Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Multicenter, Open-Label, 3 Arm Phase 3 Study of Obinutuzumab in Combination With Chlorambucil, Acalabrutinib (ACP-196) in Combination With Obinutuzumab, and Acalabrutinib Monotherapy in Subjects With Previously Untreated CLL
Brief Summary: This Primary objective is evaluating the efficacy of obinutuzumab in combination with chlorambucil (Arm A) compared with acalabrutinib in combination with obinutuzumab (Arm B) for the treatment of previously untreated chronic lymphocytic leukemia (CLL). Secondary objectives: 1) To evaluate the efficacy of obinutuzumab in combination with chlorambucil (Arm A) versus acalabrutinib monotherapy (Arm C) based on IRC assessment of PFS per IWCLL 2008 criteria.

2)To compare obinutuzumab plus chlorambucil (Arm A) versus acalabrutinib plus obinutuzumab (Arm B) and obinutuzumab plus chlorambucil (Arm A) versus acalabrutinib monotherapy (Arm C) in terms of: IRC-assessed objective response rate (ORR); Tine to next treatment (TTNT); Overall Survival (OS)


Options:
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:

* 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
C: DISEASE CHARACTERISTICS:

* Diagnosed B-cell chronic lymphocytic leukemia (CLL) defined by the National Cancer Institute (NCI) Working Group criteria
* Meets 1 of the following criteria:

  * Binet stage C disease
  * Binet stage B disease AND ≥ 1 of the following signs or symptoms\*:

    * B symptoms (night sweats, weight loss ≥ 10% within the previous 6 months, fevers \> 38°C or 100.4°F for ≥ 2 weeks without evidence of infection), or constitutional symptoms (fatigue)
    * Continuous progression (doubling of peripheral lymphocyte count within the past 6 months and absolute lymphocyte count \> 50 G/I)
    * Evidence of progressive marrow failure as manifested by the development/worsening of anemia and/or thrombocytopenia
    * Massive, progressive or painful splenomegaly or hypersplenism
    * Massive lymph nodes or lymph node clusters (\> 10 cm in longest diameter), danger of organ complications through large lymphoma (e.g., vascular compression or tracheal narrowing), or progressive lymphadenopathy
    * Occurrence of symptomatic hyperviscosity problems at leukocyte counts \> 200 G/I (symptomatic leukostasis) NOTE: \* Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease is not sufficient for eligibility
* No Binet stage A disease
* No transformation to an aggressive B-cell malignancy (e.g., diffuse large cell lymphoma, Richter's syndrome, or prolymphocytic leukemia)

PATIENT CHARACTERISTICS:

* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Cumulative Illness Rating Scale (CIRS) score \> 6
* Life expectancy \> 6 months
* Bilirubin ≤ 2 times upper limit of normal (ULN)
* Alkaline phosphatase and transaminases ≤ 2 times ULN
* Creatinine clearance ≥ 70 mL/min
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception during and for 2 months after study treatment
* No known hypersensitivity with anaphylactic reaction to humanized monoclonal antibodies or any of the study drugs
* No cerebral dysfunction that precludes chemotherapy
* No active bacterial, viral, or fungal infection
* No clinically significant autoimmune cytopenia or Coombs-positive hemolytic anemia
* No other active malignancy requiring concurrent treatment except basal cell carcinoma or tumors treated curatively by surgery
* No medical or psychological condition that would preclude study therapy
* No concurrent disease that requires prolonged (\> 1 month) therapy involving glucocorticoids

PRIOR CONCURRENT THERAPY:

* No previous treatment of CLL by chemotherapy, radiotherapy, or immunotherapy
D: Inclusion Criteria:

1. Males or females of 65 years of age or greater. Patients between the ages of 65 and 70 years of age must have 1 or more of the following comorbidities that may preclude the use of frontline chemo-immunotherapy with fludarabine, cyclophosphamide, or rituximab:

   * creatinine clearance \< 70 mL/min using the Cockcroft-Gault equation
   * platelet count \< 100,000/μL or hemoglobin \< 10 g/dL
   * clinically apparent autoimmune cytopenia (autoimmune hemolytic anemia or immune thrombocytopenia)
   * ECOG performance score = 1 or 2
2. Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria (Hallek 2008)
3. Active disease meeting at least 1 of the following IWCLL criteria (Hallek 2008) for requiring treatment:

   * Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia Massive, progressive, or symptomatic splenomegaly
   * Massive nodes or progressive or symptomatic lymphadenopathy
   * Progressive lymphocytosis
   * Autoimmune hemolytic anemia and/or immune thrombocytopenia that is poorly responsive to corticosteroids or standard therapy
   * Constitutional symptoms
4. Measurable nodal disease by computed tomography (CT)
5. ECOG performance status of 0-2
6. Life expectancy \> 4 months from randomization
7. Adequate hematologic function, defined as absolute neutrophil count (ANC) ≥ 1,000/μL (independent of growth factor support for at least 7 days prior to screening) and platelet count ≥ 50,000/μL (independent of transfusion and growth factor support for at least 7 days prior to screening)
8. Adequate hepatic function, defined as serum aspartate transaminase (AST) and alanine transaminase (ALT) \< 2.5 x upper limit of normal (ULN), and total bilirubin ≤ 1.5 x ULN
9. Adequate renal function, defined as estimated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation
10. Willingness to receive all outpatient treatment, all laboratory monitoring, and all radiological evaluations at the institution that administers study drug for the entire study
11. Willingness of male patients, if sexually active with a female of childbearing potential, to use an effective barrier method of contraception during the study and for 3 months following the last dose of study drug
12. Ability to provide written informed consent and to understand and comply with the requirements of the study

Exclusion Criteria:

1. Known involvement of the central nervous system by lymphoma or leukemia
2. History or current evidence of Richter's transformation or prolymphocytic leukemia
3. Documentation of deletion of the short arm of chromosome 17: del(17p13.1) in more than 20% of cells examined on any pretreatment fluorescence in situ hybridization (FISH) or cytogenetic evaluation
4. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura
5. Any previous treatment (chemotherapy, radiotherapy, and/or monoclonal antibodies) intended specifically to treat CLL/SLL
6. Received any immunotherapy, vaccine, or investigational drug within 4 weeks prior to randomization
7. Corticosteroid use within 1 week prior to first dose of study drug, with the exception of inhaled, topical, or other local administrations. Patients requiring systemic steroids at daily doses \> 20 mg prednisone (or corticosteroid equivalent, see Appendix N), or those who are administered steroids for leukemia control or white blood cell (WBC)-count-lowering are excluded.
8. Major surgery within 4 weeks prior to randomization
9. History of prior malignancy, with the exception of the following:

   * malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to screening and felt to be at low risk for recurrence by treating physician
   * adequately treated nonmelanomatous skin cancer or lentigo maligna melanoma without current evidence of disease
   * adequately treated cervical carcinoma in situ without current evidence of disease
10. Currently active, clinically significant cardiovascular disease or a history of myocardial infarction within 6 months prior to randomization
11. Inability to swallow capsules or tablets, or disease significantly affecting gastrointestinal function
12. Uncontrolled active systemic fungal, bacterial, viral, or other infection or requirement for intravenous (IV) antibiotics
13. Known history of infection with human immunodeficiency virus (HIV)
14. Serologic status reflecting active hepatitis B or C infection
15. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
16. Current life-threatening illness, medical condition, or organ-system dysfunction that could compromise patient safety or put the study at risk
17. Requirement for anticoagulation with warfarin
18. Requirement for treatment with a strong CYP3A4/5 and/or CYP2D6 inhibitor

Answer: A