Phase I/II clinical trial investigates the safety, tolerability, immunogenicity and preliminary efficacy of multiple doses of PolyPEPI1018 CRC vaccine as an add-on treatment to the standard-of-care maintenance therapy in patients with metastatic colorectal cancer. Clinical responses will be evaluated by indiction of T cell responses, T lymphocyte infiltration in accessible biopsy sites, and by objective tumor responses. This study will also explore the accuracy of the predicted T cell responses in each patient using the candidate companion diagnostic test and the correlations between clinical responses and predicted T cell responses.

This is a Phase I/II, open-label, single-arm, multicenter study to evaluate the safety, tolerability, immunogenicity and efficacy of a multiple subcutaneous injection of PolyPEPI1018 as an add-on immunotherapy to the standard-of-care maintenance therapy in approximately 15 subjects with metastatic colorectal cancer.

The first part of the study investigates the administration of a single vaccine dose during 12-week follow-up period on an outpatient basis. Screening is performed in parallel with the subject's completion of the standard-of-care first-line treatment and initiation of the standard-of-care maintenance treatment. A single dose of PolyPEPI1018 is administered after the subject initiates the maintenance regimen, and within 3 weeks after the eligibility CT scan was performed. Subjects are monitored every 3 weeks for 12 weeks.

The second part of the study investigates the administration of 3 vaccine doses (Weeks 0, 13, 26) then 12 weeks follow-up on an outpatient basis.

Inclusion Criteria:

1. Male or female subjects, 18-75 years of age at time of Screening who provide written informed consent prior to initiation of any study procedure
2. Histologically confirmed metastatic adenocarcinoma originating from the colon or the rectum
3. Presence of at least 1 measurable reference lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria
4. Experienced PR or stable disease during first-line treatment with a systemic chemotherapy regimen and 1 biological therapy regimen
5. Maintenance therapy with a fluoropyrimidine (5-fluorouracil or capecitabine) plus the same biologic agent (bevacizumab, cetuximab or panitumumab) used during induction, scheduled to initiate prior to the first day of treatment with the study drug
6. No more than 1 line of chemotherapy regimen for mCRC (adjuvant therapy for non-metastasized disease is allowed if terminated more than 6 months before Screening and without recurrence within 6 months after the end of adjuvant treatment)
7. Last CT scan at 3 weeks or less before the first day of treatment
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
9. Women of childbearing potential must agree to appropriately use an effective form of contraception (failure rate of <1% per year) for 3 months from the day of the treatment. An effective form of contraception is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm, cervical cap or condom
10. Men must agree to use an effective form of contraception (as defined above), and not donate sperm for 3 months from the day of the treatment
11. White blood cell count ≥3.0 × 109/L with neutrophils ≥1.5 × 109/L
12. Platelets ≥100 × 109/L, hemoglobin ≥5.6 mmol/L (corresponding to 9 g/dL)
13. Serum bilirubin ≤1.5 × upper limit of normal (ULN) set by the site
14. Alanine amino transferase (ALAT) and aspartate amino transferase (ASAT) ≤2.5 × ULN in the absence of liver metastases. ALAT and ASAT ≤5 × ULN set by the site in the presence of liver metastases
15. Serum creatinine ≤1.5 × ULN set by the site and creatinine clearance >30 mL/min using Cockroft formula
16. Relevant toxicities of prior therapies must have resolved, except for oxaliplatin-related neuropathy or alopecia
17. Anticipated life expectancy ≥6 months Subject is willing and able to comply with the requirements of the protocol

Exclusion Criteria:

1. Received chronic systemic immune therapy or immunosuppressant medication other than steroids within the last 6 weeks prior to start of study treatment
2. Received continuous systemic steroid treatment within the last 2 weeks prior to start of study treatment
3. Colorectal cancer with documented high microsatellite instability (MSI-H)
4. Colorectal cancer with documented BRAF mutations
5. Pre-existing systemic autoimmune or antibody-mediated diseases or immune deficiency diseases
6. Central nervous system (CNS) metastases
7. Active or uncontrolled severe infections or undiagnosed febrile condition >38ºC
8. Acute or subacute intestinal obstruction or history of chronic intestinal inflammatory diseases
9. Symptomatic peritoneal carcinomatosis
10. Peritonitis
11. Serious, non-healing wounds, ulcers or bone fractures
12. Nephrotic syndrome
13. Arterial thromboembolisms or severe hemorrhages within 6 months before study enrolment (except bleeding tumor before tumor resection surgery)
14. Hemorrhagic diathesis or thrombotic tendency
15. Major surgery or radiotherapy within 12 weeks prior to the study treatment or anticipation of needing such procedure during the study period
16. Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage more than once every 28 days
17. Participants with active malignancy (other than colorectal cancer) or a prior malignancy within the past 12 months
18. Participant with myocardial infarction within 6 months prior to enrollment or New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to the first dose of study treatment, any electrocardiogram (ECG) abnormality at Screening must be documented by the investigator as not medically relevant
19. Administration of a live, attenuated vaccine within 4 weeks before randomization or anticipation of a live attenuated vaccine will be required during the study
20. Participant has participated in another clinical study involving an investigational product (IP) or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study
21. Known hypersensitivity to any component of the investigational drug
22. If female, participant is pregnant (exclusion confirmed with beta-human chorionic gonadotropin [hCG] test) or lactating at the time of enrollment, or has plans to become pregnant or start breastfeeding during the study
23. Pre-existing alcohol or drug abuse
24. Medical or mental impairments which make it impossible to obtain the patient's consent or to conduct the study
25. A significant concomitant medical condition which the clinical investigator believes precludes the patient from enrolling in the study Absent or limited legal competence

All 11 subjects, Full analysis dataset

up to 41 weeks