Phase I Trial: T4 Immunotherapy of Head and Neck Cancer

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.

Study Overview

• Status: Recruiting
• Conditions: Head and Neck Cancer
• Intervention / Treatment: Other: Intra-tumoral T4 immunotherapy

Detailed Description

Further information is provided in 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. PubMed ID: 24099518

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: John Maher, MD PhD; Phone Number: 81468 (+44) 02071881468; Email: john.maher@kcl.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom, SE1 9RT
    • Recruiting
    • Clinical Research Facility, Guy's Hospital
    • Contact: John Maher

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histologically and/ or cytologically confirmed SCCHN.
2. 18 years or older.
3. 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.
4. 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.
5. Those who refuse palliative treatment may be eligible for participation. However, their reasons for not opting for palliative treatment must be explored thoroughly.
6. 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.
7. Eastern Co-operative Oncology Performance Status of 0-2.
8. 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.
9. Haematology results within seven days of enrolment: neutrophils >1.5 x 109/L, platelets >100 x 109/L, haemoglobin >9g/dl, INR <1.5.
10. 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)
11. 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.
12. Written informed consent prior to registration.
13. Eligible for NHS care in the UK.

Exclusion Criteria:

1. The presence of or imminent occurrence of airway obstruction, unless tracheostomy in place.
2. The presence of or imminent occurrence of tumour-mediated infiltration of major blood vessels.
3. Positive history of HIV-1, HIV-2, HTLV-1, HTLV-2, Hepatitis B, Hepatitis C or syphilis infection.
4. Prior splenectomy.
5. Clinically active autoimmune disease. Sub-clinical or quiescent autoimmune disease does not exclude from participation.
6. Treatment in the preceding week with systemic corticosteroids (> 20mg prednisolone/ day), any systemic immunomodulatory agent, radiotherapy, chemotherapy or investigational medicinal product.
7. Concurrent use of anticoagulant therapy is not permissible.
8. 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.
9. The presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
10. Cyclophosphamide allergy (Cohort 6 only).
11. Pregnancy.
12. Breastfeeding.
13. Prior T4 immunotherapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Intra-tumoral T4 immunotherapy; Treatment arms comprise escalating doses of T4 immunotherapy, administered alone or in combination with lymph-depleting chemotherapy

Other: Intra-tumoral T4 immunotherapy; 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.; Other Names: 4ab T1E28z positive T-cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Pre- and post-treatment absolute number of circulating T-regulatory cells will be compared.	up to 6 weeks post T4 administration
To investigate effect of T4 immunotherapy upon immune reactivity against endogenous tumour antigens	ELISPOT will be performed on blood samples taken 3 days prior and 29 days after T4 administration to measure for MAGE-reactive T-cells.	up to 6 weeks post T4 administration

Collaborators and Investigators

• Sponsor: King's College London
• Collaborators: Guy's and St Thomas' NHS Foundation Trust
• Investigators: Principal Investigator: John Maher, MD PhD, King's College London

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): January 1, 2025

Study Registration Dates

• First Submitted: March 19, 2013
• First Submitted That Met QC Criteria: March 25, 2013
• First Posted (Estimated): March 26, 2013

Study Record Updates

• Last Update Posted (Actual): October 9, 2024
• Last Update Submitted That Met QC Criteria: October 7, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Head and Neck Cancer; Immunotherapy; Maximum tolerated dose; Chimeric antigen receptor; Phase I trial
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Physiological Effects of Drugs; Immunologic Factors; Immunomodulating Agents
• Other Study ID Numbers: 2012-001654-25

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No