Please select the eligibility criteria that correspond to the clinical trial below.
Title: Prospective, Open-label, Multicentre Phase-II Trial to Evaluate Efficacy and Safety of a Sequential Regimen of Bendamustine Followed by Ofatumumab and Ibrutinib Followed by Ibrutinib and Ofatumumab Maintenance in CLL Patients
Brief Summary: A prospective, open-label, multicentre phase-II trial to evaluate the efficacy and safety of a sequential regimen of bendamustine followed by ofatumumab and ibrutinib followed by ibrutinib and ofatumumab maintenance in CLL patients.


Options:
A: Inclusion Criteria:

Disease Related:

1. Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria.
2. Age 65 yrs and older OR if less than 65 years, must have at least one of the following criteria:

   * Cumulative Illness Rating Score (CIRS) \>6
   * Creatinine clearance estimated \<70 mL/min using Cockcroft-Gault equation.
   * Del 17p by fluorescence in situ hybridization (FISH) or TP53 mutation by polymerase chain reaction (PCR) or Next Generation Sequencing
3. Active disease meeting at least 1 of the following IWCLL criteria for requiring treatment:

   * Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and thrombocytopenia
   * Massive, progressive, or symptomatic splenomegaly
   * Massive nodes (at least 10 cm longest diameter), or progressive or symptomatic lymphadenopathy.
   * Progressive lymphocytosis with an increase of more than 50 percent over a 2-month period or a lymphocyte doubling time (LDT) of \<6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In patients with initial blood lymphocyte counts of \<30,000/µL, LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded.
   * Autoimmune hemolytic anemia and/or immune thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy.
   * Autoimmune hemolytic anemia is defined by at least one marker of hemolysis (indirect bilirubin above the upper limit of normal (ULN) not due to liver disease, increased lactate dehydrogenase (above ULN) without alternative etiology, or increased absolute reticulocytosis (above ULN) or bone marrow erythropoiesis in the absence of bleeding AND at least one marker direct or indirect autoimmune mechanism (positive direct antiglobulin for immunoglobulin G \[IgG\] or C3d, cold agglutinins).
   * Immune thrombocytopenia is defined by platelets ≤100,000/µL and increased megakaryocytes on the bone marrow exam.
   * Constitutional symptoms, defined as one or more of the following disease-related symptoms or signs, documented in the patient's record prior to randomization:
   * unintentional weight loss \>10 percent within 6 months prior to screening.
   * significant fatigue (inability to work or perform usual activities).
   * fevers \>100.5°F or 38.0°C for 2 or more weeks prior to screening without evidence of infection.
   * night sweats for more than 1 month prior to screening without evidence of infection.
4. Measurable nodal disease by computed tomography (CT), defined as at least 1 lymph node \>1.5 cm in the longest diameter in a site that has not been previously irradiated. An irradiated lesion may be assessed for measurable disease only if there has been documented progression in that lesion since radiotherapy has ended.

   Laboratory
5. Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to screening and randomization.
6. Adequate hepatic and renal function
7. Men and women ≥ 18 years of age.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

Exclusion Criteria:

1. Any prior treatment of CLL or SLL
2. Evidence of central nervous system (CNS) involvement with primary disease of CLL/SLL
3. History of other malignancies, except:

   * Malignancy treated with curative intent and with no known active disease present for ≥3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician.
4. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura
5. Known or suspected history of Richter's transformation.
6. Concurrent administration of \>20mg/day of prednisone within 7 days of randomization unless indicated for prophylaxis or management of allergic reactions (eg, contrast)
7. Known hypersensitivity to one or more study drugs
8. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
9. Any uncontrolled active systemic infection or an infection requiring systemic treatment that was completed ≤ 7 days before randomization.
10. Known bleeding disorders or hemophilia.
11. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
12. Known history of human immunodeficiency virus (HIV) or active with hepatitis B virus (HBV) or hepatitis C virus (HCV).
13. Major surgery within 4 weeks of randomization.
14. 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.
15. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
16. 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.
17. Concomitant use of warfarin or other vitamin K antagonists.
18. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor.
19. Lactating or pregnant
20. Unwilling or unable to participate in all required study evaluations and procedures.
21. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations).
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:

1. Documented CLL requiring treatment (irrespective if first- or relapse treatment) according to International Working Group on CLL (iwCLL) criteria

   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-BIO trial:
   * chemotherapy within ≥ 28 days
   * antibody treatment within ≥ 14 days
   * kinase inhibitors, Bcl-2-antagonists or immunomodulatory agents within ≥ 3 days
   * corticosteroids may be applied until the start of the BIO-regimen, these have to be reduced to an equivalent of ≤ 20 mg prednisolone during treatment
2. Adequate hematologic function as indicated by a platelet count ≥ 25 x 109/L, a neutrophil count ≥ 1,0 x 109/L and a hemoglobin value ≥ 8.0 g/dL, unless directly attributable to the patient´s CLL (e.g. bone marrow infiltration)
3. Adequate renal function as indicated by a creatinine clearance ≥ 30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24 hrs urine collection
4. Adequate liver function as indicated by a total bilirubin ≤ 2x, aspartate aminotransferase (AST)/ alanin aminotransferase (ALT) ≤ 2.5x the institutional upper limit of normal (ULN) value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome
5. Negative serological testing for hepatitis B, negative testing for hepatitis-C RNA and negative HIV antibody test within 6 weeks prior to registration
6. Age ≥ 18 years
7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2, ECOG 3 is only permitted if related to CLL (e.g. due to anemia or severe constitutional symptoms)
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 (i.e. Richter's transformation, pro-lymphocytic leukemia)
2. Known central nervous system (CNS) involvement
3. Patients with confirmed progressive multifocal leukoencephalopathy (PML)
4. Malignancies other than CLL currently requiring systemic therapy
5. Uncontrolled infection requiring systemic treatment
6. 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 compromise 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)
7. Use of investigational agents which might interfere with the study drug within 3 days prior to Registration
8. Known hypersensitivity to ofatumumab, ibrutinib or any of the excipients Please note: Patients with a known hypersensitivity to bendamustine are allowed to participate but will not receive a debulking with bendamustine
9. Requirement of treatment with strong CYP3A4-inhibitors/-inducers or anticoagulant with phenprocoumon (marcumar), warfarin, or other vitamin k antagonists
10. History of stroke or intracranial hemorrhage within 6 months prior to registration
11. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment and monthly during debulking, induction and maintenance therapy)
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 12 months after end of study treatment.
13. Vaccination with a live vaccine ≤ 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

Answer: D