Clinical Trials /

Nivolumab and Tocilizumab for Relapsed Hematological Malignancy Post-allogeneic Transplant



This is a phase 1, interventional single arm, open label, treatment study designed to evaluate the safety combination programmed cell death protein 1 (PD-1) and interleukin 6 (IL-6) inhibition in participants with relapsed disease post-allogeneic transplant.

Related Conditions:
  • Acute Leukemia
  • Chronic Leukemia
  • Lymphoma
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasm
  • Myeloproliferative Neoplasm
  • T-Cell and NK-Cell Neoplasm
Recruiting Status:



Phase 1

Trial Eligibility



  • Brief Title: Nivolumab and Tocilizumab for Relapsed Hematological Malignancy Post-allogeneic Transplant
  • Official Title: Phase 1 Study of Nivolumab in Combination With Tocilizumab for Treatment of Patients With Relapsed Hematological Malignancies Post-allogeneic Transplant

Clinical Trial IDs

  • ORG STUDY ID: PRO32525
  • NCT ID: NCT03588936


  • Acute Leukemia
  • Chronic Leukemia
  • Lymphoma
  • Myelodysplastic Syndromes


NivolumabOPDIVONivolumab and Tocilizumab
TocilizumabACTEMRANivolumab and Tocilizumab


This is a phase 1, interventional single arm, open label, treatment study designed to evaluate the safety combination PD-1 and IL-6 inhibition in patients with relapsed disease post-allogeneic transplant.

Detailed Description

      Study disease: Hematologic malignancies including, but not exclusive to,acute/chronic
      leukemia, lymphoma, and myelodysplastic syndrome that has relapsed after allogeneic

      Study Rationale: Phase 1 Safety/Dose Finding Study: To determine the safety and maximum
      tolerated dose of Nivolumab in combination with Tocilizumab.

      Study Agent Description:

      Tocilizumab is a monoclonal antibody and immunosuppressant; specifically, tocilizumab is an
      interleukin-6 (IL-6) receptor antagonist.

      Nivolumab is a human immunoglobulin IgG4 monoclonal antibody that binds to the PD-1 receptor
      of T cells blocking its interaction with PD-L1 and PD-L2, thereby enhancing T-cell
      proliferation and allowing the immune system to attack the tumor.

      Number of Subjects: A maximum of 12 patients will be enrolled on this Phase 1 study.

      Duration of Follow-up: Patients will be followed for up to one year post-treatment for
      survival and response.

Trial Arms

Nivolumab and TocilizumabExperimentalPatient will receive tocilizumab 8 mg/kg IV (max dose 800 mg) on Day 0. On Day 1 patients will receive nivolumab IV (0.25 mg/kg or 0.5 mg/kg based on dose escalation design). Nivolumab will be given every ~2 weeks for up to 4 doses and a second dose of Tocilizumab will be given on ~Day 29 on the same day as Dose # 3 of Nivolumab.
  • Nivolumab
  • Tocilizumab

Eligibility Criteria

        1. Age≥18 years with hematological malignancies who have undergone allogeneic transplant
             for hematological malignancy and are ≥180 days post-transplant.

          2. Relapsed disease post-allogeneic transplant defined as follows i. Acute or Chronic
             Leukemia or myelodysplastic or myeloproliferative disorders or NK cell neoplasms: Bone
             marrow (BM) with ≥5% disease involvement or peripheral blood evidence of overt relapse
             ii. Lymphoma: BM evidence of relapsed/persistent disease or PET/CT or CT evidence of
             persistent/progressive lymphadenopathy consistent with active lymphoma. Active disease
             defined as nodal lesions ≥ 20 mm in the long axis or extranodal lesions≥10 mm in long
             and short axis or bone marrow involvement that is biopsy proven

          3. Karnofsky performance status ≥70 (See Appendix A for details)

          4. Creatinine Clearance≥60 ml/min

          5. Adequate hepatic function, defined as AST and ALT ≤3 x ULN. Serum bilirubin and
             alkaline phosphatase ≤3x x ULN, or considered not clinically significant (e.g.
             Gilbert's or indirect hyperbilirubinemia) or felt to be due to underlying disease.

          6. Without evidence of active acute or chronic GVHD

          7. Off all immunosuppression and corticosteroids (other than replacement dose steroids
             defined as equivalent to a maximum of 10 mg Prednisone daily) for ≥28 days from first

          8. Off all disease targeted treatments for ≥10 days to first treatment day

          9. Able to provide written informed consent

         10. Women of child-bearing potential and men must agree to use adequate contraception for
             the duration of study participation and for 120 days after the last treatment with

         11. No FDA approved, more appropriate therapies available for disease control as
             determined by the treating physician

        Exclusion Criteria

          1. Positive beta-HCG in female of child-bearing potential

          2. CD3 donor chimerism <5% within 4 weeks of starting study treatment

          3. Prior administration of donor lymphocyte infusion post-allogeneic transplant within
             the last 6 months of study treatment

          4. History of or active autoimmune disease, or other syndrome that requires systemic

          5. History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to nivolumab.

          6. Uncontrolled or active infections on treatment

          7. Confirmed active human immunodeficiency virus (HIV), Hepatitis B or C infection.

          8. Presence of ≥grade 3 non-hematologic toxicities as per CTCAE version 5 from any
             previous treatment unless it is felt to be due to underlying disease.

          9. Concurrent use of investigational therapeutic agents or enrollment on another
             therapeutic clinical trial at any institution.

             a. Minimum of 4 weeks from last dose of investigational agent

         10. Prior exposure to PD-1 or CTLA4 antibodies in the post-allogeneic transplant setting.
             Patients who received such agents pre-allogeneic transplant will NOT be excluded.

         11. Prior exposure to daratumumab in the post-allogeneic transplant setting within 2
             months of start date of treatment with this investigational protocol. Patients who
             received this agent pre-allogeneic transplant will NOT be excluded

         12. Concurrent therapies targeted at disease relapse. However, previous treatments for
             relapsed disease are allowed.

         13. Concurrent active malignancy (exceptions: treated solid malignancy in >2 years'
             remission, treated basal or squamous cell carcinomas of the skin)

         14. History of Crohn's disease or ulcerative colitis

         15. History of demyelinating disorder

         16. Prior intolerance or allergy to Tocilizumab
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose among Two Candidate Doses of Nivolumab in Combination with Tocilizumab
Time Frame:Up to 4 weeks after last dose of study treatment (approximately 3 months)
Safety Issue:
Description:Determine the safety and the maximum tolerated dose among two candidate doses of nivolumab in combination with tocilizumab for treatment of relapsed hematological malignancy post-allogeneic transplant. This will be measured by the number of adverse events as defined by the NCI CTCAE version 4.03 non-hematologic ≥ grade 3-5 signs/symptoms or by the development of steroid refractory grade 2-4 graft-versus-host disease or severe chronic graft-versus-host disease

Secondary Outcome Measures

Measure:Response Rates
Time Frame:Evaluate at the end of study treatment (approximately 2 months)
Safety Issue:
Description:Since patients with a variety of histologies will be treated - response will be assessed using disease appropriate imaging/marrow and international consensus criteria most applicable to the disease.
Measure:Overall Survival
Time Frame:Up to 1 year from beginning of treatment
Safety Issue:
Description:Will measure survival of patients after treatment
Measure:Progression Free Survival
Time Frame:Up to 1 year from beginning of treatment
Safety Issue:
Description:Determine the number of patients alive and in remission after treatment
Measure:Duration of response in responding patients
Time Frame:Up to 1 year from the beginning of treatment
Safety Issue:
Description:Time that a patient's disease remains stable


Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Medical College of Wisconsin

Last Updated

August 21, 2019