Nivolumab, Ipilimumab, and Immunotransplant in Treating Participants with Relapsed or Refractory Diffuse Large B Cell Lymphoma

Status: Active

Description

This phase Ib / II trial studies the side effects of nivolumab, ipilimumab, and immunotransplant and to see how well they work in treating participants with diffuse large B cell lymphoma that has come back (relapsed) or that isn't responding to treatment (refractory). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Immunotransplant is a treatment used to help the immune system fight diseases such as cancer. T cells are collected from a participant and then given back to the participant after "lymphodepleting" chemotherapy which helps the anti-tumor immune T cells preferentially expand to target and eliminate tumor cells. Giving ipilimumab and nivolumab with immunotransplant may help treat participants with diffuse large B cell lymphoma.

Eligibility Criteria

Inclusion Criteria

  • Patient must have known pathologic diagnosis of diffuse large B cell lymphoma (DLBCL), and evidence of persistent disease on PET/CT or CT.
  • Have pathologically confirmed DLBCL on biopsy
  • Be willing and able to provide written informed consent/assent for the trial
  • Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
  • Patients with cytopenias attributable to bone marrow lymphomatous bone marrow involvement per current bone marrow biopsy may be enrolled if other inclusion criteria are met
  • Absolute neutrophil count (ANC) >= 1,000 /mcL (within 14 days of treatment initiation)
  • Platelets >= 25,000 /mcL (within 14 days of treatment initiation)
  • Hemoglobin >= 8 g/dL (within 14 days of treatment initiation)
  • Serum creatinine =< 2.0 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]) >= 60 mL/min for subject with creatinine levels > 2.0 X institutional ULN (within 14 days of treatment initiation) * Creatinine clearance should be calculated per institutional standard
  • Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels 1.5 ULN (with 14 days of treatment initiation)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (within 14 days of treatment initiation)
  • Albumin >= 2.5 mg/dL (within 14 days of treatment initiation)
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT is within therapeutic range of intended use of anticoagulants (within 14 days of treatment initiation)
  • Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 14 days of treatment initiation)
  • Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of DCBA; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Female subjects of childbearing potential must be willing to use an adequate method of contraception; contraception should be used for the course of the study through 120 days after the last dose of study medication * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
  • Male subjects of childbearing potential must agree to use an adequate method of contraception; contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy
  • Patients who did not achieve PR or CR as per the Lugano criteria following at least 1 cycle of platinum‐based salvage chemotherapy, or patients not eligible for platinum based therapy or beam induction therapy due to decreased ejection fraction (< 40%)
  • Patients whom have undergone previous autologous stem cell transplant, and have recurrent or residual disease are eligible for this trial

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 28 days 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
  • Has a known history of active TB (Bacillus tuberculosis)
  • Hypersensitivity to ipilimumab or nivolumab or any of their excipients
  • Has had a prior anti‐cancer monoclonal antibody (mAb) within 28 days 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 28 days earlier
  • Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 14 days 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
  • 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) metastases and/or lymphomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 28 days prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include lymphomatous meningitis, which is excluded regardless of clinical stability
  • Has active autoimmune disease that has required systemic treatment in the past 1 year (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a systemic treatment; subjects on stable dose of corticosteroids less than or equivalent to 10mg of prednisone daily for more than 3 months may be enrolled, and continue their stable dose through treatment
  • Has known history of, or any evidence of active, non‐infectious pneumonitis
  • Has an active infection requiring systemic therapy
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • 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 (roughly two and a half years after enrollment)
  • Human immunodeficiency virus (HIV) positive with detectable viral load, or anyone not on stable anti‐viral (highly active antiretroviral therapy [HAART]) regimen
  • 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)
  • History of allogeneic stem‐cell (or other organ) transplantation
  • Has received a live vaccine within 30 days of planned start of study therapy * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu‐Mist) are live attenuated vaccines, and are not allowed

Locations & Contacts

New York

New York
Icahn School of Medicine at Mount Sinai
Status: Active
Contact: Joshua Brody
Phone: 646-543-2859
Email: joshua.brody@mssm.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. A fixed‐dose cohort to evaluate the safety and feasibility of dual checkpoint blocking antibody (DCBA) in patients treated with non‐ablative chemotherapy. (phase Ib)

II. Assess the complete response (CR) rate in patients as per the Lugano criteria, determined by positron emission tomography/computed tomography (PET/CT) imaging at 3 months following the 4th dose of DCBA (phase II).

SECONDARY OBJECTIVES:

I. Assess one and two year progression-free survival (PFS), from the time of adoptive T cell transfer (ATCT) (day 0 [D0]) until the first recurrence or progression of disease as per the Lugano criteria, or date of death if the subject dies from any cause before progression is documented (phase II).

II. Assess one and two year overall survival (OS), from the time of ATCT (D0) until recorded date of death (phase II).

III. Assess overall response rate (ORR), defined as complete remission/partial remission/stable disease (CR/PR/SD) as per the Lugano criteria, determined by PET/CT imaging at 3 months following the 4th dose of DCBA (phase II).

IV. Assess delayed CR, defined as CR as per the Lugano criteria, determined at the PET/CT imaging assessments at 6, 9, 12, 18 and 24 months (phase II).

V. Assess side effect profiles, experienced before immunotransplant (after the first 2 doses of DCBA, before chemotherapy), after ATCT, after the 4th dose of DCBA, and during the maintenance phase of DCBA (phase II).

VI. Assess rate of, and time to achieving molecular remission as determined by serum analysis for persistent immunoglobulin variable region heavy chain (IgVH) by polymerase chain reaction (PCR) (phase II).

VII. Assess effect of microbiome on efficacy of immunotransplant, looking at diversity as well as specific microorganisms which have been implicated in the success/failure of checkpoint‐inhibitor therapies (phase II).

VIII. Assess enrichment of tumor reactive T cells in circulation by flow cytometry. (Immune monitoring) (phase II).

IX. Provide detailed phenotypic description of immune repertoire (T cell subset focus) per mass cytometry (CyTOF) performed on tumor biopsy as well as peripheral blood mononuclear cells (PBMCs) harvested before initial treatment with DCBA, at time of T cell apheresis following initial two cycles of DCBA, following count recovery from immunotransplant before discharge and 6 weeks following completion of 4th dose of nivolumab/ipilimumab. (Immune monitoring) (phase II).

OUTLINE:

Patients receive standard rituximab on day -54 and -11, ipilimumab intravenously (IV) and nivolumab IV on days -53 and -32, and cyclophosphamide IV and fludarabine IV on days -5 to -3. Patients then undergo immunotransplant (ATCT) IV over 15 minutes on day 0 followed by ipilimumab IV and nivolumab IV on days 1 and 22. Beginning 21 days later, patients then receive nivolumab IV every 14 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 12 months, and then again at 18 and 24 months. Additional follow up during years 3-5 is per the discretion of the investigator and standard operation procedures (SOP) of the institution.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
Icahn School of Medicine at Mount Sinai

Principal Investigator
Joshua Brody

Trial IDs

Primary ID 17-2164
Secondary IDs NCI-2018-00677
Clinicaltrials.gov ID NCT03305445