TGR-1202 and Ibrutinib in Treating Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of PI3K delta inhibitor TGR-1202 (TGR-1202) and
ibrutinib in relapsed and refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL).

SECONDARY OBJECTIVES:

I. To determine the overall response rate (ORR) defined as the sum of complete responses (CR)
and partial responses (PR).

II. To determine the event-free survival (EFS), time to response (TTR), and duration of
response (DOR) in patients with rel/ref DLBCL.

TERTIARY OBJECTIVES:

I. To evaluate molecular profiling of patient samples (optional lymph node biopsies) obtained
at days 0 (pre-treatment; core biopsy), day 8 (fine needle aspiration) and end of treatment
(progressive disease or end of study treatment—1 year; core biopsy).

II. To evaluate the baseline characteristics and dynamic shifts in mutational Landscape,
transcriptional signatures and intracellular signaling cascades in primary tumor cells.

III. To define the mutational status of 384 genes that mutated in DLBCL, including cluster of
differentiation (CD)79B, caspase recruitment domain family member 11 (CARD11), and myeloid
differentiation primary response 88 (MYD88).

IV. To evaluate signatures of B-cell receptor signaling and the back-up pathway of oxidative
phosphorylation.

V. To measure the basal and induced level of activation of components within parallel
signaling pathways downstream of the B-cell receptor.

VI. To monitor changes in T-cell characteristics in response to exposure to TGR-1202 and
ibrutinib.

VII. To perform quantitative response evaluation by peripheral blood cell-free
deoxyribonucleic acid (DNA) sequencing at enrollment, day 8, 1 month, at every response
assessment time point compared to standard radiographic response evaluation by positron
emission tomography (PET)/ computed tomography (CT) or CT and end of treatment (progressive
disease or end of study treatment—1 year).

VIII. To evaluate the genetic profiling for drug resistance mutations. IX. To evaluate DLBCL
subtype analysis by immunohistochemistry compared to Nanostring assessment.

OUTLINE: Patients are assigned to 1 of 3 groups.

GROUP A: Patients receive PI3K delta inhibitor TGR-1202 orally (PO) once daily (QD) on days
1-28 and ibrutinib PO QD on days 9-28 of course 1 and days 1-28 of subsequent courses.
Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or
unacceptable toxicity.

GROUP B: Patients receive ibrutinib PO QD on days 1-28 and PI3K delta inhibitor TGR-1202 PO
QD and days 9-28 of course 1 and days 1-28 of subsequent courses. Treatment repeats every 28
days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

GROUP C: Patients then receive PI3K delta inhibitor TGR-1202 PO QD and ibrutinib PO QD on
days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and after 1 year.

Inclusion Criteria:

- Histologically confirmed diffuse large B-cell lymphoma (DLBCL) or transformed DLBCL

- Hematoxylin and eosin (H&E) stain and immunohistochemistry (IHC) slides or a
representative formalin-fixed, paraffin-embedded (FFPE) tissue block along with the
pathology report from initial diagnosis, (as well as, an optional 8 unstained slides
of 4 micron thickness to store for future IHC and DNA specified research use), should
be sent to be reviewed, and the diagnosis confirmed by University of Nebraska Medical
Center (UNMC) (retrospective diagnostic review: treatment may commence prior to the
UNMC review); please NOTE: the diagnostic H&E slide and IHC slides will be returned
after review; only the optional 8 unstained slides will be retained and stored for
future unspecified research use

- Patients with relapsed or refractory DLBCL that has relapsed post-transplant or that
has been determined to be ineligible or unsuitable for transplant; patients must have
to have received at least one prior systemic therapy

- Patients must have measurable (>= 1.5 cm) or evaluable disease; baseline measurements
and evaluations must be obtained within 6 weeks of registration to the study; abnormal
PET scans will not constitute evaluable disease, unless verified by CT scan or other
appropriate imaging; measurable disease must have at least one objective measurable
disease parameter; a clearly defined, bi-dimensionally measurable defect or mass
measuring at least 1.5 cm in diameter on a CT scan will constitute measurable disease;
proof of lymphoma in the liver is required by a confirmation biopsy; skin lesions can
be used as measurable disease provided bi-dimensional measurements are possible

- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L

- By automated or manual review, whichever is greatest

- Platelets >= 100 x 10^9/L:

- Unless due to bone marrow infiltration then eligible if platelets > 50 x 10^9/L)

- Total bilirubin =< 1.5 x upper normal limit if documented hepatic involvement with
lymphoma, or =< 5 x upper normal limit if history of Gilbert's disease

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upper
limit of normal (ULN) if no liver involvement or =< 5 x the ULN if documented liver
involvement

- Creatinine =< 2.0 mg/dL OR calculated creatinine clearance >= 50 mL/min (as calculated
by the Cockcroft-Gault method)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 or expected survival
duration of > 2 months

- Ability to swallow and retain oral medication

- Women must not be pregnant or breast-feeding

- All female patients of child-bearing potential must have a negative serum
pregnancy test within 2 weeks prior to treatment to rule out pregnancy

- Pregnancy testing is not required for post-menopausal or surgically sterilized
women

- Male and female patients of reproductive potential must agree to follow accepted birth
control measures throughout the study period and for 30 days after the last dose of
either study drug for females and 3 months after the last dose of study drug for males

- Patient must be able to adhere to the study visit schedule and other protocol
requirements

- Patient must be aware of the neoplastic nature of his/her disease and willingly 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

- No serious disease or condition that, in the opinion of the investigator, would
compromise the patient's ability to participate in the study

Exclusion Criteria:

- Currently receiving cancer therapy (i.e., chemotherapy, radiation therapy,
immunotherapy, biologic therapy, hormonal therapy, and surgery and/or tumor
embolization) or any investigational drug within 7 days of cycle 1/day 1, 14 days of
cycle 1/day 1 for limited palliative radiation, and/or five half-live of an oral
therapy

- Corticosteroid therapy started at least 7 days prior to initiation of treatment
(prednisone =< 10 mg daily or equivalent) is allowed as clinically warranted);
topical or inhaled corticosteroids are permitted

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

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

- Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg,
phenprocoumon)

- Vaccinated with live, attenuated vaccines within 4 weeks of enrollment

- Autologous hematologic stem cell transplant within 3 months of study entry

- Allogeneic hematologic stem cell transplant within 12 months of study entry

- Active graft versus-host disease and must not be on immunosuppression

- Wide field radiotherapy within 28 days of cycle 1/day 1 or active side effects of such
therapy

- Active hepatitis B (hepatitis B virus [HBV]) or C (hepatitis C virus [HCV]) infection
(negative serology required excluding those with are seropositive due to prior
vaccination) and/or known history of human immunodeficiency virus (HIV)

- Primary central nervous system involvement only

- Require treatment with strong cytochrome P450 family 3 subfamily A (CYP3A) inhibitors

- Known history of drug-induced liver injury, alcoholic liver disease, primary biliary
cirrhosis, ongoing extra-hepatic obstruction caused by stones, cirrhosis of the liver
or portal hypertension

- Any life-threatening illness, severe and/or uncontrolled medical condition, or organ
system dysfunction, laboratory abnormality, psychiatric illness or other condition
which, in the Investigator's opinion, could compromise the subject's safety, interfere
with the absorption or metabolism of ibrutinib capsules, put the study outcomes at
undue risk or affect their participation in the study such as

- Symptomatic, or history of documented congestive heart failure New York Heart
Association (NYHA) functional classification III-IV (NYHA)

- Corrected QT interval using Fridericia's formula (QTcF) > 470 msec (unless
related to pacemaker) on echocardiogram (EKG) within 7 days of initiation of
treatment

- Angina not well-controlled by medication

- Poorly controlled or clinically significant atherosclerotic vascular disease
including cerebrovascular accident (CVA), transient ischemic attack (TIA),
angioplasty, cardiac or vascular stenting within 6 months prior to enrollment

- Prior malignancies within the past 1 year with exception of adequately treated basal
cell, squamous cell skin cancer, or thyroid cancer; carcinoma in situ of the cervix or
breast; prostate cancer of Gleason grade 6 or less with stable prostate specific
antigen (PSA) levels

- Women who are pregnant or breastfeeding; women who agree to stop breastfeeding would
be eligible

- Known hypersensitivity to either study drug (TGR-1202 or ibrutinib)