A Safety Study of TMV-018 in Patients With Tumors of the Gastrointestinal Tract

This study aims to determine the safety and tolerability of TMV-018 when given alone or in combination with the prodrug 5-Fluorocytosine (5-FC) or an anti-PD-1 checkpoint inhibitor in patients with gastrointestinal tumors. Furthermore, the maximum tolerated dose (MTD) and recommended Phase II dose of TMV-018 shall be determined.

This is an open-label, multicenter, dose-escalation phase I trial that aims to determine the safety and tolerability of TMV-018, an oncolytic measles virus encoding the prodrug converting enzyme "super cytosine deaminase", when given alone or in combination with the prodrug 5-Fluorocytosine (5-FC) or an anti-PD-1 checkpoint inhibitor up to day 72 in patients with colorectal carcinoma (left-sided or rectal), esophageal carcinoma, or gastric cancer. Furthermore, the maximum tolerated dose (MTD) and recommended Phase II dose of TMV-018 shall be determined.

At least 15 patients will be enrolled. Patients will be randomized to different treatment groups: all patients will receive intra-tumoral TMV-018 on four visits and additionally 5-FC and/or anti-PD-1 treatment. All adverse events will be documented and analyzed for the primary safety endpoint. Blood and tumor samples will be collected up to day 72 to determine the safety, tolerability and immunogenicity of the treatment. The patients will be followed-up for another two years to determine long-term safety.

Eligibility Criteria:
Inclusion Criteria:

1. Signed informed consent form must be obtained prior to any research procedures.
2. At least 18 years of age on the day of signing the informed consent.
3. Histologically confirmed diagnosis of advanced, metastatic tumors of the gastrointestinal tract (stage IV)
4. Before enrollment (i.e., at least 4 weeks before study treatment): Prior chemotherapy, targeted therapy, radiotherapy, to treat cancer or major surgery have to be stopped at least 4 weeks prior to enrolment.
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and life expectancy ≥ 3 months as assessed during screening period.
6. All female participants of childbearing potential, defined as all woman physiologically capable of becoming pregnant, must have a negative pregnancy test at screening.
7. Willingness not to become pregnant or to father a child during study participation by practicing reliable methods of contraception.
8. Patient must have exhausted all current standard therapy lines in the target cancer indications
9. Adequate organ function as determined by laboratory parameters.

Exclusion Criteria:

1. Patients who participated in other studies of anti-tumor therapy within 2 weeks before enrolment.
2. Patients with brain metastases.
3. Patients with poorly controlled hypertension, or cardiovascular and cerebrovascular diseases with clinical significance.
4. Patients with other serious organic diseases or mental disorders.
5. Patients with active infections, which cannot be controlled with drugs or have potential impact on treatment, or patients with concurrent opportunistic infections.
6. Patients exhibiting evidence of clinically significant immunosuppression such as primary or acquired immunodeficiency state
7. Pregnancy (positive pregnancy test at screening or before end of study participation) or lactation at screening or planning to become pregnant before completion of study participation.
8. Males who have sex to conceive a child / who want to donate semen, during the study and up to 4 months after the last dose of TMV-018, 5-FC or pembrolizumab.
9. Males and female subjects of childbearing potential who are unwilling to use double barrier methods of effective contraception
10. Patients with an impaired renal function (creatinine clearance ≤ 40 mL/min).
11. Patients currently or recently (\< 2 months) taking fluconazole, itraconazole, clotrimazole troches, itraconazole, amphotericin or other oral anti-fungal medications.
12. Patients with contraindications for treatment with flucytosine (5-FC)
13. Known hypersensitivity to 5-FU, known deficiency in dihydropyrimidine dehydrogenase (DPD)
14. Known hypersensitivity to pembrolizumab, its excipients, or other monoclonal antibody.
15. Severe immune-related adverse reactions from treatment with pembrolizumab, defined as any grade 4 toxicity or grade 3 toxicity requiring corticosteroid treatment (\> 10 mg/day prednisone or equivalent) for greater than 12 weeks.
16. History or evidence of symptomatic autoimmune diseases.
17. Other medical condition or laboratory abnormality that in the judgment of the Investigator may increase the risk associated with study participation or may interfere with interpretation of study results.
18. History of severe systemic reaction or side-effect after a measles vaccination.
19. Subjects who continue to experience \> grade 1 Common Terminology Criteria for Adverse Events (CTCAE) toxicity due to cancer therapy within 4 weeks prior to enrollment will not be eligible.
20. Use of anti-cancer treatments within 4 weeks of TMV-018 treatment start.