Combining acalabrutinib and liso-cel for aggressive B-cell lymphomas

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

This study is testing if a combination of two treatments, acalabrutinib and liso-cel, can help adults with aggressive B-cell lymphomas that have come back or didn't respond to previous treatments.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 27 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Massachusetts General Hospital (Academic / other)
• Drugs / interventions: alemtuzumab, acalabrutinib, fludarabine, prednisone
• Locations: 2 sites (Boston, Massachusetts and 1 other locations)
• Trial ID: NCT05583149 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the safety and effectiveness of acalabrutinib in combination with lisocabtagene maraleucel (liso-cel) for adults with relapsed or refractory aggressive B-cell lymphomas. Participants will receive one infusion of liso-cel and take acalabrutinib capsules twice daily for up to one year, as long as the treatment is tolerated and the disease does not progress. The study includes screening for eligibility, treatment administration, and follow-up visits for up to five years, with medical records monitored for up to 15 years. The trial aims to enroll approximately 27 participants.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with histologically confirmed aggressive B-cell non-Hodgkin lymphoma who have relapsed or are refractory to at least two prior lines of systemic therapy.

Not a fit: Patients with primary CNS lymphoma or those who do not meet the eligibility criteria will not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment combination could provide a new therapeutic option for patients with aggressive B-cell lymphomas that have not responded to previous therapies.

How similar studies have performed: While this approach is being tested in this specific context, similar combinations have shown promise in other studies, indicating potential for success.

Eligibility criteria

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.

Where this trial is running

Boston, Massachusetts and 1 other locations

• Massachusetts General Hospital — Boston, Massachusetts, United States (Recruiting)
• Beth-Israel Deaconess Medical Center — Boston, Massachusetts, United States (Recruiting)

Study contacts

• Principal investigator: Connor Johnson, MD — Massachusetts General Hospital
• Study coordinator: Connor Johnson, MD

Conditions Refractory Aggressive B-cell Lymphomas; Refractory B-Cell Non-Hodgkin Lymphoma; Aggressive B-cell NHL; Diffuse Large B-cell Lymphoma; De Novo or Transformed Indolent B-cell Lymphoma; DLBCL, Nos Genetic Subtypes; T Cell/Histiocyte-rich Large B-cell Lymphoma; EBV-Positive DLBCL, Nos