Using modified immune cells and acalabrutinib to treat relapsed or refractory mantle cell lymphoma

A Phase 2 Study to Evaluate CD19-Specific Chimeric Antigen Receptor (CAR)-T Cells Combined With Acalabrutinib for Patients With Relapsed or Refractory Mantle Cell Lymphoma (MCL)

This study is testing if a new treatment that combines modified immune cells with a medication can help people with hard-to-treat mantle cell lymphoma get better.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 36 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: City of Hope Medical Center (Academic / other)
• Drugs / interventions: tocilizumab, acalabrutinib, CAR T, radiation, prednisone, chimeric antigen receptor
• Locations: 1 site (Duarte, California)
• Trial ID: NCT04484012 on ClinicalTrials.gov

What this trial studies

This phase II trial evaluates the safety and effectiveness of combining CD19 chimeric antigen receptor (CAR) T cells with acalabrutinib for patients with relapsed or refractory mantle cell lymphoma. The study aims to determine the complete response rate within six months and assess the overall safety profile of this combination therapy. Patients will receive acalabrutinib orally and CD19 CAR T cells intravenously, with the potential for a second CAR T cell infusion if the initial response is inadequate. The trial also explores various secondary and exploratory objectives related to treatment response and immune cell activity.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with documented CD19 positive mantle cell lymphoma that has relapsed or is refractory to previous treatments.

Not a fit: Patients with mantle cell lymphoma that is not CD19 positive or those who have not previously received treatment may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new effective option for patients with difficult-to-treat mantle cell lymphoma.

How similar studies have performed: Other studies have shown promise with CAR T cell therapies in hematological malignancies, suggesting potential success for this approach.

Eligibility criteria

Inclusion Criteria Informed Consent and Willingness to Participate

1. All participants must have the ability to understand and the willingness to sign a written informed consent.
2. Participants must agree to allow the use of archival tissue from diagnostic tumor biopsies.

   * If unavailable, exceptions may be granted with Study PI approval. Note: For research participants who do not speak English, a short form consent may be used with a COH certified interpreter/translator to proceed with screening and leukapheresis, while the request for a translated full consent is processed.

   Age Criteria
3. Age 18 years and older. Performance Status
4. ECOG Performance status ≤ 2 or KPS ≥ 70% (Appendix A) Nature of Illness and Treatment-Related Criteria
5. Documented CD19+ MCL by flow cytometry or IHC (from biopsy) if prior CD19 directed therapy was previously used

   a. BM is optional at enrollment IF patient already has biopsy proven disease.
6. Participants must be currently receiving acalabrutinib and have been taking acalabrutinib for between 3 and 7 months prior to initiating screening procedures on the study and:

   1. must have at least 1 prior regimen (not including single-agent corticosteroids)
   2. best response to acalabrutinib therapy is MRD+ CR, PR or SD at the time of screening b (1) must have measurable disease by CT scan (≥ 1.5 cm) or evidence of blood, spleen, skin, gastrointestinal (GI) or bone marrow involvement Note: Participants who are on other BTK inhibitors, but will thereafter be switched to acalabrutinib prior to lymphodepletion, may be eligible provided that the duration of all BTK inhibitor therapy was ≤ 3-7 months
7. No contraindications to leukapheresis, steroids or tocilizumab Clinical Laboratory Criteria (To be performed within 28 days prior to enrollment)
8. Total serum bilirubin ≤ 2.0 mg/dL Participants with Gilbert syndrome may be included if their total bilirubin is ≥ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN.
9. Blood counts:

   * Absolute Neutrophil count (ANC ≥1000 cells/ul)\*

     * Growth factor use within 7 days prior screening is not allowed
   * Platelet count ≥75,000/ul. Transfusion with 7 days prior to screening is not allowed\* \*Exception: participants with bone marrow involvement do not need to meet this criteria
10. AST \< 3 x ULN
11. ALT \< 3 x ULN
12. Creatinine clearance of ≥ 50 mL/min per the Cockcroft-Gault formula
13. International Normalized Ratio (INR) OR Prothrombin (PT) ≤ 1.5 x ULN
14. Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN
15. Female of childbearing potential: negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
16. Cardiac function (12 lead-ECG): QTc must be ≤ 480 msec
17. Left ventricular ejection fraction \>40%
18. Oxygen saturation 92% or above at room air or DLCO of 40% of best predicted Contraception
19. Participants of reproductive potential must agree to use highly effective birth control methods throughout therapy and for 2 months after final CAR T cell infusion and/or 2 days after final acalabrutinib dose, whichever is later (See Section 5.12 and Appendix B).

Exclusion Criteria Previous therapies

1. Allogeneic hematopoietic cell transplantation (HCT) within the last 6 months.
2. Autologous HCT within the last 3 months.
3. Prior failure of any BTK inhibitor therapy. (Participant WILL be allowed if, after administration of other BTK inhibitors they have switched to acalabrutinib prior to lymphodepletion, and if the duration of all BTK inhibitor therapy was ≤ 3-7 months).
4. Participants known to have mutations associated with resistance to BTK inhibitors from prior studies.

   Concomitant therapies
5. Concurrent use of systemic steroids or chronic use of immunosuppressant medications. Recent or current use of inhaled steroids is not exclusionary. Physiologic replacement of steroids (i.e., prednisone ≤ 7.5 mg /day, or hydrocortisone ≤ 20 mg /day) is allowed. During study participation, participants may receive systemic corticosteroids as needed for treatment-emergent comorbid conditions.
6. Approved anti-cancer therapies other than acalabrutinib are not allowed after enrollment, with the exception of steroids or involved field radiation to control progressive disease during cell manufacturing, prior to lymphodepletion/start of protocol therapy.
7. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer.
8. Unable to discontinue anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of leukapheresis and remain off through end of study treatment.

   Other illnesses or conditions
9. Class III/IV cardiovascular disability according to the New York Heart Association Classification. Subjects with controlled, asymptomatic atrial fibrillation can enroll.
10. Participants with clinically significant arrhythmia or arrhythmias not stable on medical management.
11. Active auto-immune disease requiring systemic immunosuppressive therapy, including uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP).
12. Suspected or confirmed progressive multifocal leukoencephalopathy (PML).
13. Requires major surgical procedure within 28 days prior to first dose of study drug. If a subject has major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
14. Participants with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system.
15. Known history of drug-specific hypersensitivity or anaphylaxis to either study agent.
16. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
17. Known bleeding disorders (e.g., von Willebrand's disease or hemophilia)
18. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
19. History of other malignancies, except for the following: malignancy surgically resected (or treated with other modalities) with curative intent, adequately treated in situ carcinoma of the breast or cervix uteri, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; early stage prostate cancer on expectant management; malignancy treated with curative intent with no known active disease present for ≥ 3 years.
20. Lactating women.
21. Active chronic graft-versus-host disease (GVHD) post-allogeneic HCT.
22. Uncontrolled active infection:

    * HIV positive or have active hepatitis B or C infection based on testing performed within 4 weeks of enrollment.
    * Hepatitis B or C serologic status: subjects 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) result. Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded.
    * Subjects who are hepatitis B core antibody positive (or have a known history of HBV infection) should be monitored quarterly with a quantitative PCR test for HBV DNA. HBV monitoring should last until 12 months after last dose of study drug. Any subject with a rising viral load (above lower limit of detection) should discontinue study drug and have antiviral therapy instituted and a consultation with a physician with expertise in managing hepatitis B. Subjects who are core Ab positive at study enrollment are strongly recommended to start Entecavir before start and until completion of study treatment.
    * 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.
    * Subjects who are positive cytomegalovirus \[CMV\] DNA polymerase chain reaction \[PCR\]).
    * Subject with any active significant bacterial, fungal or viral (other than those listed) infections.
23. Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns with clinical study procedures.

    Noncompliance
24. 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).

    * Eligibility should be confirmed per institutional policies.

Where this trial is running

Duarte, California

• City of Hope Comprehensive Cancer Center — Duarte, California, United States (Recruiting)

Study contacts

• Principal investigator: Lihua E Budde — City of Hope Medical Center

Conditions Recurrent Mantle Cell Lymphoma; Refractory Mantle Cell Lymphoma