Rituximab, Idelalisib, and Venetoclax in Relapsed/Refractory CLL

Participants will receive idelalisib by mouth twice daily and rituximab intravenously in a
lead-in phase for 8-13 weeks. Those participants who meet criteria to begin venetoclax will
receive venetoclax by mouth once daily using a stepwise dose escalation schedule, along with
idelalisib twice daily by mouth. They will continue on idelalisib and venetoclax for up to 12
months or until 6 months after negativity of MRD is achieved in peripheral blood and
confirmed in bone marrow in participants with a clinical complete response (CR) or clinical
incomplete CR (CRi).

Inclusion Criteria:

Age ≥ 18 years of age. Relapsed or refractory B-cell CLL, according to IWCLL criteria, that
requires treatment in the opinion of the investigator

Must have had at least one standard treatment with one of the following regimens:

fludarabine-containing regimens, alkylator-containing (eg, chlorambucil, bendamustine)
regimens, ibrutinib-based regimens, or rituximab-containing regimens. Eastern Cooperative
Oncology Group performance status of 0, 1, or 2.

Adequate bone marrow function as follows:

- Absolute neutrophil count (ANC) ≥ 1,000/mm3 without support of granulocyte colony
stimulating factors for at least 7 days

- Platelets ≥ 50,000/mm3 (entry platelet count must be independent of transfusion within
14 days prior to initiation of study treatment)

- Hemoglobin ≥ 9.0 g/dL

Adequate coagulation, renal, and hepatic function as follows:

- aPTT and PT ≤ 1.2 × upper limit of normal (ULN) for the laboratory

- Calculated creatinine clearance ≥ 50 mL/min as calculated by the standard Cockcroft-
Gault equation using age, actual weight, creatinine, and gender

- AST and ALT ≤ 1.5 × ULN for the laboratory

- Bilirubin ≤ 1.5 × ULN for the laboratory.

Persons with known HIV infection are eligible if they meet the following:

- CD4+ T-cell count ≥ 250/mm3

- Undetectable HIV viral load on standard PCR-based test

- On a stable regimen of highly active anti-retroviral therapy (HAART) that does not
include strong CYP3A4 inducers or inhibitors

- No ongoing requirement for concurrent antibiotics or antifungal agents for the
prevention of HIV-associated opportunistic infections For a woman of childbearing
potential (WCBP), a negative serum pregnancy test performed within 7 days prior to
initiation of study treatment. Note: WCBP is defined as any woman who has not had a
hysterectomy or bilateral oophorectomy or is not postmenopausal (ie, she has had
menses in the preceding 24 consecutive months). WCBP and male patients must agree to
use a medically accepted form of birth control for the duration of study treatment and
for at least 1 month following completion of study treatment. Ability to understand
and the willingness to sign a written informed consent document.

Exclusion Criteria:

Known histologic transformation from CLL to an aggressive lymphoma (ie, Richter's
transformation). Known history of drug-induced pneumonitis. Undergone an allogeneic stem
cell transplant, unless the transplant was ≥ 12 months prior to initiation of study
treatment and the patient has not had graft-versus-host disease and does not require
immunosuppression. Undergone an autologous stem cell transplant within 6 months prior to
inititiation of study treatment. Central nervous system involvement. Clinically significant
infection including active hepatitis B or hepatitis C requiring active treatment, or active
CMV infection. Vaccination with a live vaccine within 28 days prior to initiation of study
treatment.

Ongoing requirement for warfarin (due to potential drug-drug interactions that may increase
the exposure of warfarin and ensuing complications).

Has received any of the following within 14 days prior to initiation of study treatment:

- Anti-cancer therapy

- Investigational therapy Has not recovered to < grade 2 toxicity(s) from prior therapy.
Has not recovered to < grade 2 toxicity(s) from idelalisib and rituximab.

Ongoing or planned treatment with any of the following:

- Steroid therapy for anti-neoplastic intent

- Strong or moderate CYP3A inhibitor or inducer, and/or a narrow-therapeutic sensitive
substrate

- P-gp inhibitor or narrow-therapeutic sensitive P-gp substrate If any of these agents
have been used, patients must be off them for ≥ 1 week before initiation of study
treatment. Has consumed grapefruit, grapefruit products, Seville oranges or Star fruit
within 3 days prior to initiation of study treatment. History of a prior exposure to a
Bcl-2 family protein inhibitor (eg, venetoclax, navitoclax) or PI3K inhibitor (eg,
idelalisib, duvelisib, TGR-1202, copanlisib, buparlisib). History of a prior
significant toxicity from rituximab or other CD20 monoclonal antibodies.

A cardiovascular disability status of New York Heart Association Class ≥ II. Diagnosis or
treatment for another malignancy within 1 year of study registration, with the exception of
complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, any in
situ malignancy, or low-risk prostate cancer after curative therapy.

Patient with active liver disease, inflammatory bowel disease, or Crohn's disease.

Malabsorption syndrome or other condition that precludes enteral route of administration.

Exhibits evidence of other clinically significant uncontrolled condition(s) including, but
not limited to:

- Uncontrolled infection (viral, bacterial, or fungal)

- Grade 3 or greater neutropenic fever within 1 week prior to initiation of study
treatment

- Active autoimmune cytopenias (for 2 or more weeks), including autoimmune hemolytic
anemia (AIHA) and idiopathic thrombocytopenic purpura. Pregnancy or breastfeeding.
Medical, psychological, or social condition that, in the opinion of the investigator,
may increase the patient's risk, interfere with the patient's participation in the
study or hinder evaluation of study results.