Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in Combination With Rituximab for Previously Treated Chronic Lymphocytic Leukemia
Brief Summary: This Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the effect of idelalisib in combination with rituximab on the onset, magnitude, and duration of tumor control in participants previously treated for chronic lymphocytic leukemia (CLL). Eligible patients will be randomized with a 1:1 ratio into 1 of the 2 treatment arms to receive either idelalisib plus rituximab or placebo plus rituximab. Participants who are tolerating primary study therapy but experience definitive CLL progression are eligible to receive active idelalisib therapy in the extension study, GS-US-312-0117.


Options:
A: Inclusion:

* Adult subjects with previously treated recurrent CLL who have measurable lymphadenopathy
* Require therapy for CLL
* Have experienced CLL progression \< 24 months since the completion of the last prior therapy
* Currently not sufficiently fit to receive cytotoxic therapy because of chemotherapy-induced bone marrow damage or comorbidities.
B: Inclusion Criteria:

* Diagnosis of CLL according to the National Cancer Institute (NCI) criteria or SLL according to the World Health Organization (WHO) criteria, including previous documentation of:
* Biopsy-proven SLL
* Diagnosis of CLL according to NCI working group criteria as evidenced by all of the following:

  * Peripheral blood lymphocyte count of \> 5,000/mm\^3 consisting of small to moderate size lymphocytes, with \< 55% prolymphocytes
  * Immunophenotyping consistent with CLL defined as:

    * The predominant population of lymphocytes share both B-cell antigens (CD19, CD20 \[typically dim expression\], or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc.)
    * Clonality as evidenced by kappa or lambda light chain expression (typically dim immunoglobulin expression)
    * Note: splenomegaly, hepatomegaly, or lymphadenopathy are not required for the diagnosis of CLL
  * Before diagnosing CLL or SLL, mantle cell lymphoma must be excluded by demonstrating a negative FISH analysis for t(11;14)(immunoglobulin heavy \[IgH\]/cyclin D1 \[CCND1\]) on peripheral blood or tissue biopsy or negative immunohistochemical stains for CCND1 on involved tissue biopsy
* Patients must be previously untreated and meet at least one of the following indications for chemotherapy:

  * Evidence of progressive marrow failure as manifested by the development of or worsening anemia (=\< 11 g/dl) and/or thrombocytopenia (=\< 100,000/mm\^3) not due to autoimmune disease
  * Symptomatic or progressive lymphadenopathy, splenomegaly or hepatomegaly
  * One or more of the following disease-related symptoms:

    * Weight loss \> 10% within the previous 6 months
    * Extreme fatigue attributed to CLL
    * Fevers \> 100.5 degree Fahrenheit for 2 weeks without evidence of infection
    * Drenching night sweats without evidence of infection
  * Progressive lymphocytosis due to CLL with an increase of \> 50% over a two-month period or an anticipated doubling time of less than six months

    * Prior chemotherapy or monoclonal antibody based therapy for treatment of CLL will be considered prior therapy; nutraceutical treatments with no established benefit in CLL (such as epigallocatechin gallate \[EGCG\], found in green tea or other herbal treatments) will not be considered "prior treatment"
    * Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease are not sufficient for protocol therapy
* Serum creatinine =\< 1.5 x upper normal levels (UNL)
* Total bilirubin =\< 1.5 x UNL unless due to Gilbert's disease; if total bilirubin is \> 1.5 x UNL, a direct bilirubin should be performed and must be \< 1.5 mg/dL for Gilbert's to be diagnosed
* Aspartate aminotransferase (AST) =\< 3.0 x UNL and alanine aminotransferase (ALT) =\< 3.0 x UNL (unless due to hemolysis or CLL)
* Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0, 1, or 2
* Willingness to provide blood samples as required
* Able to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

* Any of the following comorbid conditions:

  * New York Heart Association Class III or IV heart disease
  * Recent myocardial infarction (\< 1 month)
  * Uncontrolled infection
  * Infection with the human immunodeficiency virus (HIV/acquired immunodeficiency syndrome \[AIDS\])
  * Infection with known chronic, active Hepatitis C
  * Positive serology for hepatitis B (HB) defined as a positive test for HB surface antigen (HBsAg); in addition, if negative for HBsAg but HB core antibody (HBcAb) positive (regardless of HBsAb status), a HB deoxyribonucleic acid (DNA) test will be performed and if positive the subject will be excluded
* Pregnant women
* Nursing women
* Men or women of childbearing potential who are unwilling to employ adequate contraception
* Other active primary malignancy requiring treatment or limiting survival to =\< 2 years
* Any radiation therapy =\< 4 weeks prior to registration
* Any major surgery =\< 4 weeks prior to registration
* Current use of corticosteroids; EXCEPTION: low doses of steroids (\< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical conditions; Note: previous use of corticosteroids is allowed
* Active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment; patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation
C: Inclusion Criteria:

1. documented CLL requiring treatment (irrespective if first- or relapse treatment) according to the criteria of the international Workshop of CLL \[iwCLL\]

   In case of previously treated patients, these must have recovered from acute toxicities and treatment regimen must be stopped within the following time periods before start of the study treatment in the CLL2-BIG trial:
   * chemotherapy within ≥ 28 days
   * antibody treatment within ≥ 14 days
   * kinase inhibitors, B-cell-lymphoma 2 \[BCL2\] -antagonists or immunomodulatory agents within ≥ 3 days
   * corticosteroids may be applied until the start of the BIG-regimen, these have to be reduced to an equivalent of ≤ 20mg prednisolon during treatment
2. Creatinine clearance ≥ 30 ml/min
3. Adequate hematologic function
4. Adequate liver function
5. Negative serological testing for hepatitis B, hepatitis-C RNA and negative HIV test within 6 weeks prior to registration
6. Age at least 18 years
7. Eastern Cooperative Oncology Group \[ECOG\] status 0 - 2; ECOG 3 is only permitted if related to CLL
8. Life expectancy ≥ 6 months
9. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

1. Transformation of CLL
2. Known central nervous system (CNS) involvement
3. Patients with a history of confirmed progressive multifocal leukoencephalopathy \[PML\]
4. Malignancies other than CLL currently requiring systemic therapies
5. Uncontrolled infection requiring systemic treatment
6. Use of investigational agents which would interfere with the study drug within 28 days prior to registration
7. Any comorbidity or organ system impairment rated with a cumulative illness rating scale \[CIRS\] score of 4, excluding the eyes/ears/nose/throat/larynx organ system or any other life-threatening illness, medical condition or organ system dysfunction that - in the investigator´s opinion could comprise the patients safety or interfere with the absorption or metabolism of the study drugs (e.g, inability to swallow tablets or impaired resorption in the gastrointestinal tract)
8. Known hypersensitivity to GA101, ibrutinib or any of the excipients
9. Requirement of treatment with strong cytochrome P450 3A4 \[CYP3A4\] -inhibitors/-inducers or anticoagulant with warfarin or phenprocoumon (marcumar)
10. History of stroke or intracranial hemorrhage within 6 months prior to registration
11. Pregnant women and nursing mothers
12. Fertile men or women of childbearing potential unless:surgically sterile or ≥ 2 years after the onset of menopause or willing to use two methods of reliable contraception including one highly effective (Pearl Index \<1) and one additional effective (barrier) method during study treatment and for 18 months after end of study treatment.
13. Vaccination with a live vaccine a minimum of 28 days prior to registration
14. Legal incapacity
15. Prisoners or subjects who are institutionalized by regulatory or court order
16. Persons who are in dependence to the sponsor or an investigator
D: Inclusion Criteria:

* Participants must meet the following criteria on screening examination to be eligible to participate in the study:
* Subjects must have CLL / SLL, as documented by a history at some point of an absolute peripheral blood B cell count \> 5000, with a monoclonal B cell population co-expressing CD19, CD5, and CD23, or if CD23 negative, then documentation of the absence of t(11;14) or cyclin D1 overexpression. Alternatively patients with lymphadenopathy in the absence of circulating disease will also be eligible for this study if lymph node biopsy establishes the diagnosis of CLL with the above immunophenotype.
* Participants must have measurable disease (lymphocytosis \> 5,000, or palpable or CT measurable lymphadenopathy \> 1.5 cm, or bone marrow involvement \>30%).
* Subjects must not have received any prior systemic therapy for CLL and currently have an indication for treatment as defined by the IWCLL 2008 Guidelines:
* Massive or progressive splenomegaly; OR
* Massive lymph nodes, nodal clusters, or progressive lymphadenopathy; OR
* Grade 2 or 3 fatigue; OR
* Fever ≥ 100.5°F or night sweats for greater than 2 weeks without documented infection; OR
* Presence of weight loss ≥ 10% over the preceding 6 months; OR
* Progressive lymphocytosis with an increase of ≥ 50% over a 2-month period or an anticipated doubling time of less than 6 months; OR
* Evidence of progressive marrow failure as manifested by the development of or worsening of anemia and or thrombocytopenia.
* ECOG performance status \<2 (see Appendix A).
* Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of idelalisib or ofatumumab in participants \<18 years of age, children are excluded from this study.
* Participants must have normal organ and marrow function as defined below:
* creatinine \<2.0 times upper normal limit, total bilirubin \<1.5 times upper normal limit (unless due to disease involvement of liver, hemolysis or a known history of Gilbert's disease)
* ALT \<2.5 times upper normal limit (unless due to disease involvement of liver) alkaline phosphatase \<2.5 times upper normal limit (unless due to disease involvement of the liver or bone marrow)
* Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

* Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study.
* Participants who have had any prior systemic therapy for CLL, or chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) for some other indication prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
* History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to ofatumumab or idelalisib.
* Subjects who have current active hepatic or biliary disease (with exception of participants with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
* Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or currently participating in any other interventional clinical study
* Other past or current malignancy that could interfere with the interpretation of outcome. Subjects who have been free of active malignancy for at least 2 years, or have a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma, or whose malignancy will not interfere with the interpretation of study results, are eligible.
* Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active Hepatitis C.
* History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae
* Known HIV positive. HIV-positive individuals on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with idelalisib. In addition, these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
* Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (NYHA III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities.
* Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the participant.
* Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded.
* If HBV DNA is negative, subject may be included but must undergo HBV DNA PCR testing at least every 2 months from the start of treatment until 12 months post treatment. Prophylactic antiviral therapy may be initiated at the discretion of the investigator.
* Positive serology for hepatitis C (HC) defined as a positive test for HepC Ab, in which case reflexively perform an HC RIBA immunoblot assay or hepatitis C viral load to confirm the result. If the confirmatory test is negative the subject will be eligible.
* Pregnant or lactating women.
* Women of childbearing potential, including women whose last menstrual period was less than one year prior to screening, unable or unwilling to use adequate contraception from study start to 30 days after the last dose of protocol therapy. Adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence.
* Male subjects unable or unwilling to use adequate contraception methods from study start to 30 days after the last dose of protocol therapy.
* Participants using concomitant corticosteroids are allowed as long as the subject is on the equivalent of 20mg/day or less of prednisone and has been on a stable dose for at least two weeks prior to initiating therapy.

Answer: A