Phase I Trial: T4 Immunotherapy of Head and Neck Cancer

NCT01818323 | Recruiting Phase 1 DMC

• 1 other identifier: 2012-001654-25
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The overall goal of this study is to investigate the safety of T4 immunotherapy when administered to treat loco-regional disease in Squamous Cell Cancer of the Head and Neck (SCCHN) that is not suitable for conventional active therapy. The investigators propose to conduct an open-labelled, non-randomized, dose-escalation phase I trial in which autologous T4+ T-cells are administered to patients with SCCHN. T-cells will be engineered to express a second generation chimeric antigen receptor (CAR) named T1E28z. Engineered T-cells will be injected directly into the tumour site. Patients will not be lymphodepleted. A classical 3+3 design will be employed, with dose escalation from 10\^7 through to 10\^9 transduced T4+ T-cells, dependent upon toxicity monitoring. It is anticipated that up to 30 patients will be enrolled over the course of the study.

Conditions

Head and Neck Cancer

Keywords

Chimeric antigen receptor; Immunotherapy; Head and Neck Cancer; Phase I trial; Maximum tolerated dose

Outcome Measures

Primary Outcomes (1)

• Dose limiting toxicities for T4 immunotherapy in SCCHN and determine a safe and feasible recommended dose for phase II testing of intra-tumoral T4 immunotherapy.

  Patients will be monitored intensely for the first 24 hours post T4 administration. Patients will the be assessed for signs of toxicity on days 3-4, 5-7, 8, 15, 29 and 43.

  Up to 6 weeks post T4 administration

Secondary Outcomes (6)

• To investigate serum cytokine levels after administration of T4 immunotherapy

  up to 6 weeks post T4 administration

• To investigate persistence of T4+ T-cells at the site of administration and in the peripheral circulation

  up to 6 weeks post T4 administration

• To achieve preliminary assessment of anti-tumour activity, using cross-sectional imaging to quantify objective responses

  up to 6 weeks post T4 administration

• To investigate tumour ErbB receptor phenotype, before and after administration of T4 immunotherapy

  up to 6 weeks post T4 administration

• To investigate immunomodulatory effects of metronomic cyclophosphamide on T4 immunotherapy

  up to 6 weeks post T4 administration

Study Arms (1)

Intra-tumoral T4 immunotherapy

EXPERIMENTAL

Treatment arms comprise escalating doses of T4 immunotherapy, administered alone or in combination with lymph-depleting chemotherapy

Other: Intra-tumoral T4 immunotherapy

Interventions

Intra-tumoral T4 immunotherapy OTHER

Intra-tumoral administration of a single dose of T4-positive patient-derived T-cells (at five escalating dose levels) contained within 1-4 mL. Cohort 6 patients receive CAR T-cells (dose level 3) after lymphodepletion with fludarabine and cyclophosphamide. Cohort 7-8 patients receive T4 cells after lymphodepletion as above, combined with 4 doses of nivolumab.

Also known as: 4ab T1E28z positive T-cells

Intra-tumoral T4 immunotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically and/ or cytologically confirmed SCCHN.
• years or older.
• Locally advanced and/ or recurrent head and neck cancer with or without metastatic disease (excluding brain metastases) for whom no standard therapy remains or is suitable.
• Regarding previous treatment, patients may have received prior systemic therapy, including platinum chemotherapy, at least one month earlier. In the presence of metastatic disease, recent short-course palliative radiotherapy to non-target site(s) is allowed.
• Those who refuse palliative treatment may be eligible for participation. However, their reasons for not opting for palliative treatment must be explored thoroughly.
• At least one loco-regional target lesion measurable by RECIST v1.1 criteria on CT or MRI scanning within four weeks of enrolment, and amenable to intra-tumoral injection.
• Eastern Co-operative Oncology Performance Status of 0-2.
• Normal cardiac function as assessed by electrocardiography and either echocardiography (ECHO), or multi-gated acquisition (MUGA) scanning. Left ventricular ejection fraction must be \> 50%. Assessment must take place within four weeks of enrolment.
• Haematology results within seven days of enrolment: neutrophils \>1.5 x 109/L, platelets \>100 x 109/L, haemoglobin \>9g/dl, INR \<1.5.
• Biochemistry results within seven days of enrolment: • serum creatinine \<1.5 upper limit of normal • bilirubin \<1.25 times normal; • ALT/ AST \<2.5 times upper limit of normal (\<5 times upper limit of normal if liver metastases present)
• Female patients must be postmenopausal (12 months of amenorrhea), surgically sterile or they must agree to use a physical method of contraception. Oral or injectable contraceptive agents cannot be the sole method of contraception. Women of childbearing potential (WOCB) who receive cyclophosphamide must adhere to these contraceptive requirements during the trial and until 3 months after the last dose of cyclophosphamide. Male patients, even if sterilized, must agree to use a barrier method of contraception. Male subjects must also commit to use a barrier method of contraception until at least 3 months after the end of study treatment.
• Written informed consent prior to registration.
• Eligible for NHS care in the UK.

You may not qualify if:

• The presence of or imminent occurrence of airway obstruction, unless tracheostomy in place.
• The presence of or imminent occurrence of tumour-mediated infiltration of major blood vessels.
• Positive history of HIV-1, HIV-2, HTLV-1, HTLV-2, Hepatitis B, Hepatitis C or syphilis infection.
• Prior splenectomy.
• Clinically active autoimmune disease. Sub-clinical or quiescent autoimmune disease does not exclude from participation.
• Treatment in the preceding week with systemic corticosteroids (\> 20mg prednisolone/ day), any systemic immunomodulatory agent, radiotherapy, chemotherapy or investigational medicinal product.
• Concurrent use of anticoagulant therapy is not permissible.
• The presence of major co-morbidity likely to impair ability to undergo trial therapy, such as recent myocardial infarction, congestive cardiac failure or uncontrolled hypertension.
• The presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
• Cyclophosphamide allergy (Cohort 6 only).
• Pregnancy.
• Breastfeeding.
• Prior T4 immunotherapy.

Sponsors & Collaborators

• King's College London: lead
• Guy's and St Thomas' NHS Foundation Trust: collaborator

Study Sites (1)

Clinical Research Facility, Guy's Hospital

London, London, SE1 9RT, United Kingdom

RECRUITING

Related Publications (3)

• Davies DM, Foster J, Van Der Stegen SJ, Parente-Pereira AC, Chiapero-Stanke L, Delinassios GJ, Burbridge SE, Kao V, Liu Z, Bosshard-Carter L, Van Schalkwyk MC, Box C, Eccles SA, Mather SJ, Wilkie S, Maher J. Flexible targeting of ErbB dimers that drive tumorigenesis by using genetically engineered T cells. Mol Med. 2012 May 9;18(1):565-76. doi: 10.2119/molmed.2011.00493.

  PMID: 22354215 BACKGROUND

• Wilkie S, Burbridge SE, Chiapero-Stanke L, Pereira AC, Cleary S, van der Stegen SJ, Spicer JF, Davies DM, Maher J. Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using interleukin-4. J Biol Chem. 2010 Aug 13;285(33):25538-44. doi: 10.1074/jbc.M110.127951. Epub 2010 Jun 18.

  PMID: 20562098 BACKGROUND

• van Schalkwyk MC, Papa SE, Jeannon JP, Guerrero Urbano T, Spicer JF, Maher J. Design of a phase I clinical trial to evaluate intratumoral delivery of ErbB-targeted chimeric antigen receptor T-cells in locally advanced or recurrent head and neck cancer. Hum Gene Ther Clin Dev. 2013 Sep;24(3):134-42. doi: 10.1089/humc.2013.144.

  PMID: 24099518 BACKGROUND

MeSH Terms

Conditions

Head and Neck Neoplasms

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms

Study Officials

• John Maher, MD PhD

  King's College London

  PRINCIPAL INVESTIGATOR

Central Study Contacts

John Maher, MD PhD

CONTACT

(+44) 02071881468; john.maher@kcl.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Masking Details: Open label
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Consultant and Senior Lecturer in Immunology

Model Details: In this dose escalation study, the intervention consists of intratumoral delivery of panErbB-specific CAR T cells, administered alone or following lymphodepleting chemotherapy with fludarabine and cyclophosphamide. In cohort 7, patients will also receive 3 doses of Nivolumab, the first of which is administered 24h before CAR T-cells This note has been added in response to the warning " WARNING: Phase 1/Phase 2 studies typically have at least one Intervention Type of Drug, Biological/Vaccine or Combination Product."

Study Record Dates

• First Submitted: March 19, 2013
• First Posted: March 26, 2013
• Study Start: June 1, 2015
• Primary Completion: December 1, 2024
• Study Completion: January 1, 2025
• Last Updated: October 9, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share

Locations

GB (1)