Avelumab, Utomilumab, Rituximab, Ibrutinib, and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma
A Phase I Study of Avelumab Plus Utomilumab-Based Combination Therapy for Relapsed/Refractory Diffuse Large B-Cell Lymphoma and Mantle Cell Lymphoma
2 other identifiers
interventional
16
1 country
1
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for phase_1
Started Apr 2018
Longer than P75 for phase_1
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
February 2, 2018
CompletedFirst Posted
Study publicly available on registry
February 22, 2018
CompletedStudy Start
First participant enrolled
April 2, 2018
CompletedPrimary Completion
Last participant's last visit for primary outcome
June 26, 2024
CompletedStudy Completion
Last participant's last visit for all outcomes
June 26, 2024
CompletedMarch 26, 2025
March 1, 2025
6.2 years
February 2, 2018
March 24, 2025
Conditions
Outcome Measures
Primary Outcomes (2)
Maximum tolerated dose determined by dose-limiting toxicities
Up to 21 days (cohort I) or 28 days (cohort II)
Incidence of adverse events
Will be evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Observed toxicities will be summarized by type (organ affected or laboratory determination such as absolute neutrophil count), severity (by NCI CTCAE version 4.03 and nadir or maximum values for lab measures), date of onset, duration, reversibility, and attribution.
Up to 2 years
Secondary Outcomes (4)
Overall response rate
Up to 2 years
CR rate
Up to 2 years
Duration of response
Up to 2 years
Progression-free survival
From start of treatment to time of disease progression or death due to any cause, whichever occurs first, assessed up to 2 years
Other Outcomes (1)
Immunologic and genomic biomarkers
Up to 2 years
Study Arms (2)
Cohort I (avelumab, utomilumab, RICE)
EXPERIMENTALPatients receive rituximab 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 (avelumab, utomilumab, rituximab, ibrutinib)
EXPERIMENTALPatients receive rituximab IV on day 1, avelumab IV over 60 minutes on days 2 and 16, and ibrutinib PO 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)
Interventions
Undergo autologous hematopoietic stem cell transplantation
Given IV
Given IV
Given PO
Given IV
Correlative studies
Given IV
Given IV
Eligibility Criteria
You may qualify if:
- 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)
- +17 more criteria
You may not qualify if:
- Patients who are not hematopoietic stem cell transplant candidates are excluded for the DLBCL cohort (cohort #1)
- Vaccinated with live, attenuated vaccines within 4 weeks of first dose of avelumab
- Patients may be on steroids prior to initiation of treatment, provided that, by cycle 1 day 1, steroid use is tapered down to less than or equal to 10 mg/day of prednisone
- For cohort 1 (DLBCL) only: prior organ transplantation including allogeneic stem-cell transplantation
- For cohort 1 (DLBCL) only: prior RICE chemotherapy
- Patients with prior treatment with PD-1 or PD-L1 inhibitor
- Patients may not be receiving any other investigational agents, or concurrent biological therapy, chemotherapy, or radiation therapy
- Current use of immunosuppressive medication, except for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. systemic corticosteroids at physiologic doses =\< 10 mg/day of prednisone or equivalent; c. steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
- For cohort 2 (MCL) only: strong CYP3A4 inducers/inhibitors within 14 days prior to day 1 of protocol therapy and/or requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor
- CRITERIA SPECIFIC FOR COHORT #2 (MCL): Significant screening electrocardiogram (ECG) abnormalities including, but not limited to, left bundle branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, or corrected QT interval (QTc) \>= 470 msec; subjects with a cardiac pacemaker who have a QTc interval of \>= 470 msec may be eligible if these findings are considered not clinically significant as documented via a cardiology evaluation
- CRITERIA SPECIFIC FOR COHORT #2 (MCL): Currently active, clinically significant hepatic impairment Child-Pugh class B or C according to the Child Pugh classification
- CRITERIA SPECIFIC FOR COHORT #2 (MCL): Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
- CRITERIA SPECIFIC FOR COHORT #2 (MCL): Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia
- CRITERIA SPECIFIC FOR COHORT #2 (MCL): Major surgery within 4 weeks of first dose of study drug
- Active GVHD or on immunosuppressive medication for GVHD (applies to cohort #2)
- +17 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- City of Hope Medical Centerlead
- National Cancer Institute (NCI)collaborator
Study Sites (1)
City of Hope Medical Center
Duarte, California, 91010, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Elizabeth Budde
City of Hope Medical Center
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
February 2, 2018
First Posted
February 22, 2018
Study Start
April 2, 2018
Primary Completion
June 26, 2024
Study Completion
June 26, 2024
Last Updated
March 26, 2025
Record last verified: 2025-03