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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04195373
Recruitment Status : Withdrawn (Study not started, no subjects recruited.)
First Posted : December 11, 2019
Last Update Posted : November 25, 2020
Sponsor:
Collaborators:
Assign Data Management and Biostatistics GmbH
SSS International Clinical Research GmbH
Information provided by (Responsible Party):
Themis Bioscience GmbH

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Gastrointestinal Cancer Biological: TMV-018 + 5-FC Biological: TMV-018 + anti-PD-1 Biological: TMV-018 + 5-FC + anti-PD-1 Phase 1

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Open-label, Safety Study of Intra-tumoral Application of TMV-018 in Combination With 5-FC or Anti-PD-1 Therapy in Patients With Tumors of the Gastrointestinal Tract
Actual Study Start Date : November 23, 2020
Actual Primary Completion Date : November 23, 2020
Actual Study Completion Date : November 23, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Flucytosine

Arm Intervention/treatment
Experimental: TMV-018 + 5-FC
Patients will receive intra-tumoral TMV-018 on days 0, 14, 28 and 42, and will be additionally treated with the prodrug 5-FC.
Biological: TMV-018 + 5-FC

TMV-018: liquid frozen, life attenuated, oncolytic measles virus encoding the prodrug converting enzyme "super cytosine deaminase"; 1E+06 TCID50 to 1E+08 TCID50 per dose.

5-FC: 150 mg/kg/day for 2 days during each treatment.


Experimental: TMV-018 + anti-PD-1 inhibitor
Patients will receive intra-tumoral TMV-018 on days 0, 14, 28 and 42, and will be additionally treated with an anti-PD-1 Inhibitor.
Biological: TMV-018 + anti-PD-1

TMV-018: liquid frozen, life attenuated, oncolytic measles virus encoding the prodrug converting enzyme "super cytosine deaminase"; 1E+06 TCID50 to 1E+08 TCID50 per dose.

Anti-PD-1 inhibitor dose according to its SMPC.


Experimental: TMV-018 + 5-FC + anti-PD-1 inhibitor
Patients will receive intra-tumoral TMV-018 on days 0, 14, 28 and 42, and will be additionally treated with the prodrug 5-FC and an anti-PD-1 Inhibitor.
Biological: TMV-018 + 5-FC + anti-PD-1

TMV-018: liquid frozen, life attenuated, oncolytic measles virus encoding the prodrug converting enzyme "super cytosine deaminase"; 1E+06 TCID50 to 1E+08 TCID50 per dose.

5-FC: 150 mg/kg/day for 2 days during each treatment cycle.

Anti-PD-1 Inhibitor: dose according to its SMPC.





Primary Outcome Measures :
  1. Frequency of Adverse Events [ Time Frame: 4 years ]
    Incidence of solicited and unsolicited adverse events from enrollment until end of study.

  2. Determine MTD and dose for phase II [ Time Frame: 1.5 years ]
    Determine the maximum tolerated dose (MTD) and recommended Phase II dose of TMV-018


Secondary Outcome Measures :
  1. Viral replication [ Time Frame: 2 years ]
    Assess viral replication at injected tumor sites, viremia (distribution of i.t. applied TMV-018 into the blood stream), and shedding as well as possible persistence phenomena of TMV-018

  2. Viral distribution [ Time Frame: 2 years ]
    Assess viremia (distribution of i.t. applied TMV-018 into the blood stream) and shedding as well as possible persistence phenomena of TMV-018

  3. Efficacy of therapy assessed by RECIST 1.1 [ Time Frame: 4 years ]
    Assess the therapeutic efficacy of TMV-018 with 5-FC or anti-PD-1 therapy by radiologic assessment (RECIST 1.1, time to progression).

  4. Efficacy of therapy assessed by changes in tumor marker level [ Time Frame: 4 years ]
    Assess the therapeutic efficacy of TMV-018 with 5-FC or anti-PD-1 therapy by changes in tumor marker level.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04195373


Locations
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Germany
University Hospital Bonn
Bonn, Germany
University Hospital Tübingen
Tübingen, Germany
Sponsors and Collaborators
Themis Bioscience GmbH
Assign Data Management and Biostatistics GmbH
SSS International Clinical Research GmbH
Investigators
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Principal Investigator: Ulrich Lauer, MD University Hospital Tuebingen
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Responsible Party: Themis Bioscience GmbH
ClinicalTrials.gov Identifier: NCT04195373    
Other Study ID Numbers: TMV-018-101
First Posted: December 11, 2019    Key Record Dates
Last Update Posted: November 25, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Themis Bioscience GmbH:
Colorectal cancer
Esophageal cancer
Gastric cancer
TMV-018
anti-PD-1
5-FC
oncolytic virus
Additional relevant MeSH terms:
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Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Flucytosine
Antifungal Agents
Anti-Infective Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action