| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult patients with locally advanced/unresectable and/or metastatic soft-tissue sarcoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Adult patients with advanced soft-tissue sarcoma |
|
| 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 | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039494 |
| E.1.2 | Term | Sarcoma NOS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
In patients with advanced STS: to assess the feasibility of high throughput molecular analysis (next generation sequencing exome [NGS]).
- Primary objective will be assessed in patients randomized in the arm “NGS”.
- Feasibility will be defined as the proportion of patients for whom results from NGS are (i) interpretable and (ii) for whom a validated report of exome sequencing including a clinical recommendation from the molecular tumor board is available within 7 weeks (i.e. within at most 49 calendar days) after reception of blood and tumor samples by one of the molecular platform. |
|
| E.2.2 | Secondary objectives of the trial |
1) Comparison of the efficacy of the 2 treatment strategies (NGS vs No NGS) in terms of:
- Progression-free survival (median PFS, PFS after 1- and 2-year follow-up),
- Overall survival (median OS, OS after 1- and 2-year follow-up).
2) Assessment of the feasibility of high throughput molecular analysis NGS (exome, RNASeq) in terms of additional feasibility endpoints:
- Proportion of patients with interpretable NGS results
- For patients with interpretable NGS: results delay from the date of signature of the informed consent to the date of the molecular tumor board.
3) Assessment of the proportion of patients with advanced STS presenting at least one targetable genomic alteration.
4) Assessment of the efficacy of first-line anthracycline-based chemotherapy.
5) Assessment of the efficacy and the safety profile of each targeted treatment.
6) Assessment of the cost-effectiveness of the NGS strategy (vs. no NGS).
7) Impact of the result of immunosequencing on OR, PFS and OS. |
|
| 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 |
- PATIENTS TREATED BY NILOTINIB, V1.0 du 10.09.2018
To assess the efficacy of Nilotinib in participants with advanced soft-tissue sarcomas [STS] following first-line chemotherapy. Efficacy will be assessed in terms of 6-month non-progression rate as per RECIST v1.1.
- PATIENTS TREATED BY CERITINIB, V1.0 du 10.09.2018
To assess the efficacy of Ceritinib in participants with advanced soft-tissue sarcomas [STS] following first-line chemotherapy. Efficacy will be assessed in terms of 6-month non-progression rate as per RECIST v1.1.
- PATIENTS TREATED BY CAPMATINIB, V1.0 du 10.09.2018
To assess the efficacy of Capmatinib in participants with advanced soft-tissue sarcomas [STS] following first-line chemotherapy. Efficacy will be assessed in terms of 6-month non-progression rate as per RECIST v1.1.
- PATIENTS TREATED BY LAPATINIB, V1.0 du 10.09.2018
To assess the efficacy of Lapatinib in participants with advanced soft-tissue sarcomas [STS] following first-line chemotherapy. Efficacy will be assessed in terms of 6-month non-progression rate as per RECIST v1.1.
- PATIENTS TREATED BY TRAMETINIB, V1.0 du 10.09.2018
To assess the efficacy of Trametinib in participants with advanced soft-tissue sarcomas [STS] following first-line chemotherapy. Efficacy will be assessed in terms of 6-month non-progression rate as per RECIST v1.1.
- PATIENTS TREATED BY TRAMETINIB AND DABRAFENIB, V1.0 du 10.09.2018
To assess the efficacy of Trametinib + Dabrafenib in participants with advanced soft-tissue sarcomas [STS] following first-line chemotherapy. Efficacy will be assessed in terms of 6-month non-progression rate as per RECIST v1.1
- PATIENTS TREATED BY OLAPARIB AND DURVALUMAB, V1.0 du 10.09.2018
To assess the efficacy of Durvalumab + Olaparib in participants with advanced soft-tissue sarcomas [STS] following first-line chemotherapy. Efficacy will be assessed in terms of 6-month non-progression rate as per RECIST v1.1.
- PATIENTS TREATED BY PALBOCICLIB, V1.0 du 10.09.2018
To assess the efficacy of Palbociclib in participants with advanced soft-tissue sarcomas [STS] following first-line chemotherapy. Efficacy will be assessed in terms of 6-month non-progression rate as per RECIST v1.1.
- PATIENTS TREATED BY GLASDEGIB, V1.0 du 10.09.2018
To assess the efficacy of Glasdegib in participants with advanced soft-tissue sarcomas [STS] following first-line chemotherapy. Efficacy will be assessed in terms of 6-month non-progression rate as per RECIST v1.1.
- PATIENTS TREATED BY TAS-120, V1.0 du 10.09.2018
To assess the efficacy of TAS-120 in participants with advanced soft-tissue sarcomas [STS] following first-line chemotherapy. Efficacy will be assessed in terms of 6-month non-progression rate as per RECIST v1.1. |
|
| E.3 | Principal inclusion criteria |
1) Age ≥ 18 years,
2) Histology: soft-tissue sarcoma confirmed by the RRePS Network, as recommended by the French NCI,
3) Metastatic STS,
4) No previous systemic treatment for metastatic disease,
5) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1,
6) Adequate hematological and metabolic functions:
a. Hemoglobin ≥ 9 g/dl
b. Albumin ≥ 30 g/dl
7) Measurable disease according to RECIST 1.1. At least one site of disease must be uni-dimensionally > 10 mm,
8) Availability of suitable frozen archive tumor material from a metastatic or advanced disease (not previously treated),
9) Archived FFPE block of specimen tumor sampling obtained anytime during disease development for research purpose,
10) Eligible to first-line standard chemotherapy regimen,
11) No prior or concurrent malignant disease diagnosed or treated in the last two years before inclusion, except for in situ carcinoma of the cervix and adequately treated basal cell or squamous cell carcinoma of the skin and prostate cancer,
12) Patient with a social security in compliance with the French law,
13) Voluntary signed and dated written informed consent prior to any study specific procedure (ICF1). |
|
| E.4 | Principal exclusion criteria |
1) Radiological evidence of symptomatic or progressive brain metastases,
2) Inability to swallow,
3) Major problem with intestinal absorption,
4) Previous allogeneic bone marrow transplant,
5) Evidence of severe or uncontrolled systemic disease (uncontrolled hypertension, active bleeding diatheses, or active Hepatitis B, C and HIV or active autoimmune disease),
6) Any condition which in the Investigator’s opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol,
7) Individuals deprived of liberty or placed under guardianship
8) Pregnant or breast feeding women,
9) Men or women refusing contraception,
10) Previous enrolment in the present study,
11) Any contraindication to first-line chemotherapy treatment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Feasibility of high throughput molecular analysis (next generation sequencing exome, NGS)
NGS (exome) will be considered feasible if (i) NGS results are available and interpretable, and (ii) a report of exome sequencing including a clinical recommendation from a molecular tumor board is provided to investigators within 7 weeks from reception of the samples by one of the MULTIPLI platforms.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Feasibility will be assessed within 7 weeks from reception of the samples by one of the MULTIPLI platforms. |
|
| E.5.2 | Secondary end point(s) |
EFFICACY ENDPOINTS
- Efficacy of an innovative treatment strategy guided by high throughput molecular analysis (next generation exome sequencing, RNASeq [NGS], immunological profiling) in participants with advanced soft-tissue sarcomas [STS]
* Overall survival (OS): OS is defined as the delay from the date of randomization to the date of death (whatever the cause).
* Progression-free survival (PFS): PFS will be defined as the delay from the date of randomization to the date of progression as per RECIST v1.1 or death, whichever occurs first.
- Participants with targetable alteration(s)
A participant will be considered as “presenting at least one targetable genomic alteration”, if the MTB considers that at least one genetic alteration identified can be matched with one of the drugs available through the MULTISARC study.
- Efficacy of first-line anthracycline-based chemotherapy (in all participants)
* OS
* PFS
* Best response: best response recorded from the date of onset of first-line treatment until the end of first-line treatment taking into account any requirement for confirmation as per RECIST v1.1 criteria
* 6-month objective response: objective response is defined as complete or partial response (CR, PR) as per RECIST v1.1 under first-line treatment
* 6-month non-progression: non-progression is defined as complete or partial response (CR, PR) or stable disease (SD) under first-line treatment as defined as per RECIST v1.1
- Efficacy of each targeted treatment
* Following RECIST v1.1 recommendation, each participant will be assigned one of the following categories: complete response, partial response, stable disease, progression, invaluable for response
* 6-month non-progression
* OS
* PFS
* Best response
* Objective response
* Change in tumor size (CTS): CTS is defined as the difference (in percentage) in tumor size burden from the date of targeted treatment initiation (baseline) to the tumor assessment.
SAFETY ENDPOINTS
For STS participants, progressive, stable and/or responding after first-line induction treatment, and presenting at least one targetable genomic alteration and included in a single-arm phase II sub-trial, the safety profile of targeted treatments (independently for each targeted treatment) will be assessed:
- Toxicity will be evaluated using the NCI-CTCAE scale, version 5. All appropriate treatment areas should have access to a copy of the CTCAE version 5.
- The safety evaluation will comprise an evaluation of the participant’s general condition (ECOG), a physical exam, regular blood tests and the recording of adverse events occurring throughout the study.
COST-EFFECTIVENESS ENDPOINTS
- Cost data:
* Real cost of NGS: a micro-costing study will be conducted, in collaboration with the FCRIN-RECAP network, to estimate the real cost of NGS. Micro-costing studies collect detailed data on resources utilized (consumables, technician time, devices…) and the value of those resources. Such studies are useful for estimating the cost of new technologies or new community-based interventions, for producing estimates in studies that include non-market goods, and for studying within-procedure cost variation.
* Cost of other resources: the French National Health Insurance reimburses the vast majority of other resources involved in the care of patients in this trial. These costs will be extracted from the French National Health Insurance data. To do so, with the authorization of patients, we will gather their unique Health Insurance identification number. This number will enable us to merge the MULTISARC data with the National Health Insurance data of each included patient.
Some of the resources involved in the MULTISARC trial are not yet reimbursed by the French National Health Insurance as they are part of the innovative care strategy involving NGS. These ressources will be gathered into the MULTISARC CRF and valorized by national conventional tarifs.
* Per diem allowances: In case of sick leave, the French National Health Insurance pays per diem allowance for employed individuals. These costs will then be recorded in the French National Health Insurance database.
- Utility data and Quality Adjusted Life Years
Utility scores will be assessed through the EuroQol-5D-5L questionnaire. It is an autoquestionnaire. Patients will complete it each month during the first 6 months of follow-up, and every 6 month thereafter. An utility score is between 0 (death) and 1 (perfect health status).
A Quality Adjusted Life Year is the survival (in years) weighted by a utility score.
- Incremental cost utility ratio
Our incremental cost-utility ratio is difference in cost between both strategies (NGS and no NGS) divided by the difference in QALYs. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Progression-free survival (PFS): the end-of-treatment (safety follow-up visit) visit will be scheduled 30 days (4 weeks) after the last treatment administration (a window of ±1 week is allowed).
- Overall survival (OS): participants' vital status will be recorded throughout study period.
- Best response under treatment: the end-of-treatment visit will be scheduled 30 days (4 weeks) after the last treatment administration (a window of ±1 week is allowed).
- Overall responses: the end-of-treatment visit will be scheduled 30 days (4 weeks) after the last treatment administration (a window of ±1 week is allowed).
Proportion of participants with targetable alteration(s): data will be extracted in real time from the genetic profiling qualification report |
|
| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | No |
| 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 | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | No |
| 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 | 15 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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