Immunotherapy using CAR T-cells for treating high-risk blood cancers

Immunotherapy for High Risk/Relapsed CD19+ Acute Lymphoblastic Leukaemia, B-cell Non-Hodgkin's Lymphoma (B-NHL) and Chronic Lymphocytic Leukaemia (CLL)/ Small Lymphocytic Lymphoma (SLL) Using CAR T-cells to Target CD19

This study is testing a new treatment using modified immune cells to see if it can help adults with high-risk blood cancers like leukemia and lymphoma feel better and live longer.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 60 (estimated)
• Ages: 16 Years and up
• Sex: All
• Sponsor: University College, London (Academic / other)
• Drugs / interventions: Rituximab, blinatumomab, Pembrolizumab, Ibrutinib, CAR T, radiation, chemotherapy, cyclophosphamide, fludarabine
• Locations: 1 site (London)
• Trial ID: NCT02935257 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the safety and efficacy of a gene therapy product, specifically CD19CAR T-cells, in adults with high-risk or relapsed forms of CD19+ B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). Participants will undergo a procedure to collect their own T-cells, which will then be genetically modified to target CD19, a protein found on the surface of these cancer cells. Following the modification, patients will receive lymphodepleting chemotherapy to prepare their bodies for the CAR T-cell infusion. The study aims to assess how well these modified cells can control or eliminate the cancer and how long the response lasts.

Who should consider this trial

Good fit: Ideal candidates are adults aged 16 and older with high-risk or relapsed/refractory CD19+ B-ALL, DLBCL, CLL/SLL, FL, or MCL who have undergone at least two prior lines of therapy.

Not a fit: Patients with CD19 negative disease or those with overt central nervous system involvement may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new, effective option for patients with high-risk or relapsed blood cancers that have not responded to standard therapies.

How similar studies have performed: Other studies using CAR T-cell therapy for similar conditions have shown promising results, indicating a potential for success in this approach.

Eligibility criteria

Inclusion Criteria:

1. Age ≥162. B-ALL: high risk or relapsed histologically confirmed CD19+ B-ALL following standard therapy requiring salvage in whom alternative therapies are deemed inappropriate by their treating physician Or DLBCL: relapsed/refractory DLBCL (incl. transformed FL but not Richter's transformation) following ≥2 prior lines of therapy including Rituximab and anthracycline Or CLL/SLL: relapsed/refractory CLL/SLL following ≥2 prior lines of therapy including Ibrutinib or other Bruton's Tyrosine Kinase (BTK) inhibitors Or Follicular Lymphoma which is relapsed / refractory following ≥2 prior lines of therapy Or Mantle Cell Lymphoma which is relapsed / refractory following ≥2 prior lines of therapy 3. Agreement to have a pregnancy test, use adequate contraception (if applicable) 4.Written informed consent

Exclusion criteria for registration:

1. CD19 negative disease
2. B-ALL and CLL: overt CNS involvement (i.e.: patients with CNS2 with neurological symp-toms or patients with CNS3; appendix 2)
3. DLBCL, FL, MCL and CLL/SLL: primary or secondary CNS lymphoma
4. Isolated extramedullary disease (B-ALL and CLL)
5. Active hepatitis B, C or HIV infection
6. Oxygen saturation ≤ 90% on air
7. Bilirubin \>2 x upper limit of normal
8. GFR \<50ml/min
9. Women who are pregnant or breast feeding
10. Stem Cell Transplant patients only: active significant acute GVHD (overall Grade ≥ II, Seattle criteria) or moderate/severe chronic GVHD (NIH consensus criteria) requiring im-munosuppressive therapy and/or systemic steroids
11. Inability to tolerate leucapheresis
12. Karnofsky score \<60% (see appendix 3)
13. Patients who have experienced significant neurotoxicity following blinatumomab
14. Known allergy to albumin or DMSO
15. Life expectancy \<3months
16. Significant cardiac disease, left ventricular ejection fraction \<40% and uncontrolled cardiac arrhythmias (patients with rate-controlled atrial fibrillation are not excluded)
17. Pre-existing neurological disorders (other than CNS involvement of underlying haemato-logical malignancy)
18. DLBCL only:

    * Any contraindications to PD-1 antibody Pembrolizumab
    * History of autoimmune disease (e.g. Crohn's, rheumatoid arthritis, systemic lupus) re-sulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 24 months
    * Evidence of active pneumonitis on chest computed tomography (CT) scan at screening or history of drug-induced pneumonitis, idiopathic pulmonary fibrosis, organising pneu-monia (e.g. bronchiolitis obliterans), or idiopathic pneumonitis. Prior radiation pneu-monitis in the radiation field (fibrosis) is allowed (if \>24 weeks since the event)
    * Chest/mediastinal radiation within 24 weeks of CAR T-cellinfusion

Exclusion criteria: for CD19CAR T-cell infusion at Day 0 (all patients):

1. Severe intercurrent infection at the time of scheduled CD19CAR T-cell infusion
2. Requirement for supplementary oxygen or active pulmonary infiltrates at the time of scheduled CD19CAR T-cell infusion
3. Allogeneic transplant recipients with active significant acute GVHD overall grade ≥II or moderate/severe chronic GVHD requiring systemic steroids or other immunosuppres-sion at the time of scheduled CD19CAR T-cell infusion. Note: Such patients will be ex-cluded until the patient is GVHD free and off steroids

Exclusion criteria: for supplementary CD19CAR T-cell infusion Day 9 (B-ALL and CLL/SLL patients):

1. Severe intercurrent infection at the time of scheduled CD19CAR T-cell infusion
2. Requirement for supplementary oxygen or active pulmonary infiltrates at the time of scheduled CD19CAR T-cell infusion
3. Grade 3-4 CRS and or grade 3-4 neurotoxicity following Day 0 CD19CAR T-cell dose
4. Grade 1-2 neurotoxicity (if occurred) following Day 0 CD19CAR T-cell dose that has not fully resolved prior to proposed administration of 2nd CD19CAR T-cell dose
5. Persisting Grade 2 CRS following Day 0 CD19CAR T-cell dose that has not resolved to ≤ Grade 1 CRS prior to proposed administration of 2nd CD19CAR T-cell dose
6. Allogeneic transplant recipients with active significant acute GVHD overall grade ≥II or moderate/severe chronic GVHD requiring systemic steroids or other immunosuppression at the time of scheduled CD19CAR T-cell infusion\* \*Note: Such patients will be excluded until the patient is GVHD free and off steroids

Where this trial is running

London

• University College London Hospital — London, United Kingdom (Recruiting)

Study contacts

• Study coordinator: ALLCAR19 Trial Coordinator

Conditions Leukemia, Lymphoblastic, Acute, Lymphoma