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About
This phase I trial studies the side effects and best dose of avelumab, utomilumab, rituximab, ibrutinib, and combination chemotherapy in treating patients with diffuse large B-cell lymphoma or mantle cell lymphoma that has come back or does not respond to treatment. Monoclonal antibodies, such as avelumab, utomilumab, and rituximab, may interfere with the ability of tumor cells to grow and spread. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as etoposide phosphate, carboplatin, and ifosfamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving avelumab, utomilumab, rituximab, ibrutinib, and combination chemotherapy may work better in treating patients with diffuse large B-cell lymphoma or mantle cell lymphoma.
Full description
PRIMARY OBJECTIVES:
I. Evaluate the safety and tolerability of the combination of avelumab (Ave) plus utomilumab (Uto) plus rituximab, ifosfamide, carboplatin, and etoposide phosphate (RICE) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) as first (1st) line salvage therapy.
II. Evaluate the safety and tolerability of Ave plus Uto plus rituximab (R)/ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL).
III. Determine the maximum tolerated dose (MTD) of the combination of Ave plus Uto with RICE for DLBCL.
IV. Determine the MTD of the combination of Ave plus Uto with R/ibrutinib for MCL.
SECONDARY OBJECTIVES:
I. Estimate overall response rate (ORR), complete response (CR) rate, duration of response (DOR), and progression-free survival (PFS) of the combination therapy.
II. Evaluate the stem cell mobilization rate after Ave+Uto+RICE therapy in DLBCL patients.
EXPLORATORY OBJECTIVES I. Explore immunologic and genomic biomarkers of response to Ave+Uto-based combination therapy.
II. Explore the use of CCND1 messenger (m)ribonucleic acid (RNA) for minimal residual disease (MRD) monitoring for MCL.
OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 cohorts.
COHORT I: Patients receive rituximab intravenously (IV) on day 1, etoposide phosphate IV on days 1-3, avelumab IV over 60 minutes on day 2, ifosfamide IV over 24 hours on day 2, and carboplatin IV on day 2 or rituximab IV on day 1, etoposide phosphate IV on days 1-3, avelumab IV over 60 minutes on days 2, utomilumab IV over 60 minutes on day 2, ifosfamide IV over 24 hours on day 2, and carboplatin IV on day 2. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients may then undergo autologous hematopoietic stem cell transplantation.
COHORT II: Patients receive rituximab IV on day 1, avelumab IV over 60 minutes on days 2 and 16, and ibrutinib orally (PO) once daily (QD) or rituximab IV on day 1, avelumab IV over 60 minutes on days 2 and 16, utomilumab IV on day 2, and ibrutinib PO QD. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. (Closed as of 12/12/2019)
After completion of study treatment, patients in cohort I are followed up for up to 3 months or 2 years and patients in cohort II are followed up at 30 and 90 days and then every 6 months for up to 2 years.
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Inclusion criteria
All patients and/or their parents or legal guardians must have the ability to understand and the willingness to sign a written informed consent
Voluntary written informed consent must be obtained before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care
Weight over 40 kilograms (kg)
Life expectancy of greater than 3 months
Cohort #1: histologically confirmed CD20-positive, relapsed or refractory DLBCL, including de novo and transformed DLBCL (from follicular or marginal zone lymphoma); this includes patients with DLBCL who are found to have small cell infiltration of the bone marrow or other diagnostic material (representing a discordant lymphoma)
Cohort #1: patients must be either refractory to or relapsed after up to 2 lines of prior therapy
Cohort #2: histologic confirmation of relapsed or relapsed/refractory MCL confirmed by presence of cyclin D1 by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH)
Patients must have measurable disease > 1.5 cm evidenced by computed tomography (CT) scan of the neck/chest/abdomen (abd)/pelvis or CT/positron emission tomography (PET) scans
Cohort #2: patients must be either refractory to or relapsed after at least 1 line of prior therapy
Eastern Cooperative Oncology Group (ECOG) performance score of 0-2
Cohort #1: received only frontline CD20-directed immunotherapy with anthracycline- or anthracenedione-based multi-agent chemotherapy for patients with DLBCL; monotherapy rituximab or other CD20-directed immunotherapy prior to frontline chemotherapy, as maintenance therapy, and radiotherapy in a limited field or as a part of the frontline treatment plan are permitted; last treatment dose should be 3 weeks before start of study treatment
Cohort #1: considered eligible for high-dose chemotherapy followed by autologous stem cell transplantation (ASCT)
Cohort #2: patients with MCL with prior allogeneic hematopoietic stem cell transplant, minimum 6 months after transplant, not on immunosuppression, and without prior or active graft versus host disease (GVHD), are allowed
Cohort #2: prior treatment with ibrutinib is allowed; patients should not have received any anti-lymphoma therapy within 3 weeks from start of study treatment, with the exception of ibrutinib
Absolute neutrophil count (ANC) >= 1,000/mm^3 (performed within 14 days prior to day 1 of protocol therapy)
Platelets >= 50,000/mm^3 for MCL cohort and platelets >= 75,000/mm^3 for DLBCL cohort (performed within 14 days prior to day 1 of protocol therapy)
Hemoglobin >= 8.5 g/dL (performed within 14 days prior to day 1 of protocol therapy)
Total bilirubin within 1.5 x the upper limit of normal institutional limits; patients with elevation of unconjugated bilirubin alone, as in Gilbert's disease, are eligible (performed within 14 days prior to day 1 of protocol therapy)
Aspartate aminotransferase (AST) =< 3 x upper limit of normal (ULN) unless demonstrated lymphoma involvement of the liver (performed within 14 days prior to day 1 of protocol therapy)
Alanine aminotransferase (ALT) =< 2.5 x ULN unless demonstrated lymphoma involvement of the liver (performed within 14 days prior to day 1 of protocol therapy)
Creatinine clearance >= 50 mL/min for Cohort #1 (DLBCL) and >= 30 mL/min for Cohort #2 (MCL) per the Cockcroft-Gault formula (performed within 14 days prior to day 1 of protocol therapy)
If not receiving anticoagulants: international normalized ratio (INR) OR prothrombin (PT) =< 1.5 x ULN (performed within 14 days prior to day 1 of protocol therapy)
If not receiving anticoagulants: activated partial thromboplastin time (aPTT) =< 1.5 x ULN (performed within 14 days prior to day 1 of protocol therapy)
Female of childbearing potential: negative urine or serum pregnancy test, performed within 14 days prior to day 1 of protocol therapy
Cardiac function (12 lead- electrocardiogram [ECG] versus [vs] non-12 lead ECG), performed within 14 days prior to day 1 of protocol therapy
Female subjects must be either post-menopausal, surgically sterilized, or willing to use an acceptable method of birth control (i.e. a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) beginning prior to study entry, for the duration of the study, and for six months following last dose of avelumab/utomilumab; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
Male subjects must agree to use an acceptable method of contraception beginning prior to study entry, for the duration of the study, and for six months following last dose of avelumab/utomilumab
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16 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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