status :
Recruiting
First Posted : January 10, 2017
Last Update Posted : June 2, 2022
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Condition or disease | Intervention/treatment | Phase |
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Grade 3a Follicular Lymphoma Recurrent Burkitt Lymphoma Recurrent Diffuse Large B-Cell Lymphoma Recurrent Follicular Lymphoma Recurrent Grade 1 Follicular Lymphoma Recurrent Grade 2 Follicular Lymphoma Recurrent Lymphoplasmacytic Lymphoma Recurrent Mantle Cell Lymphoma Recurrent Marginal Zone Lymphoma Recurrent Waldenstrom Macroglobulinemia Refractory Burkitt Lymphoma Refractory Diffuse Large B-Cell Lymphoma Refractory Follicular Lymphoma Refractory Lymphoplasmacytic Lymphoma Refractory Mantle Cell Lymphoma | Other: Laboratory Biomarker Analysis Drug: Lenalidomide Biological: Nivolumab | Phase 1 Phase 2 |
PRIMARY OBJECTIVES:
I. To determine the safety and tolerability of the combination of lenalidomide and nivolumab in patients with relapsed/refractory non-Hodgkin lymphoma (NHL). (Phase I) II. To determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of the combination of lenalidomide and nivolumab in patients with relapsed/refractory NHL. (Phase I) III. To evaluate the feasibility and toxicities of the combination of lenalidomide and nivolumab in patients with relapsed/refractory Hodgkin's disease (HD). (Phase IB) IV. To evaluate the efficacy of the combination of lenalidomide and nivolumab in terms of overall response rate in patients with relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). (Phase II)
SECONDARY OBJECTIVES:
I. To evaluate the efficacy of the combination of lenalidomide and nivolumab in patients with relapsed/refractory NHL in terms of overall response rate (ORR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). (Phase I) II. To evaluate the efficacy of the combination of lenalidomide and nivolumab in patients with relapsed/refractory HD in terms of complete response rate (CR). (Phase IB) III. To evaluate the efficacy of the combination of lenalidomide and nivolumab in patients with relapsed/refractory HD in terms of duration of response (DOR), progression-free survival (PFS) and overall survival (OS). (Phase IB) IV. To evaluate the efficacy of the combination of lenalidomide and nivolumab in patients with relapsed/refractory FL and DLBCL in terms of duration of response (DOR), progression-free survival (PFS) and overall survival (OS). (Phase II)
TERTIARY OBJECTIVES:
I. To explore the relationship between prognostic parameters including ki-67 staining, PD-1 staining and cell of origin (activated B-cell or ABC versus germinal center B-cell or GCB) with ORR to the combination of lenalidomide and nivolumab in patients with relapsed/refractory NHL. (Phase I) II. To evaluate and monitor effects on B-, T-, and natural killer (NK)-cell function with the combination of lenalidomide and nivolumab in patients with relapsed/refractory NHL. (Phase I) III. To explore the relationship between prognostic parameters including ki-67 staining, PD-1 staining and cell of origin (activated B-cell or ABC versus germinal center B-cell or GCB) with ORR to the combination of lenalidomide and nivolumab in patients with relapsed/refractory FL and DLBCL. (Phase II) IV. To evaluate and monitor effects on B-, T-, and NK-cell function with the combination of lenalidomide and nivolumab in patients with relapsed/refractory FL and DLBCL. (Phase II)
OUTLINE: This is a phase I, dose-escalation study of lenalidomide followed by a phase II study.
Patients receive lenalidomide orally (PO) on days 1-21 and nivolumab intravenously (IV) over 60 minutes on days 1 and 15 of courses 1-4 and on day 1 of courses 5-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for up to 3 years.
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 102 participants |
Allocation: | N/A |
Intervention Model: | Single Group Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | A Phase I/II Study of the PD-1 Antibody Nivolumab in Combination With Lenalidomide in Relapsed/Refractory Non-Hodgkin's Lymphoma (NHL) and Hodgkin's Disease (HD) |
Actual Study Start Date : | February 14, 2017 |
Estimated Primary Completion Date : | December 31, 2022 |
Estimated Study Completion Date : | December 31, 2022 |

Arm | Intervention/treatment |
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Experimental: Treatment (lenalidomide, nivolumab)
Patients receive lenalidomide PO on days 1-21 and nivolumab IV over 60 minutes on days 1 and 15 of courses 1-4 and on day 1 of courses 5-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
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Other: Laboratory Biomarker Analysis
Correlative studies Drug: Lenalidomide Given PO
Other Names:
Biological: Nivolumab Given IV
Other Names:
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- Incidence of adverse events summarized by NCI CTCAE version 4 [ Time Frame: Up to 5 years ]Will be assessed and tabulated across all patients who received any treatment with a focus on severe (grade 3+) adverse events and toxicities (ie those deemed at least possibly related to study treatment). Will also assess tolerability of the regimens through assessing the number of patients who required dose modifications and/or dose delays. Will capture the proportion of patients who go off treatment due to adverse events or those who refuse to continue treated for lesser toxicities.
- Maximum tolerated dose (MTD) defined as the dose level at which no more than one of 6 patients experiences a dose-limiting toxicity summarized by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4 [ Time Frame: Up to 28 days ]Will be assessed and tabulated across all patients who received any treatment with a focus on severe (grade 3+) adverse events and toxicities (ie those deemed at least possibly related to study treatment). Will also assess tolerability of the regimens through assessing the number of patients who required dose modifications and/or dose delays. Will capture the proportion of patients who go off treatment due to adverse events or those who refuse to continue treated for lesser toxicities.
- Complete response rate (CR) in patients [ Time Frame: Up to 5 years ]Complete response rate (CR) in patients with relapsed/refractory HD receiving the combination of lenalidomide and nivolumab
- Overall Response Rate (ORR) [ Time Frame: Up to 5 years ]Overall Response Rate in patients with relapsed/refractory HD receiving the combination of lenalidomide and nivolumab
- Overall Survival (OS) [ Time Frame: From study entry to the time of death due to any cause, assessed up to 5 years ]Will be evaluated for each of the cohorts and graphically summarized using the methods of Kaplan and Meier.
- Progression free survival (PFS) [ Time Frame: From study entry to the time of progression and/or death, assessed up to 5 years ]Will be evaluated for each of the cohorts and graphically summarized using the methods of Kaplan and Meier.

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- PHASE I: Histologically confirmed B-cell NHL with any of the following subtypes: DLBCL, mantle cell lymphoma (MCL), FL, marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia (LL/WM), Burkitt's lymphoma (BL); patients with histological transformation to DLBCL from indolent lymphoma, primary mediastinal lymphoma and grey zone lymphoma are eligible
- PHASE I: Histologically confirmed classical or lymphocyte predominant Hodgkin's disease that is relapsed or refractory after at least one prior chemotherapy
- PHASE I: Patients must have received at least one prior therapy; prior autologous stem cell transplant is permitted; patients with DLBCL who have not had prior high-dose therapy (HDT)/autologous stem cell transplant (ASCT) must be ineligible for transplant; prior lenalidomide is not permitted if patients have progressed on therapy
- PHASE IB DOSE EXPANSION: Histologically confirmed classical or lymphocyte predominant Hodgkin's disease
- PHASE IB DOSE EXPANSION: Patients must have received at least one prior therapy; prior autologous stem cell transplant is permitted; patients who have not had prior HDT/ASCT must be ineligible for transplant; prior lenalidomide is not permitted if patients have progressed on therapy
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PHASE II: Histologically confirmed B-cell NHL:
- Cohort 1: with only de novo DLBCL or transformed indolent Non-Hodgkin's lymphoma (excludes Richter's syndrome).
- Cohort 2: with only FL of grade 1, 2 or 3a
- PHASE II: Patients must have received at least one prior therapy (in patients with transformed DLBCL must have received at least one prior therapy; prior autologous stem cell transplant is permitted; patients with DLBCL who have not had prior HDT/ASCT must be ineligible for transplant; prior lenalidomide is not permitted if patients have progressed on therapy
- Be willing and able to provide written informed consent/assent for the trial
- Have evaluable disease
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- Absolute neutrophil count (ANC) >= 1,500 /mcL
- Platelets >= 100,000 /mcL in the absence of transfusion support within 7 days of determining eligibility
- Hemoglobin >= 8 g/dL
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 40 mL/min creatinine clearance
- Serum total bilirubin =< 1.5 X ULN OR except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 X ULN
- Female subject of childbearing potential should have a negative urine or serum pregnancy at screening and within 24 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects should agree to ongoing pregnancy testing during the course of the study and after the end of study therapy; female subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
- Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy; males must refrain from donating sperm during study participation and for 120 days after the last dose of study medication
- Willing and able to receive adequate prophylaxis and/or therapy for thromboembolic events
- Be willing and able to understand and give written informed consent and comply with all study related procedures
Exclusion Criteria:
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 3 weeks of the first dose of treatment
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment; subjects may use topical or inhaled corticosteroids or low-dose steroids (=< 20 mg of prednisone or equivalent per day) as therapy for comorbid conditions; during study participation, subjects may receive systemic or enteric corticosteroids as needed for treatment-emergent comorbid conditions
- Has a known history of active TB (bacillus tuberculosis)
- Hypersensitivity to nivolumab or lenalidomide or any of their excipients
- Has had a prior anti-cancer monoclonal antibody (mAb) within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
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Has had prior chemotherapy or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent
- Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study
- Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy; patients must be 4 weeks out from major procedures
- Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
- Has known active central nervous system (CNS) lymphoma
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment; conditions expected to not recur in the absence of an external trigger
- Has an active infection requiring intravenous systemic therapy
- Is unable to swallow capsules or malabsorption syndrome, disease or condition significantly affecting gastrointestinal function
- Clinically significant cardiovascular disease with uncontrolled arrhythmia, New York Association class 3 or 4 congestive heart failure, history of myocardial infarction within 6 months, or prolonged corrected QT (QTc) > 500 msec
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
- Has progressed on prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
- Has progressed on prior therapy with lenalidomide
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
- Has a history of deep venous thrombosis/embolism, threatening thromboembolism or known thrombophilia or are at a high risk for a thromboembolic event in the opinion of the investigator and who are not willing/able to take venous thromboembolic event prophylaxis during the entire treatment period
- Has a history of prior allogeneic hematopoietic cell transplant with a history of prior Graft Versus Host Disease

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03015896
Contact: The Ohio State University Comprehensive Cancer Center | 800-293-5066 | OSUCCCClinicaltrials@osumc.edu |
United States, Georgia | |
Emory University | Recruiting |
Atlanta, Georgia, United States, 30322 | |
Contact: Vanessa Smith, BSHM, CCRP 404-778-2419 vanessa.smith@emory.edu | |
Principal Investigator: Kristie Blum, MD | |
United States, Ohio | |
Ohio State University Comprehensive Cancer Center | Recruiting |
Columbus, Ohio, United States, 43210 | |
Contact: David Bond, MD 614-293-8054 David.Bond@osumc.edu | |
Contact: Sarah Mustric 614-685-9233 Sarah.mustric@osumc.edu | |
Principal Investigator: David Bond, MD |
Principal Investigator: | David Bond, MD | Ohio State University Comprehensive Cancer Center |
Responsible Party: | David Bond, MD, Principal Investigator, Ohio State University Comprehensive Cancer Center |
ClinicalTrials.gov Identifier: | NCT03015896 |
Other Study ID Numbers: |
OSU-16167 NCI-2016-01966 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) |
First Posted: | January 10, 2017 Key Record Dates |
Last Update Posted: | June 2, 2022 |
Last Verified: | May 2022 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Burkitt Lymphoma Lymphoma Lymphoma, Follicular Lymphoma, B-Cell Lymphoma, Mantle-Cell Lymphoma, Large B-Cell, Diffuse Waldenstrom Macroglobulinemia Recurrence Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Disease Attributes |
Pathologic Processes Lymphoma, Non-Hodgkin Epstein-Barr Virus Infections Herpesviridae Infections DNA Virus Infections Virus Diseases Infections Tumor Virus Infections Neoplasms, Plasma Cell Hemostatic Disorders Vascular Diseases Cardiovascular Diseases Paraproteinemias Blood Protein Disorders Hematologic Diseases |