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

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.

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)