Duvelisib and Venetoclax in Relapsed or Refractory CLL or SLL

This is a Phase I/II clinical trial. A Phase I clinical trial tests the safety of an
investigational drugs and also tries to define the appropriate dose of the investigational
drugs to use for further studies. "Investigational" means that the drugs are being studied
together for the first time.

This phase I study tests the safety of the drug duvelisib when used in combination with the
drug venetoclax. Since duvelisib is still being studied, the FDA (the U.S. Food and Drug
Administration) has not approved duvelisib as a treatment for any disease.

Duvelisib is a drug that is given in capsule form and taken by mouth. This drug is designed
to stop cancer growth by blocking a protein called phosphatidylinositide 3-kinase (PI3K),
which is important for the survival of CLL cells. In laboratory studies and in other clinical
trials that included participants with CLL, duvelisib was effective at killing CLL cells.

Venetoclax is a tablet that is taken by mouth. Venetoclax targets a protein called BCL-2,
which helps cancer cells survive. Venetoclax is an effective treatment for many participants
with CLL who do not respond to chemotherapy or other approved drugs or who have relapsed
after prior therapy. Venetoclax is FDA approved for participants with CLL who have a genetic
changes (called a deletion 17p abnormality) and have had their CLL worsen after at least one
prior therapy for their CLL.

In the phase I portion of this study, the investigators are looking to determine the dose of
venetoclax that is safe to give with duvelisib and to see what the side effects are of this
combination.

Inclusion Criteria:

- Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic
lymphoma requiring therapy, as per IW-CLL 2008 criteria

- Disease that has progressed during or relapsed after at least one previous CLL/SLL
therapy

- Age greater to or equal to 18 years

- ECOG performance status ≤2 (Karnofsky ≥60%)

- Patients must meet the following hematologic criteria at screening, unless they have
significant bone marrow involvement of CLL confirmed on biopsy:

- Absolute neutrophil count ≥500 cells/mm3 (0.5 x 109/L). Growth factor is allowed
in order to achieve this

- Platelet count ≥25,000 cells/mm3 (25 x 109/L) independent of transfusion within 7
days of screening

- Adequate hepatic function defined as:

--Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x upper
limit of normal (ULN), bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's
syndrome or of non-hepatic origin

- Adequate renal function as defined as:

--Serum creatinine ≤1.5 times the upper limit of normal or creatinine clearance ≥ 50
mL/min using a 24-hour urine collection

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal, barrier method or abstinence) prior to study entry and for the duration of
study participation

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Previous treatment with venetoclax or duvelisib

- Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy,
immunotherapy, biologic therapy, surgery within 2 weeks of Cycle 1/Day 1 with the
following exceptions:

- For patients on targeted therapies, a washout of least five half lives is
required

- Patients who experience clinical deterioration may start therapy after a shorter
washout period with prior approval by the PI

- Corticosteroid therapy (prednisone or equivalent <20 mg daily) is allowed

- Confirmed central nervous system involvement

- Allogeneic hematologic stem cell transplant within 6 months of starting study
treatment or active graft vs. host disease (GVHD) requiring treatment or prophylaxis

- History of active malignancy requiring therapy with the exception of hormonal therapy

- Any active systemic infection requiring IV antibiotics or uncontrolled, active
infections

- Known history of human immunodeficiency virus (HIV), hepatitis C virus (HCV), or
hepatitis B virus (HBV)

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

- Currently active gastrointestinal disease, including colitis, inflammatory bowel
disease and diarrhea requiring therapy

- Currently active, clinically significant cardiovascular disease, such as uncontrolled
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart
Association Functional Classification; or a history of myocardial infarction, unstable
angina, or acute coronary syndrome within 6 months prior to randomization

- 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

- Use of Coumadin for anticoagulation (other anticoagulants permitted)

- Lactating or pregnant

- Concurrent administration of medications or foods that are strong inhibitors or
inducers of CYP3A (see Appendix D) . The concomitant use of drugs or foods that are
strong or moderate inhibitors or inducers of CYP3A are not allowed beginning 1 week
prior to the first dose of duvelisib.

- Patients with ongoing use of prophylactic antibiotics are eligible as long as there is
no evidence of active infection and the antibiotic is not included on the list of
prohibited medications

- 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 resulting in malabsorption or chronic diarrhea

- Active abuse of alcohol