A Clinical Trial of Buparlisib and Ibrutinib in Lymphoma

Inclusion Criteria:

- Patient is ≥ 18 years of age at the time of signing Informed Consent

- Patient is able and willing to adhere to the study visit schedule and other protocol
requirements

- Patient has histologically confirmed diagnosis of R/R mantle cell lymphoma, follicular
lymphoma or diffuse large B cell lymphoma

- Diffuse large B cell lymphoma patients has received at least 1 prior regimen and
received, declined, or is ineligible for autologous or allogeneic stem cell
transplant.

- Follicular lymphoma patients have received at least 2 lines of therapy.

- Mantle cell lymphoma patients has received at least 1 line of therapy

- Allogeneic stem cell transplant recipients be greater than 6 months post
transplant, not on immunosuppression for prevention of graft versus host disease
for >3 months and without active graft versus host disease are eligible

- Autologous stem cell transplant recipients must have adequate bone marrow
recovery and transfusion independent

- Transformed histologies are permitted

- Patient has at least one measurable lesion (≥ 2 cm) according to Lugano Classification

- Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

- Patient has adequate bone marrow and organ function by:

- Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L , independent of growth factor
support unless with bone marrow involvement for 14 days

- Platelets ≥100 x 109/L, or ≥50 x 10^9/L if bone marrow involvement and
independent of transfusion support for 14 days in either situation

- Hemoglobin (Hgb) ≥ 9.0 g/dL (no RBC transfusion within past 14 days)

- Hgb >/= 8.0 g/dL for patients with anemia associated disease

- International Normalized Ratio (INR) ≤ 1.5

- Serum Creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance ≥ 25
mL/min as determined by the Cockcroft-Gault equation or a 24 hour urine
collection

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ ULN (or ≤3
x ULN if liver involved with disease

- Total serum bilirubin ≤ ULN (or ≤ 1.5 x ULN if documented hepatic involvement; or
total bilirubin ≤ 3 x ULN with direct bilirubin ≤ 1.5 x ULN in patients with
documented Gilbert's Syndrome

- LVEF ≥ 50%

- Fasting plasma glucose (FPG) ≤ 120mg/dL or ≤ 6.7 mmol/L

- Hemoglobin A1c ≤ 9%

- Potassium and calcium (corrected for albumin), within normal limits for the
institution, or ≤ Grade 1 if judged not clinically significant by the
investigator

- 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 trial. 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 4 months after the last dose of study drug.

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

- Patient is able to swallow and retain oral medications

Exclusion Criteria:

- Patients previously treated with ibrutinib or PI3K inhibitor

- Patient has a history of non-compliance to medical regimen or inability to grant
consent

- Patient has not recovered to Grade 1 or better (except alopecia) from related side
effects of any prior antineoplastic therapy.

- Patient is concurrently using other approved or investigational antineoplastic agent

- Patient has had major surgery or a wound that has not fully healed within 4 weeks of
starting study drugs.

- Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 2 weeks earlier

- Patient has evidence of active graft versus host disease (GVHD)

- Patient has active or history of central nervous system (CNS) disease or meningeal
involvement.

- Patient has history of stroke or intracranial hemorrhage ≤ 6 months from starting
study drugs.

- Patient has a score ≥ 12 on the PHQ-9 questionnaire, selects a response of "1, 2 or 3"
to question number 9 on the PHQ-9 questionnaire regarding potential for suicidal
thoughts or ideation (independent of the total score of the PHQ-9), score ≥ 15 on
GAD-7 mood scale.

- Patient has ≥ CTCAE grade 3 anxiety Patient has a medically documented history of or
active major depressive episode, bipolar disorder (I or II), obsessive-compulsive
disorder, schizophrenia, a history of suicidal attempt or ideation, homicidal ideation
(e.g. risk of doing harm to self or others)

- Patient has impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of study drug (e.g., ulcerative diseases,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel
resection)

- Patient has 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. Left Ventricular
Ejection Fraction (LVEF) <50% as determined by Multiple Gated acquisition (MUGA) scan
or echocardiogram (ECHO), unstable angina pectoris, symptomatic pericarditis, QTcF >
480 msec on the screening ECG (using the QTcF formula)

- Patient has a concurrent active malignancy. Malignancies treated with a curative
intent with an expected life expectancy ≥ 5 years or a non-competing life expectancy
risk are eligible (i.e. adequately treated basal or squamous cell carcinoma,
non-melanomatous skin cancer, early stage breast cancer, treated prostate cancer or
any other cancer from which the patient has been disease free for >/= 3 years).

- Patient with known history of human immunodeficiency virus (HIV), or any uncontrolled
active systemic infection.

- Patient has acute viral hepatitis (typically defined by elevated AST/ALT), or a
history of chronic or active HBV or HCV infection. HBV infection is defined as having
HBsAg and/or HBcAb positive test HBsAg and/or HBcAb positive test detectable HBV DNA
levels. HCV infection is defined as detectable HCV RNA levels.

- Patient is currently receiving increasing or chronic treatment (> 5 days) with
corticosteroids or another immunosuppressive agent. The following uses of
corticosteroids are permitted: single doses; e.g. with standard premedication for
taxanes; topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways
diseases), eye drops or local injections (e.g., intra-articular); patients requiring
chronic therapy with steroids may take no more than 10mg daily of prednisone or
equivalent.

- Patient requires treatment with a strong or moderate cytochrome P450 (CYP) 3A4
inhibitors, and inducers, or drugs known to induce Torsades de Pointes and the
treatment cannot be discontinued or switched to a different medication prior to
starting study drug

- Patients with known bleeding diathesis (e.g. von Willebrand 's disease) or hemophilia

- Patient is currently receiving warfarin or other Vitamin K antagonist. Therapy with
heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed. Refer to
Section 9.5 for Concomitant medication

- Patients with Child Pugh Class B or C hepatic cirrhosis

- Vaccinated with live attenuated vaccines ≤ 4 weeks from starting study drugs.

- Patients with any life threatening illness, medical condition or organ system
dysfunction that in the opinion of the investigator could compromise the subject's
safety, interfere with absorption of metabolism of study drugs or put the study
outcomes at undue risk.