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

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ClinicalTrials.gov Identifier: NCT03920631
Recruitment Status : Recruiting
First Posted : April 19, 2019
Last Update Posted : September 25, 2019
Sponsor:
Information provided by (Responsible Party):
Ahmed Galal, MD, Duke University

Tracking Information
First Submitted Date  ICMJE April 8, 2019
First Posted Date  ICMJE April 19, 2019
Last Update Posted Date September 25, 2019
Estimated Study Start Date  ICMJE October 31, 2019
Estimated Primary Completion Date May 15, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 17, 2019)
  • Maximum Tolerated Dose of nivolumab in combination with Microtransplantation [ Time Frame: 1.5 years ]
    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.
  • Incidence of dose limiting toxicity (DLT) [ Time Frame: 4 years ]
    Dose limiting toxicity will be estimated based on the incidence and intensity of drug related adverse events (AEs) due to microtransplantation and/or nivolumab infusion. DLT will be graded according to the NCI CTCAE version 5.0 criteria and GVHD will be graded by consensus criteria (Przepiorka D et al, BMT, 1995).
  • Number of subjects experiencing AE [ Time Frame: 4 years ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03920631 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 17, 2019)
  • 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 ]
  • Progression-free Survival (PFS) [ Time Frame: 4 years ]
    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
  • Overall Survival [ Time Frame: 4 years ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Microtransplantation and Checkpoint Blockade Immunotherapy for Relapsed or Refractory B Cell Lymphomas
Official Title  ICMJE MicroBLITZ: Microtransplantation and Checkpoint Blockade Immunotherapy for Relapsed or Refractory B Cell Lymphomas
Brief Summary 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE B Cell Lymphomas
Intervention  ICMJE
  • Drug: Nivolumab
    Nivolumab (1 mg/Kg or 3 mg/kg) every 2 weeks per cohort dose level and schedule
    Other Name: OPDIVO™, BMS-936558, MDX1106, ONO-4538
  • Biological: Microtransplantation
    HLA-mismatched peripheral blood stem cells
Study Arms  ICMJE
  • Experimental: Cohort 1: Microtransplantation (MST)
    MST:Infusion of granulocyte colony stimulating factor (G-CSF) mobilized HLA-mismatched peripheral blood stem cells (GPBSC)
    Intervention: Biological: Microtransplantation
  • Experimental: Cohort 2/2b: MST + Nivolumab

    2: 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).

    Interventions:
    • Drug: Nivolumab
    • Biological: Microtransplantation
  • Experimental: Cohort 3/3b: MST + Nivolumab

    3: 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).

    Interventions:
    • Drug: Nivolumab
    • Biological: Microtransplantation
  • Experimental: Cohort 4: Expansion
    Microtransplantation (Day 0) + nivolumab (at RP2D)
    Interventions:
    • Drug: Nivolumab
    • Biological: Microtransplantation
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 17, 2019)
38
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 15, 2023
Estimated Primary Completion Date May 15, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Rachel Stowe, RN (919) 681-4769 rachel.stowe@duke.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03920631
Other Study ID Numbers  ICMJE Pro00101349
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Ahmed Galal, MD, Duke University
Study Sponsor  ICMJE Ahmed Galal, MD
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Ahmed Galal, MD Duke University Health System
PRS Account Duke University
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP