Nivolumab and Lenalidomide in Treating Patients with Relapsed or Refractory Non-Hodgkin or Hodgkin Lymphoma
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 two prior chemotherapy regimens; patients who have not had prior high-dose therapy (HDT)/autologous stem cell transplant (ASCT) must be ineligible for transplant
- PHASE I: Patients 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
- PHASE IB DOSE EXPANSION: Histologically confirmed classical or lymphocyte predominant Hodgkin’s disease
- 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
- PHASE II: Histologically confirmed B-cell NHL: * Cohort 1: with only de novo DLBCL, * Cohort 2: with only FL of grade 1, 2 or 3a
- PHASE II: Patients with de novo DLBCL must have received at least one prior therapy; patients with FL grade 1, 2 or 3a must have received at least two prior therapies; 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 (within 16 days of treatment initiation)
- Platelets >= 100,000 /mcL in the absence of transfusion support within 7 days of determining eligibility (within 16 days of treatment initiation)
- Hemoglobin >= 8 g/dL (within 16 days of treatment initiation)
- 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)
- 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)
- 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)
- 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 at least 24 consecutive months
- 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 (=< 10 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
- 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 received 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
Georgia
Atlanta
Ohio
Columbus
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 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 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 FL and 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 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. Courses 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 courses 1-4 and on day 1 of courses 5-12. Treatment repeats every 28 days for up to 12 courses 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 5 years.
Trial Phase Phase I/II
Trial Type Treatment
Lead Organization
Ohio State University Comprehensive Cancer Center
Principal Investigator
Kami Jo Maddocks
- Primary ID OSU-16167
- Secondary IDs NCI-2016-01966, 2016C0166
- Clinicaltrials.gov ID NCT03015896