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A Phase 1/2, Open-label, Dose Finding Study to Evaluate CC-122 in Combination With Ibrutinib and Obinutuzumab in Subjects With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (ENHANCE)

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ClinicalTrials.gov Identifier: NCT02406742
Recruitment Status : Active, not recruiting
First Posted : April 2, 2015
Last Update Posted : October 2, 2018
Sponsor:
Information provided by (Responsible Party):
Celgene

Brief Summary:

Safety, pharmacokinetics, and preliminary efficacy of CC-122 alone and in combination with ibrutinib and obinuzutumab.

CC-122 has multiple activities, including immune modulation of several immune cell subsets and antiproliferative activity in CLL. CC-122 has also been shown to have a tolerable safety profile with some preliminary signs of efficacy with early human experience.


Condition or disease Intervention/treatment Phase
Leukemia, Lymphocytic, Chronic, B-Cell Drug: CC-122 Drug: Ibrutinib Drug: Obinutuzumab Phase 1 Phase 2

Detailed Description:
The primary objectives of this Phase 1/2 Study are to determine the safety of single agent CC-122 and the safety, tolerability, and RP2D of CC-122 when administered in combination with ibrutinib and in combination with obinutuzumab to subjects with CLL/SLL. The secondary objectives are to evaluate the PK profiles of subjects administered CC-122 in combination with ibrutinib and in combination with obinutuzumab, to determine ibrutinib concentrations when given alone and in combination with CC-122 and to evaluate the preliminary efficacy of CC-122 at selected dose levels/regimens.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 47 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1/2 Study to Determine the Safety, Pharmacokinetics, and Efficacy of Single Agent CC-122 and the Combinations CC-122 AND Ibrutinib and CC-122 and Obinutuzumab in Subjects With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Actual Study Start Date : July 27, 2015
Estimated Primary Completion Date : July 28, 2020
Estimated Study Completion Date : July 28, 2020


Arm Intervention/treatment
Experimental: CC-122 Single Agent
An intrasubject dose escalation design was selected to determine the safety of single agent CC-122 (Arm A) in order to reach an optimal, clinically active dose and to mitigate the risk of early tumor flare reactions, based on earlier experience with lenalidomide monotherapy in CLL.
Drug: CC-122
CC-122 will be administered daily starting at Cycle 1 Day 1 in 28-day cycles until disease progression, unacceptable toxicity, or discontinuation for any other reason.

Experimental: CC-122 in combination with ibrutinib
Ascending fixed dose cohorts evaluated in a 3 + 3 dose-finding design will be used to determine the safety and tolerability of the combination of CC-122 and ibrutinib to determine the NTD, MTD, and Recommended Phase 2 Dose (RP2D). An intrasubject dose escalation cohort may also be evaluated at the discretion of the Safety Review Committee. The RP2D of the combination may be evaluated in ibrutinib-naïve and high-risk CLL patients in the dose expansion phase to continue to evalute safety and efficacy.
Drug: CC-122
CC-122 will be administered daily starting at Cycle 2 Day 1 in 28-day cycles until disease progression, unacceptable toxicity, or discontinuation for any other reason.

Drug: Ibrutinib
Experimental: CC-122 in combination with obinutuzumab
Ascending fixed dose cohorts evaluated in a 3 + 3 dose-finding design will be used to determine the safety and tolerability of the combination of CC-122 and obinutuzumab to determine the , MTD, and Recommended Phase 2 Dose (RP2D). An intrasubject dose escalation cohort may also be evaluated at the discretion of the Safety Review Committee.. The RP2D of the combination may be evaluated in CLL patients who failed a B-cell receptor pathway inhibitor or venetoclax in the dose expansion phase to continue to evalute safety and efficacy.
Drug: CC-122
CC-122 will be administered daily starting at Cycle 1 Day 9 in 28-day cycles until disease progression, unacceptable toxicity, or discontinuation for any other reason.

Drug: Obinutuzumab
Obinutuzumab will be administered as an intravenous (IV) infusion at a dose of 100 mg on Cycle 1 Day 1 and 900 mg on Cycle 1 Day 2 and 1000 mg on Cycle 1 Days 8 and 15. The dose of obinutuzumab on Days 1 and 2 of Cycle 1 may be adjusted per institutional practice as long as the combined dose equals 1000 mg. Obinutuzumab will be administered at a dose of 1000 mg on Day 1 of Cycles 2 through 6.




Primary Outcome Measures :
  1. Adverse Events (AEs) [ Time Frame: Approximately 5 years ]
    Number of participants with adverse event

  2. Dose-Limiting Toxicity (DLT) [ Time Frame: Approximately 2 years ]
    Number of participants with a DLT

  3. Not Tolerated Dose (NTD) [ Time Frame: Approximately 2 years ]
    A dose level will be considered NTD when ≥ 2 out of 6 DLT evaluable subjects in a fixed-dose cohort experience an IP-related DLT.

  4. Maximum Tolerated Dose (MTD) [ Time Frame: Approximately 2 years ]
    Last dose level below the NTD with ≤ 1 out of 6 DLT evaluable subjects experiencing DLT during the DLT evaluation period.


Secondary Outcome Measures :
  1. Overall Response (OR) [ Time Frame: Approximately 5 years ]
    Is the complete response (CR), complete response with incomplete marrow recovery (CRi), nodular partial response (nPR), partial response (PR), partial response with lymphocytosis (PRL)

  2. CC-122 pharmacokinetic parameters/plasma concentrations when administered alone or in combination with ibrutinib or obinutuzumab [ Time Frame: Approximatly 5 years ]
    Pharmacokinetics of CC122 in plasma

  3. Ibrutinib plasma concentrations when given alone and administered in combination with CC-122 [ Time Frame: Approximatly 5 years ]
    Is the pharmacokinetics of ibrutinib in plasma

  4. Minimal Residual Disease (MRD) [ Time Frame: Approximatly 5 years ]
    Is the measure of residual disease by flow cytometry in blood and bone marrow with a sensitivity of at least 1 out of 10,000 cells.

  5. Duration of response (DoR) [ Time Frame: Approxomatly 5 years ]
    Duration of response is defined as the time from first PRL, nPR, PR, CRi, or CR to PD.

  6. Progression-free survival (PFS) [ Time Frame: Approxomatly 5 years ]
    Is the measure of disease progression per IWCLL criteria

  7. Pharmacokinetics ‐ Cmax - CC-122 [ Time Frame: Approxomatly 5 years ]
    Maximum observed concentration in plasma

  8. Pharmacokinetics - AUC - CC-122 [ Time Frame: Approximatly 5 years ]
    Area under the plasma concentration‐time curve

  9. Pharmacokinetics ‐ T1/2 - CC-122 [ Time Frame: Approximatly 5 years ]
    Terminal half‐life (T1/2)

  10. Progression-f Pharmacokinetics ‐ Vz/f - CC-122 [ Time Frame: Approximatly 5 years ]
    Apparent volume of distribution

  11. Pharmacokinetics - CL/F - CC-122 [ Time Frame: Approximatly 5 years ]
    Apparent total body clearance

  12. Pharmacokinetics ‐ Cmax - Ibrutinib [ Time Frame: Approximatly 5 years ]
    Maximum observed concentration in plasma

  13. Pharmacokinetics - AUC - Ibrutinib [ Time Frame: Approximatly 5 years ]
    Area under the plasma concentration‐time curve

  14. Pharmacokinetics ‐ T1/2 - Ibrutinib [ Time Frame: Approximatly 5 years ]
    Terminal half‐life (T1/2)

  15. Progression-f Pharmacokinetics ‐ Vz/f - Ibrutinib [ Time Frame: Approximatly 5 years ]
    Apparent volume of distribution

  16. Pharmacokinetics - CL/F - Ibrutinib [ Time Frame: Approximatly 5 years ]
    Apparent total body clearance

  17. Plasma concentration for CC-122 [ Time Frame: Approximatly 5 years ]
    Is the measure of concentration of CC122 in plasma

  18. Plasma concentration for Ibrutinib [ Time Frame: Approximatly 5 years ]
    Is the measure of plasma concentration for ibrutinib



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 79 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Subjects ≥ 18 years age and ≤ 80 years of age at the time of signing the informed consent form.
  2. Understand and voluntarily sign an informed consent form prior to any study related assessments/procedures being conducted.
  3. Able to adhere to the study visit schedule and other protocol requirements.
  4. Must have a documented diagnosis of CLL/ SLL requiring treatment (per IWCLL guidelines). In addition:

    a. Presence of at least one clinically measurable lesion: i. nodal lesion that measures ≥ 1.5 cm in longest dimension (LD) and ≥ 1.0 cm in longest perpendicular dimension (LPD), or ii. spleen that measures ≥ 14 cm in longest vertical dimension (LVD) with a minimum of 2 cm enlargement, or iii. liver that measures ≥ 20 cm in LVD with a minimum of 2 cm enlargement, or iv. peripheral blood B lymphocyte count > 5000/uL.

  5. Must meet the criteria for relapsed and/or refractory disease according to the IWCLL guidelines (Hallek, 2008) to ≥ 1 prior treatment (with the exception of Arm B) and have evidence of disease progression requiring treatment at the time of study entry as follows:

    a. For Arms A and C, subjects must have received either prior chemoimmunotherapy or therapy with an approved BTK inhibitor with the following exceptions: i. Chemoimmunotherapy is not required if subjects have specific comorbidities that preclude the use of standard chemoimmunotherapy meeting at least 1 of the following criteria;

1. CIRS ≥ 6; 2. Creatinine Clearance < 70 mL/min; 3. Subject is not a candidate for a chemoimmunotherapy in the opinion of investigator. ii. Treatment with an approved BTK inhibitor is not required if subject has contraindications or is not a candidate for such a therapy in the opinion of the investigator. b. For Arm B, subjects with treatment-naïve or R/R CLL must meet the following criteria: i. Dose Escalation Phase: Subjects must not have received prior treatment with ibrutinib (or any other approved BTK inhibitors) and must have either R/R CLL or treatment naïve (ie, first-line) CLL if the subject:

  1. has 17p- and/or TP53 mutation; or
  2. is unfit for standard chemoimmunotherapy meeting at least 1 of the following co-morbidity criteria: a. CIRS ≥ 6; b. Creatinine Clearance < 70 mL/min; c. Subject is not a candidate for a chemoimmunotherapy in the opinion of the investigator. The reason for not being a candidate must be documented in CRF. ii. Dose Expansion Phase: Subjects must not have received prior treatment with ibrutinib (or any other approved BTK inhibitors) and must have high risk CLL. High risk is defined as: 1) 17p- and/or TP53 mutation positive in treatment naïve CLL; or 2) 17p- and/or TP53 mutation positive, and/or complex karyotype, and/or progression < 24 months after completion of 1st line chemoimmunotherapy in R/R CLL c. Subjects with R/R SLL or CLL with bulky disease (at least one lymph node measuring > 5.0 cm in diameter) are considered at higher risk for developing a TFR and may only be enrolled upon discussion with the sponsor's medical monitor and agreement to close medical management.

6. Subjects must have the following lab values:

  1. Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 or ≥ 1000 cells/mm3 if secondary to bone marrow involvement by disease.
  2. Platelet count ≥ 100,000 cells/mm3 (100 x 109/L) or ≥ 50,000 cells/mm3 (50 x 109/L) if secondary to bone marrow involvement by disease.
  3. Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) < 3.0 x upper limit of normal (ULN) unless due to disease.
  4. Serum bilirubin < 1.5 x ULN unless due to Gilbert's syndrome.

    o Serum bilirubin ≤ 1.0 x ULN unless due to Gilbert's syndrome, Treatment Arm B only (CC-122 in combination with ibrutinib)

  5. Calculated creatinine clearance of ≥ 60 ml/min.
  6. No evidence of TLS per the Cairo-Bishop definition of laboratory TLS (subjects may be enrolled upon correction of electrolyte abnormalities).

    7. ECOG PS (Eastern Cooperative Group Performance Status) of 0 or 1. 8. Ability to swallow oral capsules without difficulty. 9. Pregnancy Prevention Risk Management Plan:

  1. Females of childbearing potential (FCBP) must undergo pregnancy testing based on the frequency outlined in the Pregnancy Prevention Risk Management Plan (PPRMP) and pregnancy results must be negative.
  2. Unless practicing complete abstinence from heterosexual intercourse, sexually active FCBP must agree to use adequate contraceptive methods as specified in the PPRMP.

    *For Arm C, subjects must agree to use adequate contraceptive methods for 18 months (please refer to the obinutuzumab IB, PI, and SmPC).

    - Complete abstinence is only acceptable in cases where this is the preferred and usual lifestyle of the subject.

    - Periodic abstinence (calendar ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable.

  3. Males (including those who have had a vasectomy) must practice complete abstinence or use barrier contraception (condoms) when engaging in sexual activity with FCBP as specified in the PPRMP.
  4. Males must agree not to donate semen or sperm for the duration of the study and for 3 months after the last dose of CC-122.
  5. All subjects must:

    - Understand that the (investigational Product) IP could have a potential teratogenic risk.

    - Agree to abstain from donating blood while taking IP and following discontinuation of IP.

    • Agree not to share IP with another person.
  6. Other than the subject, FCBP and males should not handle the IP or touch the capsules, unless gloves are worn.
  7. Be counseled about pregnancy precautions and risks of fetal exposure.

ARM B ONLY:

10. Enrollment into Arm B will be permitted if ibrutinib is considered the standard of care in the clinical practice.

EXPANSION COHORT 2 OF ARM C:

11. Subjects in Cohort 2 of Arm C must meet the following criteria:

  1. Subject must have received at least one BCR PI (ibrutinib, idelalisib, or other approved BTK or PI3K inhibitor) and/or venetoclax;
  2. Subject must be either resistant to or intolerant of (ie., treatment failures) the last BCR PI and/or venetoclax. Resistant is defined as relapsed or refractory per

IWCLL2008:

i. Relapse is defined as a patient who has previously achieved a CR or PR, but after a period of 6 or more months, demonstrates evidence of disease progression. ii. Refractory is defined as failing to achieve a CR or PR, or disease progression within 6 months after initiation of treatment with an approved BTK or PI3K inhibitor (eg, ibrutinib, idelalisib) or venetoclax. iii. Intolerance is defined as the inability to continue treatment with a BCR PI or venetoclax due to toxicities or due to development of a contraindication that makes the subject ineligible to receive further treatment with a BCR PI or venetoclax.

Exclusion Criteria:

  1. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
  2. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
  3. Any condition that confounds the ability to interpret data from the study.
  4. Prior autologous or allogeneic stem cell transplant (SCT)/bone marrow transplant within 12 months of signing the ICD. Subjects who received allogeneic SCT ≥ 12 months before signing the ICD may be eligible provided there is no ongoing graft-versus-host disease and no ongoing immune suppression therapy.
  5. Uncontrolled intercurrent illness including, but not limited to:

    1. Ongoing or active infection requiring parenteral antibiotics.
    2. Uncontrolled diabetes mellitus.

    i. The glycemic targets for subjects with diabetes should take into consideration age, comorbidities, life expectancy, and functional status of the subjects and follow established guidelines (eg, International Diabetes Federation, the European Diabetes Working Party guidelines, and the American Diabetes Association). For younger (< 70 years old) or subjects with life expectancy ≥ 10 years, the target glycosylated hemoglobin, type A1C (HbA1c) should be < 7.0%. The target HbA1c for older (≥ 70 years old) subjects or subjects with life expectancy < 10 years should be < 8.0%. Consultation with an endocrinologist is recommended when deciding if diabetes is optimally controlled.

    c. Chronic symptomatic congestive heart failure (Class III or IV of the New York Heart Association Classification for Heart Disease). d. Active central nervous system involvement as documented by spinal fluid cytology or imaging. e. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia. f. Other concurrent severe and/or uncontrolled concomitant medical conditions that could cause unacceptable safety risks or compromise compliance with protocol.

  6. History of second malignancies with life expectancy of < 2 years or requirement of therapy that would confound study results. This does not include the following:

    1. Basal cell carcinoma of the skin.
    2. Squamous cell carcinoma of the skin.
    3. Carcinoma in situ of the cervix.
    4. Carcinoma in situ of the breast.
    5. Carcinoma in situ of the bladder.
    6. Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b).
  7. Known seropositivity for or history of active viral infection with human immunodeficiency virus (HIV), or hepatitis B or C virus (HBV, HCV).

    a. Hepatitis B screening is mandatory for all patients (HBsAg and anti-HBc). Patients with active hepatitis B disease should not be treated with obinutuzumab. Patients should be referred to a specialist if they are carriers before treatment starts (see PI or SmPC). Subjects who are positive for anti-HBc and/or anti-HBs but negative for HBsAg and HBV DNA may be treated after consultation with a hepatologist.

  8. Any peripheral neuropathy ≥ NCI CTCAE Grade 2.
  9. Use of systemic corticosteroids in doses greater than prednisone equivalent to 20 mg/day.
  10. Medicines with high probability to cause QT prolongation or torsades de pointes. Subjects on chronic medications in this category may enroll after discussion with the medical monitor if changing these medications are not in the best medical interest of the patient.
  11. History of hypersensitivity to IMiDs® (lenalidomide, pomalidomide, thalidomide).
  12. Impaired cardiac function or clinically significant cardiac diseases, including any of the following:

    1. Left ventricular ejection fraction (LVEF) < 45% as determined by MUGA scan or echocardiogram (ECHO).
    2. Complete left bundle branch, or bifasicular, block.
    3. Congenital long QT syndrome.
    4. Persistent or uncontrolled ventricular arrhythmias or atrial fibrillation.
    5. QTcF > 470 msec on Screening ECG (mean of triplicate recordings).
    6. Unstable angina pectoris or myocardial infarction ≤ 6 months prior to starting CC 122.
    7. Uncontrolled congestive heart failure or uncontrolled hypertension.
    8. Troponin-T value >0.4 ng/mL or BNP >300 pg/mL. Subjects with baseline troponin-T >ULN or BNP >100 pg/mL are eligible but must have cardiologist evaluation prior to enrollment in the trial for baseline assessment and optimization of cardioprotective therapy.
  13. Chemotherapy, radiotherapy, investigational anticancer therapy or major surgery within 28 days of Day 1 dosing with the following exceptions:

    a. Arm A: A minimum 5-day washout after discontinuation of ibrutinib therapy (or other BTK inhibitors) is required; only those subjects without rapid disease progression during the 5-day washout will be allowed to enroll into Arm A.

    i. Rapid disease progression is defined as follows:

1. For subjects with measurable nodal disease, the increase in the sum of diameters of the largest lymph nodes (up to 3 nodes) exceeds

1 cm per day OR the diameter of the largest lymph node exceeds 5 cm during the 5 day wash out. 2. For subjects with lymphocytosis, the increase in the ALC exceeds 2x109/L per day OR the ALC exceeds 100,000 x109/L during the 5-day wash out; b. Arm C: No minimum washout is required after discontinuation of ibrutinib (or other BTK inhibitors) c. Approved PI3 kinase inhibitors: Subjects may start study treatment within 3 days of discontinuation of approved PI3 kinase inhibitors.

14. Persistent diarrhea or malabsorption ≥ NCI CTCAE Grade 2, despite medical management 15. Active disease transformation (ie, Richter's Syndrome); subjects with Richter's Syndrome that has resolved > 2 years from signing the ICD are eligible.

16. Known acute or chronic pancreatitis 17. Pregnant or lactating females

Arm B only (CC-122 in combination with ibrutinib):

18. Prior treatment with a BTK inhibitor 19. Presence of transfusion-dependent thrombocytopenia or a history of bleeding disorders or clinical conditions (eg, gastrointestinal bleeding or constitutional disorders) that may increase risk of life-threatening bleeding when thrombocytopenic 20. History of stroke or intracranial hemorrhage within 6 months prior to signing the ICD 21. Medications that are strong inhibitors or inducers of CYP3A4/5 (eg, itraconazole, ketoconazole, clarithromycin, ritonavir, phenytoin, pentobarbital, and rifampin) should be changed; subjects who cannot change these medications must be excluded.

22. Use of concomitant anticoagulation with warfarin or other vitamin K antagonists is prohibited, as is treatment with these agents in the 7 days prior to signing the ICD. The use of other anticoagulants (eg, heparins) and anti-platelet agents is allowed per investigator's discretion.

Arm C only (CC-122 in combination with obinutuzumab):

23. Hypersensitivity to obinutuzumab


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02406742


Locations
United States, California
University of California San Diego
La Jolla, California, United States, 92093
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, New Jersey
Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
United States, New York
Weill Cornell Medical College Dr. Feldman's Office
New York, New York, United States, 10065
United States, Ohio
Ohio State University Medical CenterJames Cancer Hospital
Columbus, Ohio, United States, 43210
United States, Tennessee
The West Clinic
Memphis, Tennessee, United States, 38120
United States, Texas
MD Anderson Cancer Center The University of Texas
Houston, Texas, United States, 77030
United States, Washington
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States, 98118
Austria
University Hospital Innsbruck
Innsbruck, Austria, 6020
University Hospital of Salzburg St Johanns Spital
Salzburg, Austria, 5020
Allgemeines Krankenhaus Wien
Wien, Austria, 1090
Germany
Universitaetsklinikum EssenInnere Klinik und Poliklinik
Essen, Germany, 45147
University of Schleswig-Holstein
Kiel, Germany, 24116
Universitat zu Koln
Köln, Germany, 50937
Universitatsklinikum Würzburg
Würzburg, Germany, 97080
Italy
Fondazione Centro San Raffaele del Monte Tabor
Milano, Italy, 20132
Ospedale Niguarda Milano
Milano, Italy, 20162
Arcispedale Santa Maria Nuova
Reggio Emilia, Italy, 42100
Istituto Clinico Humanitas
Rozzano (MI), Italy, 20089
Spain
Hospital Universitario Vall D hebron
Barcelona, Spain, 08035
Fundacion Jimenez Daaz
Madrid, Spain, 28040
Hospital Universitario 12 de Octubre
Madrid, Spain, 28041
Hospital Universitario de Salamanca
Salamanca, Spain, 37007
Hospital Universitario Virgen Del Rocio
Sevilla, Spain, 41013
Sponsors and Collaborators
Celgene
Investigators
Study Director: Jeffrey Jones, MD Celgene Corporation

Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT02406742     History of Changes
Other Study ID Numbers: CC-122-CLL-001
First Posted: April 2, 2015    Key Record Dates
Last Update Posted: October 2, 2018
Last Verified: October 2018

Keywords provided by Celgene:
CC-122
Pharmacokinetics
Safety
Ibrutinib
Obinutuzumab
GA101
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma

Additional relevant MeSH terms:
Lymphoma
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Obinutuzumab
Antineoplastic Agents