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

This study is currently recruiting participants.
Verified September 2017 by Autolus Limited
Sponsor:
ClinicalTrials.gov Identifier:
NCT03287817
First Posted: September 19, 2017
Last Update Posted: November 2, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Autolus Limited
  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 consolidation with anti-PD1 antibody in patients with DLBCL

Condition Intervention Phase
Diffuse Large B Cell Lymphoma Relapsed Diffuse Large B-Cell Lymphoma Refractory Diffuse Large B-Cell Lymphoma DLBCL Biological: AUTO3 Phase 1 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Intervention Model Description:
A dose escalation phase (Phase 1) followed by a dose expansion phase (Phase 2; to further assess the recommended Phase II dose [RP2D]).
Masking: None (Open Label)
Primary Purpose: Treatment
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 Followed by Consolidation With Anti PD1 Antibody in Patients With Relapsed or Refractory Diffuse Large B Cell Lymphoma

Resource links provided by NLM:


Further study details as provided by Autolus Limited:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 120
Actual Study Start Date: September 5, 2017
Estimated Study Completion Date: March 2021
Estimated Primary Completion Date: March 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: AUTO3
Patient with relapsed or refractory DLBCL
Biological: AUTO3
Following preconditioning with chemotherapy (cyclophosphamide and fludarabine) patients will be treated with doses from 50 x 10⁶ to 300 x 10⁶ CD19/ CD22 Chimeric Antigen Receptor (CAR) positive T cells followed by limited duration of consolidation with anti-PD1 antibody (pembrolizumab).

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 following which they will receive limited duration of consolidation therapy with an anti-PD1 antibody and will then enter a 24-month follow-up period
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 (at last relapse) and subsets.
  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).
  6. Relapse after ≥two lines of therapy or after ASCT.
  7. At least one measurable lesion per revised International Working Group Response Criteria.
  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 a barrier method of contraception should be used.
  10. Adequate renal, hepatic, pulmonary, and cardiac function defined as:

    1. Creatinine clearance (as estimated by Cockcroft Gault) ≥60 cc/min.
    2. Serum alanine aminotransferase / aspartate aminotransferase ≤2.5 x ULN.
    3. Total bilirubin ≤25 µmol/L (1.5 mg/dL), 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 bone marrow function without the requirement for ongoing blood products or granulocyte-colony stimulating factor support within 21 days prior to pre conditioning.

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

  1. Creatinine clearance (as estimated by Cockcroft Gault) ≥60 cc/min.
  2. Serum alanine aminotransferase / aspartate aminotransferase ≤2.5 x ULN.
  3. Total bilirubin ≤25 µmol/L (1.5 mg/dL), 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. 12. No contra-indications for leukapheresis.

Exclusion Criteria:

  1. Prior allogeneic haematopoietic stem cell transplant.
  2. Females who are pregnant or lactating.
  3. 13. 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. Current or history of CNS involvement by malignancy.
  5. Clinically significant, uncontrolled heart disease or a recent (within 12 months) cardiac event.
  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 infectious bacterial or viral disease or fungal requiring treatment.
  10. History of autoimmune disease resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years.
  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 neoplasms unless disease free for at least 2 years (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.
  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 with any Grade 4 toxicity or ≥refractory Grade 3 cytokine release syndrome (CRS), or ≥ Grade 3 drug-related CNS toxicity.
  17. The following medications are excluded:

    a 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.

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

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

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

    e Live vaccine ≤4 weeks prior to enrolment.

  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.

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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03287817


Contacts
Contact: Autolus Limited +44 (0)2038296230 contact@autolus.com

Locations
United Kingdom
University College London Hospitals NHS Foundation Trust Recruiting
London, United Kingdom
Principal Investigator: Dr Kirit Ardeshna         
The Christie NHS Foundation Trust Not yet recruiting
Manchester, United Kingdom
Principal Investigator: Dr Adrian Bloor         
Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust Not yet recruiting
Newcastle upon Tyne, United Kingdom
Principal Investigator: Dr Wendy Osborne         
Sponsors and Collaborators
Autolus Limited
Investigators
Study Director: Autolus Limited Sponsor GmbH
  More Information

Responsible Party: Autolus Limited
ClinicalTrials.gov Identifier: NCT03287817     History of Changes
Other Study ID Numbers: AUTO3-DB1
2016-004682-11 ( EudraCT Number )
First Submitted: September 11, 2017
First Posted: September 19, 2017
Last Update Posted: November 2, 2017
Last Verified: September 2017

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

Keywords provided by Autolus Limited:
Diffuse Large B Cell Lymphoma
CD19 Positive
CD22 Positive
Relapsed Diffuse Large B Cell Lymphoma
Refractory Diffuse Large B Cell Lymphoma
AUTO3
PD-1
Anti PD-1 antibody

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Antibodies
Immunologic Factors
Physiological Effects of Drugs