Please select the eligibility criteria that correspond to the clinical trial below.
Title: An Open Label, Multicenter Study Investigating the Safety and Efficacy of Ofatumumab Therapy Versus Physicians' Choice in Patients With Bulky Fludarabine-Refractory Chronic Lymphocytic Leukaemia (CLL)
Brief Summary: The purpose of this study was to confirm the clinical benefit observed in the pivotal registration study, Hx-CD20-406. The Committee for Medicinal Products for Human Use (CHMP) required that a randomized study be conducted in CLL patients with bulky fludarabine-refractory disease as a specific obligation for grant of conditional approval for ARZERRA™ in the European Union (EU). This study compared ofatumumab with the physicians' choice of therapy.


Options:
A: Inclusion Criteria:

* Adults with documented diagnosis of active CLL requiring treatment
* Bulky lymphadenopathy, defined as at least 1 lymph node \>5 cm
* Must be refractory to fludarabine treatment
* Age 18 yrs or older
* At least 2 prior therapies for CLL
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Signed written informed consent

Exclusion Criteria:

* Prior allogeneic stem cell transplant at any time, or autologous stem cell transplant within 6 months
* Treatment with any unapproved drug substance or experimental therapy within 4 weeks, or currently participating in another interventional clinical study
* CLL transformation, prolymphocytic leukemia, or central nervous system (CNS) involvement of CLL
* Active autoimmune hemolytic anemia (AIHA) requiring treatment except if associated with progressive disease requiring anti-CLL treatment
* Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment
* Human immunodeficiency virus (HIV) positive
* Significant concurrent, uncontrolled medical condition
* Other past or current malignancy (with the exception of basal cell carcinoma of the skin or in situ carcinoma of the cervix or breast) unless the tumor was successfully treated with curative intent at least 2 years prior to trial entry
* Non-protocol corticosteroid usage except a maintenance dose corresponding to less than or equal to 10 mg prednisone
* Abnormal lab values: Creatinine \> 2.0 times upper normal limit (unless normal creatinine clearance), or total bilirubin \> 2.0 times upper normal limit (unless due to liver involvement of CLL or due to Gilbert's syndrome), or alanine transaminase (ALT) \> 2.5 times upper normal limit (unless due to liver involvement of CLL)
* Known or suspected hypersensitivity to ofatumumab
* Lactating or pregnant women or female patients of child-bearing potential (or male patients with such partners) not willing to use adequate contraception
B: Inclusion Criteria:

1. 1.Patients must have a diagnosis of high-risk CLL/SLL and be previously treated with up to 3 lines of prior therapy. High-risk CLL and high-risk SLL is defined by the presence of a 17p deletion or 11q deletion or TP53 mutation. Any CLL and SLL patient who has a short remission duration of less than 3 years after prior first-line chemo-immunotherapy, such as the FCR regimen, also fulfills criteria of high-risk CLL/SLL, regardless of the presence or absence of cytogenetic abnormalities.
2. 2.CLL and SLL patients with 17p deletion or TP53 mutation will not be required to have received any prior therapy, given the poor outcome of CLL/SLL patients to standard frontline chemo-immunotherapy, such patients will be eligible if they are untreated or if they have received up to 3 lines of prior therapy.
3. Patients must have an indication for treatment by 2008 IWCLL Criteria.
4. Patients age \> 18 years at the time of signing informed consent. Understand and voluntarily sign an informed consent. Be able to comply with study procedures and follow-up examinations.
5. Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) performance status of 0-1.
6. Patients of childbearing potential must be willing to practice highly effective birth control (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices \[IUDs\], sexual abstinence, or sterilized partner) during the study and for 30 days after the last dose of study drug. Women of childbearing potential include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as follows: Amenorrhea \>/= 12 consecutive months without another cause and a documented serum follicle stimulating hormone (FSH) level \>35 mIU/mL; a male of childbearing potential is any male that has not been surgically sterilized.
7. Adequate renal and hepatic function as indicated by all of the following: Total bilirubin \</=1.5 x institutional Upper Limit of Normal (ULN) except for patients with bilirubin elevation due to Gilbert's disease who will be allowed to participate; an Alanine (ALT) \</=2.5 x ULN; and an estimated creatinine clearance (CrCl) of \> 30 mL/min, as calculated by the Cockcroft-Gault equation unless disease related.
8. Free of prior malignancies for 3 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast.
9. A Urine Pregnancy Test (within 7 days of Day 1) is required for women with childbearing potential

Exclusion Criteria:

1. Pregnant or breast-feeding females.
2. Treatment including chemotherapy, chemo-immunotherapy , monoclonal antibody therapy, radiotherapy, high-dose corticosteroid therapy (more than 60 mg prednisone or equivalent daily), or immunotherapy within 21 days prior to enrollment or concurrent with this trial.
3. Investigational agent received within 30 days prior to the first dose of study drug or have previously taken PCI-32765. If received any investigational agent prior to this time point, drug-related toxicities must have recovered to Grade 1 or less prior to first dose of study drug.
4. Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
5. Patients with uncontrolled Autoimmune Hemolytic Anemia (AIHA) or autoimmune thrombocytopenia (ITP).
6. Patients with severe hematopoietic insufficiency, as defined by an absolute neutrophil count of less than 500/micro-L and/or a platelet count of less than 30,000/micro-L at time of screening for this protocol.
7. Any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver or other organ system that may place the patient at undue risk to undergo therapy with PCI-32765 and rituximab.
8. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification.
9. Significant screening ECG abnormalities including left bundle branch block, 2nd degree AV block type II, 3rd degree block, bradycardia, and QTc \> 470 msec.
10. Any serious medical condition, laboratory abnormality, or psychiatric illness that places the subject at unacceptable risk if he/she were to participate in the study.
11. History of stroke or cerebral hemorrhage within 6 months.
12. Evidence of bleeding diathesis or coagulopathy.
13. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1, anticipation of need for major surgical procedure during the course of the study.
14. Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to Day 1. Bone marrow aspiration and/or biopsy are allowed.
15. Serious, non-healing wound, ulcer, or bone fracture.
16. Treatment with Coumadin. Patients who recently received Coumadin must be off Coumadin for at least 7 days prior to start of the study.
17. Any chemotherapy (e.g., bendamustine, cyclophosphamide, pentostatin, or fludarabine), immunotherapy (e.g., alemtuzumab, or ofatumumab), bone marrow transplant, experimental therapy, or radiotherapy is prohibited during therapy on this study.
18. Use of medications known to prolong QTc interval or that may be associated with Torsades de Pointes (refer to Appendix F) are prohibited within 7 days of starting study drug and during study-drug treatment.
19. Requires treatment with strong CYP3A4/5 and/or CYP2D6 inhibitors.
C: Inclusion Criteria:

* ECOG performance status of 0-1.
* Diagnosis of CLL or SLL that meets IWCLL 2008 criteria.
* Active disease meeting at least 1 of the IWCLL 2008 criteria for requiring treatment.
* Must have received at least one prior therapy for CLL/SLL.
* Considered not appropriate for treatment or retreatment with purine analog based therapy.
* Measurable nodal disease by CT.
* Patients must be able to receive outpatient treatment and laboratory monitoring at the institution that administers study drug for the entire study.

Exclusion Criteria:

* Known CNS lymphoma or leukemia.
* No documentation of cytogenetic and/or FISH in patient records prior to first dose of study drug.
* Any history of Richter's transformation or prolymphocytic leukemia.
* Uncontrolled Autoimmune Hemolytic Anemia (AIHA) or idiopathic thrombocytopenia purpura (ITP).
* Prior exposure to ofatumumab or to ibrutinib.
* Prior autologous transplant within 6 months prior to first dose of study drug.
* Prior allogeneic stem cell transplant within 6 months or with any evidence of active graft versus host disease or requirement for immunosuppressants within 28 days prior to first dose of study drug.
* History of prior malignancy, with the exception of certain skin cancers and malignancies treated with curative intent and with no evidence of active disease for more than 3 years.
* Serologic status reflecting active hepatitis B or C infection.
* Unable to swallow capsules or disease significantly affecting gastrointestinal function.
* Uncontrolled active systemic fungal, bacterial, viral, or other infection.
* History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug.
* Requires anticoagulation with warfarin.
D: Inclusion Criteria:

* Diagnosis of CLL according to the National Cancer Institute (NCI)/Internal Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria or small lymphocytic lymphoma (SLL) according to the World Health Organization (WHO) criteria; this includes previous documentation of:

  * Biopsy-proven small lymphocytic lymphoma or
  * Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the following:

    * Peripheral blood lymphocyte count of greater than 5 x 10\^9/L
    * Immunophenotype consistent with CLL defined as:

      * The predominant population of lymphocytes share both B-cell antigens (cluster of differentiation \[CD\]19, 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 restriction (typically dim immunoglobulin expression)
  * Negative FISH analysis for t(11;14)(immunoglobulin heavy locus \[IgH\]/cyclin D1 \[CCND1\]) on peripheral blood or tissue biopsy (e.g. marrow aspirate) or negative immunohistochemical stains for cyclin D1 staining on involved tissue biopsy (e.g. marrow aspirate or lymph node biopsy)
* No prior chemotherapy, Bruton's tyrosine kinase (BTK) inhibitor therapy, or monoclonal anti-body therapy for treatment of CLL or SLL
* Has met at least one of the following indications for treatment:

  * Evidence of progressive marrow failure as manifested by the development of worsening anemia (hemoglobin \[Hg\] \< 11 g/dl) and/or thrombocytopenia (platelets \< 100 x 10\^9/L)
  * Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly
  * One or more of the following disease-related symptoms:

    * Weight loss \>= 10% within the previous 6 months
    * Grade 2 or 3 fatigue attributed to CLL
    * Fevers \> 100.5 Fahrenheit (F) for 2 weeks without evidence of infection
    * Clinically significant night sweats without evidence of infection
  * Progressive lymphocytosis (not due to the effects of corticosteroids) with an increase of \> 50% over a two-month period or an anticipated doubling time of less than six months
* ECOG performance status between 0-2
* Life expectancy of \>= 12 months
* Ability to tolerate FCR based therapy
* No deletion of 17p13 on cytogenetic analysis by FISH
* Glomerular filtration rate (GFR) \> 40 mL/minute as calculated by the Cockcroft-Gault formula (obtained =\< 14 days prior to registration)
* Total bilirubin =\< 2.5 x upper limit of normal (ULN) (obtained =\< 14 days prior to registration) unless due to Gilbert's disease; for those with a total bilirubin \> 2.5 x ULN, a direct bilirubin should be performed and must be \< 1.5 mg/dL for Gilbert's to be diagnosed

  * If value is higher due to hepatic involvement by CLL, patient is eligible
* Serum glutamic oxaloacetic transaminase (SGOT) (aspartate transaminase \[AST\])/serum glutamate-pyruvate transaminase (SGPT) (alanine transaminase \[ALT\]) =\< 3.0 x the institutional ULN (obtained =\< 14 days prior to registration)

  * If value is higher due to hepatic involvement by CLL, patient is eligible
* Prothrombin time (PT)/international normalized ratio (INR) \< 1.5 ULN and partial thromboplastin time (PTT) (activated partial thromboplastin time \[aPTT\]) \< 1.5 X ULN (obtained =\< 14 days prior to registration)

  * If value is higher due to hepatic involvement by CLL, patient is eligible
* No 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
* No 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 condition (e.g. chronic adrenal insufficiency) is permitted
* No previous use of corticosteroids for autoimmune complications that have developed since the initial diagnosis of CLL; prior use of corticosteroids for reasons other than treatment of autoimmune complications is allowed
* No other active primary malignancy (other than non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting expected survival to =\< 2 years; NOTE: if there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy for their cancer)
* Able to adhere to the study visit schedule and other protocol requirements
* No major surgery within the last 4 weeks (28 days) of first dose of study drug or minor surgery within 3 days of first dose of study drug
* No radiation therapy =\< 4 weeks prior to registration
* Patients with human immunodeficiency virus (HIV) infection may be eligible provided they meet the following criteria:

  * CD4-positive cell count \>= lower limit of institutional normal
  * HIV viral load \< 10,000 copies HIV ribonucleic acid (RNA)/mL (if not on anti-HIV therapy) OR \< 50 copies HIV RNA/mL (if on anti-HIV therapy)
  * No evidence of hepatitis B or C infection
  * No evidence of resistant strains of HIV
  * No history of acquired immune deficiency syndrome (AIDS)-defining condition
* Patients must not have any of the following conditions:

  * Congestive heart failure or New York Heart Association Functional Classification III or IV congestive heart failure
  * History of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to registration
  * Recent infections requiring systemic treatment; need to have completed anti-biotic therapy \> 14 days before the first dose of study drug
  * Cerebral vascular accident or intracranial bleed within the last 6 months
  * Infection with known chronic, active hepatitis C
  * Serologic status reflecting active hepatitis B or C infection; patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment (PCR positive patients will be excluded)
* Patients are not eligible if they require treatment with a strong cytochrome P450 (CYP) family 3, subfamily A (3A) inhibitor
* Patients may not be on any other investigational agents
* Patients may not have received warfarin or another vitamin K antagonist in the preceding 30 days
* Women must not be pregnant or breast-feeding since this study involves an investigational agent whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown; female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to registration to rule out pregnancy; female patients who are of non-reproductive potential are those who are post-menopausal by history (i.e. no menses for \>= 1 year); OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy)
* Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for 90 days after the last dose of study drug
* Patient must be able to swallow capsules and not have the following conditions:

  * Disease significantly affecting gastrointestinal function
  * Resection of the stomach or small bowel
  * Symptomatic inflammatory bowel disease
  * Ulcerative colitis
  * Partial or complete bowel obstruction
* Patient must not be on any other systemic immunosuppressant therapy other than corticosteroids within 28 days of the first dose of study drug
* Patient must not be vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
* Patient must not have any known bleeding disorders (e.g., von Willebrand's disease) or hemophilia
* Patient must not have currently active, clinically significant hepatic impairment (\>= moderate hepatic impairment according to the NCI/Child Pugh)

Answer: A