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 | 16.0 |
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 | 16.0 |
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: 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 compare Overall Survival (OS) between the TG4010 arm and the placebo arm in the identified patient population based on the results of the Phase IIb part of the study. |
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E.2.2 | Secondary objectives of the trial |
Phase IIb part:
1/ To compare the 2 treatment arms with respect to OS and Overall Response Rate (ORR)
2/ To describe the Duration of Response (DoR)
3/ To evaluate and to compare the safety profiles
Phase III part:
1/ To compare the two treatment arms with respect to PFS and ORR
2/ To describe the DoR
3/ To evaluate and to compare the safety profiles
4/ To evaluate the two treatment arms with respect to change in quality of life (QoL)
Exploratory objectives:
1/ To evaluate the effect of TG4010 on response at scheduled evaluation
#2
2/To evaluate the effect of TG4010 on tumor size over time
3/ To evaluate efficacy of TG4010 in subgroups of patients
4/ To evaluate the safety of TG4010 in subgroups of patients
5/ To describe the effects of TG4010 on peripheral blood parameters (Phase IIb only)
6/ To describe measures of viral genome (Phase IIb only) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male or female patients, age ≥ 18 years old
- Histologically confirmed NSCLC (adenocarcinoma, squamous cell carcinoma, large cell carcinoma, undifferentiated carcinoma or other)
- Stage IV cancer according to TNM classification
- Tumor biopsy specimen with ≥ 50% of MUC1 expressing tumor cells determined by Immunohistochemistry (IHC) staining on fixed pathological 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 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 ≤ 5 x upper limit of normal (ULN) (except in patients with documented bone or liver 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
* 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)
- Written informed consent
- For Phase III part: additional inclusion criterion for the level of TrPAL may be added according to the results observed in Phase IIb part
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E.4 | Principal exclusion criteria |
- Patients having Central Nervous System metastases. Patients who have had brain metastases surgically removed or irradiated with no residual disease confirmed by imaging are allowed
- Documented EGFR activating mutations leading to eligibility for TKI treatment (if already tested)
- 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 (> 5 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 or gentamicin
- 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
- Bevacizumab will be allowed for patients with non-squamous carcinoma. Prescribing information must be followed and precautions have to be taken into consideration (e.g., patients having presented a serious hemorrhage or recent hemoptysis should not receive bevacizumab) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase IIb part: 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:
- 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 version 1.1
- Response rate at evaluation #2: proportion of patients having
presented a CR or PR (even if not confirmed) at the second tumor assessment after treatment start.
- 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 serious adverse events (SAEs) assessed by the NCI CTCAE
Phase III part:
- PFS: defined in E.5.1
- ORR, DoR & safety: defined above
- QoL: questionnaire QLQC30-LC13-EORTC
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 (Phase IIb only): 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 (Phase IIb only): skin swabs analyses by qPCR
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints:
- PFS and OS: see E.5.1.1
- ORR & DoR: see E.5.1.1
- Safety: evaluated throughout the study
- QoL: every 6 weeks starting on D1 of Cycle 1 until end of study treatment
The exploratory endpoints:
- 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 exploratory end point 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 and 6 hours after the first IMP injection and before IMP injections on Day 8, Day 15 and Day 22
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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 | No |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 75 |
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 |
India |
Israel |
Italy |
Korea, Republic of |
Philippines |
Poland |
Russian Federation |
Singapore |
Spain |
Sweden |
Thailand |
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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The end of the study will correspond to the primary completion date for final analysis i.e. the last date of death for the number of events required by the primary endpoint (Phase III; OS) to be reached. Beyond this date, still alive patients will be followed up. |
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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 | 4 |
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 | 4 |
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 |