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.
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.
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.
