E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Stage IV non small cell lung cancer (NSCLC) |
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E.1.1.1 | Medical condition in easily understood language |
Advanced non small cell lung cancer |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025055 |
E.1.2 | Term | Lung cancer non-small cell stage IV |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025048 |
E.1.2 | Term | Lung cancer non-small cell recurrent |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Phase IIb part (completed): to prospectively validate the level of
CD16+CD56+CD69+ lymphocytes, designed as TrPAL, as a predictive biomarker of TG4010's activity by comparing Progression-Free Survival (PFS) between the TG4010 arm (TG4010 + first-line therapy) and the placebo arm (placebo + first-line therapy) in the two subgroups of patients according to their level of TrPAL before randomization (normal and high level of TrPAL).
Phase III part: To demonstrate that TG4010 improves overall survival (OS) as compared to placebo in stage IV NSCLC patients with non-squamous tumor histology receiving first-line chemotherapy:
• in the whole study population
• in the subgroup of patients with non-elevated TrPAL at baseline |
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E.2.2 | Secondary objectives of the trial |
Phase IIb part (completed):
- Compare the 2 treatment arms with respect to OS, Overall Response Rate (ORR) and Time to Overall Response
- Describe the Duration of Response (DoR)
- Evaluate and to compare the safety profiles
Phase III part:
- To compare the 2 treatment arms with respect to the following endpoints repeated in the whole study population and in subgroups of patients with non-elevated TrPAL at baseline: PFS based on RECIST 1.1, 9-month PFS, ORR, and DoR
- Quality of Life and pharmacoeconomic
- Evaluate safety as assessed based on NCI-CTCAE in the whole study population, in patients with non-elevated TrPAL at baseline, and in patients with elevated TrPAL at baseline.
- Compare PFS and OS in patients with elevated TrPAL at baseline
Exploratory objectives of phase III:
- Assess blood and cellular biomarkers or biomarker “profiles” with potential prognostic and/or predictive value on efficacy outcomes or biomarkers associated with TG4010 mechanism of action. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PBMC isolation and banking – (substudy for 250 patients) |
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E.3 | Principal inclusion criteria |
- Male or female patients, age ≥ 18 years old
- Histologically confirmed NSCLC. NSCLC Not Otherwise Specified (NOS) are eligible except large cell neuroendocrine carcinoma.
- Stage IV cancer according to TNM classification
- Availability of histological material for Immunohistochemistry (IHC) staining on fixed paraffin embedded material; biopsy may come either from the primary tumor or from a metastasis
- Patient's naïve to first-line therapy for the advanced stage of the disease. Previous neoadjuvant or adjuvant therapy or radiotherapy is allowed for patients who successfully underwent complete radical surgery and if last treatment was administered more than 12 months prior to the start of the study treatment, i.e., D1 of Cycle 1.
- At least one measurable lesion by computorized tomography scan or magnetic resonance imaging based on RECIST version 1.1 (CT is preferred for the chest exam)
- Performance status 0 or 1 on the ECOG scale
- Adequate hematological, hepatic, and renal function:
* Hemoglobin ≥ 10.0 g/dL
* White Blood Cells ≥ 3.0x1E+09/L including:
Neutrophils ≥ 1.5x1E+09/L
Total lymphocytes count ≥ 0.5x1E+09/L
* Platelets count ≥ 100x1E+09/L
* Serum alkaline phosphatase ≤3 x upper limit of normal (ULN) in the absence of liver or bone metastases, and ≤5 ULN in patients with such metastases
* Serum transaminases alanine aminotransferase and aspartate aminotransferase ≤ 2.5 x ULN in the absence of liver metastases and ≤ 5 x ULN in case of liver metastases
* Total bilirubin ≤1.5 x ULN
* Glomerular Filtration Rate ≥ 60 mL/min (according to Modification of the Diet in Renal Disease (MDRD) formula or Cockroft & Gault formula)
* Serum albumin ≥ 30 g/L
- Effective contraception during the study period and for 3 months after the last study treatment administration (male and female patient)
- Signed informed consent |
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E.4 | Principal exclusion criteria |
- NSCLC with predominant squamous cell histology (mixed tumors will be categorized by the predominant cell type unless small cell elements are present, in which case the patient is not eligible). Large cell neuroendocrine carcinoma are excluded
- Patients having Central Nervous System (CNS) metastases (including leptomeningeal metastases). Patients who have had brain metastases surgically removed or irradiated with no residual disease confirmed by imaging and not treated by corticosteroids are allowed are allowed
- EGFR activating mutations or ALK rearrangements leading to eligibility for TKI treatment (tests mandatory). Patients with documented ROS1-rearrangement (if already tested) are not eligible
- Prior history of other malignancy except:
* Basal cell carcinoma of the skin
* Cervical intra epithelial neoplasia
* Other cancer curatively treated with no evidence of disease for at least 5 years
- Patients under chronic treatment with systemic corticoids or other immunosuppressive drugs (e.g., cyclosporine) for a period of at least 4 weeks and whose treatment was not stopped 1 week prior to the start of the study treatment (i.e., D1 of Cycle 1)
- Positive serology for Human Immunodeficiency Virus or Hepatitis C Virus; presence in the serum of the antigens HBs
- Patient with any underlying medical condition that the treating physician considers might be aggravated by treatment or which is not controlled (e.g., elevated troponin or creatinine, uncontrolled diabetes)
- Patient with major surgery or radiotherapy within 4 weeks prior to the start of the study treatment (i.e., D1 of Cycle 1). However, prior surgery or radiation therapy aimed at local palliation or attempted local disease control is permitted within the 4 weeks before treatment start
- Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 10 mIU/mL)
- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they are:
* women whose sexual orientation precludes intercourse with a male partner
* women whose partners have been sterilized by vasectomy or other means
* using a highly effective method of birth control (i.e. one that results in a less than 1% per year failure rate when used consistently and correctly, such as implants, injectables, combined oral contraceptives, and some intrauterine devices [IUDs]; periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) is not acceptable)
- Patient with an organ allograft
- Known allergy to eggs, gentamicin or platinum containing compounds
- Participation in a clinical study with an investigational product within 4 weeks prior to the start of the study treatment (i.e., D1 of Cycle 1)
- Patient unable or unwilling to comply with the protocol requirements |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase IIb part (completed): PFS (time from the date of randomization to the date of first documented tumor progression or death due to any cause, whichever occurs first)
Phase III part: OS (time from date of randomization to the date of death due to any cause) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
PFS: tumor progression evaluated by RECIST every 6 weeks from start of treatment until documented progression or for a period of 9 months after start of study treatment, whichever occurs first. Beyond 9 months of treatment, the evaluations will be performed every 12 weeks until documented progression
OS will be evaluated at the date of a subject's death due to any cause; patients will be followed for survival on a 3-monthly basis |
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E.5.2 | Secondary end point(s) |
Phase IIb part (completed), secondary endpoints:
- OS: defined in E.5.1
- ORR: proportion of patients whose best overall response is either complete response (CR) or partial response (PR) according to RECIST v.1.1
- Response rate at evaluation #2: proportion of patients having presented a CR or PR (even if not confirmed) at the 2nd tumor assessment after treatment start.
- TOR: the start date is the date of randomization and the end date is the date of first documented response (CR or PR).
- DoR: time from the date of first documented response (CR or PR) to the date of first documented disease progression or death due to underlying cancer
- Safety: Incidence of AEs and SAEs assessed by the NCI CTCAE
Phase IIb part (completed), exploratory endpoints:
- Response rate at evaluation #2, change in tumor size over time: tumor size is defined as the sum of the longest diameters for all target lesions as identified at baseline
- Efficacy and safety in subgroups of patients
- Peripheral blood parameters: cellular and humoral response, immunophenotyping of lymphocytes, inflammatory and immune cytokines and related proteins, transcriptomics and genomics
- Blood biomarkers with potential prognostic and/or predictive value on efficacy outcomes or biomarkers associated with TG4010 mechanism of action
- Viral dissemination: skin swabs analyses by qPCR
Phase III part, secondary endpoints:
- PFS: defined in E.5.1
- ORR, DoR & safety: defined above
- QoL: questionnaire QLQC30-LC13-EORTC
- Pharmacoeconomic: Information obtained from the collection of medical care utilization data through eCRF may be combined with other data such as cost data or other clinical parameters
Phase III part, exploratory endpoint:
- Immune related biomarker evaluation |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PFS & OS: see E.5.1.1
ORR & DoR: see E.5.1.1
TOR: 1st response or last tumor assessment
Safety: evaluated throughout the study
QoL: every 6 wks starting on D1 of Cycle 1 until end of study treatmnt
Pharmacoecon. data: separately from CSR
Change in tumor size over time: same as for PFS; see E.5.1.1
Peripheral blood parameters (Phase IIb only): at single time points and over time
The explor. endpoint relating to the identification of biomarkers with potential prognostic and/or predictive value on efficacy outcomes, or associated with TG4010 mechanism of action, may be conducted after patient participation has ended
Viral dissemination: before & 6 hrs after the 1st IMP injection & before IMP injections on D8, D15 and D22
Immune rel. biomarker evaluation: on D1 of Cycles 1, 2, 3 & 5 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 112 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Bulgaria |
Canada |
Denmark |
France |
Germany |
Hungary |
Israel |
Italy |
Netherlands |
New Zealand |
Poland |
Romania |
Russian Federation |
Serbia |
South Africa |
Spain |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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For the Phase IIb part: after a follow-up of 30 months after last patient randomization and providing that all patients have completed the study with regard to PFS.
For the Phase III part: after a follow-up of 48 months from last patient randomization. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 9 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 9 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |