Clinical Trials /

Microtransplantation and Checkpoint Blockade Immunotherapy for Relapsed or Refractory B Cell Lymphomas

NCT03920631

Description:

The purpose of this study is to find out if microtransplantation (MST) in combination with nivolumab is safe and effective in patients with relapsed or refractory B cell lymphomas.

Related Conditions:
  • B-Cell Lymphoma, Unclassifiable, with Features Intermediate between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma
  • B-Cell Non-Hodgkin Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Double-Hit Lymphoma
  • Follicular Lymphoma
  • Hodgkin Lymphoma
  • Lymphoplasmacytic Lymphoma
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • Mediastinal Large B-Cell Lymphoma
  • Triple-Hit Lymphoma
  • Waldenstrom Macroglobulinemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Microtransplantation and Checkpoint Blockade Immunotherapy for Relapsed or Refractory B Cell Lymphomas
  • Official Title: MicroBLITZ: Microtransplantation and Checkpoint Blockade Immunotherapy for Relapsed or Refractory B Cell Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: Pro00101349
  • NCT ID: NCT03920631

Conditions

  • B Cell Lymphomas

Interventions

DrugSynonymsArms
NivolumabOPDIVO™, BMS-936558, MDX1106, ONO-4538Cohort 2/2b: MST + Nivolumab
MicrotransplantationCohort 1: Microtransplantation (MST)

Purpose

The purpose of this study is to find out if microtransplantation (MST) in combination with nivolumab is safe and effective in patients with relapsed or refractory B cell lymphomas.

Detailed Description

      This is a non-randomized, open-label, phase 1 study to assess the safety of nivolumab
      (OPDIVO™, also referred to as BMS-936558, MDX1106, and ONO-4538) in combination with
      microtransplantation (MST) in patients ≥ 18 years of age with relapsed or refractory B cell
      lymphomas. A conventional cohorts-of-3 dose-escalation phase I design will be used to
      determine the optimal dosing strategy of nivolumab in combination with MST. The safety of
      microtransplantation without nivolumab will be evaluated at the first dose level. If
      significant, unexpected toxicity is observed at Dose Levels 2 or 3, subsequent cohorts will
      switch to the alternate dosing schedule to evaluate the safety of dose-reduced nivolumab.
      After determination of the maximum tolerated dose level, patients will be recruited into an
      expansion cohort at that level.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1: Microtransplantation (MST)ExperimentalMST:Infusion of granulocyte colony stimulating factor (G-CSF) mobilized HLA-mismatched peripheral blood stem cells (GPBSC)
  • Microtransplantation
Cohort 2/2b: MST + NivolumabExperimental2: Microtransplantation (Day 0) + nivolumab (3 mg/kg) every 2 weeks (beginning on Day+14) 2b: Microtransplantation (Day 0) + nivolumab (1 mg/kg) every 2 weeks (beginning on Day+14).
  • Nivolumab
  • Microtransplantation
Cohort 3/3b: MST + NivolumabExperimental3: Microtransplantation (Day 0) + nivolumab (3 mg/kg) every 2 weeks (beginning on Day-1). 3b: Microtransplantation (Day 0) + nivolumab (1 mg/kg) every 2 weeks (beginning on Day-1).
  • Nivolumab
  • Microtransplantation
Cohort 4: ExpansionExperimentalMicrotransplantation (Day 0) + nivolumab (at RPD2P)
  • Nivolumab
  • Microtransplantation

Eligibility Criteria

        Inclusion Criteria:

          1. Patients with relapsed/refractory B cell lymphomas of the following subtypes:

               -  Diffuse large B-cell lymphoma (DLBCL)

               -  High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 translocations
                  (DHL/THL)

               -  B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and
                  classical Hodgkin lymphoma (GZL)

               -  Primary mediastinal large B-cell lymphoma (PMBCL)

               -  Mantle cell lymphoma (MCL)

               -  Follicular lymphoma (FL)

               -  Marginal zone lymphoma (MZL)

               -  Lymphoplasmacytic Lymphoma / Waldenstrom Macroglobulinemia (LPL/WM)

               -  Hodgkin lymphoma (HL)

          2. Ability to provide written informed consent for the protocol and understand the
             investigational nature of the study.

          3. Willingness and ability to comply with scheduled visits, treatment plans, laboratory
             tests, and other procedures.

          4. Age ≥ 18 years old.

          5. Eastern Cooperative Oncology Group performance status of ≤ 2.

          6. Evidence of at least one measurable lesion on imaging, defined as nodes/nodal masses >
             1.5 cm, extranodal masses >1.0 cm or PET avid lesions consistent with lymphoma.

          7. Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, and men who are sexually active must use effective methods of
             contraception from the time of enrollment to 1 month after last therapy administered
             as part of the protocol.

          8. Must have biopsy-proven primary refractory disease or relapsed disease after frontline
             therapy.

          9. Adequate organ function parameters:

               1. Renal function: Creatinine clearance ≥ 45ml/min (Cockrauft-Gault Formula)

               2. Liver function:

                    -  AST/ALT ≤ 3x the institutional ULN.

                    -  Total bilirubin ≤ 2x the institutional ULN with the exception of patients
                       with Gilbert syndrome; patients with Gilbert syndrome may be included if
                       their total bilirubin is ≤ 3.0x ULN and direct bilirubin is ≤ 2x ULN

               3. Pulmonary function: PFTs with DLCO ≥ 40%.

               4. Cardiac function: Must have LVEF ≥ 40% confirmed by echocardiogram or MUGA scan.

               5. Bone marrow reserve without transfusion defined as:

                    -  Absolute neutrophil count (ANC) ≥ 1,000/mm3

                    -  Platelets ≥ 50,000/mm3

         10. Subjects must have a potential 3-5/6 HLA-matched (A, B, DRB1) related haploidentical
             donor (either a first or second- degree relative) that will be evaluated for
             eligibility to provide hematopoietic cells for infusion.

        Exclusion Criteria:

          1. Prior Treatments:

               1. Prior treatment with allogeneic HSCT.

               2. Treatment with CAR-T cells within 6 months of study enrollment.

               3. Treatment with an immune checkpoint inhibitor within 3 months of study
                  enrollment.

               4. Prior grade 3 or higher toxicities with immune checkpoint inhibitor use,
                  excluding lymphopenia, asymptomatic amylase or lipase elevation or laboratory
                  abnormalities that correct to grade 1 within 72 hours.

               5. Chemotherapy, radiation or surgical resection of malignancy within 2 weeks prior
                  to the start of lymphodepleting chemotherapy (washout period).

          2. Active, uncontrolled serious infection or medical or psychiatric illness, that in the
             investigator's opinion is likely to interfere with participation in this clinical
             trial.

          3. Known active CNS involvement by malignancy.

          4. History of seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar
             disease, or any autoimmune disease with CNS involvement.

          5. Active replication of hepatitis B or active hepatitis C (HCV RNA positive). Those with
             prior disease who are PCR negative at enrollment and meet liver function eligibility
             criterion are eligible.

          6. Known HIV positive patients.

          7. Patients with unstable angina and/or myocardial infarction within 6 months prior to
             screening.

          8. Cardiac arrhythmia not controlled with medical management, evidence of pericardial
             effusion on imaging that is compromising function.

          9. History of a second malignancy requiring treatment at any time within the 3 years
             prior to study enrollment. The following are allowed within 3 years of study
             enrollment if subject has received definitive local therapy (i.e., surgical excision,
             external beam radiation, or other local therapy with curative intent): non-melanoma
             skin cancers, organ-confined localized prostate cancer treated with curative intent,
             or carcinoma in situ.

         10. Active autoimmune disease, history of primary immunodeficiency, or any syndrome that
             requires systemic corticosteroids or immunosuppressive medications (excluding
             Hashimoto's thyroiditis, vitiligo, or DM type I).

         11. History of solid organ transplantation.

         12. Pregnant or lactating women.

         13. Prisoners or those compulsorily detained.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose of nivolumab in combination with Microtransplantation
Time Frame:1.5 years
Safety Issue:
Description:In the dose escalation portion, patients will be sequentially enrolled in 3 cohorts at dose levels in a standard 3+3 design until the maximum tolerated dose (MTD) of nivolumab in combination with microtransplantation is reached. The MTD will be defined as the dose level where at most 1 out of 6 patients experience a dose limiting toxicity (DLT) and will also be the recommended phase 2 dose (RP2D) strategy.

Secondary Outcome Measures

Measure:Overall response rate (%) is defined as the number of patients achieving a complete response or partial response as a proportion of total patients evaluable for response.
Time Frame:2.5 years
Safety Issue:
Description:
Measure:Progression-free Survival (PFS)
Time Frame:4 years
Safety Issue:
Description:progression-free survival (PFS) is defined as the time interval from the time of enrollment on this study to the date of progressive disease (PD) or death, whichever is first reported. Patients are evaluable for PFS if they receive any treatment as part of this study. One- and two-year PFS estimates will also be calculated
Measure:Overall Survival
Time Frame:4 years
Safety Issue:
Description:Overall Survival (OS) is defined as the time interval from the time of enrollment in this study to the date of death from any cause. If the subject is alive or the vital status is unknown, OS will be censored at the date that the subject is last known to be alive, or their last contact date. One- and two-year survival estimates will be generated.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Duke University

Trial Keywords

  • B Cell Lymphomas
  • Microtransplantation
  • Nivolumab

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