Acalabrutinib + Liso-Cel In R/R Aggressive B-Cell Lymphomas

Study Overview
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Brief Summary
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This research is being done to assess the effectiveness and safety of acalabrutinib combined with lisocabtagene maraleucel (liso-cel) for people with relapsed/refractory aggressive B-cell lymphoma. This research study involves the study drug acalabrutinib in combination with lisocabtagene maraleuce

Detailed Description
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This research study involves the study drug acalabrutinib in combination with lisocabtagene maraleucel. The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. - Participants will receive one infusion of liso-cel and will receive acalabrutinib capsules twice daily as long as treatment is tolerated and disease does not worsen (disease progression) for up to one year. Participants will be followed by clinical visits for up to 5 years and the medical record will be monitored for up to 15 years. It is expected that about 27 people will take part in this research study. This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. Investigational means that the intervention is being studied. The U.S. Food and Drug Administration (FDA) has not approved acalabrutinib for this specific disease, but it has been approved for other uses. The U.S. FDA has approved lisocabtagene maraleucel for this specific disease. AstraZeneca, a pharmaceutical company, is supporting this research study by providing funding for the research study and supplying acalabrutinib.

Official Title
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A Phase 2 Study of Acalabrutinib in Combination With Lisocabtagene Maraleucel in Relapsed/Refractory Aggressive B-cell Lymphomas

Conditions
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Refractory Aggressive B-cell Lymphomas, Refractory B-Cell Non-Hodgkin Lymphoma, Aggressive B-cell NHL, Diffuse Large B-cell Lymphoma (DLBCL), De Novo or Transformed Indolent B-cell Lymphoma, DLBCL, Nos Genetic Subtypes, T Cell/Histiocyte-rich Large B-cell Lymphoma, EBV-Positive DLBCL, Nos, Primary Mediastinal [Thymic] Large B-cell Lymphoma (PMBCL), High-Grade B-Cell Lymphoma, Nos, C-MYC/BCL6 Double-Hit High-Grade B-Cell Lymphoma, Grade 3b Follicular Lymphoma, C-MYC/BCL2 Double-Hit High-Grade B-Cell Lymphoma

Intervention / Treatment
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* Drug: ACALABRUTINIB
* Drug: LISOCABTAGENE MARALEUCEL
* Drug: Lymphodepleting chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients ≥18 years with histologically confirmed aggressive B-cell NHL including diffuse large B-cell lymphoma (DLBCL), either de novo or transformed from any indolent B-cell lymphoma, and including DLBCL NOS, T cell/histiocyte-rich large B-cell lymphoma, Epstein-Barr virus [EBV] positive DLBCL NOS, primary mediastinal [thymic] large B-cell lymphoma (PMBCL), high grade B-cell lymphoma NOS, or high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements [double/triple hit lymphoma (DHL/THL)]; and grade 3B follicular lymphoma. Patients with primary CNS lymphoma are not eligible. Patients with secondary CNS involvement by lymphoma are eligible if they otherwise meet all eligibility criteria. Relapsed or refractory to at least 2 prior lines of systemic lymphoma therapy. Previous therapy must have included a CD20-targeted agent and an anthracycline or alkylating agent. PET-positive measurable disease ECOG Performance status 0-2 Estimated creatinine clearance of ≥30 mL/min, calculated using the Cockcroft and Gault equation (if male, [140Age] x Mass [kg] / [72 x creatinine g/dL];multiply by 0.85 if female) Alanine Aminotransferase (ALT) <= 2.5 times the ULN Bilirubin <= 2 x ULN (or <= 3.0 mg/dL for patients with Gilbert-Meulengracht syndrome or lymphomatous involvement of the liver) Hemodynamically stable and Left Ventricle Ejection Fraction (LVEF) >= 40% confirmed by echocardiogram or Multigated Radionuclide Angiography (MUGA) For subjects with atrial fibrillation, atrial fibrillation must be controlled and asymptomatic Absolute neutrophil count (ANC) >= 1000/mm3 Platelets >= 50,000/mm3 Adequate pulmonary function, defined as <= CTCAE Grade 1 dyspnea and SaO2 > 91% on room air Adequate vascular access for leukapheresis procedure (either peripheral line or surgically-placed line) Woman of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception during treatment and for 2 days after the last dose of acalabrutinib. Willing and able to participate in all required evaluations and procedures in this study protocol. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information. Exclusion Criteria: Another active malignancy which requires concurrent cancer-directed therapy Previous treatment with gene therapy product or adoptive T cell therapy Allogeneic stem cell transplant within 90 days of leukapheresis Active acute or chronic GVHD HIV infection Serologic status reflecting active hepatitis B or C infection Subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative PCR result before enrollment 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. Subjects who are hepatitis C antibody positive will need to have a negative PCR result before enrollment. Those who are hepatitis C PCR positive will be excluded. Uncontrolled infection Clinically relevant CNS pathology History of cardiovascular conditions within the past 6 months, including class III or IV heart failure as defined by New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or clinically significant arrhythmias: Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better. Autoimmune disease requiring chronic systemic corticosteroids at a dose of greater than 10 mg of prednisone daily or an equivalent dose of another corticosteroid Treatment with alemtuzumab within 6 months leukapheresis or fludarabine or cladribine within 3 months of leukapheresis Therapeutic anticoagulation Bleeding diathesis Has difficulty with or is unable to swallow oral medication, or has significant gastrointestinal disease that would limit absorption of oral medication. Known history of hypersensitivity or anaphylaxis to study drug(s) including active product or excipient components. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. Prothrombin time (PT)/INR or aPTT (in the absence of lupus anticoagulant) >2x ULN. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Note: Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study. History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug. Major surgical procedure within 28 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug. Breastfeeding or pregnant: Pregnant women are excluded from this study because acalabrutinib is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with acalabrutinib, breastfeeding should be discontinued if the mother is treated with acalabrutinib.

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: ACALABRUTINIB and LISOCABTAGENE MARALEUCEL<br>The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits, as tolerated for one year Liso-cel Acalabrutinib | Drug: ACALABRUTINIB<br>* Oral, twice daily, timing and dosage per protocol<br>* Other names: Calquence;Drug: LISOCABTAGENE MARALEUCEL<br>* via IV timings and dosage per protocol<br>* Other names: Breyanzi;Drug: Lymphodepleting chemotherapy<br>* lymphodepleting chemotherapy with cyclophosphamide and fludarabine once a day for 3 days via IV about 2-4 hours. This will occur only once prior to lisocabtagene maraleucel infusion.<br>* Other names: cyclophosphamide and fludarabine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate (CRR) | The CRR is defined as the proportion of subjects achieving an objective response of complete response (CR) according to the Lugano Classification, prior to start of another non-study anticancer therapy | up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate |  | 3 Months | 
| Overall Response Rate |  | 6 Months | 
| Overall Response Rate |  | 12 Months | 
| Progression Free Survival | PFS will be summarized using Kaplan-Meier estimates. | as the time from registration to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation up to 15 years | 
| Overall Survival | OS will be summarized using Kaplan- Meier estimates. | defined as the time from registration to death due to any cause, or censored at date last known alive up to 15 years | 
| Duration of Response | The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started, or death due to any cause. Participants without events reported are censored at the last disease evaluation).DOR will be summarized using Kaplan-Meier estimates. | time from first response to disease progression or death up to 15 years | 
| Event free survival | Time to event outcomes will be estimated using Kaplan Meier method or cumulative incidence curves | from registration to death from any cause, disease progression, or starting a new anti-lymphoma therapy, whichever occurs first up to 15 years | 
| Rates of bridging therapy | Rates of bridging therapy defined as the percentage of participants requiring any lymphoma-directed therapy other than the investigational therapy in order to control the disease prior to liso-cel infusion. Reported with descriptive statistics | 1 years | 
| FACT-G QOL | Functional Assessment of Cancer Treatment-General (FACT-G). The FACT-G consists of four subscales assessing well-being across four domains. These self-reported measures possess strong psychometric properties and have been validated for patients with cancer | baseline, day -5 (+/- 3 days), day +7 (+/- 3 days), day +30 (+/- 7 days), day +90 (+/- 14 days), and day +180 (+/- 14 days) after liso-cel infusion | 
| ICU Rates | ICU admission rates defined as the percentage of participants with an ICU admission within 90 days of liso-cel infusion. Reported with descriptive statistics | up to 90 days | 
| Re-hospitalization rates | All cause re-hospitalization rates defined as the percentage of participants who experience an unplanned hospitalization within 90 days of liso-cel infusion. Planned hospital admissions for a procedure or treatment will be excluded. Reported with descriptive statistics | up to 90 days | 
| ER visit rates | All cause ER visit rates defined as the percentage of participants who experience an unplanned ER visit within 90 days of liso-cel infusion. Planned ER visits/hospital admissions for a procedure or treatment will be excluded. | within 90 days | 
| Length of Stay | Length of stay (LOS) defined as the number of days a participant is hospitalized for liso-cel infusion. | 1 year | 
| Rates of acalabrutinib discontinuation due to toxicity | Rates of acalabrutinib discontinuation in participants due to acalabrutinib toxicity NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 | time of their first treatment up to 3 years | 
| Number of Participants treatment related Adverse Event NCI CTCAE 5.0 | The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 | up to 3 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Refractory aggressive B-cell lymphomas, Refractory B-Cell Non-Hodgkin Lymphoma, Aggressive B-cell NHL, Diffuse Large B-cell Lymphoma (DLBCL), De novo or transformed indolent B-cell lymphoma, DLBCL, nos Genetic Subtypes, T cell/histiocyte-rich large B-cell lymphoma, EBV-Positive DLBCL, nos, Primary mediastinal [thymic] large B-cell lymphoma (PMBCL), High-Grade B-Cell Lymphoma, nos, C-MYC/BCL6 Double-Hit High-Grade B-Cell Lymphoma, Grade 3b Follicular Lymphoma, C-MYC/BCL2 Double-Hit High-Grade B-Cell Lymphoma