Safety and Efficacy of the ONCOlytic VIRus Armed for Local Chemotherapy, TG6002/5-FC, in Recurrent Glioblastoma Patients

NCT03294486 | Unknown Phase 1 DMC

• 2 other identifiers: P1509362015-004452-21
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 1

Brief Summary

Glioblastoma is the most common and the most aggressive primary brain cancer in adults. Indeed, despite very intensive treatments (i.e. maximal safe surgery, radiotherapy and several lines of cytotoxic chemotherapies), inducing significant adverse events, the prognosis of glioblastoma patients remains dismal with a median overall survival of \~15 months. Therefore, more efficient and less toxic therapies are urgently needed to improve survival and quality of life of glioblastoma patients. The oncolytic virus TG6002 has shown efficacy and good safety profile in several preclinical models of glioblastoma in vitro (i.e. cell line) and in vivo (i.e. xenografts in Swiss/Nude mice). Comprehensive toxicology studies of TG6002/Flucytosine have been completed in rabbits and monkeys supporting safety investigations of TG6002/Flucytosine in human patients. Taken these data all together, TG6002/Flucytosine appears as a very promising therapeutic strategy in glioblastoma patients that merits consideration for early phase clinical trial.

Conditions

Glioblastoma; Brain Cancer

Keywords

Glioblastoma; Oncolytic viruses

Outcome Measures

Primary Outcomes (2)

• Number of Participant with Dose Limiting Toxicities defined as Any of the following treatment-related adverse events (AEs) is evaluated and reported from Day 1 through Day 26; as assessed by NCI-CTCAE, version 4.03

  For Phase 1 Assessment of safety and tolerability : Number of Participant with Dose Limiting Toxicities defined as Any of the following treatment-related adverse events (AEs) is evaluated and reported from Day 1 through Day 26; as assessed by NCI-CTCAE, version 4.03: * Any Grade 4 toxicity (except isolated Grade 4 lymphopenia lasting ≤ 7 days); * Grade 3 or 4 hypotension, disseminated intravascular coagulation (DIC), or allergic reaction/hypersensitivity; * Grade 3 skin lesions: ulcerative dermatitis or skin changes with pain interfering with function; * Number of skin lesions ≥ 10 corresponding to infection possibly or probably related to the administration of TG6002; * Grade 3 non-hematologic toxicity persisting for \>7 days except increase in ASAT and/or ALAT (\> 5x ULN), which may last \>7 days if total bilirubin is normal or Grade 1; * Flu-like symptoms that do not respond to standard treatments; * Grade 3 hematologic toxicity persisting for \> 7 days

  Through day 1 to day 26

• Number of patients without documented tumor progression at 6 months from date of first TG6002 infusion according to Response Assessment Neuro-Oncology Criteria (Wen et al., 2010, JCO, PMID:20231676)

  For Phase 2a Number of patients without documented tumor progression at 6 months from date of first TG6002 infusion according to Response Assessment Neuro-Oncology Criteria (Wen et al., 2010, JCO, PMID:20231676)

  at 6 months according to RANO criteria

Secondary Outcomes (26)

• TG6002 recommended dose prior to the Phase 2a part of the study (RP2D) in combination with 5-FC (Maximum Plasma Concentration [Cmax])

  through study completion an average of 24 months

• Overall Survival (OS)

  through study completion : every 2 months the first year and then every 3 months from day 67 until the date of first documented progression or date of death from any cause wichever came first, assessed up to 51 months

• Relative quantification of circulating viral DNA

  Day1, Day2, Day 15, Day 26

• Blood pharmacokinetics of 5-FC

  Day0, Day7, Day 14, Day 26

• Blood pharmacokinetics of 5-FC

  Day0, Day7, Day 14, Day 26

Study Arms (1)

Combination of TG6002 and flucytosine (5-FC, Ancotil®)

EXPERIMENTAL

All patients within a given cohort will be treated with the same dose schedule of TG6002, administred as 3 weekly IV infusions at days 1, 8 and 15. following the 1st and 2nd infusions of TG6002, patients will be given oral 5-FC for 3 days starting on day 5 and 12 . following the 3rd infusion, patients will be given oral 5-FC for 21 days starting on day 19.

Drug: Combination of TG6002 and 5-flucytosine (5-FC, Ancotil®)

Interventions

Combination of TG6002 and 5-flucytosine (5-FC, Ancotil®) DRUG

Phase 1, TG6002 administered in a total volume of 250mL of saline solution (0.9 %) as three intravenous infusions at the following doses: * Dose 1 : 5.0 log10 pfu •Dose 2 : 6.0 log10 pfu •Dose 3 : 7.0 log10 pfu •Dose 4 : 7.5 log10 pfu * Dose 5 : 8.0 log10 pfu •Dose 6 : 8.5 log10 pfu Additional dose levels •Dose 2-1 : 5.5 log10 pfu •Dose 3-2 : 6.5 log10 pfu Phase 2a, treatment IV at the recommended Phase 2 dose 5-Flucytosine (5-FC) is provided in its commercial packaging with brand name ANCOTIL 500 mg, tablet (Ancotil®) marketed by MEDA Pharma: polypropylene tube containing 100 tablets. 5-FC administered orally as 500 mg tablets taken 4 times per day (qid). Daily starting dose is 200 mg/kg. The daily dose will be adjusted at Day 19 following the measurement of 5-FC plasma concentration at steady state (Day 7), which should be kept below 100 mg/L.

Combination of TG6002 and flucytosine (5-FC, Ancotil®)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \> 18 years.
• Karnofsky performance status ≥ 70.
• Histologically confirmed primary glioblastoma with unequivocal progression after at least the first line standard of care (concurrent chemoradiotherapy and adjuvant chemotherapy) at least 3 months after the completion of radiotherapy.
• At least one measurable lesion, according to RANO criteria.
• Availability of biological material (tumor) for review processes.
• If reoperation is conducted an early post-surgery MRI, within 48 hours is needed.
• Stable or decreasing dosage of steroids for 7 days prior to the baseline MRI scan.
• No previous cancer except: (i) cancer in remission for at least 5 years, (ii) skin carcinoma, or (iii) in situ carcinoma of the uterine cervix.
• Absence of any unstable disease (heart, liver, renal and respiratory failure).
• Absence of serious conditions (as judged by the investigator) that could interfere with the treatment (i.e. infection, immunosuppression defined as CD4+ lymphocytes \< 200/µL).
• Normal hematological functions: neutrophils ≥ 1.5 x 109 cells/L, platelets ≥ 100 x 109 cells/L and Hb ≥ 10.0 g/dL).
• Normal liver function: bilirubin \< 1.5 x upper limit of the normal range (ULN), alkaline phosphatase and transaminases (ASAT, ALAT) \< 3 x ULN.
• Normal renal function: calculated (Cockcroft-Gault) or measured creatinine clearance ≥ 60 mL/min.
• Absence of pregnancy:
• Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and 6 months beyond stop of treatment and must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product;

You may not qualify if:

• Immunodeficiency:
• CD4+ lymphocyte count \<200/µL, in any case ;
• HIV infection;
• History of severe exfoliative skin condition (e.g. eczema or atopic dermatitis) requiring systemic therapy for more than 4 weeks within 2 years of TG6002 treatment initiation.
• History of a severe systemic reaction or side-effect as a result of a previous smallpox vaccination, such as systemic vaccinia, eczema vaccinatum, encephalitis, myocarditis, or pericarditis.
• Patients with significant gastro-intestinal (GI) tract disease or resection leading to significant impairment of GI absorption or bacterial overgrowth.
• Known deficiency in dihydropyrimidine dehydrogenase (DPD).
• Hypersensitivity to flucytosine.
• Hypersensitivity to egg proteins.
• Hypersensitivity to gentamicin.
• History of severe drug allergy.
• Received systemic anti-cancer therapy within 4 weeks prior to first administration of TG6002.
• Prior gene therapy.
• Other medical condition or laboratory abnormality or active infection that in the judgment of the principal investigator may increase the risk associated with study participation or may interfere with interpretation of study results and /or otherwise make the patient inappropriate for entry into this study.
• Patient unable or unwilling to comply with the protocol requirements and/or unwilling to sign an informed consent form.

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Transgene: collaborator

Study Sites (1)

Groupe Hospitalier Pitié-Salpêtrière

Paris, 75651, France

RECRUITING

MeSH Terms

Conditions

Glioblastoma; Brain Neoplasms

Interventions

Flucytosine

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Cytosine; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Ahmed IDBAIH, MD

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ahmed IDBAIH, MD

CONTACT

01 42 16 03 85; ahmed.idbaih@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 1
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase 1 : Dose-escalation trial using an accelerated titration 3+3 design. Eligible patients will first be consecutively enrolled in a one-patient cohort at lowest dose level and then in 3-patients cohorts up to a DLT observation. All patients within a given cohort will be treated with the same dose schedule of TG6002. Following the 1st and 2nd infusion of TG6002 patients will be given oral 5-FC for 3 days starting on Day 5 and 12 and ending on Day 7 and 14, respectively. Following the 3rd infusion of TG6002 on Day 15, patients will be given oral 5-FC for 21 days starting on Day 19 and ending on Day 39 (end of treatment). Phase 2a Patients will be treated IV at the Recommended Phase 2 dose (RP2D).

Study Record Dates

• First Submitted: August 2, 2017
• First Posted: September 27, 2017
• Study Start: October 12, 2017
• Primary Completion: May 1, 2019
• Study Completion: September 1, 2021
• Last Updated: November 6, 2017

Record last verified: 2017-11

Locations

FR (1)