Ibrutinib in Treating Patients With Refractory or Relapsed Lymphoma After Donor Stem Cell Transplant

PRIMARY OBJECTIVES:

I. To study the use of ibrutinib starting between day 60 and day 90 after allogeneic
hematopoietic cell transplant (HCT) until 12 months post hematopoietic cell transplant to
improve the progression-free survival (PFS) at 12 months post hematopoietic cell transplant
by 25% compared to historical controls.

SECONDARY OBJECTIVES:

I. To increase the incidence of successful outcome (defined as lack of requirement of second
line therapy for acute graft-versus-host disease, lack of National Institutes of Health [NIH]
severe chronic graft-versus-host disease, lack of progression or relapse of chronic
lymphocytic leukemia/mantle cell lymphoma [MCL], lack of death from disease or non-relapse
causes) to at least 60% at 1 year post hematopoietic cell transplant. (Cohort A) II. To study
the safety and tolerability of ibrutinib post hematopoietic cell transplant in patients with
non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma. (Cohort A and B combined) III. To study the
incidence of grade 3-4 acute graft-versus-host disease in the first 6 months post
hematopoietic cell transplant in patients with non-Hodgkin lymphoma and Hodgkin lymphoma.
(Cohort A and B combined) IV. To study the incidence of second line therapy (systemic only)
for acute graft-versus-host disease in the first 6 months post hematopoietic cell transplant
in patients with non-Hodgkin lymphoma and Hodgkin lymphoma. (Cohort A and B combined) V. To
study the incidence of recurrent acute graft-versus-host disease in the first 6 months post
hematopoietic cell transplant in patients with non-Hodgkin lymphoma and Hodgkin lymphoma.
(Cohort A and B combined) VI. To study the incidence and severity of chronic
graft-versus-host disease in the first 12 months post hematopoietic cell transplant in
patients with not-Hodgkin lymphoma and Hodgkin lymphoma. (Cohort A and B combined) VII. To
study the incidence of lung involvement with graft-versus-host disease in the first 12 months
post hematopoietic cell transplant in patients with non-Hodgkin lymphoma and Hodgkin
lymphoma. (Cohort A and B combined) VIII. To study the incidence of sclerotic skin chronic
graft-versus-host disease in the first 12 months post hematopoietic cell transplant in
patients with non-Hodgkin lymphoma and Hodgkin lymphoma. (Cohort A and B combined) IX. To
study the incidence of infectious deaths not related to graft-versus-host disease in patients
with non-Hodgkin and Hodgkin lymphoma. (Cohort A and B combined)

TERTIARY OBJECTIVES:

I. To study the association of minimal residual disease (MRD) as detected by immunoglobulin
heavy chain (IgH) sequencing prior to starting ibrutinib and compare to post ibrutinib at
month 6, 9 and 12 after HCT. (Cohort A)

II. To study the impact of onset of new acute or chronic graft-versus-host disease on minimal
residual disease. (Cohort A)

III. To study the association of T-cell clonality by T cell receptor (TCR) Vb sequencing
prior to starting ibrutinib and compare to post ibrutinib at month 6, 9 and 12 after
hematopoietic cell transplant. (Cohort A)

IV. To study the impact of onset of new acute or chronic graft-versus-host disease on T cell
receptor sequencing. (Cohort A)

V. To study the association of B cell receptor signaling pathways and immune function with
response by single cell mass cytometry prior to starting ibrutinib and compare to post
ibrutinib at month 6, 9 and 12 after hematopoietic cell transplant. (Cohort A)

VI. To study the association of single cell mass cytometry that investigates B cell receptor
signaling and its association with new acute or chronic graft-versus-host disease on B-cell
receptor (BCR) signaling. (Cohort A)

OUTLINE:

Beginning between 60-90 days post donor stem cell transplant, patients receive ibrutinib
orally (PO) once daily (QD) until 1 year post donor stem cell transplant in the absence of
disease progression or unacceptable toxicity.

After completion of treatment, patients are followed up for 1 year.

Inclusion Criteria:

PRE-STEM CELL TRANSPLANT (SCT)

- Patients undergoing their first T cell replete allo-HCT for chronic lymphocytic
leukemia (CLL), Hodgkin Lymphoma (HL), or the following subtypes of Non-Hodgkin
lymphoma: Mantle cell lymphoma (MCL) and follicular center cell lymphoma (FL)

- Meeting institutional criteria for allo-HCT. Ejection fraction by echocardiogram or
MUGA >40%, pulmonary function test with adjusted DLCO ≥ 60%

- Matched (8/8) or mismatched (7/8) related, unrelated HCT

- Stem cell source: bone marrow, peripheral blood stem cell

- Disease criteria:

Cohort A

Chronic lymphocytic leukemia

- Disease burden: lymph node size < 5 cm and/or extra-nodal involvement < 5 cm AND

- 17 p deletion (detected by any assay) (> or equal to 20% of cells involved if assay is
conventional cytogenetics or fluorescence in situ hybridization [FISH]) or NOTCH
mutation at any time point during disease course; patient should have received at
least 1 line of therapy; prior ibrutinib therapy is permitted OR

- Relapsed/refractory chronic lymphocytic leukemia > or equal to 2 lines of therapy;
prior ibrutinib therapy is permitted

Mantle cell lymphoma

- Disease burden: lymph node size < 5 cm and/or extra-nodal involvement < 5 cm AND

- Relapsed/refractory mantle cell lymphoma > or equal to 1 line of therapy. Prior
ibrutinib therapy is permitted. Prior autologous hematopoietic cell transplant is
permitted. OR

- Mantle cell lymphoma blastoid variant in first complete response (CR1) or high risk
mantle cell lymphoma being considered for allo hematopoietic cell transplant in CR1

Cohort B

Follicular lymphoma

Disease burden: lymph node size < 5 cm and/or extra-nodal involvement < 5 cm AND
Relapsed/refractory follicular lymphoma > or equal to 2 lines of therapy. Prior ibrutinib
therapy is permitted

Hodgkin disease

- Disease burden: lymph node size < 5 cm and/or extra-nodal involvement < 5 cm AND

- Relapsed/refractory Hodgkin disease > or equal to 2 lines of therapy.

- Preparative regimen: both reduced intensity and ablative regimens are permitted.
Each center will pre-specify the regimen they intend to use during the conduct of
the study

- Donor criteria: HLA ≥ 7/8 related or unrelated donors.

- Women of childbearing potential and men who are sexually active must be
practicing a highly effective method of birth control during and after the study
consistent with local regulations regarding the use of birth control methods for
subjects participating in clinical trials. Men must agree to not donate sperm
during and after the study. For females, these restrictions apply for 1 month
after the last dose of study drug. For males, these restrictions apply for 3
months after the last dose of study drug.

- Women of childbearing potential must have a negative serum (beta-human chorionic
gonadotropin [beta-hCG]) or urine pregnancy test at screening. Women who are
pregnant or breastfeeding are ineligible for this study

- Sign (or their legally-acceptable representatives must sign) an informed consent
document indicating that they understand the purpose of and procedures required
for the study, including biomarkers, and are willing to participate in the study

- Prior to Administration of Ibrutinib (Day 60 to Day 90 post hematopoietic cell
transplant)

- Karnofsky performance status (KPS) > or equal to 60%

- Engraftment of neutrophils (absolute neutrophil count [ANC] >= 1.0 X 10^9/L) for 3
days without granulocyte colony-stimulating factor (g-csf) support

- Platelets > or equal to 100,000/mm^3 or > or equal to = 50,000/mm^3 if bone marrow
involvement independent of transfusion support in either situation

- Glomerular filtration rate (GFR) > or equal to 30 ml/min

- Liver function tests (LFTs) (alanine aminotransferase [ALT] and aspartate
aminotransferase [AST]) equal to or < 3 X upper limit of normal (ULN)

- Total bilirubin equal to or < 1.5 mg/dL X ULN unless bilirubin rise is due to
Gilbert's syndrome or of non-hepatic origin

- Predominant donor chimerisms of > or equal to 51% as measured by CD3 and CD33 (or
other myeloid marker)

Exclusion Criteria:

PRE-SCT

- Progression of chronic lymphocytic leukemia or mantle cell lymphoma or follicular
lymphoma or HD at time of transplant

- Use of Coumadin (warfarin) or other vitamin-K antagonists for anticoagulation;
non-Coumadin anticoagulation is permitted

- Known central nervous system involvement

- Active uncontrolled bacterial or invasive fungal infections

- History of malignancy other than the underlying disease unless treated with a curative
intent and/or no evidence of disease for at least 3 years (y) OR expected to be cured
with SCT

- Planned use of post-hematopoietic cell transplant cyclophosphamide for graft versus
host disease prophylaxis

- Anticipated planned donor lymphocyte infusion in the first 3 months post-SCT

- T deplete hematopoietic cell transplant

- Umbilical cord hematopoietic cell transplant

- History of stroke or intracranial hemorrhage within 6 months of enrollment

- Clinically significant cardiovascular disease such as uncontrolled or symptomatic
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by
the New York Heart Association Functional Classification

- Known HIV

- Active Hepatitis B or C virus

- Child-Pugh Class C

PRIOR TO ADMINISTRATION OF IBRUTINIB (DAY 60-DAY 90 POST SCT)

- In the critical care unit, or use of mechanical ventilation or use of renal
replacement therapy at any time post hematopoietic cell transplant and prior to
administration of ibrutinib

- Active uncontrolled stage 3-4 acute gastrointestinal (GI) graft versus host disease
prior to administration of ibrutinib

- Active uncontrolled stage 4 acute liver graft versus host disease prior to
administration of ibrutinib

- Evidence of progressive disease as compared to pre-hematopoietic cell transplant
(persistence of disease is permitted)

- Anticipated planned donor lymphocyte infusion in the first 3 months post-SCT

- Active uncontrolled bacterial or invasive fungal infections

- Prednisone equivalent of > 2m/kg for treatment of graft versus host disease prior to
administration of ibrutinib

- Use of second line systemic therapy for treatment of acute graft versus host disease
prior to administration of ibrutinib

- Any life-threatening illness, medical condition, or organ system dysfunction which, in
the investigator's opinion, could compromise the subject's safety, interfere with the
absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue
risk. Including the presence of chronic/active HBV and HBC infections and Child-Pugh
Class C.ibrutinib.

- Major surgery or a wound that has not fully healed within 4 weeks of starting.

- Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g.,
phenprocoumon)

- Requires chronic treatment with strong cytochrome P450, family 3, subfamily A (CYP3A)
inhibitors

- Vaccinated with live, attenuated vaccines within 4 weeks of starting ibrutinib