Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Prospective, Open-label, Multicenter Phase-II Trial to Evaluate the Efficacy and Safety of a Sequential Regimen of Bendamustine Followed by GA101 and Ibrutinib (BIG) Followed by GA101 and Ibrutinib Maintenance in CLL Patients (CLL2-BIG Protocol)
Brief Summary: A prospective, open-label, multicenter Phase-II trial to evaluate the efficacy and safety of a sequential regimen of Bendamustine followed by GA101 and Ibrutinib followed by Ibrutinib and GA101 maintenance in CLL patients.


Options:
A: 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
B: Inclusion Criteria:

* Adult patients, \>=18 years of age;
* Phase 1 only: CD20+ malignant disease (B-cell lymphoma or B-CLL);
* Phase 2 only: relapsed or refractory indolent NHL, relapsed or refractory aggressive NHL or relapsed or refractory B-CLL
* Have a clinical indication for treatment as determined by the investigator
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
* Life expectancy \>12 weeks

Exclusion Criteria:

* Prior use of any investigational antibody therapy or other agent within 6 months of study start;
* Prior use of any anti-cancer vaccine;
* Prior use of standard anti-lymphoma/leukemia therapy or radiation therapy within 4 weeks of enrollment;
* Prior use of MabThera (rituximab) within 8 weeks of study entry;
* Prior administration of radioimmunotherapy 3 months prior to study entry;
* Central nervous system (CNS) lymphoma.
C: 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.
D: Inclusion Criteria:

1. Must understand and voluntarily sign an informed consent form.
2. Must be greater than or equal to 18 years at the time of signing the informed consent form.
3. Must be able to adhere to the study visit schedule and other protocol requirements.
4. Must have a documented diagnosis of B-cell CLL (IWCLL guidelines for the diagnosis and treatment of chronic lymphocytic leukemia \[Hallek, 2008\]).
5. Must have been treated with one of the following in first and/or second line:

   * a purine analog-containing regimen
   * a bendamustine-containing regimen
   * an anti-CD20 antibody-containing regimen
   * a chlorambucil-containing regimen
   * an alemtuzumab-containing regimen (for those subjects with a 17p deletion)
6. Must have achieved a minimum response of partial response (PR, nPR, CRi, CR, and MRD-negative CR) (IWCLL guidelines for the diagnosis and treatment of chronic lymphocytic leukemia \[Hallek, 2008\]) following completion of second-line induction therapy prior to randomization (documentation of response status must be available). Second-line induction therapy must be documented to have been of sufficient duration.
7. Must have completed last cycle of second-line induction no less than 8 weeks (56 days) and no greater than 20 weeks (140 days) prior to randomization.
8. Must have an ECOG performance status score of less than or equal to 2.
9. Females of childbearing potential (FCBP)† must:

   * Have two negative medically supervised pregnancy tests prior to starting of study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices complete and continued sexual abstinence.
   * Either commit to continued abstinence from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting study drug, during the study therapy (including dose interruptions), and for 28 days after discontinuation of study therapy.
10. Male subjects must:

    * Commit to continued abstinence from heterosexual contact or agree to use a condom during sexual contact with a FCBP, even if they have had a vasectomy, throughout study drug therapy, during any dose interruption and after cessation of study therapy.
    * Agree to not donate semen during study drug therapy and for a period after end of study drug therapy.
11. All subjects must:

    * Have an understanding that the study drug could have a potential teratogenic risk.
    * Agree to abstain from donating blood while taking study drug therapy and following discontinuation of study drug therapy. • Agree not to share study medication with another person.
    * All subjects must be counseled about pregnancy precautions and risks of fetal exposure.

Exclusion Criteria:

1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
2. Active infections requiring systemic antibiotics.
3. Systemic infection that has not resolved \> 2 months prior to initiating lenalidomide treatment in spite of adequate anti-infective therapy
4. Autologous or allogeneic bone marrow transplant as second-line therapy.
5. Pregnant or lactating females.
6. Systemic treatment for B-cell CLL in the interval between completing the last cycle of second-line induction therapy and randomization.
7. Participation in any clinical study or having taken any investigational therapy for a disease other than CLL within 28 days prior to initiating maintenance therapy.
8. Known presence of alcohol and/or drug abuse.
9. Central nervous system involvement as documented by spinal fluid cytology or imaging. Subjects who have signs or symptoms suggestive of leukemic meningitis or a history of leukemic meningitis must have a lumbar puncture procedure performed within two weeks prior to randomization.
10. Prior history of malignancies, other than CLL, unless the subject has been free of the disease for ≥5 years. Exceptions include the following:

    * Basal cell carcinoma of the skin
    * Squamous cell carcinoma of the skin
    * Carcinoma in situ of the cervix
    * Carcinoma in situ of the breast
    * Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)
11. History of renal failure requiring dialysis.
12. Known Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV), and/or active Hepatitis C Virus (HCV) infection.
13. Prior therapy with lenalidomide.
14. Evidence of TLS per the Cairo-Bishop definition of laboratory TLS (subjects may be enrolled upon correction of electrolyte abnormalities).
15. Any of the following laboratory abnormalities:

    * Calculated (method of Cockroft-Gault) creatinine clearance \<60 mL/min.
    * Absolute neutrophil count (ANC) \<1,000/μL (1.0 X 109/L)
    * Platelet count \<50,000/μL (50 X 109/L)
    * Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) \> 3.0 x upper limit of normal (ULN)
    * Serum total bilirubin \>2.0 mg/dL (with the exception of Gilbert's Syndrome)
16. Grade 4 rash due to prior thalidomide treatment
17. Uncontrolled hyperthyroidism or hypothyroidism
18. Venous thromboembolism within one year
19. Greater than or equal to Grade-2 neuropathy
20. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia
21. Disease transformation (active) (ie, Richter's Syndrome, prolymphocytic leukemia)
22. Known allergy to allopurinol for subjects assessed with PR following their second-line induction therapy.
23. Prisoners.
24. More than 2 prior lines of CLL therapy.

Answer: A