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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: Pembrolizumab+T3P-Y058-739
* Drug: T3P-Y058-739 (IV)
* Drug: T3P-Y058-739 (IT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients, all parts of the study 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. At least one measurable lesion Male or female, 18 years of age or older at the time of signing informed consent. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Estimated life expectancy of ≥12 weeks. Resolution of all acute reversible toxic effects of prior therapy or surgical procedure to baseline or Grade ≤1 (except alopecia). Adequate iron stores without significant iron overload Adequate organ function Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF). 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 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. Known central nervous system (CNS) metastases. 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. 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. 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). 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). 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. 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. Patients who are allergic to chloramphenicol or to all of the following antibiotics: co-trimoxazole, doxycycline, ceftriaxone and cefotaxime. 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. Previous severe hypersensitivity reaction to treatment with Check Point Inhibitor (CPI) or other monoclonal antibody. 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. 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. Patients at high risk of bowel perforation, history of acute diverticulitis, intra-abdominal abscess or abdominal carcinomatosis).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: dose-finding, safety, and proof-of-concept study
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gene, Advanced, Solid, Tumor, Cancer, Oncology, Genetically, Bacterium