Molecular Profiling of Advanced Soft-tissue Sarcomas

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

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.

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.

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. At least one site of disease must be uni-dimensionally > 10 mm,
• 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.