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A Study of Acalabrutinib Plus Venetoclax Versus Venetoclax Plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (MAJIC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05057494
Recruitment Status : Recruiting
First Posted : September 27, 2021
Last Update Posted : December 21, 2022
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
A study of acalabrutinib plus venetoclax (AV) versus venetoclax plus obinutuzumab (VO) in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Drug: Acalabrutinib Drug: Venetoclax Drug: Obinutuzumab Phase 3

Detailed Description:

This is a phase III prospective, multicenter, randomized, open-label trial.

After completion of the screening period, eligible participants will be randomized in a 1:1 ratio to each of the following intervention arms:

Arm A: Minimal Residual Disease (MRD)-limited finite AV therapy Arm B: MRD-limited finite VO therapy

The study consists of screening, treatment, and post-intervention follow-up periods. Participants will undergo safety and efficacy assessments during each period for each study arm. The duration of individual participant involvement in the study will be approximately 5 years.

All participants who discontinue study intervention will be followed for safety assessments and survival status. Safety/survival follow-up is not required if the participant permanently discontinues study intervention due to withdrawal of consent, loss to follow-up, or death

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 600 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase III Prospective, Multicenter, Randomized, Open-Label Trial of Acalabrutinib Plus Venetoclax Versus Venetoclax Plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Actual Study Start Date : September 12, 2022
Estimated Primary Completion Date : April 11, 2029
Estimated Study Completion Date : April 11, 2029


Arm Intervention/treatment
Experimental: Arm A: Acalabrutinib plus Venetoclax (AV)
Participants will receive acalabrutinib and venetoclax orally.
Drug: Acalabrutinib
Dose formulation: Capsule

Drug: Venetoclax
Dose formulation: Tablet

Experimental: Arm B: Venetoclax plus Obinutuzumab (VO)
Participants will receive Venetoclax orally and Obinutuzumab via IV infusion.
Drug: Venetoclax
Dose formulation: Tablet

Drug: Obinutuzumab
Dose formulation: Injection




Primary Outcome Measures :
  1. Progression-free Survival (PFS) [ Time Frame: Until progressive disease (PD) [assessed Up to 6.6 Years]. ]
    To assess whether minimal residual disease (MRD)-driven finite AV treatment is NI to MRD-driven finite VO treatment with respect to PFS. PFS is defined as the time from the date of randomization until date of objective progressive disease per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria as assessed by the investigator or death from any cause in the absence of progression.


Secondary Outcome Measures :
  1. Rate of peripheral blood (PB) undetectable minimal residual disease (uMRD) based on a clonoSEQ^® [ Time Frame: Screening (Days -45 through -1); Cycle 8 (each Cycle length 28 days) Day 28 and Cycle 14 Day 28 for Arm A (AV); Cycle 6 Day 28 and Cycle 12 Day 28 for Arm B (VO) and Post-treatment follow-up visits (assessed Up to 6.6 Years) ]
    To assess the effect of AV treatment compared with VO treatment on uMRD at sequential timepoints. Rate of PB uMRD is defined as proportion of participants achieving remission based on a clonoSEQ^® assay result of < 1 CLL cell per 100,000 leukocytes (< 10 ^-5 ), after completion of 6 and 12 cycles of venetoclax (assessed at approximately 13 and 15 months for VO and AV, respectively), and at 24 months and 36 months.

  2. Rate of peripheral blood (PB) and Bone marrow (BM) undetectable minimal residual disease (uMRD) by flow cytometry [ Time Frame: Cycle 14 (each Cycle length 28 days) Day 28 for Arm A (AV); Cycle 12 Day 28 for Arm B (VO) and Post treatment follow-up visits (assessed Up to 6.6 Years) ]
    To assess the effect of AV treatment compared with VO treatment on uMRD at sequential timepoints. Rate of PB and BM uMRD is defined as < 1 CLL cell per 10,000 leukocytes (< 10^-4) by flow cytometry, after completion of 12 cycles of venetoclax (assessed at approximately 13 and 15 months for VO and AV, respectively) and at 36 months.

  3. Overall Survival (OS) [ Time Frame: Date of randomization until death from any cause (Assessed Up to 6.6 Years) ]
    To assess the effect of AV treatment compared with VO treatment on OS. OS is defined as the time from the date of randomization until death from any cause.

  4. Event-free Survival (EFS) [ Time Frame: Date of randomization until first occurrence of disease progression (Assessed Up to 6.6 Years) ]
    To assess the effect of AV treatment compared with VO treatment on EFS. EFS is defined as the time from the date of randomization to the first occurrence of disease progression, initiation of subsequent CLL therapy, or death from any cause.

  5. Overall Response Rate (ORR) [ Time Frame: Date of randomization until PD (Assessed Up to 6.6 Years) ]
    To assess the effect of AV treatment compared with VO treatment on ORR. ORR is defined as the proportion of participants who achieve best response of Complete Response (CR), complete response with incomplete marrow recovery (Cri), nodular partial remission (nPR), or partial remission (PR) per iwCLL 2018 criteria as assessed by the investigator.

  6. Complete Response (CR) rate [ Time Frame: Date of randomization until PD (Assessed Up to 6.6 Years) ]
    To assess the effect of AV treatment compared with VO treatment on ORR. CR rate (uMRD per iwCLL guidelines 2018) after completion of 12 cycles of venetoclax.

  7. Change from baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 scales [ Time Frame: For AV: Cycle 1-Cycle 2, Cycle 3-Cycle 14; After End of Treatment (EoT); Post treatment follow-up For VO: Cycle 1 Day 1-21, Cycle 1 Day 22-Cycle 6, Cycle 7-Cycle 24 (Each cycle is 28 days); After EoT, Post treatment follow-up (assessed Up to 6.6 years) ]

    To assess symptoms, functional status and global health status/quality of life (QoL), in participants treated with AV versus VO using the EORTC QLQ-C30.

    EORTC QLQ-C30 consists of 30 items and measures symptoms, functioning, and global health status/QoL for all cancer types. Questions are grouped into 5 multi-item functional scales, 3 multi-item symptom scales, a 2-item global QoL scale, 5 single items assessing additional symptoms commonly reported by cancer participants, and 1 item on the financial impact of the disease.

    The EORTC QLQ-C30 will be scored according to the EORTC QLQ-C30 Scoring Manual. An outcome variable consisting of a score from 0 to 100 will be derived for each of the symptom scales, each of the functional scales, and the global measure of health status scale. Higher scores on the global measure of health status and functional scales indicate better health status/function, but higher scores on symptom scales represent greater symptom severity.


  8. Change from baseline in EORTC QLQ-CLL17 scales [ Time Frame: For AV: Cycle 1-Cycle 2, Cycle 3-Cycle 14; After End of Treatment (EoT); Post treatment follow-up For VO: Cycle 1 Day 1-21, Cycle 1 Day 22-Cycle 6, Cycle 7-Cycle 24 (Each cycle is 28 days); After EoT, Post treatment follow-up (assessed Up to 6.6 years) ]

    To assess symptoms, functional status, and global health status/QoL, participants treated with AV versus VO using the EORTC QLQ-CLL17.

    EORTC QLQ-CLL17 comprises 17 items grouped into 3 multi-item scales: 1) symptom burden, 2) physical condition/fatigue, and 3) worries/fears about health and functioning.

    The EORTC QLQ-CLL17 will be scored according to the EORTC QLQ-C30 Scoring Manual. An outcome variable consisting of a score from 0 to 100 will be derived for each of the symptom scales, each of the functional scales, and the global measure of health status scale. Higher scores on the global measure of health status and functional scales indicate better health status/function, but higher scores on symptom scales represent greater symptom severity.


  9. Proportion of participants experiencing bruising as measured by the National Cancer Institute (NCI) Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) item for Bruising [ Time Frame: For AV: Cycle 1-Cycle 2, Cycle 3-Cycle 14; After End of Treatment (EoT); Post treatment follow-up For VO: Cycle 1 Day 1-21, Cycle 1 Day 22-Cycle 6, Cycle 7-Cycle 24 (Each cycle is 28 days); After EoT, Post treatment follow-up (assessed Up to 6.6 years) ]

    To assess symptomatic toxicities patient perceived benefit-risk in participants treated with AV versus VO using the NCI PRO-CTCAE item for Bruising.

    It was designed to be used as a companion to the Common Terminology Criteria for Adverse Events (CTCAE), the standard lexicon for adverse event reporting in cancer trials. The bruising item, which has a dichotomous yes/no response option, will be included in this study to capture patient-reported bruising.


  10. Proportion of participants reporting each response option of the Patient Global Impression of Benefit-Risk (PGI-BR) [ Time Frame: For AV: Cycle 1-Cycle 2, Cycle 3-Cycle 14 (Each cycle is 28 days); and End of treatment, E/D, disease progression, and post-treatment follow-up visits (assessed up to 6.6 years) ]

    To assess patient perceived benefit-risk of treatment in participants treated with AV versus VO using the PGI-BR.

    PGI-BR consists of 4 study medication-related questions, one each on efficacy, side effects, convenience of use, and overall benefit-risk. Each item is scored separately, with the final item providing a single metric of a participant's overall benefit-risk assessment.

    The response from each question will be semi-quantitative. Each question ranges from Very (negative, Somewhat [negative]), Neutral, Somewhat [positive], Very [positive].


  11. Number of participants with adverse events (AEs) [ Time Frame: From screening (Days -45 through -1) until survival follow-up (Up to 6.6 years) ]
    To assess the safety and tolerability of AV treatment versus VO treatment in participants with previously untreated CLL/SLL.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Participant must be ≥ 18 years at the time of screening.
  2. Documented TN CLL/SLL requiring treatment according to iwCLL guidelines 2018 (Hallek et al 2018).
  3. Adequate BM function independent of growth factor or platelet transfusion support within 2 weeks of screening initiation as follows, unless cytopenia is due to CLL/SLL:

    1. Absolute neutrophil count ≥ 1.0 × 10 9 /L.
    2. Platelet counts ≥ 30 × 10 9 /L; in cases of thrombocytopenia clearly due to CLL/SLL (per the discretion of the investigator), platelet count should be ≥ 10 × 10 9 /L.
  4. Estimated CrCL > 30 mL/min calculated according to Cockcroft-Gault (using actual body weight) or directly measured with 24-hour urine collection,.

    Males:

    CrCL = Weight (kg) × (140 Age) (mL/min) 72 × serum creatinine (mg/dL)

    Females:

    CrCL = Weight (kg) × (140 Age) × 0.85 (mL/min) 72 × serum creatinine (mg/dL)

  5. Adequate liver function, as indicated by a total bilirubin ≤ 1.5 × ULN, AST and ALT ≤ 3 × ULN value, unless directly attributable to the participant's CLL/SLL or to Gilbert's Syndrome (The ULN is based on institutional values).
  6. Eastern Cooperative Oncology Group Performance Status performance status 0 to 2 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing.
  7. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations).
  8. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules and tablets without difficulty.

Exclusion Criteria:

  1. As judged by the investigator, any evidence of past or current diseases that, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize their safety or compliance with the protocol or would put the study at risk.
  2. Clinically significant cardiovascular disease, such as 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. Note: Participants with controlled, asymptomatic atrial fibrillation can enroll in the study.
  3. Active bleeding or history of bleeding diathesis (eg, hemophilia or von Willebrand disease).
  4. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura.
  5. History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study intervention.
  6. Child-Pugh B/C liver cirrhosis.
  7. History of prior or current malignancy (including but not limited to known CNS lymphoma/leukemia or known prolymphocytic leukemia or history of, or currently suspected, Richter's syndrome) that could affect compliance with the protocol or interpretation of results. Exceptions can be made for the following based on physician discretion:

    1. Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or carcinoma in situ of the prostate at any time prior to study.
    2. Other cancers not specified above that have been curatively treated by surgery and/or radiation therapy from which the participant is disease-free for ≥ 3 years without further treatment.
  8. An individual organ system dysfunction limiting the ability to receive the study intervention or any other life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the participants' safety or interfere with the absorption, distribution, metabolism, or excretion of the study interventions (eg, refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow the formulated product, previous significant bowel resection, or impaired resorption in the gastrointestinal tract).
  9. Known history of infection with HIV or any active significant infection (eg, bacterial, viral, or fungal; including participants with positive cytomegalovirus DNA PCR).
  10. History of or ongoing confirmed PML.
  11. Serologic status reflecting active hepatitis B or C infection:

    1. Participants who are anti-HBc positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative PCR result before randomization and must be willing to undergo DNA PCR testing during the study. Those who are HbsAg-positive or hepatitis B PCR positive will be excluded.
    2. Participants who are hepatitis C antibody positive will need to have a negative PCR result before randomization. Those who are hepatitis C PCR positive will be excluded.
  12. Any prior CLL/SLL-specific therapies, except prior rituximab if used for autoimmune cytopenias and not as anti-CLL/SLL treatment.
  13. Corticosteroid use > 20 mg within 1 week before the first dose of study intervention, except as indicated for other medical conditions, such as autoimmune cytopenias, inhaled steroid for asthma, topical steroid use, or as premedication for administration of study intervention or contrast. Participants requiring steroids at daily doses > 20 mg prednisone equivalent systemic exposure daily, or those who are administered steroids for leukemia control or white blood cell count lowering, are excluded. Of note, patients may receive corticosteroids as doses > 20 mg as per institutional standards for obinutuzumab pre-medication prior to C1D1.
  14. Prior radio- or toxin-conjugated antibody therapy.
  15. Prior allogeneic stem cell or autologous transplant.
  16. Known history of hypersensitivity or anaphylaxis to study intervention(s), including active product or excipient components.
  17. Requires treatment with a strong cytochrome CYP3A4 inhibitor/inducer. The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of study drug is prohibited.
  18. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (other anticoagulants allowed).
  19. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Note: Participants receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.
  20. Vaccination with live vaccines 28 days prior to registration for study screening.
  21. Major surgical procedure within 28 days of first dose of study intervention. Note: If a participant had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study intervention.
  22. Concurrent participation in another therapeutic clinical trial. Use of investigational agents that interfere with the study intervention(s) within 28 days or 5 half-lives (whichever is shorter) prior to registration for study screening.
  23. Prothrombin time (PT)/INR or activated partial thromboplastin time, in the absence of lupus anticoagulant, > 2 × ULN.
  24. Currently pregnant (confirmed with positive pregnancy test) or breast feeding.
  25. Women of Childbearing Potential (WOCBP) a negative pregnancy test is required for all WOCBP within 21 days before start of study intervention, followed by immediate highly effective contraception; further pregnancy testing will be performed monthly).
  26. Fertile men or WOCBP unless the following criteria are met: Willing to use 2 methods of reliable contraception, including one highly effective contraceptive method (Pearl Index < 1) and one additional effective (barrier) method during study intervention and for 2 days after last acalabrutinib dose (for WOCBP), 30 days after last venetoclax dose (fertile men and WOCBP), and 6 months after last obinutuzumab dose for fertile men and 18 months after last obinutuzumab dose for WOCBP.

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): NCT05057494


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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United States, Arizona
Research Site Recruiting
Tucson, Arizona, United States, 85710
United States, California
Research Site Not yet recruiting
La Jolla, California, United States, 92093-0052
United States, Colorado
Research Site Recruiting
Longmont, Colorado, United States, 80501
United States, Florida
Research Site Recruiting
Jacksonville, Florida, United States, 32256
United States, Massachusetts
Research Site Not yet recruiting
Boston, Massachusetts, United States, 02114
Research Site Recruiting
Boston, Massachusetts, United States, 02115
United States, New York
Research Site Not yet recruiting
Buffalo, New York, United States, 14263
Research Site Not yet recruiting
New Hyde Park, New York, United States, 11040
Research Site Recruiting
New York, New York, United States, 10065
Research Site Not yet recruiting
Rochester, New York, United States, 14642
United States, North Carolina
Research Site Recruiting
Charlotte, North Carolina, United States, 28204
Research Site Not yet recruiting
Charlotte, North Carolina, United States, 28204
United States, Ohio
Research Site Recruiting
Cleveland, Ohio, United States, 44195
United States, Oregon
Research Site Recruiting
Eugene, Oregon, United States, 97401
United States, Pennsylvania
Research Site Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
Research Site Recruiting
Nashville, Tennessee, United States, 37203
United States, Utah
Research Site Recruiting
Salt Lake City, Utah, United States, 84112
United States, Virginia
Research Site Recruiting
Charlottesville, Virginia, United States, 22908
United States, Washington
Research Site Not yet recruiting
Seattle, Washington, United States, 98104
Research Site Not yet recruiting
Seattle, Washington, United States, 98109
Australia
Research Site Not yet recruiting
Clayton, Australia, 3168
Research Site Recruiting
Geelong, Australia, 3220
Research Site Not yet recruiting
Nedlands, Australia, 6009
Research Site Not yet recruiting
Waratah, Australia, 2298
Czechia
Research Site Withdrawn
Brno, Czechia, 625 00
Research Site Recruiting
Hradec Kralove, Czechia, 500 05
Research Site Not yet recruiting
Ostrava - Poruba, Czechia, 708 52
Research Site Recruiting
Pilsen, Czechia, 30460, CZ
France
Research Site Not yet recruiting
Bobigny Cedex, France, 93009
Research Site Not yet recruiting
Montpellier Cedex 5, France, 34295
Research Site Not yet recruiting
Tours, France, 37044
Hungary
Research Site Not yet recruiting
Budapest, Hungary, 1097
Research Site Not yet recruiting
Debrecen, Hungary, 4032
Poland
Research Site Not yet recruiting
Bydgoszcz, Poland, 85-168
Research Site Not yet recruiting
Gdansk, Poland, 80-219
Research Site Recruiting
Katowice, Poland, 40-519
Research Site Not yet recruiting
Katowice, Poland, 40-568
Research Site Not yet recruiting
Lublin, Poland, 20-090
Research Site Not yet recruiting
Lódz, Poland, 93-513
Spain
Research Site Recruiting
Barcelona, Spain, 08025
Research Site Recruiting
Palma de Mallorca, Spain, 07010
Sponsors and Collaborators
AstraZeneca
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT05057494    
Other Study ID Numbers: D8220C00027
2021-003936-10 ( EudraCT Number )
First Posted: September 27, 2021    Key Record Dates
Last Update Posted: December 21, 2022
Last Verified: December 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Chronic lymphocytic leukemia
Small lymphocytic lymphoma
Acalabrutinib
Venetoclax
Obinutuzumab
B-cell lymphoma 2 inhibitors
Additional relevant MeSH terms:
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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
Venetoclax
Obinutuzumab
Acalabrutinib
Antineoplastic Agents
Antineoplastic Agents, Immunological