Molecular Profiling of Advanced Soft-tissue Sarcomas

Study Overview
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Brief Summary
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MULTISARC is a randomized multicenter study assessing whether high throughput molecular analysis (next generation sequencing exome - NGS) is feasible in advanced/metastatic soft-tissue sarcoma patients, that is, whether NGS can be conducted for a large proportion of patients, with results available within reasonnable delays. In parallel, MULTISARC aims to assess efficacy of an innovative treatment strategy guided by high throughput molecular analysis (next generation sequencing exome, RNASeq [NGS]) in patients with Advanced/metastatic soft-tissue sarcomas. At the end of first-line treatment, participant's tumor profile of experimental Arm NGS (treatment strategy based on NGS results) will be discussed within a multidisciplinary tumor board which aims at discussing the genomic profiles and at providing a therapeutic decision for each participant. Participants for whom a targetable genomic alteration has been identified will be proposed to enter in one of the subsequent phase II single-arm sub-trial.

Detailed Description
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Screening phase: frozen tumor sample (archived or newly obtained) and blood sample will be used for genetic profiling. Patients can be considered as pre-eligible for the randomized phase when all genetic material have been received by the Platform. Randomization phase: the randomization will allocate the following arms with a ratio 1:1: experimental Arm NGS : treatment strategy based on NGS results [exome, RNASeq] standard Arm No NGS: treatment strategy not based on NGS (Note that for these participants and under specific conditions, subsequent NGS analyses may be allowed within the scope of the trial) Single-arm phase II sub-trial: at the end of the first-line treatment and regardless of tumor response as per RECIST v1.1, patients randomized in Arm NGS and for whom a targetable alteration has been identified by the Molecular Tumor Board will be considered as pre-eligible for the targeted sub-study. The mandatory post-chemotherapy wash-out period of 21 days will provide time to achieve all the required tests and examinations.

Official Title
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Molecular Profiling of Advanced Soft-tissue Sarcomas. A Phase III Study

Conditions
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Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: Nilotinib
* Drug: Ceritinib
* Drug: Capmatinib
* Drug: Lapatinib
* Drug: Trametinib
* Combination Product: Trametinib and Dabrafenib
* Combination Product: Olaparib and Durvalumab
* Drug: Palbociclib
* Drug: Glasdegib
* Drug: TAS-120
* Other: Next Generation sequencing exome


Participation Criteria
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Eligibility Criteria
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Randomized phase Inclusion Criteria: Age ≥ 18 years, Histology: soft-tissue sarcoma confirmed by the RRePS Network, as recommended by the French NCI Unresectable locally advanced and/or metastatic STS No previous systemic treatment for advanced disease, ECOG ≤ 1 Adequate hematological and metabolic functions: Hemoglobin > 9 g/dL and albumin > 30 g/L Measurable disease according to RECIST 1.1. Availability of suitable frozen archive tumor material obtained from a metastatic lesion or advanced disease (not previously treated), or at least one lesion that can be biopsied for research purpose, Archived FFPE block of specimen tumor sampling obtained anytime during disease development for research purpose, Eligible to first-line systemic treatment, No prior or concurrent malignant disease diagnosed or treated in the last two years before inclusion. Note that patients with in situ carcinoma of the cervix, or adequately treated basal cell or squamous cell carcinoma of the skin, or adequately treated localized prostate cancer, or other localized cancer under maintenance therapy can be included as long as they don't limit assessment of efficacy of first-line systemic therapy Participant with a social security in compliance with the French law, Voluntary signed and dated written informed consent prior to any study specific procedure (ICF1) Exclusion Criteria: Radiological evidence of symptomatic or progressive brain metastases, Inability to swallow, Major problem with intestinal absorption, Previous allogeneic bone marrow transplant, Evidence of severe or uncontrolled systemic disease (uncontrolled hypertension, active bleeding diatheses, or active Hepatitis B, C and HIV or active autoimmune disease), 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, Individuals deprived of liberty or placed under guardianship Pregnant or breast feeding women, Men or women refusing contraception, Previous enrolment in the present study, Any contraindication to first-line chemotherapy treatment. Phase II Sub-trials Inclusion Criteria: Participants already enrolled in MULTISARC and randomized/switched in Arm NGS, ECOG performance status < 1, Measurable disease according to RECIST v1.1, Molecular alteration identified by molecular profiling, Participants who have received a first-line systemic treatment at the inclusion, Participants must have advanced disease and must not be a candidate for other approved therapeutic regimen known to provide significant clinical benefit based on investigator judgement, Participants will have had a minimum of 21 days gap from last chemotherapy or immunotherapy or any other pharmacological therapy and/or radiotherapy prior to the first dose of study treatment, Women of childbearing potential must have a negative serum pregnancy test within 3 days of enrolment and serum/urine pregnancy test within 24 hours prior to the administration of the study drug, Female with child bearing potential and male participants with partners of child bearing potential must be willing to use two effectives forms of contraception (1 highly effective method and 1 barrier method), from beginning 3 weeks before the first dose of investigational product and until 3 months after discontinuing the study. Participant with a social security in compliance with the French law, Voluntary signed and dated written informed consent (ICF2) prior to any study specific procedure. Main exclusion Criteria: Previous treatment with the targeted therapy, No targetable genomic alteration generated during the screening phase either due to the lack of alteration or due to ineligible samples for genomic analysis (MULTISARC), Participants with total gastrectomy, Major surgery within 30 days prior to entry into the study (excluding placement of vascular access) or minor surgery within 14 days of entry into the study, History of hypersensitivity to involved study drug(s) or of its excipients, Radiological evidence of symptomatic or progressive brain metastases, Participant with oral anticoagulation therapy, Inability to swallow, Major problem with intestinal absorption, Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. Participants with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Sponsor. Previous allogeneic bone marrow transplant, Altered hematopoietic or organ function, Mean resting corrected QT interval (QTcF)>470msec obtained from 3 consecutive ECGs Previous or current maligancies of other histologies within the last 2 years, with the exception of in situ carcinoma of the cervix, and adequately treated basal cell or squamous cell carcinoma of the skin and prostate cancer, Evidence of severe or uncontrolled systemic disease (uncontrolled hypertension, active bleeding diatheses), active uncontrolled systemic bacterial, viral, or fungal infection > Grade 2 as per NCI CTCAE v5.0 Chronic or active hepatitis B or hepatitis C. Testing for hepatitis B surface antigen (HBs Ag) and hepatitis B core antibody (anti HBc) will be performed at screening, Human immunodeficiency virus (HIV) positive, 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, Individuals deprived of liberty or placed under guardianship, Pregnant or breast feeding women.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: MULTISARC is a randomized multicenter study assessing whether high throughput molecular analysis (next generation sequencing exome - NGS) is feasible in advanced soft tissue sarcoma participants. In parallel, MULTISARC aims to assess efficacy of an innovative treatment strategy guided by high throughput molecular analysis, in participants with advanced soft-tissue sarcomas. Randomization 1:1 with 1 participant randomized in experimental Arm NGS (treatment strategy based on NGS) and 1 participant randomized in standard Arm No NGS (treatment strategy not based on NGS). At the end of first-line treatment, participant's tumor profile of experimental Arm NGS will be discussed within a multidisciplinary tumor board which aims at discussing the genomic profiles and at providing a therapeutic decision for each participant. Participants for whom a targetable genomic alteration has been identified will be proposed to enter in one of the subsequent phase II single-arm sub-trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Arm No NGS<br>Patients will be treated by standard first-line systemic treatment and tumor assessment will be performed every 2 cycles during treatment. Thereafter, disease will be managed as per standard care depending on tumor response observed at the end of the first-line treatment. Note that for these participants and under specific conditions, subsequent NGS analyses may be allowed within the scope of the trial | |
| Experimental: Arm NGS<br>Patients will be treated by standard first-line systemic treatment and tumor assessment will be performed every 2 cycles during treatment. After tumor assessment at the end of first-line systemic treatment and regardless of tumor response as per RECIST v1.1, participants will be discussed within a multidisciplinary tumor board (molecular tumor board-MTB) which aims at discussing the genomic profiles and at providing a therapeutic decision for each participant. Patients for whom a targetable genomic alteration has been highlighted will be proposed to enter in a subsequent single-arm phase II sub-trials. Otherwise, thereafter, disease will be managed as per standard care depending on tumor response observed at the end of the first-line treatment | Other: Next Generation sequencing exome<br>* Both frozentumor material (archived or newly obtained) and blood sample collection will be used for genetic profiling<br>* Other names: High throughput sequencing;|
| Experimental: Arm NGS - Targeted therapy<br>Targeted therapy from a list of 10 targeted treatment strategies, guided by the genomic analyses: Nilotinib capsule per os 400 mg bd, continuous dosing ; Ceritinib capsule per os 450 mg od, continuous dosing; Capmatinib tablet per os 400 mg bd, continuous dosing; Lapatinib tablet per os 1500 mg od, continuous dosing; Trametinib tablet per os 2 mg od, continuous dosing; association of Trametinib tablet per os 2 mg od and Dabrafenib capsule per os 150 mg bd, continuous dosing; association of Olaparib tablet per os 300 mg bd, continuous dosing and Durvalumab intra-veinous 1500 mg on day 1, Q4W; Palbociclib capsule 125 mg od, 3 weeks on/1 week off; Glasdegib tablet per os 300 mg od, continuous dosing; TAS-120 tablet per os 20 mg od, continuous dosing. | Drug: Nilotinib<br>* Target: KIT, PDGFRA, CSF1R Nilotinib will be administered orally, 400 mg twice daily on a continuous basis. A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation.<br>* Other names: TASIGNA;Drug: Ceritinib<br>* Target: ALK, ROS. Ceritinib will be administered orally, 450mg once daily on a continuous basis. A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation.<br>* Other names: ZYKADIA;Drug: Capmatinib<br>* Target: MET. Capmatinib will be administered orally, 400mg twice daily on a continuous basis. A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation.<br>Drug: Lapatinib<br>* Target: ERBB2, EGFR. Lapatinib will be administered orally, 1500mg once daily on a continuous basis. A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation.<br>* Other names: TYVERB;Drug: Trametinib<br>* Target: KRAS, NRAS, HRAS, PTPN11, NF1, MAP2K. Trametinib will be administered orally, 2 mg once daily on a continuous basis. A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation.<br>* Other names: MEKINIST;Combination Product: Trametinib and Dabrafenib<br>* Target: KRAS, NRAS, HRAS, PTPN11, NF1, MAP2K, BRAF. Trametinib will be administered orally, 2mg once daily on a continuous basis. Dabrafenib will be administered orally, 150mg twice daily, on a continuous basis. A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation.<br>* Other names: MEKINIST and TAFINLAR;Combination Product: Olaparib and Durvalumab<br>* Target: PDL1, PARP. Olaparib will be administered orally, 300mg twice daily on a continuous basis. Dabrafenib will be administered intraveinously, 1500mg on day 1 every 4 weeks. A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation.<br>* Other names: MEDI4736;Drug: Palbociclib<br>* Target: CDK4, CDK6. Palbociclib will be administered orally, 125mg once daily, 3 weeks on/1 week off. A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation.<br>* Other names: PD-0332991;Drug: Glasdegib<br>* Target: SMO. Glasdegib will be administered orally, 300 mg once daily on a continuous basis. A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation.<br>* Other names: PF-04449913;Drug: TAS-120<br>* Target: FGFR. TAS-120 will be administered orally, 20 mg once daily on a continuous basis. A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the feasibility of high throughput molecular analysis (next generation sequencing exome [NGS] | Feasibility will be defined as the proportion of participants 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. | 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the efficacy of the 2 treatment strategies (NGS vs No NGS) in terms of 1-year 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 | 1 year | 
| Comparison of the efficacy of the 2 treatment strategies (NGS vs No NGS) in terms of 2-year 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 | 2 years | 
| Comparison of the efficacy of the 2 treatment strategies (NGS vs No NGS) in terms of 1-year overall survival (OS) | OS will be defined as the delay from the date of randomization to the date of death (whatever the cause) | 1 year | 
| Comparison of the efficacy of the 2 treatment strategies (NGS vs No NGS) in terms of 2-year overall survival (OS) | OS will be defined as the delay from the date of randomization to the date of death (whatever the cause) | 2 years | 
| Assessment of the feasibility of high throughput molecular analysis in terms of delay to obtain a clinical recommendation from the molecular tumor board for patients randomized in arm NGS with interpretable NGS | Delay from the date of signature of the informed consent to the date of the molecular tumor board | an average of 7 weeks | 
| Assessment of the proportion of patients with Advanced STS presenting at least one targetable genomic alteration | 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 | An average of 7 weeks | 
| Assessment of the efficacy of first-line systemic treatment in terms of 1-year progression-free survival | PFS will be defined as the delay from the date of onset of first-line treatment to the date of progression as per RECIST v1.1 (or death, whichever occurs first) | 1 year | 
| Assessment of the efficacy of first-line systemic treatment in terms of 2-year progression-free survival | PFS will be defined as the delay from the date of onset of first-line treatment to the date of progression as per RECIST v1.1 (or death, whichever occurs first) | 2 years | 
| Assessment of the efficacy of first-line systemic treatment in terms of 1-year overall survival | OS will be defined as the delay from the date of onset of first-line treatment to the date of death (whatever the cause). | 1 year | 
| Assessment of the efficacy of first-line systemic treatment in terms of 2-year overall survival | OS will be defined as the delay from the date of onset of first-line treatment to the date of death (whatever the cause). | 2 years | 
| Assessment of the efficacy of first-line systemic treatment in terms of best overall response under first-line treatment | Best response is 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 | Throughout the treatment period, an average of 18 weeks | 
| Assessment of the efficacy of first-line systemic treatment in terms of 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 months | 
| Assessment of the efficacy of first-line systemic treatment in terms of 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 | 6 months | 
| Assessment of the efficacy of each targeted treatment in terms of 6-month non progression | Non progression is defined as complete or partial response (CR, PR) or stable disease (SD) under targeted treatment as defined as per RECIST v1.1 | 6 months | 
| Assessment of the efficacy of each targeted treatment in terms of 1-year progression-free survival | PFS will be defined as the delay from the date of targeted treatment initiation to the date of progression as per RECIST v1.1 or death, whichever occurs first | 1 year | 
| Assessment of the efficacy of each targeted treatment in terms of 1-year overall survival | OS is defined as the delay from the date of targeted treatment initiation to the date of death (whatever the cause) | 1 year | 
| Assessment of the efficacy of each targeted treatment in terms of best overall response under treatment | Best response (partial or complete, as per RECIST v1.1) recorded from date of targeted treatment initiation taking into account any requirement for confirmation as per RECIST v1.1 criteria | Throughout the treatment period, an average of 6 months | 
| Assessment of the efficacy of each targeted treatment in terms of objective response under treatment | Complete response or partial response under targeted treatment as defined as per RECIST evaluation criteria v1.1 | Throughout the treatment period, an average of 6 months | 
| Assessment of the efficacy of each targeted treatment in terms of 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 | Throughout the treatment period, an average of 6 months | 
| Assessment of the safety profile of each targeted treatment using the CTCAE v5 | Safety will be assessed as per CTCAE v5 | Throughout the treatment period, an average of 6 months | 
| Impact of the results of immunosequencing during first-line treatment | Correlation of TCR-sequencing data with objective response (OR) | At cycle 2 day 1 | 
| Impact of the results of immunosequencing during first-line treatment | Correlation of TCR-sequencing data with progression-free survival (PFS) | At cycle 2 day 1 | 
| Impact of the results of immunosequencing during first-line treatment | Correlation of TCR-sequencing data with overall survival (OS) | At cycle 2 day 1 | 
| Impact of the results of immunosequencing during targeted treatment | Correlation of TCR-sequencing data with objective response (OR) | At cycle 2 day 1 of targeted treatment | 
| Impact of the results of immunosequencing during targeted treatment | Correlation of TCR-sequencing data with progression-free survival (PFS) | At cycle 2 day 1 of targeted treatment | 
| Impact of the results of immunosequencing during targeted treatment | Correlation of TCR-sequencing data with overall survival (OS) | At cycle 2 day 1 of targeted treatment | 
| To estimate the cost-effectiveness of the strategy usdin NGS as compared to the strategy without NGS | The outcome will be the incremental cost-utility ratio or the incremental cost per incremental Quality Adjusted Life Year (QALY) | Trhoughout the study period, an average of 2 years | 
| To assess the feasibility of NGS in participants who have switched treatment arm for NGS arm in terms of proportion of participants with interpretable NGS results | Proportion of participants with interpretable NGS results | an average of 7 weeks | 
| To assess the feasibility of NGS in participants who have switched treatment arm for NGS arm in terms of delays | Delay from the date of treatment failure (progression, investigator decision, end of last treatment line) to the date of the molecular tumor board | an average of 7 weeks | 
| To assess the feasibility of NGS in participants who have switched treatment arm for NGS arm in terms of proportion of participants with interpretable NGS results | Proportion of participants presenting at least one targetable genomic alteration | an average of 7 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced disease, metastatic disease, Next generation sequencing exome