Clinical Trials /

CD19/22 CAR T Cells (AUTO3) for the Treatment of Diffuse Large B Cell Lymphoma

NCT03287817

Description:

The purpose of this study is to test the safety and efficacy of AUTO3, a CAR T cell treatment targeting CD19 and CD22 followed by limited duration of anti-PD1 antibody in patients with DLBCL

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
  • High Grade B-Cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements
  • High Grade B-Cell Lymphoma, Not Otherwise Specified
  • Primary Mediastinal B-Cell Lymphoma
  • Transformed Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: CD19/22 CAR T Cells (AUTO3) for the Treatment of Diffuse Large B Cell Lymphoma
  • Official Title: A Single Arm, Open-label, Multi-centre, Phase I/II Study Evaluating the Safety and Clinical Activity of AUTO3, a CAR T Cell Treatment Targeting CD19 and CD22 With Anti PD1 Antibody in Patients With Relapsed or Refractory Diffuse Large B Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: AUTO3-DB1
  • SECONDARY ID: 2016-004682-11
  • NCT ID: NCT03287817

Conditions

  • Diffuse Large B Cell Lymphoma
  • Relapsed Diffuse Large B-Cell Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma
  • DLBCL

Interventions

DrugSynonymsArms
AUTO3AUTO3

Purpose

The purpose of this study is to test the safety and efficacy of AUTO3, a CAR T cell treatment targeting CD19 and CD22 followed by limited duration of anti-PD1 antibody in patients with DLBCL

Detailed Description

      The study will consist of 2 phases, a Phase I or dose escalation phase and a Phase II or
      expansion phase. Patients with relapsed or refractory DLBCL will be enrolled in both phases
      of the study. Eligible patients will undergo leukapheresis in order to harvest T cells, which
      is the starting material for the manufacture of the autologous CAR T product AUTO3 which is a
      CD19 and CD22 dual targeting CAR T cell product. Following pre-conditioning by a
      chemotherapeutic regimen, the patient will receive AUTO 3 intravenously as a single dose and
      in addition a limited duration of treatment with an anti-PD1 antibody (either as part of the
      pre-conditioning regimen or consolidation). Patients will then enter a 24-month follow-up
      period.
    

Trial Arms

NameTypeDescriptionInterventions
AUTO3ExperimentalPatient with relapsed or refractory DLBCL
  • AUTO3

Eligibility Criteria

        Inclusion Criteria:

          1. Male or female, aged ≥18 years.

          2. Willing and able to give written, informed consent.

          3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1.

          4. Histologically confirmed DLBCL and large B cell lymphoma (at last relapse) subsets,
             including:

             Phase I and Phase II Cohort 1:

               1. DLBCL, not otherwise specified (NOS), per World Health Organisation
                  classification and DLBCL with MYC and BCL2 and/or BCL6 rearrangements
                  (double/triple hit).

               2. Transformed DLBCL from FL.

               3. High-grade B cell lymphoma with MYC expression (excluding Burkitt's lymphoma)

                  Phase I and Phase II Cohort 2:

               4. Transformed DLBCL from other indolent lymphomas (excluding Richter's
                  transformation).

               5. Primary mediastinal large B cell lymphoma.

          5. Chemotherapy-refractory disease, defined as one or more of the following:

               1. Stable disease (≤12 months) or progressive disease as best response to most
                  recent chemotherapy containing regimen. Refractory disease after frontline
                  chemo-immunotherapy is allowed.

               2. Disease progression or recurrence in ≤12 months of prior autologous
                  haematopoietic stem cells transplantation (ASCT).

             OR

          6. Relapse after ≥two lines of therapy or after ASCT. At a minimum:

               1. Patients must have received rituximab or another anti-CD20 monoclonal antibody
                  (unless Investigator determines that tumour is CD20-negative) and an
                  anthracycline-containing chemotherapy regimen.

               2. Patients must have either failed ASCT, or be ineligible for or not consenting to
                  ASCT.

               3. Patients with transformed DLBCL must have received at least one line of therapy
                  after transformation to DLBCL.

          7. PET-positive disease per Lugano classification.

          8. For females of childbearing potential, a negative serum or urine pregnancy test must
             be documented at screening, prior to pre-conditioning and confirmed before receiving
             the first dose of study treatment.

             For females who are not postmenopausal or surgically sterile, highly effective methods
             of contraception must be used during the treatment period and for at least 12 months
             after the last dose of study treatment.

          9. For males, it must be agreed that that two acceptable methods of contraception are
             used.

         10. Adequate renal, hepatic, pulmonary, and cardiac function defined as:

               1. Creatinine clearance ≥40 cc/min.

               2. Serum alanine aminotransferase / aspartate aminotransferase ≤2.5 x ULN.

               3. Total bilirubin ≤1.5 x ULN, except in subjects with Gilbert's syndrome.

               4. LVEF ≥50% (by ECHO or MUGA) unless the institutional lower limit of normal is
                  lower.

               5. Baseline oxygen saturation >92% on room air and ≤Grade 1 dyspnoea.

         11. Patient has adequate BM function without requiring ongoing blood product or
             granulocyte-colony stimulating factor support and meets the following criteria:

               1. Absolute neutrophil count ≥1.0 × 109/L.

               2. Absolute lymphocyte count ≥0.3 × 109/L (at enrolment and prior to leukapheresis).

               3. Haemoglobin ≥80 g/L.

               4. Platelets ≥75 × 109/L

         12. No contra-indications for leukapheresis.

        Exclusion Criteria:

          1. Prior allogeneic haematopoietic stem cell transplant.

          2. Females who are pregnant or lactating.

          3. History or presence of clinically relevant CNS pathology such as epilepsy, paresis,
             aphasia, stroke within prior 3 months, severe brain injuries, dementia, Parkinson's
             disease, cerebellar disease, organic brain syndrome, uncontrolled mental illness, or
             psychosis.

          4. Patients with active CNS involvement by malignancy. Patients with history of CNS
             involvement with malignancy may be eligible if CNS disease has been effectively
             treated and provided treatment was at least 4 weeks prior to enrolment (at least 8
             weeks prior to AUTO3 infusion).

          5. Clinically significant, uncontrolled heart disease or a recent (within 12 months)
             cardiac event.

               1. Uncontrolled cardiac arrhythmia (patients with rate-controlled atrial
                  fibrillation are not excluded).

               2. Evidence of pericardial effusion

          6. Patients with a history (within 3 months) or evidence of deep vein thrombosis or
             pulmonary embolism requiring ongoing therapeutic anticoagulation at the time of
             pre-conditioning.

          7. Patients with active gastrointestinal bleeding.

          8. Patients with any major surgical intervention in the last 3 months.

          9. Active bacterial, viral or fungal infection requiring systemic treatment. Active or
             latent hepatitis B infection or hepatitis C infection. Testing positive for human
             immunodeficiency virus, human T cell lymphotropic virus (HTLV1 and 2) or syphilis.

         10. History of autoimmune disease resulting in end organ injury or requiring systemic
             immunosuppression/systemic disease modifying agents within the last 24 months.

         11. Patients with a known history or prior diagnosis of optic neuritis or other
             immunologic or inflammatory disease affecting the CNS.

         12. Evidence of active pneumonitis on chest computed tomography (CT) scan at screening or
             history of drug-induced pneumonitis, idiopathic pulmonary fibrosis, organising
             pneumonia, or idiopathic pneumonitis.

         13. History of other malignant neoplasms unless disease free for at least 24 months
             (carcinoma in situ, non-melanoma skin cancer, breast or prostate cancer on hormonal
             therapy allowed).

         14. Prior treatment with PD1, PD-L1, or cytotoxic T lymphocyte-associated
             protein-4-targeted therapy, or tumour necrosis factor (TNF) receptor superfamily
             agonists within 6 weeks prior to AUTO3 infusion.

         15. Prior treatment with investigational or approved gene therapy or cell therapy products
             until a dose level has treated at least three patients and has been declared safe.

         16. Prior CD19 or CD22 targeted therapy.

         17. The following medications are excluded:

               1. Steroids: Therapeutic doses of corticosteroids within 7 days of leukapheresis or
                  72 hours prior to AUTO3 administration. However, physiological replacement,
                  topical, and inhaled steroids are permitted.

               2. Immunosuppression: Immunosuppressive medication must be stopped ≥2 weeks prior to
                  leukapheresis or AUTO3 infusion.

               3. Cytotoxic chemotherapies within 2 weeks of AUTO3 infusion and 1 week prior to
                  leukapheresis (2 weeks for lymphodepleting chemotherapy).

               4. Antibody therapy use including anti-CD20 therapy within 2 weeks prior to AUTO3
                  infusion, or 5 half-lives of the respective antibody, whichever is shorter.

               5. Granulocyte-colony stimulating factor less than 10 days prior to leukapheresis.

               6. Live vaccine ≤4 weeks prior to enrolment.

               7. Prophylactic intrathecal therapy: Methotrexate within 4 weeks and other
                  intrathecal chemotherapy (e.g. Ara-C) within 2 weeks prior to starting
                  pre-conditioning chemotherapy.

         18. Prior limited radiation therapy within 4 weeks of AUTO3 infusion or within 24 weeks
             for definitive radiation to chest.

         19. Research participants receiving any other investigational agents, or concurrent
             biological, chemotherapy, or radiation therapy.

         20. Known allergy to albumin, dimethyl sulphoxide (DMSO), cyclophosphamide or fludarabine,
             pembrolizumab or tocilizumab.

         21. Any contraindications to receive anti-PD1 antibody pembrolizumab will be excluded from
             cohorts requiring administration of pembrolizumab.

         22. Patients, who in the opinion of the Investigator, may not be able to understand or
             comply with the safety monitoring requirements of the study.

         23. Any other condition that in the Investigator's opinion would make the patient
             unsuitable for the clinical trial.

        For AUTO3 Infusion: Patients meeting any of the following exclusion criteria must not be
        treated with AUTO3 or have treatment delayed until they no longer meet these criteria:

          1. Severe intercurrent infection.

          2. Requirement for supplementary oxygen or active pulmonary infiltrates.

          3. Clinical deterioration of organ function (renal and hepatic) exceeding the criteria
             set at study entry.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I - Safety (incidence of Grade 3-5 toxicities) and confirmation of phase II dose and schedule.
Time Frame:Within 75 days of AUTO3 infusion.
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Feasibility of generating AUTO3: number of patients' cells successfully manufactured as a proportion of the number of patients undergoing leukapheresis.
Time Frame:Up to 8 weeks post leukapheresis.
Safety Issue:
Description:
Measure:Complete response rate, as per Lugano criteria.
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Duration of response (DOR).
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Progression-free survival (PFS).
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Overall survival (OS).
Time Frame:Up to 2 years
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Autolus Limited

Trial Keywords

  • Diffuse Large B Cell Lymphoma
  • Relapsed Diffuse Large B Cell Lymphoma
  • Refractory Diffuse Large B Cell Lymphoma
  • AUTO3
  • PD-1
  • Anti PD-1 antibody

Last Updated

February 24, 2020