Exploratory Study of TG02-treatment as Monotherapy or in Combination With Pembrolizumab to Assess Safety and Immune Activation in Patients With Locally Advanced Primary and Recurrent Oncogenic RAS Exon 2 Mutant Colorectal Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine safety and anti-tumor immune activation generated by TG02 and Granulocyte macrophage colony stimulating factor (GM-CSF), first as monotherapy (Part I), thereafter in combination with the checkpoint inhibitor pembrolizumab (Part II), in patients with locally advanced primary and recurrent colorectal cancer scheduled to have surgery. Part I will include 4-6 patients and Part II will include up to 10 patients. Part I and Part II are separate and independent sequential components of the study. Patients will only be able to participate in either the Part I cohort or Part II cohort. Main objective of the study is to investigate safety and immune response after TG02-treatment.

Official Title
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A Non-Randomised Open-Label Phase Ib Exploratory Study of TG02-treatment as Monotherapy or in Combination With Pembrolizumab to Assess Safety and Immune Activation in Patients With Locally Advanced Primary and Recurrent Oncogenic RAS Exon 2 Mutant Colorectal Cancer

Conditions
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Rectal Cancer

Intervention / Treatment
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* Biological: TG02-treatment
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with locally advanced primary and recurrent colorectal cancer (CRC) (histologically or cytologically confirmed adenocarcinoma), with a confirmed oncogenic KRAS exon 2, codon 12 or 13 mutations, eligible for radical pelvic surgery at time of enrolment. Patient is ≥18 years of age and able to consent Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 Patient has adequate organ and bone marrow function within 28 days of study Neutrophil count >1.5 x10^9/L Platelets >100 x10^9/L Hb >90g/L Total bilirubin <1.5 upper limit of normal, ULN ALT and AST <3.0 x ULN Serum creatinine <3 x ULN or Creatinine Clearance ≥ 30ml/min (Cockroft-Gault or Nuclear GFR method) PT and APTT <1.3 x ULN The patient is willing to provide study specific pre TG02-treatment biopsy of tumour mass and allow use of archival tumour biopsies. For patients where there are technical reasons a baseline biopsy cannot be performed but who fulfil all the other inclusion criteria, the investigator shall contact the medical monitor to discuss the possibility of including such patient. The patient is willing and able to comply with the protocol, and agrees to return to the hospital for study visits and examinations Men and women of childbearing potential must use adequate contraception to prevent pregnancy during the study. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care. An adequate contraception includes hormonal contraception with implants or combined oral, transdermal or injectable contraceptives, certain intrauterine devices, bilateral tubal ligation, hysterectomy, or vasectomy of partner. A combination of male condom with either cap, diaphragm or sponge with spermicide are also considered acceptable. For women of childbearing potential a negative pregnancy test needs to be confirmed before inclusion. The patient has been fully informed about the study and is willing to participate in the study, and has provided written informed consent form prior to any trial specific screening procedures. Exclusion Criteria: The patient has previously received an anticancer vaccine or immune checkpoint inhibitor, or participated in a trial involving the use of an anticancer vaccine or immune checkpoint inhibitor Patients where pre-surgery radiotherapy, chemotherapy or other anti-cancer therapy has not been completed ≥ 2 weeks prior to TG02-treatment The patients is receiving anti-cancer therapy for concurrent illness The patient has had a prior different malignancy within the last 3 years (excluding adequately treated basal cell or squamous cell carcinoma of the skin cancer, or localised low grade tumours considered cured and not requiring systemic therapy) The patient has uncontrolled or significant intercurrent or recent illness including: auto-immune disorder or history of autoimmune disease requiring immunosuppressive treatment. cardiac disorder such as uncontrolled cardiac failure, unstable angina or non-ST segment elevation myocardial infarction (NSTEMI) or myocardial infarction, uncontrolled arrhythmia less than 3 months before screening stroke or thromboembolic event within 3 months of study commencement active or uncontrolled severe infection history of solid organ transplantation or any condition requiring chronic treatment with corticosteroids or other immunosuppressive agents active coagulopathy/bleeding diathesis cirrhosis, chronic active or untreated persistent hepatitis history of adverse reactions to peptide vaccines The patient is pregnant or lactating. Has received an investigational drug within 4 weeks prior to study drug administration, or unless other has been agreed with the medical monitor Is currently receiving any agent with a known effect on the immune system, unless at dose levels that are not immunosuppressive (e.g. prednisone at 10 mg/day or less or as inhaled steroid at doses used for the treatment of asthma) Known history of positive tests for HIV/AIDS Are planned to receive yellow fever or other live (attenuated) vaccines during the course of study For Part II - any contraindication to receiving pembrolizumab: If using the 50 mg lyophilized powder; hypersensitivity to the active substance (pembrolizumab) or to any of the excipients; L-histidine, L-histidine hydrochloride monohydrate, Sucrose, Polysorbate 80. If using the 100 mg concentrate; hypersensitivity to the active substance (pembrolizumab) or to any of the excipients; L-histidine, Sucrose, Polysorbate 80

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TG02-treatment<br>Part I: The TG02-treatment consists of an intradermal injection of GM-CSF followed by an injection of TG02. The GM-CSF is to be given 15-30 minutes before TG02. TG02-treatment will be administered on Days 1, 8, 15, 22 and 36. If surgery after week 10, TG02-treatment will also be given at week 10 (Day 64). Part II: TG02-treatment will be given as described under Part I. In addition pembrolizumab will be administered. | Biological: TG02-treatment<br> <br> Drug: Pembrolizumab<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients Safety During Study | Safety of TG02-treatment by assessment of laboratory parameters (routine haematology and biochemistry), vital signs and recording of adverse events | From start of study until End of study, which is approximately 4 weeks after surgery and maximum 20 weeks after start of TG02-treatment | 
| Patients' Immune Response Assessed by Delayed Type Hypersensitive (DTH) Test | Number of patients with systemic TG02 specific immune response assessed by a Delayed Type Hypersensitivity (DTH) test | 8 weeks | 
| Systemic Immune Response: T-cell Response | Systemic immune response assessed as change in presence of TG02 specific T-cells in peripheral blood | 8 weeks | 
| Immunological Activation in Tumour Mass by Assessing Number of Patients With Increased Intra-tumoural Lymphocytes. | Immunological activation in tumour mass by assessing fold changes from baseline of intra-tumoural lymphocytes. | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Immune Suppression Factors e.g. PD-1 and T-reg From Pre to Post Treatment | Number of patients with changes from baseline in immune suppression factors (such as PDL1, Treg and MSDC) from tumour samples collected pre TG02/GMCSF treatment | 8 weeks | 
| Change in Pathological Responses and Markers of Apoptosis in Tumour Tissue |  | 8 weeks | 
| Changes in Standard Uptake Values (SUV) Will be Assessed by FDG PET-CT Images |  | From screening until surgery | 
| Changes in the Tumour Marker Carcinoembryonic Antigen (CEA) Throughout Treatment Will be Assessed by Analysis of Blood Samples to Follow the Evolution of Disease Under Treatment |  | From screening until surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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locally recurrent