Summary

This phase I/II trial studies the side effects and best dose of lenalidomide when given together with nivolumab and to see how well they work in treating patients with non-Hodgkin or Hodgkin lymphoma that has come back (recurrent) and does not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Lenalidomide may stop or slow non-Hodgkin or Hodgkin lymphoma by blocking the growth of new blood vessels necessary for tumor growth. Giving nivolumab and lenalidomide may work better than nivolumab alone in treating patients with non-Hodgkin or Hodgkin lymphoma.

Objectives

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) and Hodgkin disease (HD). (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 and HD. (Phase I)
III. To evaluate the feasibility and toxicities of the combination of lenalidomide and nivolumab in patients with relapsed/refractory 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 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 and HD 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 DLBCL in terms of duration of response (DOR), progression-free survival (PFS) and overall survival (OS). (Phase II)

EXPLORATORY 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 and HD. (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 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 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. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive nivolumab intravenously (IV) over 60 minutes on days 1 and 15 of cycles 1-4 and on day 1 of cycles 5-12. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Eligibility

1. 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
2. PHASE I: Histologically confirmed classical or lymphocyte predominant Hodgkin’s disease that is relapsed or refractory after at least two prior chemotherapy regimens; patients who have not had prior high-dose therapy (HDT)/autologous stem cell transplant (ASCT) must be ineligible for transplant
3. PHASE I: Patients with DLBCL, BL, transformed DLBCL, primary mediastinal lymphoma and grey zone lymphoma must have received at least one prior therapy; patients with MCL, FL, MZL and LL/WM must have failed at least two prior therapies; prior autologous stem cell transplant is permitted; patients with DLBCL, BL, transformed DLBCL, primary mediastinal lymphoma and grey zone lymphoma who have not had prior HDT/ASCT must be ineligible for transplant; prior lenalidomide is not permitted if patients have progressed on therapy
4. PHASE IB DOSE EXPANSION: Histologically confirmed classical or lymphocyte predominant Hodgkin’s disease
5. PHASE IB DOSE EXPANSION: Patients must have received at least two prior therapy regimens; 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
6. PHASE II: Histologically confirmed DLBCL including transformed DLBCL from indolent Non-Hodgkin’s lymphoma (excludes Richter’s Syndrome). (Cases of DLBCL with MYC and BCL2 and/or BCL6 rearrangement, know referred to as High Grade B Cell Lymphoma with MYC and BCL2 and/or BCL6 rearrangement are eligible as are patients with DLBCL subtypes such as T cell histiocyte rich large B cell lymphoma)
7. PHASE II: Patients with DLBCL must have received at least one prior therapy for DLBCL. 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
8. Be willing and able to provide written informed consent/assent for the trial
9. Have evaluable disease by imaging, computed tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography (PET) evaluable imaging is acceptable
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
11. Absolute neutrophil count (ANC) >= 1,000 /mcL (within 16 days of treatment initiation)
12. Platelets >= 50,000 /mcL in the absence of transfusion support within 7 days of determining eligibility (within 16 days of treatment initiation)
13. Hemoglobin >= 8 g/dL (within 16 days of treatment initiation)
14. 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 (within 16 days of treatment initiation) * Creatinine clearance should be calculated per institutional standard
15. Serum total bilirubin =< 1.5 X ULN OR except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL (within 16 days of treatment initiation)
16. Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 X ULN (within 16 days of treatment initiation)
17. 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
18. 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 at least 24 consecutive months
19. 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
20. Willing and able to receive adequate prophylaxis and/or therapy for thromboembolic events
21. Be >= 18 years of age on day of signing informed consent.
22. Be willing and able to understand and give written informed consent and comply with all study related procedures

Treatment Sites in Georgia