Ibrutinib, Fludarabine, and Pembrolizumab in High-Risk or Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Background:

- Chronic lymphocytic leukemia and small lymphocytic lymphoma (hereby referred as CLL) are
tumors of B cells. A subset of patients categorized as high-risk CLL has a poor clinical
outcome when treated with conventional chemotherapy. High-risk CLL is defined by
relapsed/refractory disease status, or the presence of high-risk mutations, such as
deletion 17p, TP53, and NOTCH1. While the cause of CLL is still unclear, studies have
indicated critical factors required for the tumor cells. First, CLL cells grow and
survive because they receive signals through the B-cell receptor (BCR); and second, CLL
cells benefit from interactions with other cells, especially T cells.

- The stimulation through the BCR can be blocked by ibrutinib, which is an oral drug that
selectively inhibits Bruton s tyrosine kinase (BTK). In clinical trials, ibrutinib
demonstrated safety and high response rates in patients with high-risk disease.
Ibrutinib has gained FDA approval as a treatment for CLL regardless of prior treatment
or cytogenetic status. However, single-agent ibrutinib has limitations; the drug does
not eliminate all tumor cells and, with time, the tumor cells may become resistant.
Therefore, combination of ibrutinib with other drugs could be beneficial.

- This study investigates the combination of ibrutinib, fludarabine and pembrolizumab for
treatment of CLL. Fludarabine is a well-tolerated drug that has been used widely to
treat CLL. Also, fludarabine can kill both malignant B cells and T cells that support
the growth of leukemia cells. Pembrolizumab targets immune checkpoint molecules and
enhances the cell-killing activity of T cells. With this approach we hope to achieve a
greater reduction in CLL cells than with single agent ibrutinib and to restore healthier
immune system that could contribute to durable responses.

Objectives:

-To investigate the rate of complete response to ibrutinib, short course fludarabine and
pembrolizumab.

Key eligibility criteria:

- Patients with active CLL meeting treatment indications defined by 2008 International
Workshop on CLL (IWCLL) consensus guideline.

- High-risk CLL defined by one of the following:

- Relapsed/refractory disease status (except patients with deletion 13q AND mutated
IgHV), or

- Presence of high-risk mutations regardless of prior treatment status: deletion 17p,
TP53 mutation, NOTCH1 mutation, or complex cytogenetics.

Design:

- This is a single-arm, open-label phase II study.

- Timeline: Treatment on this study is given in cycles from cycle -3 to 17, then in months
beyond cycle 17. Cycles -3 to -1 are 28-day cycles. Cycles 1 to 17 are 21-day cycles.
After completion of 1 year of pembrolizumab, the time on study is by chronological
months on study from starting pembrolizumab.

- Treatment plan: Ibrutinib is given daily until disease progression or intolerable side
effects occur. Fludarabine is given on cycle -2 only. Pembrolizumab is given every 3
weeks starting from cycle 1 for 1 year. Minimal residual disease will be measured at 2
years from cycle 1 to determine the need for long- term treatment with ibrutinib.

- INCLUSION CRITERIA:

- Men and women with histologically confirmed CLL or SLL as defined by the following:

- CLL: clonal B lymphocytosis 2: greater than or equal to 5,000 cells/microliter.

- SLL: lymphadenopathy with the tissue morphology of CLL but are not leukemic (<
5,000 circulating clonal B lymphocytes/microliter).

- Immunophenotypic profile or immunohistochemistry read by an expert pathologist as
consistent with CLL. This will include CD5, CD19, and CD20 expression by the CLL
cells typically also with CD23 expression, but CD23 negative cases may be
included if there is an absence of t(11;14).

- Active disease as defined by at least one of the following (IWCLL consensus criteria):

- Weight loss greater than or equal to 10% within the previous 6 months.

- Extreme fatigue.

- Fevers of greater than 100.5 degrees F for greater than or equal to 2 weeks
without evidence of infection.

- Night sweats for more than one month without evidence of infection.

- Evidence of progressive marrow failure as manifested by the development of, or
worsening of, anemia and/or thrombocytopenia.

- Massive or progressive splenomegaly.

- Massive nodes or clusters or progressive lymphadenopathy.

- Progressive lymphocytosis with an increase of >50% over a 2-month period, or an
anticipated doubling time of less than 6 months.

- High-risk disease defined by meeting at least one of the following three criteria:

- Relapsed and/or refractory CLL/SLL. Exceptions are patients with mutated IGHV and
isolated 13q deletion. These patients are not considered to be high-risk by prior
treatment history alone, and will be excluded from the trial.

- Presence of high-risk mutations detected by FISH or targeted sequencing,
regardless of prior treatments status.

- FISH: deletion 17p (or TP53), complex cytogenetics (3 or more abnormalities)

- Targeted sequencing: TP53, or NOTCH1 mutation. Pathologic mutations
occurring at the coding regions are accepted as relevant mutations.

- CLL or SLL with disease transformation with Hodgkin-like cells regardless of
prior treatment status.

- Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to
1.

- Adequate organ function as defined below:

- Summary of adequate organ function for eligibility: System/Laboratory Value

- Hematological

- Absolute neutrophil count (ANC): greater than or equal to 750/microliter

- Platelets: greater than or equal to 50,000/microliter

- Hemoglobin: greater than or equal to 9 g/dL or greater than or equal to 5.6
mmol/L without EPO dependency (within 7 days of assessment).
Post-transfusion hemoglobin is accepted.

- Renal

---Measured or calculated GFR: GFR greater than or equal to 30ml/min/1.73m^2
based on CKD-EPI

- Hepatic

- Serum total bilirubin: less than or equal to 1.5 X ULN OR Direct bilirubin
less than or equal to ULN for subjects with total bilirubin levels greater
than or equal to 1.5 ULN due to Gilbert's disease

- AST (SGOT) and ALT (SGPT): less than or equal to 2.5 X ULN

- Coagulation

- International Normalized Ratio (INR) or Prothrombin Time (PT): less than or
equal to 1.5 X ULN unless subject is receiving anticoagulant therapy; as
long as PT or PTT is within therapeutic range of intended use of
anticoagulants

- Activated Partial Thromboplastin Time (aPTT): less than or equal to 1.5 X
ULN unless subject is receiving anticoagulant therapy; as long as PT or PTT
is within therapeutic range of intended use of anticoagulants.

- Agreement to use acceptable methods of contraception during the study and for 90 days
after the last dose of study drug if sexually active and able to bear or beget
children.

- Female subjects who are of non-reproductive potential (i.e., post-menopausal by
history - no menses for greater than or equal to 1 year; OR history of
hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral
oophorectomy).

- Female subjects of childbearing potential must have a negative serum pregnancy
test upon study entry.

- Male and female subjects who agree to use both a highly effective methods of
birth control (i.e., implants, injectables, combined oral contraceptives, some
intrauterine devices, complete abstinence, or sterilized partner) and a barrier
method (i.e., condoms, vaginal ring, sponge, etc) during the period of therapy
and for 90 days after the last dose of study drug

- Willing and able to participate in all required evaluations and procedures in this
study protocol including swallowing capsules without difficulty.

- Ability to understand the purpose and risks of the study and provide signed and dated
informed consent and authorization to use protected health information (in accordance
with national and local subject privacy regulations).

- Individuals greater than or equal to 18 years old

EXCLUSION CRITERIA:

- Transformation of CLL into lymphomas other than those with Hodgkin-like cells.

- Currently receiving or previously participated to receive an investigational agent
within 4 weeks prior to study treatment.

- Currently receiving or previously received monoclonal antibodies, immunomodulatory
therapy, chemotherapy, radiation, or radioimmunotherapy within 4 weeks prior to study
treatment, or has not recovered (i.e., less than or equal to Grade 1 or at baseline)
from non-hematologic adverse events due to a previously administered agent.

--Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved
to CTCAE, v4.03, grade 0 or 1, or to the levels dictated in the inclusion/exclusion
criteria with the exception of alopecia.

- Major surgery within 4 weeks of first dose of study drug

--Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting therapy.

- Currently receiving systemic steroid therapy (i.e. prednisone) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of trial treatment.

- Prior therapy with BTK inhibitor, anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

--Note: Prior therapy with fludarabine is not excluded.

- Active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g.., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.

- Known additional malignancy that is progressing or requires active treatment.

--Note: Exceptions include basal cell carcinoma of skin, squamous cell carcinoma of
skin, and in situ cervical cancer that has undergone potentially curative therapy.
Exceptions include other cancers from which the subject has been disease-free for
greater than or equal to 2 years or which will not limit survival to < 2 years

- Known history of, or any evidence of active, non-infectious pneumonitis that required
steroids.

- Known bleeding disorders (i.e., von Willebrand s disease or hemophilia).

- Known HIV infection (i.e., HIV 1 and 2 antibodies).

- Active hepatitis B (i.e., HBsAg reactive) or hepatitis C (i.e. HCV RNA is detected by
a qualitative test) infection.

- Recent Known active infection requiring systemic therapy that was completed less than
or equal to 14 days before the first dose of study drug.

- Known history of active tuberculosis.

- Any uncontrolled active systemic infection.

- Known hypersensitivity to ibrutinib, fludarabine, or pembrolizumab.

- Requires concomitant anticoagulation with Coumadin (warfarin) or other vitamin K
antagonists.

- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel or ulcerative colitis, symptomatic
inflammatory bowel disease, or partial or complete bowel obstruction

- History of stroke or intracranial hemorrhage within 6 months before the first dose of
study drug

- Subjects who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior
to the first dose of ibrutinib or subjects who require continuous treatment with a
strong CYP3A inhibitor

- Currently active, clinically significant cardiovascular disease including uncontrolled
or symptomatic arrhythmias, Class 3 or 4 congestive heart failure as defined by New
York Heart Association Functional Classification, or a history of myocardial
infarction, unstable angina or acute coronary syndrome within 6 months of screening.

- 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 and fludarabine, or put the study outcomes at
undue risk

- Female patients who are currently in pregnancy, or unwilling to use acceptable methods
of contraception or refrain from pregnancy if of childbearing potential or currently
breastfeeding. Male patients who are unwilling to follow the contraception
requirements described in this protocol.

- Psychiatric illness/social situations that would limit the patient s ability to
tolerate and/or comply with study requirements.

- Unable to understand the investigational nature of the study or give informed consent.

- Currently active, clinically significant hepatic impairment Child-Pugh class B or C
according to the Child Pugh classification.

- Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.