Patients with histologically confirmed diagnosis of colorectal carcinoma (left-sided or rectal), esophageal carcinoma, or gastric cancer. MedDRA version: 21.1 Level: LLT Classification code 10062240 Term: Tumor vaccine therapy System Organ Class: 100000004865
Conditions
Interventions
Product Name: TMV-018
Product Code: TMV-018
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: n.a.
CAS Number: n.a.
Current Sponsor code: TMV-018
Other descriptive name: TMV-018
Concentr
Sponsors
Themis Bioscience GmbH
Eligibility
Sex/Gender
All
Inclusion 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 tumors of the gastrointestinal tract (colo¬rectal cancer (left side or rectal), gastric cancer, esophageal cancer being accessible for endoscope guided injection (without intake of oral laxatives) and sub¬sequent repetitive biopsy taking. 4. Before enrolment (i.e., at least 4 weeks before study treatment): Prior chemotherapy, targeted therapy (e.g., bevacizumab), 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. In case of gastric or esophageal cancer, subjects must have under¬gone at least one line of anti-tumoral therapy. Patients with colorectal cancer (left side or rectal) must have undergone at least two lines of anti-tumoral therapy. 9. Adequate organ function (hematological, renal, hepatic, coagulation within 2 weeks prior to enrollment defined as follows: • ANC = 1500/mm3 (1.5 x 109/L) • Platelet count = 100 000/mm3 (100 x 109/L) • Hemoglobin = 9 g/dL (90 g/L) • Serum creatinin = 1.5 x ULN or creatinine clearance = 60 mL/min for subjects with creatinine levels > 1.5 x ULN • Serum total bilirubin = 1.5 x ULN • AST = 2.5 x ULN • ALT = 2.5 x ULN • Prothrombin time (PT) or INR = 1.5 x ULN partial thromboplastin time (PTT) or activated PTT (aPTT) = 1.5 x ULN Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 20 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 20
Exclusion criteria
Exclusion criteria: 1. The participant may not be enrolled in the study if any of the following applies: 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 (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 90 mmHg), or cardiovascular and cerebrovascular diseases with clinical significance, such as cerebrovascular accident (within 6 months before signing informed consent), myocardial infarction (within 6 months before signing informed consent), unstable angina pectoris, congestive heart failure (New York Heart Association Class II or above), or severe arrhythmia, which cannot be controlled with drugs or have potential impact on treatment. 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. 6. Patients with known history of human immunodeficiency virus (HIV). 7. Patients who have received an organ transplant and who are under continuous immunosuppression. 8. Use of immunosuppressive drugs like corticosteroids (excluding topical preparations) within 30 days prior to the first TMV-018 injection or anticipated use before completion of study visit 6 (day 182). 9. 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. 10. reliable contraception methods. 11. Patients with an impaired renal function (creatinine clearance = 40 mL/min). 12. Patients currently or recently ( 10 mg/day prednisone or equivalent) for greater than 12 weeks. 16. Patients with active autoimmune disease. 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. Known deficiency in dihydropyrimidine dehydrogenase (DPD) or total DPD deficiency diagnosed at baseline in those patients not previously treated with 5-FU-related compounds. 20. 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. Note: Subjects with = grade 2 neuropathy and alopecia are an exception to this criterion. 21. Use of anti-cancer treatments within 4 weeks of TMV-018 treatment start: • Chemotherapy (at least 4 weeks for e.g. 5-FU containing chemotherapies, oxaliplatin, cisplatin, and taxanes). • Agents targeting the vascular endothelial growth factor (VEGF) pathway (e.g., bevacizumab, ramucirumab, aflibercept, etc.), EGFR (e.g. cetuximab and panitumumab), Her2neu (e.g. trastuzumab). • Other signal transduction inhibitors and monoclonal antibodies. • I
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: ? To determine the safety and tolerability of TMV-018 when given alone or in combination with the prodrug 5-FC and/or the anti-PD-1 therapy up to day 72 in patients with colorectal carcinoma (left-sided or rectal), esophageal carcinoma, or gastric cancer. ? To determine the maximum tolerated dose (MTD) of TMV-018 in these patients if it is at or below 1x108 TCID50. • To determine the recommended phase II dose. ;Secondary Objective: To assess viral replication at injected tumor sites, viremia (distribution of i.t. applied TMV-018 into the blood stream), shedding and possible persistence phenomena of TMV-018. ? To quantify rates of T cell infiltration into TMV-018 injected and non-injected tumor tissues. ? To assess the therapeutic efficacy of the TMV-018/5-FC, TMV-018/anti-PD-1, and TMV-018/5-FC/anti-PD-1 therapy regime by RECIST version 1.1 criteria, time to progression, as well as changes in tumor marker levels (CEA, CA19-9).;Primary end point(s): • Determination of the MTD: If one patient experiences a DLT, up to six patients will be treated at the same dose level. If a DLT is observed in only one of six patients treated at 1x108 TCID50, the remaining patients will also be treated with 1x108 TCID50. In case a DLT is observed in two of six patients, the remaining patients will be treated with 1x107 TCID50. Furthermore, if the same specific NTE occurs in 2 or more patients after the first administration of the same or higher dose level, the trial will also be continued using a classic 3 + 3 dose escalation design. • Recommended phase II dose: The recommended phase II dose will be evaluated based on toxicity data, pharmacokinetic and pharmacodynamic behavior, as well as anti-tumor responses.;Timepoint(s) of evaluation of this end point: At Study Visits 1-11 (SFU) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Viral replication at injected tumor sites, viremia (distribution of i.t. applied TMV-018 into the blood stream), and shedding will be analyzed using TCID50 assays using samples obtained from tumor, blood, urine, saliva, sputum, as well as feces at different times post TMV-018 treatment initiation ? T cell infiltration into tumor tissue will be analyzed using immunohistochemical assays. ? Number of Responses (Complete and Partial, Stable and Progressive Disease) [Time Frame: up to 24 months after SFU]. Responses will be summarized for TMV-018 by simple descriptive summary statistics delineating Complete and Partial Responses as well as Stable and Progressive Disease. RECIST (version 1.1) criteria will be used. For target lesions: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), = 30% decrease in the sum of the longest diameter (LD) of target lesions; Progressive disease (PD), at least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD. Tumor marker levels (CEA and CA19-9) and time to progression target lesions: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), = 30% decrease in the sum of the longest diameter (LD) of target lesions; Progressive disease (PD), at least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD. Tumor marker levels (CEA and CA19-9) and time to Progression. ;Timepoint(s) of evaluation of this end point: At study Visit | — |
Countries
Germany
Contacts
Public ContactCRO
SSS International Clinical Research GmbH
Outcome results
None listed