First in Human Study of T3P-Y058-739 (T3P)

An Open-label, Phase I/II Study of T3P-Y058-739, a Genetically-modified Strain of the Bacterium Yersinia Enterocolitica, in Patients With Advanced Solid Tumours

This is a first in human, phase I/II open-label, dose-finding, safety, and proof-of-concept clinical trial of T3P-Y058-739, a genetically-modified, live attenuated strain of the bacterium Yersinia enterocolitica, in patients with advanced solid tumors.

Study Overview

• Status: Recruiting
• Conditions: Advanced Solid Tumor
• Intervention / Treatment: Drug: T3P-Y058-739 (IV); Drug: T3P-Y058-739 (IT); Drug: Pembrolizumab+T3P-Y058-739

Detailed Description

The study, which has a modular design with up to 6 parts, anticipates enrolling approximately 100 participants. Part A will open first. Part B and subsequent parts will open later. The study will evaluate T3P-Y058-739 monotherapy given by intratumoural (IT) injection (Part A) and by intravenous (IV) infusion (Part B). In addition, either IT or IV T3P-Y058-739 (route of administration to be chosen based on emerging data) will be evaluated in combination with pembrolizumab. All patients will receive low doses of desferrioxamine (which provides iron in a form that can be used by the bacteria) to support bacterial survival and growth. All patients will receive antibiotics on completion of therapy to eradicate any residual T3P-Y058-739.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Claire Barton; Phone Number: +44 (0)7843 560 419; Email: c.barton@t3pharma.com
• Study Contact Backup: Name: Gabriella Galli; Phone Number: +4179.355.9741; Email: g.galli@t3pharma.com

Study Locations

• Switzerland
  • Lausanne, Switzerland, 1011
    • Recruiting
    • Centre Hospitalier Universitaire Vaudois Lausanne (CHUV)
    • Contact: Berangere Midez; Phone Number: +41 (0)21 314 52 26; Email: berangere.midez@chuv.ch
    • Principal Investigator: Martina Imbimbo
  • Zürich, Switzerland, 8091
    • Recruiting
    • University Hospital of Zürich (Universitätsspital Zürich)
    • Principal Investigator: Reinhard Dummer
    • Contact: Julia Pueschel; Phone Number: +41 44 255 94 85; Email: Julia.Pueschel@usz.ch
• United Kingdom
  • Glasgow, United Kingdom, G12 0YN
    • Recruiting
    • Cancer Research UK Clinical trials; Unit Partner in CaCTUS- Cancer clinical trials Unit Scotland; Beatson West of Scotland Cancer Centre
    • Principal Investigator: Jeff Evans
    • Contact: Victoria Withers; Phone Number: +44 0141 301 7224; Email: Victoria.Withers@ggc.scot.nhs.uk
  • Leeds, United Kingdom, LS9 7TF
    • Recruiting
    • Leeds Clinical Research Facility
    • Contact: Angela Bennett; Phone Number: +44 0113 206 8801; Email: angela.bennett11@nhs.net
    • Principal Investigator: Adel Samson
  • London, United Kingdom, SW3 6JJ
    • Recruiting
    • Royal Marsden NHS Foundation Trust
    • Contact: Abigail Temple; Phone Number: +44 0207 1535030; Email: Abigail.Temple@rmh.nhs.uk
    • Principal Investigator: Kevin Harrington

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

All patients, all parts of the study

1. Histologically- or cytologically-proven advanced, solid tumour that cannot be removed surgically and for which there is no curative therapy and no alternative therapy is felt to be appropriate.
2. At least one measurable lesion
3. Male or female, 18 years of age or older at the time of signing informed consent.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
5. Estimated life expectancy of ≥12 weeks.
6. Resolution of all acute reversible toxic effects of prior therapy or surgical procedure to baseline or Grade ≤1 (except alopecia).
7. Adequate iron stores without significant iron overload
8. Adequate organ function
9. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF).
10. At least one lesion that is measurable according to iRECIST/RECIST 1.1 and amenable to direct IT injection, i.e., a lesion that is visible, palpable, or detectable by ultrasound, and accessible for direct IT injection (injection via an endoscope is not allowed for Part A at least; ultrasound and/or radiological guidance is allowed).

Exclusion Criteria:

All patients, all parts of the study

1. Prior malignancy that could affect compliance with the protocol or interpretation of results. Patients curatively treated more than 2 years prior to enrolment, and patients with adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ, are generally eligible.
2. Known central nervous system (CNS) metastases.
3. Patients who have previously received an allogeneic bone marrow or stem cell transplant or with congenital or acquired immunodeficiency or receiving immunosuppressive therapy (including any dose of systemic corticosteroids). Patients should have recovered immunologically from any prior immunomodulatory therapies such as CD20-targeted antibodies. Patients receiving inhaled corticosteroids for asthma or chronic obstructive pulmonary disease, and patients on steroid replacement therapy (e.g. due to prior adrenalectomy or hypophysectomy) are eligible at the investigator's discretion. Patients likely to require immunosuppressive treatment with systemic steroids or other agent (e.g., patients with frequent exacerbations of asthma) should not enter the study.
4. Patients with active uncontrolled infection or known to be serologically positive for human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection. Patients with recent major infection (such as pneumonia in the previous 4 weeks) should have recovered to preillness levels with resolution of reversible infection-related symptoms for at least one week prior to starting T3P.
5. Patients with a documented Yersinia infection in the 12 weeks prior to treatment or with detectable Y. enterocolitica in a baseline stool sample (based on routine culture at site).
6. Patients who have recently received antibiotics that could affect the viability of T3P (at least 5 half-lives should have elapsed since the last dose).
7. Patients with known cardiac valvular disease or arterial aneurysms, artificial heart valves and other implanted prostheses (such as joint replacements) that cannot be easily removed or replaced. Patients with central venous access devices are allowed in the study but T3P should be administered by peripheral vein, whenever possible. Patients with a history of bacterial endocarditis, regardless of the organism, are excluded from the study.
8. Patients with a history of clinically significant autoimmune conditions, major cardiac arrhythmia or ischaemia, New York Heart Association class III/ IV cardiac failure or coronary angioplasty in the previous 6 months.
9. Patients who are allergic to chloramphenicol or to all of the following antibiotics: co-trimoxazole, doxycycline, ceftriaxone and cefotaxime.
10. Patients with a bleeding diathesis or receiving therapeutic doses of anticoagulants unless the lesion(s) to be injected are superficial and at low risk of bleeding. Patients receiving lower doses of anticoagulants, aspirin or clopidogrel may be eligible at the investigator's discretion, depending on the site of lesions to be injected and perceived risk of bleeding.
11. Previous severe hypersensitivity reaction to treatment with Check Point Inhibitor (CPI) or other monoclonal antibody.
12. History of severe immune-related adverse effects (irAEs) for greater than 12 weeks. CPI-related AEs (including irAEs) must have resolved back to Grade 0-1 and patients received no corticosteroids for irAEs for at least two weeks prior to first dose of pembrolizumab in the study.
13. History of interstitial lung disease or prior pneumonitis requiring systemic corticosteroid therapy. In case of uncertainty, a high-resolution computed tomography (HRCT) should be performed at baseline.
14. Patients at high risk of bowel perforation, history of acute diverticulitis, intra-abdominal abscess or abdominal carcinomatosis).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: T3P-Y058-739 Intravenous (IV); Intravenous infusion	Drug: T3P-Y058-739 (IV); Intravenous infusion
Experimental: T3P-Y058-739 Intratumoural (IT); Intratumoural injection	Drug: T3P-Y058-739 (IT); Intratumoral use
Experimental: T3P-Y058-739 plus pembrolizumab; Intravenous infusion	Drug: Pembrolizumab+T3P-Y058-739; intravenous infusion or intratumoural injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: To assess the safety and determine the recommended phase II dose (RP2D) when given by IT injection and by IV infusion, as monotherapy and in combination with pembrolizumab.	AEs(adverse events), SAEs(serious adverse events) will be graded by the investigator according to National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE Version 5.0).	up to 45 months
Phase 2: To assess the safety and preliminary antitumor response T3P when given by IT injection and/or IV infusion, as monotherapy and in combination with pembrolizumab.	Response according to immune Response Evaluation Criteria in Solid Tumors (iRECIST) (Seymour et al, 2017).	up to 45 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of Duration of response (DoR)	DoR and PFS according to RECIST 1.1 (Eisenhauer et al, 2009) or modified criteria for selected malignancies, as appropriate(e.g., Verslype et al, 2012 for hepatocellular carcinoma).	up to 45 months
Assessment of progression free survival (PFS)	PFS according to RECIST 1.1 (Eisenhauer et al, 2009) or modified criteria for selected malignancies, as appropriate(e.g., Verslype et al, 2012 for hepatocellular carcinoma).	up to 45 months
To evaluate the distribution of T3P	Microbiological culture and/or quantitative polymerase chain reaction (qPCR) of samples of blood, urine, stool and (in patients with tumor's close to or involving the oropharynx) saliva.	up to 45 months
To evaluate the clearance of T3P	Shedding will also be evaluated in swabs taken from lesions that ulcerate following T3P administration.	up to 45 months
To evaluate the shedding of T3P	Tumor colonisation will also be evaluated in tumor biopsies (optional).	up to 45 months
Assessment of Overall survival (OS)	Overall survival (OS) (maximum 16 months of follow-up).	Maximum 16 months of follow-up

Collaborators and Investigators

• Sponsor: T3 Pharmaceuticals AG

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2022
• Primary Completion (Anticipated): October 29, 2024
• Study Completion (Anticipated): February 1, 2025

Study Registration Dates

• First Submitted: September 14, 2021
• First Submitted That Met QC Criteria: November 3, 2021
• First Posted (Actual): November 15, 2021

Study Record Updates

• Last Update Posted (Actual): May 9, 2023
• Last Update Submitted That Met QC Criteria: May 8, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Cancer; Advanced; Oncology; Tumor; gene; Solid; Genetically; Bacterium
• Additional Relevant MeSH Terms: Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab
• Other Study ID Numbers: T3P1001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No