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
Condition: Rectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: TG02-treatment; Pembrolizumab
Intervention MeSH terms: Pembrolizumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: locally recurrent

Summary:

      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.
    

Eligibility criteria:

        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