Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy vs Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients With Chronic Lymphocytic Leukemia (CLL)
Brief Summary: This phase III trial studies ibrutinib and rituximab to see how well they work compared to fludarabine phosphate, cyclophosphamide, and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. It is not yet known whether fludarabine phosphate, cyclophosphamide, and rituximab may work better than ibrutinib and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.


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A: Inclusion Criteria

1. Men and women:

   a. ≥ 65 years of age OR b. \> 18 and \< 65 years of age, provided that they meet at least one of the following criteria: i. Creatinine clearance 30 to 69 mL/min using the Cockcroft-Gault equation ii. A score higher than 6 on the CIRS-G (Appendix L).
2. ECOG performance status of 0, 1, or 2.
3. Diagnosis of CD20+ CLL that meets published diagnostic criteria (Hallek 2008):

   1. Monoclonal B cells (either kappa or lambda light chain restricted) that are clonally co-expressing ≥ 1 B-cell marker (CD19, CD20, or CD23) and CD5.
   2. Prolymphocytes may comprise ≤ 55% of blood lymphocytes.
   3. Presence of ≥ 5 x 109 B lymphocytes/L (5000 μL) in the peripheral blood (at any point since diagnosis)
4. Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment:

   1. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin \< 10 g/dL) and/or thrombocytopenia (platelets \< 100,000/μL).
   2. Massive (i.e., ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
   3. Massive nodes (i.e., ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy.
   4. Progressive lymphocytosis with an increase of \> 50% over a 2-month period or a LDT of \< 6 months. LDT may be obtained by linear regression extrapolation of ALC obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts of \< 30 x 109/L (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 (e.g., infections) should be excluded.
   5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy.
   6. Constitutional symptoms documented in the subject's chart with supportive objective measures, as appropriate, defined as ≥ 1 of the following disease-related symptoms or signs:

   i. Unintentional weight loss ≥ 10% within the previous 6 months before Screening.

   ii. Significant fatigue (i.e., ECOG performance status 2; inability to work or perform usual activities).

   iii. Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before Screening without evidence of infection.

   iv. Night sweats for \> 1 month before Screening without evidence of infection.
5. This criterion was deleted as of Protocol Amendment 3.
6. Meet the following laboratory parameters:

   1. ANC ≥ 750 cells/μL (0.75 x 109/L), or ≥ 500 cells/μL (0.50 x 109/L) in subjects with documented bone marrow involvement, and independent of growth factor support 7 days before assessment.
   2. Platelet count ≥ 50,000 cells/μL (50 x 109/L), or ≥ 30,000 cells/μL (30 x 109/L) in subjects with documented bone marrow involvement, and without transfusion support 7 days before assessment. Subjects with transfusion-dependent thrombocytopenia are excluded.
   3. Serum AST and ALT/SGPT ≤ 3.0 x ULN.
   4. Total bilirubin ≤ 1.5 x ULN.
   5. Estimated creatinine clearance (i.e., eGFR using Cockcroft-Gault) ≥ 30 mL/min
7. Able to receive all outpatient treatment, all laboratory monitoring, and all radiologic evaluations.
8. Women who are sexually active and can bear children must agree to use highly effective forms of contraception while on the study and for 2 days after the last dose of acalabrutinib or 18 months after the last dose of obinutuzumab in combination with chlorambucil, whichever is longer. Highly effective forms of contraception are defined in Section 6.4.4.
9. Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of obinutuzumab or chlorambucil, whichever is later. Highly effective forms of contraception are defined in Section 6.4.4.
10. Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of obinutuzumab or chlorambucil, whichever is later.
11. Must be willing and able to adhere to the study visit schedule, understand and comply with other protocol requirements, and provide written informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations). Note vulnerable subjects, as defined in International Conference on Harmonisation (ICH) GCP, are not allowed on this protocol (e.g., prisoners or institutionalized subjects).

Exclusion Criteria:

1. Any prior systemic treatment for CLL (note: Prior localized radiotherapy is allowed).
2. Known CNS lymphoma or leukemia.
3. Known prolymphocytic leukemia or history of, or currently suspected, Richter's syndrome.
4. Missing or incomplete documentation of FISH results reflecting the presence or absence of 17p del and the percentage of cells with the deletion in subject records before randomization.
5. Uncontrolled AIHA or ITP defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (\> 20 mg daily of prednisone daily or equivalent).
6. Corticosteroid use \> 20 mg within 1 week before first dose of study drug, except as indicated for other medical conditions such as inhaled steroid for asthma, topical steroid use, or as premedication for administration of study drug or contrast. For example, subjects requiring steroids at daily doses \> 20 mg prednisone equivalent systemic exposure daily, or those who are administered steroids for leukemia control or WBC count lowering are excluded.
7. Major surgery within 4 weeks before first dose of study drug.
8. History of prior malignancy except for the following:

   1. Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years before Screening and felt to be at low risk for recurrence by treating physician.
   2. Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer.
   3. Adequately treated cervical carcinoma in situ without current evidence of disease.
9. 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, or QTc \> 480 msec at screening.
10. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
11. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) or ongoing intravenous anti-infective treatment.
12. Known history of infection with HIV. 13. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.

14. Serologic status reflecting active hepatitis B or C infection. Subjects with hepatitis B core antibody positive who are surface antigen negative or who are hepatitis C antibody positive will need to have a negative PCR result before randomization. Those who are hepatitis B surface antigen positive or hepatitis B PCR positive and those who are hepatitis C PCR positive will be excluded.

15. History of stroke or intracranial hemorrhage within 6 months before randomization.

16. Known history of a bleeding diathesis (e.g., hemophilia, von Willebrand disease).

17. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug.

18. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).

19. Breast feeding or pregnant. 20. Current life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the subject's safety or put the study at risk.

21. Concurrent participation in another therapeutic clinical trial. 22. Requires treatment with a strong CYP3A inhibitor/inducer. 23. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
B: 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)
C: Inclusion Criteria:

* Documented previously untreated CLL according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria
* CLL requiring treatment according to IWCLL criteria
* Total Cumulative Illness Rating Scale (CIRS score) greater than (\>) 6
* Adequate marrow function independent of growth factor or transfusion support within 2 weeks of screening as per protocol, unless cytopenia is due to marrow involvement of CLL
* Adequate liver function
* Life expectancy \> 6 months
* Agreement to use highly effective contraceptive methods per protocol

Exclusion Criteria:

* Transformation of CLL to aggressive Non-Hodgkin's lymphoma (Richter's transformation or pro-lymphocytic leukemia)
* Known central nervous system involvement
* Participants with a history of confirmed progressive multifocal leukoencephalopathy (PML)
* An individual organ/ system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the treatment regimen of this trial with the exception of eyes, ears, nose, throat organ system
* Participants with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
* Inadequate renal function
* History of prior malignancy, except for conditions as listed in the protocol if participants have recovered from the acute side effects incurred as a result of previous therapy
* Use of investigational agents or concurrent anti-cancer treatment within the last 4 weeks of registration
* Participants with active bacterial, viral, or fungal infection requiring systemic treatment within the last two months prior to registration
* History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
* Hypersensitivity to chlorambucil, obinutuzumab, or venetoclax or to any of the excipients
* Pregnant women and nursing mothers
* Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive hepatitis B surface antigen \[HBsAg\] serology) or positive test result for hepatitis C (hepatitis C virus \[HCV\] antibody serology testing)
* Participants with known infection with human immunodeficiency virus (HIV) or human T-cell leukemia virus-1 (HTLV-1)
* Requires the use of warfarin, marcumar, or phenprocoumon
* Received agents known to be strong and moderate Cytochrome P450 3A inhibitors or inducers within 7 days prior to the first dose of study drug
D: 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).

Answer: B