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

• ClinicalTrials.gov Identifier: NCT03287817
• Recruitment Status: Active, not recruiting
• First Posted: September 19, 2017
• Last Update Posted: October 20, 2022
• Sponsor: Autolus Limited
• Information provided by (Responsible Party): Autolus Limited

Tracking Information

• First Submitted Date: September 11, 2017
• First Posted Date: September 19, 2017
• Last Update Posted Date: October 20, 2022
• Actual Study Start Date: September 5, 2017
• Estimated Primary Completion Date: November 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 12, 2020)

• Phase I Escalation - Safety (incidence of Grade 3-5 toxicities) and identification of recommended Phase II dose and schedule. [ Time Frame: Within 75 days of AUTO3 infusion ]
• Phase I Expansion - Safety (incidence of Grade 3-5 toxicities) in the outpatient / ambulatory care setting [ Time Frame: Within 75 days of AUTO3 infusion ]
• Phase II - Overall response rate as per Lugano criteria [ Time Frame: Up to 2 years ]

Original Primary Outcome Measures (submitted: September 18, 2017)

• 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. ]
• Phase II - Overall response rate as per Lugano criteria [ Time Frame: Up to 2 years ]

Current Secondary Outcome Measures (submitted: September 18, 2017)

• 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. ]
• Complete response rate, as per Lugano criteria. [ Time Frame: Up to 2 years ]
• Duration of response (DOR). [ Time Frame: Up to 2 years ]
• Progression-free survival (PFS). [ Time Frame: Up to 2 years ]
• Overall survival (OS). [ Time Frame: Up to 2 years ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• Brief Summary: 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 and expansion phase, and a Phase II. 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 36-month follow-up period.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

A dose escalation and expansion phase (Phase I) followed by Phase II

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

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

Intervention

Biological: AUTO3

Following preconditioning with chemotherapy (cyclophosphamide and fludarabine) patients will be treated with doses from 50 x 10⁶ to 900 x 10⁶ CD19/ CD22 Chimeric Antigen Receptor (CAR) positive T cells followed by limited duration of anti-PD1 antibody (pembrolizumab).

Study Arms

Experimental: AUTO3

Patient with relapsed or refractory DLBCL

Intervention: Biological: AUTO3

• Publications *: Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: November 19, 2021): 73
• Original Estimated Enrollment (submitted: September 18, 2017): 120
• Estimated Study Completion Date: November 2024
• Estimated Primary Completion Date: November 2024 (Final data collection date for primary outcome measure)

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.

    Phase I outpatient cohort:

24. Subjects who do not have caregiver support (in line with institutional outpatient transplant guidelines) for outpatient/ambulatory care setting.
25. Subjects who are staying greater than 60 minutes (or whatever is permissible per institutional outpatient transplant guidelines) from the clinical trial site at the time of treatment.

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom, United States
• Removed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT03287817
• Other Study ID Numbers: AUTO3-DB1; 2016-004682-11 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Autolus Limited
• Original Responsible Party: Same as current
• Current Study Sponsor: Autolus Limited
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Autolus Limited
• Verification Date: October 2022