A First-In-Human Trial of pTTL in Advanced Colorectal Cancer

Inclusion criteria

• Signed informed consent.
• Adult (age ≥18 years).
• Histological or cytological confirmation of CRC.
• Verified metastatic disease (stage IV classification) and have received all possible standard of care therapies, OR further standard of care therapies are currently not considered to be in the patient's best interest, OR toxicity from previous therapy limits the choice of suitable standard of care therapy OR scheduled pause in palliative standard of care therapy as judged by the Investigator.
• Measurable disease according to RECIST1.1.
• Minimum life expectancy of 6 months at primary inclusion and 3 months at pTTL administration.
• Minimum life expectancy of 3 months from the time that the individual pTTL DP is estimated to be available (as per Investigators clinical assessment). 7. ECOG performance status 0 to 1
• Adequate hematopoietic, hepatic and renal function defined as:
• Haemoglobin≥ 95 g/L (blood transfusion not less than 21 days prior to screening),
• Absolute neutrophil count ≥ 1.0x 109/L, platelets ≥100 x 109/L
• Total bilirubin \< 1.5 x ULN (does not apply to patients with Gilberts Syndrome)
• AST and ALT ≤ 1.5 x ULN (or ≤ 5 x ULN in the presence of liver metastases)
• Serum creatinine ≤ ULN (if serum creatinine is between 1 and 1.5 x ULN, patients may be eligible provided that the calculated GFR is at least 35 mL/min using Cockcroft- Gault method).
• Albumin ≥24 g/L
• Patients of childbearing potential or their partners of childbearing potential must be willing to take the appropriate precaution to avoid pregnancy or fathering a child for the duration of Part I and Part II and practice an approved, highly effective method of birth control during treatment and for 6months after receiving pTTL.
• Approved methods of birth control include:
• Combined (oestrogen and progesterone containing) hormonal birth control associated with inhibition of ovulation: oral, intravaginal, transdermal
• Progesterone-only hormonal birth control associated with inhibition ofovulation: oral, injectable, implantable
• Intrauterine device (IUD)or intrauterine hormone-releasing system (IUS)•Bilateral tubal occlusion
• Vasectomised partner
• True sexual abstinence when this is in line with the preferred and usuallifestyle of the patient. Periodic abstinence (e.g., calendar ovulation,symptothermal, post-ovulation methods) is not acceptable
• Able to undergo surgery or biopsy to obtain tumour tissue for neoantigen evaluation and to retrieve RLNs as starting material for pTTL manufacturing
• The area from which the RLNs will be obtained shall not have been exposed to radiotherapy.

Exclusion criteria

• Less than 4 months at primary inclusion and 6 months at pTTL administration since a clinically significant cardiovascular event such as myocardial infarction, unstable angina, angioplasty, bypass surgery, stroke or transient ischemic attack (TIA). Atrial fibrillation if treated and well controlled is not considered a bar to inclusion even if diagnosed less than 6 months ago.
• Congestive heart failure New York Heart Association (NYHA)class III or IV.
• Significantly reduced lung function with clinical implications. If such is suspected, spirometry should be performed. Spirometry should also be considered in patients who have been hospitalised due to Covid-19 infection during the last 6 months, and in patients with any other lung affectation judged significant by the Principal Investigators, in discussion withSponsor's Medical Representative, such as treatment-related pneumonitis or severe lung infection. Spirometry results of less than 65% of the expected value regarding forced expiratory volume in 1 second(FEV1) and/or diffusion capacity (diffusing capacity of the lung for carbon monoxide, DLCO,corrected for haemoglobinvalue, DLCOco) is regarded as a criterium for exclusion.
• Any severe acute or chronic medical condition that places the patient at increased risk or interferes with the interpretationof trial results (as judged by the Principal Investigators, in agreement with Sponsor's Medical Representative).
• Immunodeficiency disorders which may pose a risk for patients treated with pTTL, and/or affect the outcome of the pTTL treatment, as judged by Investigator at the Treatment Site and/or the Investigator at the Recruitment and Follow-Up Site Immunodeficiency disorders are here defined as including inborn and acquired disorders reducing immunity but excluding human immunodeficiency virus (HIV), which is discussed below. Examples include common variable immunodeficiency and status post transplantation of a solid organ or stem cells. Immunodeficiency caused by the cancer disorder to be treated within the trial or such cancer treatments as have already been administered is considered a separate entity. This, if severe, might impact the production of pTTL and potentially also the treatment outcome, and needs to be carefully assessed as regards patient and pTTL production risks before inclusion.
• Autoimmunity disorders which may pose a risk for patients treated with pTTL, and/or affect the outcome of the pTTL treatment, as judged by Investigator at the Treatment Site and/or the Investigator at the Recruitment and Follow-Up Site.
• Leptomeningeal metastases (patient with previously treated brain metastases are eligible if there is no evidence of disease progression for a minimum of 8 weeks prior to inclusion
• in these cases a CNS MRI is required within the screening period. These patients must not have symptoms from their brain metastases or treatment thereof and must not be taking steroid medications for treatment of CNS symptoms).
• Patients are not allowed to have ongoing systemic immunosuppressive concomitant medications. Systemic immunosuppressive treatments should be completed 2 weeks prior to surgery and/or 2 weeks prior to dose. Steroid medications are allowed if they are used as substitution or are administrated topically or as inhalation steroids for asthma.
• Previous Grade 3 or greater immune-related toxicity from checkpoint modulation or other immunotherapy (unless the toxicity has resolved and the patient rechallenged with the therapy without recurrence of toxicity, in which situation the patient can be considered).
• Acute or chronic infection with hepatitis B or C or syphilis.
• HIV infection.
• Pregnancy or breast-feeding.
• Investigator considers the patient unlikely to comply with trial procedures, restrictions and requirements.
• For patients required to undergo trial-specific surgery to obtain starting material:
• Less than 3 identifiable enlarged lymph nodes on pre-surgery radiology accessible for surgical excision.
• Previous surgical removal of the primary CRC tumour (would entail a high risk surgery)
• Unable to withstand the planned surgery (including ineligibility for general anaesthesia)
• At decision to proceed to pTTL administration:
• Less than 4 weeks since stopping previous systemic cancer treatment.
• Less than 2 weeks since stopping radiotherapy.
• Less than 4 weeks after major surgery and less than 3 weeks after minor surgery.
• Participation in any other clinical cancer therapy trial, and planned treatment or treatment with another investigational drug, within the previous 4 weeks.
• Less than 4 weeks since administration of live attenuated vaccines.