Clinical Trials /

Avelumab, Utomilumab, Rituximab, Ibrutinib, and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma

NCT03440567

Description:

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.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Mantle Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Avelumab, Utomilumab, Rituximab, Ibrutinib, and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma
  • Official Title: A Phase I Study of Avelumab Plus Utomilumab-Based Combination Therapy for Relapsed/Refractory Diffuse Large B-Cell Lymphoma and Mantle Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 17428
  • SECONDARY ID: NCI-2018-00098
  • SECONDARY ID: 17428
  • NCT ID: NCT03440567

Conditions

  • CCND1 Positive
  • CD20 Positive
  • Recurrent Diffuse Large B-Cell Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma
  • Refractory Mantle Cell Lymphoma
  • Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma

Interventions

DrugSynonymsArms
AvelumabBavencio, MSB-0010718C, MSB0010718CCohort I (avelumab, utomilumab, RICE)
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboCohort I (avelumab, utomilumab, RICE)
Etoposide PhosphateEtopophosCohort I (avelumab, utomilumab, RICE)
IbrutinibBTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765Cohort II (avelumab, utomilumab, rituximab, ibrutinib)
IfosfamideAsta Z 4942, Asta Z-4942, Cyfos, Holoxan, Holoxane, Ifex, IFO, IFO-Cell, Ifolem, Ifomida, Ifomide, Ifosfamidum, Ifoxan, IFX, Iphosphamid, Iphosphamide, Iso-Endoxan, Isoendoxan, Isophosphamide, Mitoxana, MJF 9325, MJF-9325, Naxamide, Seromida, Tronoxal, Z 4942, Z-4942Cohort I (avelumab, utomilumab, RICE)
RituximabABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, RTXM83Cohort I (avelumab, utomilumab, RICE)
UtomilumabPF 05082566, PF 5082566, PF-05082566, PF-2566Cohort I (avelumab, utomilumab, RICE)

Purpose

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.

Detailed 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.

      TERTIARY 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.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
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.
  • Avelumab
  • Carboplatin
  • Etoposide Phosphate
  • Ifosfamide
  • Rituximab
  • Utomilumab
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.
  • Avelumab
  • Ibrutinib
  • Rituximab
  • Utomilumab

Eligibility Criteria

        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

             * Filgrastim can be given prior to enrollment to achieve target ANC >= 1000/uL

          -  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

             * NOTE: platelet transfusions and packed red blood cell transfusion can be given prior
             to enrollment to achieve a target platelet (Plt) >= 50,000/uL for MCL and >= 75,000/uL
             for DLBCL and hemoglobin of >= 8.5 g/dL

          -  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 on anticoagulant therapy: PT must be within therapeutic range of intended use of
             anticoagulants

          -  If not receiving anticoagulants: activated partial thromboplastin time (aPTT) =< 1.5 x
             ULN, performed within 14 days prior to day 1 of protocol therapy

             * If on anticoagulant therapy: aPTT must be within therapeutic range of intended use
             of anticoagulants

          -  Female of childbearing potential: negative urine or serum pregnancy test, performed
             within 14 days prior to day 1 of protocol therapy

             * If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
             test will be required

          -  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

        Exclusion Criteria:

          -  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 >= 470msec
             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 (eg, 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)

          -  Recent infection requiring intravenous anti-infective treatment that was completed =<
             14 days before enrollment; active infection requiring systemic therapy

          -  Persisting toxicity related to prior therapy (National Cancer Institute [NCI] Common
             Terminology Criteria for Adverse Events [CTCAE] version [v]. 4.03 grade > 1); however,
             alopecia, sensory neuropathy grade =< 2, or other grade =< 2 not constituting a safety
             risk based on investigator's judgement are acceptable

          -  Hypersensitivity to chemotherapy or history of allergic reactions attributed to
             compounds of similar chemical or biologic composition to rituximab, ibrutinib, ICE,
             Ave, or Uto

          -  Patients should not have any uncontrolled illness including ongoing or active
             infection

          -  Any life-threatening illness, medical condition, or organ system dysfunction that, in
             the investigator's opinion, could compromise the subject's safety or put the study
             outcomes at undue risk

          -  Myocardial infarction within 6 months prior to enrollment or New York Heart
             Association (NYHA) class III or IV heart failure, uncontrolled angina, severe
             uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
             ischemia or active conduction system abnormalities; prior to study entry, any ECG
             abnormality at screening has to be documented by the Investigator as not medically
             relevant

          -  Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
             accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months
             prior to enrollment), unstable angina, congestive heart failure (>= New York Heart
             Association classification class II), or serious cardiac arrhythmia requiring
             medication

          -  Diagnosed or treated for another malignancy within 3 years of enrollment, with the
             exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
             the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy

          -  Patients with active central nervous system (CNS) disease or history of brain
             metastases are excluded from study

          -  Active human immunodeficiency virus (HIV) or hepatitis C virus (HCV) or hepatitis B
             virus (HBV); subjects who have an undetectable HIV viral load with CD4 >= 200 and are
             on highly active antiretroviral therapy (HAART) medication are allowed; subjects who
             are positive for hepatitis B core antibody or hepatitis B surface antigen must have a
             negative polymerase chain reaction (PCR) result before enrollment; those who are PCR
             positive will be excluded; patients who have had hepatitis C but have finished
             treatment and are PCR negative will be allowed; (testing to be done only in patients
             suspected of having infections or exposures)

          -  Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory
             agent; patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid
             diseases not requiring immunosuppressive treatment are eligible

          -  Other severe acute or chronic medical conditions including immune colitis,
             inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric
             conditions including recent (within the past year) or active suicidal ideation or
             behavior; or laboratory abnormalities that may increase the risk associated with study
             participation or study treatment administration or may interfere with the
             interpretation of study results and, in the judgment of the investigator, would make
             the patient inappropriate for entry into this study

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued

          -  Other active malignancy

          -  Any other condition that would, in the investigator's judgment, contraindicate the
             patient's participation in the clinical study due to safety concerns with clinical
             study procedures

          -  Prospective participants who, in the opinion of the investigator, may not be able to
             comply with all study procedures (including compliance issues related to
             feasibility/logistics)

          -  Unable to understand the purpose and risks of the study and to provide a signed and
             dated informed consent form (ICF) and authorization to use protected health
             information (in accordance with national and local subject privacy regulations)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose determined by dose-limiting toxicities
Time Frame:Up to 21 days (cohort I) or 28 days (cohort II)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:CR rate defined as the proportion of response-evaluable participants that have a documented CR at any time
Time Frame:Up to 2 years
Safety Issue:
Description:Will be estimated by the proportion of evaluable patients achieving CR, along with the 95% exact binomial confidence interval.
Measure:Duration of response defined as the duration from the time a patient first achieves CR or PR until the time that relapse or progressive disease is objectively documented
Time Frame:Up to 2 years
Safety Issue:
Description:Will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of standard error; 95% confidence interval will be constructed based on log-log transformation.
Measure:Overall response rate defined as the proportion of response-evaluable participants that have a documented complete response (CR) or partial response (PR) at any time
Time Frame:Up to 2 years
Safety Issue:
Description:Will be estimated by the proportion of evaluable patients achieving either CR or PR, along with the 95% exact binomial confidence interval.
Measure:Progression-free survival
Time Frame:From start of treatment to time of disease progression or death due to any cause, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:Will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of standard error; 95% confidence interval will be constructed based on log-log transformation.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

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