Clinical Trials /

Nivolumab and Lenalidomide in Treating Patients With Relapsed or Refractory Non-Hodgkin or Hodgkin Lymphoma

NCT03015896

Description:

This 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 and does not respond to treatment. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as lenalidomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab and lenalidomide may work better in treating patients with non-Hodgkin or Hodgkin lymphoma.

Related Conditions:
  • Burkitt Lymphoma
  • Classical Hodgkin Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • Lymphoplasmacytic Lymphoma
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • Primary Mediastinal B-Cell Lymphoma
  • Transformed Lymphoma
  • Waldenstrom Macroglobulinemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and Lenalidomide in Treating Patients With Relapsed or Refractory Non-Hodgkin or Hodgkin Lymphoma
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: OSU-16167
  • SECONDARY ID: NCI-2016-01966
  • NCT ID: NCT03015896

Conditions

  • 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

Interventions

DrugSynonymsArms
LenalidomideCC-5013, CC5013, CDC 501, RevlimidTreatment (lenalidomide, nivolumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (lenalidomide, nivolumab)

Purpose

This 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 and does not respond to treatment. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as lenalidomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab and lenalidomide may work better in treating patients with non-Hodgkin or Hodgkin lymphoma.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (lenalidomide, nivolumab)ExperimentalPatients 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.
  • Lenalidomide
  • Nivolumab

Eligibility Criteria

        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

          -  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 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
             (=< 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events summarized by NCI CTCAE version 4
Time Frame:Up to 5 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Complete response rate (CR) in patients
Time Frame:Up to 5 years
Safety Issue:
Description:Complete response rate (CR) in patients with relapsed/refractory HD receiving the combination of lenalidomide and nivolumab
Measure:Overall Response Rate (ORR)
Time Frame:Up to 5 years
Safety Issue:
Description:Overall Response Rate in patients with relapsed/refractory HD receiving the combination of lenalidomide and nivolumab
Measure:Overall Survival (OS)
Time Frame:From study entry to the time of death due to any cause, assessed up to 5 years
Safety Issue:
Description:Will be evaluated for each of the cohorts and graphically summarized using the methods of Kaplan and Meier.
Measure:Progression free survival (PFS)
Time Frame:From study entry to the time of progression and/or death, assessed up to 5 years
Safety Issue:
Description:Will be evaluated for each of the cohorts and graphically summarized using the methods of Kaplan and Meier.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Kami Maddocks

Last Updated

October 18, 2019