Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multicenter, Phase III, Open-Label, Randomized Study in Relapsed/Refractory Patients With Chronic Lymphocytic Leukemia to Evaluate the Benefit of Venetoclax (GDC-0199/ABT-199) Plus Rituximab Compared With Bendamustine Plus Rituximab
Brief Summary: The purpose of this open-label, multicenter, randomized, Phase III study is to evaluate the benefit of venetoclax in combination with rituximab compared with bendamustine in combination with rituximab in participants with relapsed or refractory CLL. Participants will be randomly assigned in 1:1 ratio to receive either venetoclax + rituximab (Arm A) or bendamustine + rituximab (Arm B).


Options:
A: Inclusion Criteria:

1. Patients with untreated CLL or small lymphocytic lymphoma (SLL) with indication to treatment according to NCI Working Group guidelines.Patients that have received single agent rituximab will be allowed to participate in this study.
2. Age 65 or older
3. Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) performance status of 0-2.
4. Adequate renal function indicated by serum creatinine less or equal to 2 and adequate hepatic function indicated as total bilirubin less or equal to upper level of normal and as alanine aminotransferase (ALT) less or equal 2 upper limit of normal (ULN).
5. Able to understand and sign Informed Consent after the investigational nature, study design, risks and benefits have been explained.
6. Able to adhere to the study visit schedule and other protocol requirements.
7. Disease free of prior malignancies for 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast. Patients with malignancies with indolent behavior such as prostate cancer treated with radiation can be enrolled in the study as long as they have a reasonable expectation to have been cured with treatment modality received.
8. Females of childbearing potential (FCBP). A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence
9. Continued from above. from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 4 weeks before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing.
10. Men must agree to use a condom during sexual contact with a female of child bearing potential even if they have had a successful vasectomy.
11. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.
12. All patients must be able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to Acetylsalicylic Acid (ASA) may use warfarin or low molecular weight heparin.

Exclusion Criteria:

1. Known sensitivity to thalidomide or its derivatives.
2. Documented prolymphocytic leukemia (prolymphocytes more than 55% in the blood).
3. Known positivity for HIV or active hepatitis (B or C).
4. A serious medical condition, laboratory abnormality or psychiatric illness that would interfere with the ability of the patient to participate in this program according to the judgement of the Principal Investigator.
5. Active cardiovascular disease as defined by the New York Heart Association Class 3 or 4.
6. History of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
7. Concurrent use of other chemotherapy agents.
8. Pregnant or breast feeding females. Lactating females must agree not to breast feed while taking lenalidomide.
9. No known history of tuberculosis or recent exposure to tuberculosis.
B: Inclusion Criteria:

* Diagnosis of CLL per diagnostic criteria for relapsed or refractory CLL per the international workshop on chronic lymphocytic leukemia (iwCLL) guidelines
* Previously treated with 1-3 lines of therapy (example: completed greater than or equal to \[\>/=\] 2 treatment cycles per therapy), including at least one standard chemotherapy-containing regimen
* Participants previously treated with bendamustine only if their duration of response was \>/= 24 months
* Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to (\</=) 1
* Adequate bone marrow function
* Adequate renal and hepatic function
* Participants must use effective birth control throughout study until at least 30 days after study treatment or 1 year after rituximab treatment, whichever is later; female participants must not be pregnant or breast-feeding
* For participants with the 17p deletion, previously treated with 1-3 lines of therapy, including at least one prior standard chemotherapy-containing regimen or at least one prior alemtuzumab-containing therapy

Inclusion Criteria R/C Substudy:

* Participants randomized to Arm A or Arm B with a confirmed disease progression of CLL per iwCLL criteria
* Participants who have not received new anti-CLL therapy following disease progression in Arm A or Arm B
* Adequate renal and hepatic function per laboratory reference range

Exclusion Criteria:

* Transformation of CLL to aggressive non-Hodgkin lymphoma or central nervous system (CNS) involvement by CLL
* Undergone an allogenic stem cell transplant
* A history of significant renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular or hepatic disease
* Hepatitis B or C or known human immunodeficiency virus (HIV) positive
* Receiving warfarin treatment
* Received an anti-CLL monoclonal antibody within 8 weeks prior to the first dose of study drug
* Received any anti-cancer or investigational therapy within 28 days prior to the first dose of study drug or has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(ies) of any previous therapy
* Received cytochrome P450 3A4 (CYP3A4) inhibitors (such as fluconazole, ketoconazole and clarithromycin) or inducers (such as rifampin, carbamazapine, phenytoin, St. John's Wort) within 7 days prior to the first dose of venetoclax
* History of prior venetoclax treatment
* Participants with another cancer, history of another cancer considered uncured on in complete remission for \<5 years, or currently under treatment for another suspected cancer except non-melanoma skin cancer or carcinoma in situ of the cervix that has been treated or excised and is considered resolved
* Malabsorption syndrome or other condition that precludes enteral route of administration
* Other clinically significant uncontrolled condition(s) including, but not limited to, systemic infection (viral, bacterial or fungal)
* Vaccination with a live vaccine within 28 days prior to randomization
* Consumed grapefruit or grapefruit products, seville oranges (including marmalade containing seville oranges), or star fruit within 3 days prior to the first dose of study treatment
* A cardiovascular disability status of New York Heart Association Class \>/=3. Class 3 is defined as cardiac disease in which participants are comfortable at rest but have marked limitation of physical activity due to fatigue, palpitations, dyspnea, or anginal pain
* Major surgery within 30 days prior to the first dose of study treatment
* A participant who is pregnant or breastfeeding
* Known allergy to both xanthine oxidase inhibitors and rasburicase

Exclusion Criteria R/C Substudy:

* Transformation of CLL to aggressive NHL (e.g., Richter's transformation, prolymphocytic leukemia, or DLBCL) or CNS involvement by CLL
* Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal)
* Development of other malignancy since enrollment into the study, with the exception of curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
* Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
* History of severe (i.e., requiring permanent discontinuation of prior rituximab therapy) prior allergic or anaphylactic reactions to rituximab
* Known HIV positivity
* Positive test results for chronic hepatitis B infection (defined as positive hepatitis B surface antigen \[HbsAg\] serology)
* Positive test results for hepatitis C virus (HCV; HCV antibody serology testing)
* Requires the use of warfarin (due to potential drug interactions that may potentially increase the exposure of warfarin)
* Has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(ies) of any previous therapy
* Received potent CYP3A4 inhibitors (such as fluconazole, ketoconazole, and clarithromycin) within 7 days prior to the first dose of study treatment
* Received potent CYP3A4 inducers (such as rifampin, carbamazepine, phenytoin, St. John's wort) within 7 days prior to the first dose of study treatment
* Consumed grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of study treatment
* A cardiovascular disability status of New York Heart Association Class \>/= 3
* A significant history of renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, or hepatic disease that, in the opinion of the investigator, would adversely affect the participants's participation in this study or interpretation of study outcomes
* Major surgery within 30 days prior to the first dose of study treatment
* A participant who is pregnant or breastfeeding
* Malabsorption syndrome or other condition that precludes enteral route of administration
* Known allergy to both xanthine oxidase inhibitors and rasburicase
* Vaccination with a live vaccine within 28 days prior to randomization
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:

* Subject must have either:

  * (Arm A) relapsed or refractory CLL/SLL and require treatment in the opinion of the Investigator. Subject must have relapsed following or be refractory to standard treatments such as fludarabine based regimens (F, FC, FR, FCR) or alkylator (chlorambucil, bendamustine) based regimens. In addition, there are no other curative options, and the subject has exhausted options that would be considered standard of care, or
  * (Arm B) relapsed or refractory NHL and require treatment in the opinion of the Investigator. Subject must have histologically documented diagnosis of NHL as defined in the World Health Organization classification scheme, except as noted in the exclusion criteria. Subject must have relapsed following or be refractory to standard treatments such as R-CHOP, R-CVP, or fludarabine based regimens. In addition, there are no other curative options, and the subject has exhausted options that would be considered standard of care. Subjects with other lymphoproliferative diseases can be considered in consultation with the Abbott medical monitor.
* Subject has an Eastern Cooperative Oncology Group (ECOG) performance score less than or equal to 1.
* Subject must have adequate bone marrow independent of growth factor support per local laboratory reference range at Screening.
* Subject must have adequate coagulation, renal, and hepatic function, per laboratory reference range at Screening.

Exclusion Criteria:

* CLL subject has undergone an allogeneic or autologous stem cell transplant or NHL subject has undergone an allogeneic stem cell transplant or has been diagnosed with Post-Transplant Lymphoproliferative Disease, Burkitt's lymphoma, Burkitt-like lymphoma, or lymphoblastic lymphoma/leukemia.
* Subject has tested positive for HIV.
* Subject has a cardiovascular disability status of New York Heart Association Class greater or equal to 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity, results in fatigue, palpitations, dyspnea or anginal pain.
* Subject has a significant history of renal, neurologic, psychiatric, pulmonary, endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease that in the opinion of the Investigator would adversely affect his/her participating in this study.
* Subject has received a monoclonal antibody for anti-neoplastic intent within 8 weeks prior to the first dose of study drug.

Answer: B