Acalabrutinib for the Treatment of Relapsed or Refractory Autoimmune Hemolytic Anemia in Patients With Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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This phase II trial studies the effect of acalabrutinib in treating autoimmune hemolytic anemia that has come back (relapsed) or has not responded to previous treatment (refractory) in patients with chronic lymphocytic leukemia. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVE: I. Assess the efficacy of acalabrutinib in chronic lymphocytic leukemia (CLL) patients with relapsed or refractory autoimmune hemolytic anemia (AIHA). SECONDARY OBJECTIVES: I. Evaluate acalabrutinib's ability to induce short term and sustained hemoglobin response. II. Assess the toxicity of acalabrutinib. III. Evaluate efficacy of acalabrutinib in CLL. EXPLORATORY OBJECTIVE: I. Assess the effect of acalabrutinib on T-cell functionality in an autoimmune disorder. OUTLINE: Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Treatment with acalabrutinib may be continued beyond 12 cycles for a maximum of 36 cycles if, in the opinion of the treating physician, the patient might benefit from ongoing therapy. After completion of study treatment, patients are followed up at 30 days and at least every 4 months for up to 12 months.

Official Title
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A Phase 2 Trial of Acalabrutinib for the Treatment of Relapsed/Refractory Autoimmune Hemolytic Anemia

Conditions
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Autoimmune Hemolytic Anemia, Chronic Lymphocytic Leukemia, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Warm Antibody Autoimmune Hemolytic Anemia

Intervention / Treatment
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* Drug: Acalabrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented informed consent of the participant and/or legally authorized representative Assent, when appropriate, will be obtained per institutional guidelines Agreement to allow the use of archival tissue from diagnostic tumor biopsies If unavailable, exceptions may be granted with study principal investigator (PI) approval Eastern Cooperative Oncology Group (ECOG) =< 2 Warm or cold AIHA in patients with CLL, relapsed/refractory (RR) after first line treatment with oral prednisone (with or without rituximab), defined as: Anemia (hemoglobin [Hgb] =< 10 g/dL; or Hgb > 10 g/dL dependent on transfusions or maintenance therapy (rituximab, cyclosporin, etc) to maintain this level of hemoglobin, and Laboratory evidence of hemolysis - presence of 3 of 4 markers (increased reticulocyte count, increased indirect bilirubin, increased lactate dehydrogenase, absent haptoglobin) Positive direct antiglobulin test (DAT) (score >= 1+) - either immunoglobulin G (IgG) DAT, C3 DAT, or both. Eligibility of patients with Coombs-negative AIHA should be confirmed by the trial investigator at each respective study site Histologically or flow cytometry confirmed diagnosis of CLL/small lymphocytic lymphoma (SLL) Participant must be able to swallow tablets or capsules Absolute neutrophil count (ANC) >= 500/mm^3 unless due to disease involvement in the bone marrow or autoimmune neutropenia (within 30 days prior to day 1 of protocol therapy) Platelets >= 30,000/mm^3 unless due to disease involvement in the bone marrow or autoimmune thrombocytopenia (Evans syndrome) (within 30 days prior to day 1 of protocol therapy) Direct bilirubin =< 3.0 x upper limit of normal (ULN) (within 30 days prior to day 1 of protocol therapy) Aspartate aminotransferase (AST) =< 3.0 x ULN (within 30 days prior to day 1 of protocol therapy) Alanine aminotransferase (ALT) =< 3.0 x ULN (within 30 days prior to day 1 of protocol therapy) Creatinine clearance of >= 30 mL/min per 24 hour urine test or the Cockcroft-Gault formula (within 30 days prior to day 1 of protocol therapy) If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin (prothrombin time [PT]) < 2 x ULN (within 30 days prior to day 1 of protocol therapy). If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants (within 30 days prior to day 1 of protocol therapy) If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) < 2 x ULN (within 30 days prior to day 1 of protocol therapy). If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants (within 30 days prior to day 1 of protocol therapy) Seronegative for human immunodeficiency virus (HIV) Ag/Ab combo, hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative), and syphilis (rapid plasma reagin [RPR]) (within 30 days prior to day 1 of protocol therapy) If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed Women of childbearing potential (WOCBP): negative urine or serum pregnancy test within the screening window prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required Agreement by females of childbearing potential to use highly effective methods of birth control or abstain from heterosexual activity starting with the first dose of study therapy through 2 days after the last dose of protocol therapy Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only) Exclusion Criteria: Therapeutic anticancer antibodies within 3 weeks Radio- or toxin-immunoconjugates within 10 weeks BH3-mimetic venetoclax, PI3K inhibitors and other targeted therapy- within 6 half-lives Ibrutinib, acalabrutinib or another BTK inhibitor within 12 months Patients on stable chronic AIHA treatments are allowed provided the dose has not changed in the 4 weeks prior to enrollment Allogeneic stem cell transplant within 1 year prior to day 1 of protocol therapy, or ongoing immunosuppressive therapy for chronic graft versus host disease (cGVHD) Chemotherapy, radiation therapy, biological therapy, immunotherapy within 21 days prior to day 1 of protocol therapy Strong CYP3A4 inducers/ inhibitors. If the patient requires a strong CYP3A inhibitor/inducer, they should not be enrolled even if it could be held for 14 days before the first dose of study drug Proton pump inhibitors (but patients who switch to H2-receptor antagonists or antacids are eligible for enrollment) Chronic use of corticosteroids (> 2 weeks) in excess of prednisone 60 mg/day or its equivalent within 4 weeks prior to start of study therapy. Rescue steroids are allowed during trial Vitamin K antagonists Known intolerance to acalabrutinib History of bleeding disorders or with active bleeding Patients with suspected or confirmed progressive multifocal leukoencephalopathy (PML) Patients with history of stroke or intracranial hemorrhage within 6 months Inadequate recovery from adverse events related to prior therapy to grade 1 or baseline (excluding grade 2 alopecia and neuropathy) Active uncontrolled infection Known history of immunodeficiency virus (HIV) infection Subjects who have an undetectable or unquantifiable HIV viral load with CD4 > 300 and are on highly active antiretroviral therapy (HAART) medication are allowed. Testing to be done only in patients suspected of having infections or exposures Active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) Participants who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Note that intravenous immunoglobulin therapy (IVIG) administration may lead to positive anti-HBc test result Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded Major surgery (requiring general anesthesia) within 28 days prior to initiation of therapy Has difficulty with or is unable to swallow oral medication, or has significant gastrointestinal disease that would limit absorption of oral medication History of prior malignancy except: Malignancy treated with curative intent and no known active disease present for >= 2 years prior to initiation of therapy on current study Adequately treated non-melanoma skin cancer or lentigo maligna (melanoma in situ) without evidence of disease Adequately treated in situ carcinomas (e.g., breast, cervical, esophageal, etc.) without evidence of disease Asymptomatic prostate cancer managed with watch and wait strategy 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 left ventricular ejection fraction (LVEF) =< 40% Psychiatric illness/social situations that would limit compliance with study requirements Participant is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (acalabrutinib)<br>Patients receive acalabrutinib PO BID on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Treatment with acalabrutinib may be continued beyond 12 cycles for a maximum of 36 cycles if, in the opinion of the treating physician, the patient might benefit from ongoing therapy. | Drug: Acalabrutinib<br>* Given PO<br>* Other names: Calquence;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Autoimmune hemolytic anemia (AIHA) - overall response rate (ORR) | ORR is defined as proportion of patients who achieve complete response (CR) and partial response (PR). The probability of having AIHA-ORR at 6 cycles will be measured and reported with 95% exact confidence interval (CI). An exact binomial test against a null hypothesis of 30% rate will be performed at the 1-sided alpha of 0.05 to determine whether the AIHA-ORR rate at 6 cycles is disappointing or promising. | After 6 cycles of therapy (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Autoimmune hemolytic anemia - overall response rate | ORR is defined as proportion of patients who achieve complete and partial response. The probability of having AIHA-ORR at 3 or 12 cycles will be measured and reported with 95% exact CI. | After 3 and 12 cycles of therapy (each cycle is 28 days) | 
| Frequency of packed red blood cell (PRBC) transfusion while receiving acalabrutinib | Will be defined as the number of PRBC transfusions from start of protocol treatment through end of treatment. The frequency of PRBC transfusion will be summarized by descriptive statistics. The difference between the average number of PRBC transfusion per month during protocol treatment versus the average number of PRBC transfusion at baseline (in the past 6 months before protocol treatment, if available) will be assessed by paired t-test. | Up to 30 days after last dose of study drug | 
| Autoimmune hemolytic anemia - specific relapse-free survival (RFS) | AIHA-specific RFS will be estimated using Kaplan-Meier methods along with 95% CI. | From first dose of study drug until time of relapse, death, or end of follow-up, whichever occurs first, assessed up to 12 months after the last dose of study drug | 
| Autoimmune hemolytic anemia sustained response | Will be estimated among patients who achieve AIHA CR/PR on protocol treatment. | From the first documented AIHA CR/PR until death or relapse of AIHA, whichever is earlier, assessed up to 12 months after the last dose of study drug | 
| Incidence and type of treatment-related toxicity | Incidence, type, severity, and attribution of toxicities on the study will be assessed by Common Terminology Criteria for Adverse Events version 5.0 (non-hematologic) and International Workshop on Chronic Lymphocytic Leukemia 2018 (hematologic). Toxicity events will be tabulated and summarized using descriptive statistics such as count and percentages, by severity, attribution, and system organ class. | Up to 30 days after last dose of study drug | 
| Chronic lymphocytic leukemia (CLL) overall response rate | Will be defined as the proportion of patients achieving CLL CR/PR after 6 or 12 cycles respectively. Will be assessed and reported with 95% CI. | After 6 or 12 cycles of therapy (each cycle is 28 days) | 
| Chronic lymphocytic leukemia - specific event-free survival (EFS) | The Kaplan-Meier method will be used to estimate CLL-specific EFS, and the summary statistics (e.g., 12-month survival, median survival, 95% confidence intervals) will be provided. | From first dose of study drug until time of progression, death, start of new therapy, or end of follow-up, whichever occurs first, assessed up to 12 months after the last dose of study drug | 
| Duration of chronic lymphocytic leukemia response | Will be estimated among patients who achieve CLL CR/PR on protocol treatment. The Kaplan-Meier method will be used to estimate duration of CLL response, and the summary statistics (e.g., 12-month survival, median survival, 95% confidence intervals) will be provided. Duration of CLL response will be estimated only among responders (i.e. participants achieving CLL CR/PR at least once). | From when CR/PR is first documented until time of progression, death, start of new therapy, or end of follow-up, whichever occurs first, assessed up to 12 months after the last dose of study drug |