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Phase I/II Study Evaluating AUTO4 in Patients With TRBC1 Positive T Cell Lymphoma

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ClinicalTrials.gov Identifier: NCT03590574
Recruitment Status : Recruiting
First Posted : July 18, 2018
Last Update Posted : January 16, 2019
Sponsor:
Information provided by (Responsible Party):
Autolus Limited

Brief Summary:
The purpose of this study is to test the safety and efficacy of AUTO4 a CAR T cell treatment targeting TRBC1 in patients with relapsed or refractory TRBC1 positive selected T-Non-Hodgkin Lymphoma.

Condition or disease Intervention/treatment Phase
T Cell Non-Hodgkin Lymphoma Peripheral T-Cell Lymphoma, Not Otherwise Specified Angioimmunoblastic T-cell Lymphoma Anaplastic Large Cell Lymphoma Biological: AUTO4 Phase 1 Phase 2

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 TRBC1 positive selected T-Non-Hodgkin Lymphoma 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 AUTO4 which is a TRBC1 targeting CAR T cell product. Following pre-conditioning by a chemotherapeutic regimen, the patient will receive AUTO4 intravenously as a single dose following which they will then enter a 24-month follow-up period

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 55 participants
Intervention Model: Single Group Assignment
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 AUTO4, a CAR T-cell Treatment Targeting TRBC1, in Patients With Relapsed or Refractory TRBC1 Positive Selected T Cell Non-Hodgkin Lymphoma
Actual Study Start Date : July 16, 2018
Estimated Primary Completion Date : July 2021
Estimated Study Completion Date : December 2022


Arm Intervention/treatment
Experimental: AUTO4
Relapsed or refractory T cell non-Hodgkin Lymphoma patients
Biological: AUTO4
AUTO4 (RQR8/aTRBC1 CAR T cells) Following pre-conditioning with chemotherapy (cyclophosphamide and fludarabine) patients will be treated with doses from 25 to 225 x 10^6 RQR8/aTRBC1 CAR T cells. Following Phase 2 dose determination patients will be treated with selected doses of RQR8/aTRBC1 CAR T cells (AUTO4).




Primary Outcome Measures :
  1. Phase I: Safety (Frequency and severity of adverse events and serious AEs) and confirmation of Phase II dose and schedule. [ Time Frame: 24 months post treatment ]
  2. Phase II: Objective Response (CR + PR) Rate post AUTO4 infusion. [ Time Frame: 24 months post treatment ]

Secondary Outcome Measures :
  1. Assess overall safery and tolerability in terms of frquecny and severity of all AEs and SAEs and incidence and severity of opportunistic infections following AUTO4 infusion. [ Time Frame: 24 months post treatment ]
  2. Feasibility of generating AUTO4: Number of patients whose cells achieve successful AUTO4 manufacture as a proportion of the number of patients undergoing leukapheresis. [ Time Frame: Up to 8 weeks post leukapheresis ]
  3. Time to response (PR and CR) [ Time Frame: 24 months post treatment ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
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 to be screened for TRBC1 positive T-NHL and to enter the main study.
  3. Confirmed diagnosis of selected T-NHL, including:

    1. Peripheral T cell lymphoma NOS, or
    2. Angioimmunoblastic T cell lymphoma, or
    3. Anaplastic large cell lymphoma
  4. Confirmed TRBC1 positive tumour.
  5. Relapsed or refractory disease and have had ≥1 prior lines of therapy.
  6. Has measurable disease with ≥1 measurable lesion(s).
  7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
  8. Adequate bone marrow function without the requirement for ongoing blood products and meets the following criteria:

    1. Absolute neutrophil count ≥1.0 x 109/L
    2. Absolute lymphocyte count ≥0.5 x 109/L (at entry and prior to leukapheresis).
    3. Haemoglobin ≥80 g/L
    4. Platelets ≥75 x 109/L
  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 upper limit of normal (ULN).
    3. Total bilirubin ≤25 µmol/L (1.5 mg/dL), except in patients with Gilbert's syndrome.
    4. Left ventricular ejection fraction (LVEF) ≥50% by echocardiogram (ECHO) or multiple gated acquisition (MUGA) cardiac scan, unless the institutional lower limit of normal is lower.
    5. Baseline oxygen saturation ≥92% on room air and ≤Grade 1 dyspnoea.
  10. For females of childbearing potential (defined as <2 years after last menstruation or not surgically sterile), 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 (<24 months of amenorrhea) or who are not surgically sterile (absence of ovaries and/or uterus), a highly effective method of contraception together with a barrier method must be used from the start of the pre-conditioning stage and for at least 12 months after the last dose of AUTO4 (study treatment). They must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 12 months after receiving the last dose of study drug
  11. For males, it must be agreed that two acceptable methods of contraception are used from the start of the pre-conditioning stage and for at least 12 months after the last dose of AUTO4 (one by the patient - usually a barrier method, and one by the patient's partner. Also, that sperm will not be donated during the treatment period and for at least 12 months after the last dose of study treatment.
  12. No contra-indications for leukapheresis, or the pre-conditioning regimen.

Exclusion Criteria:

Patients meeting any of the following exclusion criteria must not be enrolled into the study:

  1. Patients with T cell leukaemia.
  2. Females who are pregnant or lactating.
  3. Prior treatment with investigational gene therapy or approved gene therapy or genetically engineered cell therapy product or allogeneic stem cell transplant.
  4. Known history or presence of clinically relevant central nervous system (CNS) pathology. Patients with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the CNS.
  5. Current or history of CNS involvement by malignancy.
  6. Clinically significant, uncontrolled heart disease

    1. Uncontrolled cardiac arrhythmia (patients with rate-controlled atrial fibrillation are not excluded).
    2. Evidence of pericardial effusion.
  7. Patients with evidence of uncontrolled hypertension or with a history of hypertension crisis or hypertensive encephalopathy.
  8. 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.
  9. Patients with active gastrointestinal (GI) bleeding.
  10. Patients with any major surgical intervention in the last 3 months.
  11. Active infectious bacterial, viral disease or fungal disease (hepatitis B virus, hepatitis C virus, human immunodeficiency virus [HIV], human T cell lymphotropic virus [HTLV] or syphilis) requiring treatment.
  12. Active autoimmune disease requiring immunosuppression.
  13. History of other neoplasms unless disease free for at least 2 years (adequately treated carcinoma in situ, curatively treated non-melanoma skin cancer, breast or prostate cancer on hormonal therapy are allowed).
  14. Prior treatment with programmed cell death protein 1 (PD1), programmed death ligand 1 (PD-L1), or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) targeted therapy, or tumour necrosis factor (TNF) receptor superfamily agonists including CD134 (OX40), CD27, CD137 (41BB), and CD357 (glucocorticoid induced TNF receptor family related protein).
  15. The following medications are excluded:

    1. Steroids: Therapeutic doses of corticosteroids within 72 hours of leukapheresis or pre-conditioning chemotherapy administration.
    2. Cytotoxic chemotherapies within 2 weeks prior to leukapheresis or AUTO4 infusion.
    3. Antibody therapy use within 2 weeks prior to AUTO4 infusion, or five half-lives of the respective antibody, whichever is shorter.
    4. Live vaccine within 4 weeks prior to enrolment.
  16. Research participants receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy.
  17. Use of rituximab (or rituximab biosimilar) within the last 3 months prior to AUTO4 infusion.
  18. Patients, who in the opinion of the Investigator, may not be able to understand or comply with the safety monitoring requirements of the study.

For pre-conditioning chemotherapy and AUTO4 Infusion: Patients meeting any of the following exclusion criteria must not be treated with pre-conditioning chemotherapy or

AUTO4 - and have treatment delayed until they no longer meet these criteria:

  1. Severe intercurrent infection at the time of pre-conditioning chemotherapy or the scheduled AUTO4 infusion.
  2. Requirement for supplementary oxygen or active pulmonary infiltrates or significant deterioration of organ function at the time of pre-conditioning chemotherapy or scheduled AUTO4 infusion.
  3. Significant clinical deterioration of organ functions from screening, as determined by the investigator.

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): NCT03590574


Contacts
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Contact: Autolus Limited +44 (0)203 911 4385 clinicaltrials@autolus.com

Locations
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United Kingdom
University College London Hospitals NHS Foundation Trust Recruiting
London, United Kingdom
Contact: Dr Kate Cwynarski         
The Christie NHS Foundation Trust Not yet recruiting
Manchester, United Kingdom
Contact: Professor John Radford         
Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust Recruiting
Newcastle Upon Tyne, United Kingdom
Contact: Dr Tobias Menne         
Sponsors and Collaborators
Autolus Limited

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Responsible Party: Autolus Limited
ClinicalTrials.gov Identifier: NCT03590574     History of Changes
Other Study ID Numbers: AUTO-TL1
2017-001965-26 ( EudraCT Number )
First Posted: July 18, 2018    Key Record Dates
Last Update Posted: January 16, 2019
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Keywords provided by Autolus Limited:
T cell lymphoma
Relapsed T cell Non-Hodgkin Lymphoma
Refractory T cell Non-Hodgkin Lymphoma
AUTO4

Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, T-Cell
Lymphoma, Large-Cell, Anaplastic
Lymphoma, T-Cell, Peripheral
Immunoblastic Lymphadenopathy
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphadenopathy