Phase III Study on Molecular Profiling and Drug Combination Therapy in Advanced Unresectable Soft-Tissue Sarcoma Using Futibatinib, Durvalumab, and Olaparib

The primary objective of this study is to assess the **feasibility** of high throughput molecular analysis using next-generation sequencing (NGS) in participants with advanced soft-tissue sarcomas. This is clinically relevant as it aims to determine the proportion of participants for whom NGS results are interpretable and for whom a validated exome sequencing report, including a clinical recommendation from the molecular tumor board, is available within 7 weeks after sample reception. This assessment is crucial for integrating molecular profiling into clinical practice, potentially guiding personalized treatment strategies.

Secondary objectives include:

• Comparison of the efficacy of two treatment strategies (NGS vs. No NGS) in terms of progression-free survival (PFS) and overall survival (OS).
• Feasibility of NGS, including the proportion of participants with interpretable results and the delay from informed consent to the molecular tumor board.
• Proportion of participants with advanced soft-tissue sarcomas presenting at least one targetable genomic alteration.
• Efficacy of first-line systemic treatment in terms of PFS, OS, and response rates, including exploratory analyses of genomic alterations' prognostic value.
• Efficacy and safety profile of each targeted treatment, including non-progression rates, PFS, OS, and safety as per CTC AE v5.0.
• Cost-effectiveness of the NGS strategy compared to the non-NGS strategy, assessed through the incremental cost-utility ratio.
• Impact of immunosequencing results on objective response, PFS, and OS.
• Feasibility of NGS in participants who switched to the NGS arm, including interpretable results and genomic alterations.
• Exploratory objectives for participants initially randomized in the "No NGS" arm, assessing the feasibility of high throughput molecular analysis and the prognostic value of genomic alterations.

The clinical trial involves participants diagnosed with **unresectable locally advanced and/or metastatic soft-tissue sarcoma**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include vulnerable populations. Participants must have adequate hematological and metabolic functions, with hemoglobin levels greater than 9 g/dL and albumin levels exceeding 30 g/L. The selection criteria ensure that participants have not received prior systemic treatment for advanced disease and have no concurrent malignant diseases diagnosed or treated in the last two years, except for certain localized cancers. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified as part of the trial's considerations. Participants must provide informed consent and have a confirmed histological diagnosis of soft-tissue sarcoma. The trial requires the availability of suitable frozen archive tumor material or a lesion that can be biopsied for research purposes.

The clinical trial is designed to evaluate the feasibility of high throughput molecular analysis using **next generation sequencing** (NGS) in participants with advanced soft-tissue sarcomas. This is a phase III, randomized, double-blind, controlled study. The trial is expected to run from October 16, 2019, to October 16, 2025. Participants will be involved in the study for a duration that aligns with the trial's objectives, with the primary endpoint being the feasibility of obtaining interpretable NGS results and a validated exome sequencing report within 49 days of sample reception.

Study visits are structured to ensure comprehensive data collection and participant monitoring. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, disease status, and previous treatments. Follow-up visits will occur at regular intervals to monitor treatment efficacy and safety, as well as to collect necessary biological samples. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary post-study care is arranged.

Participants are expected to remain in the study for its full duration unless specific conditions necessitate early termination. These conditions include significant adverse events, withdrawal of consent, or any situation where continued participation is deemed not in the participant's best interest. The trial's design and procedures are meticulously planned to ensure the integrity of the data collected and the safety of all participants involved.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Futibatinib** is provided as a film-coated tablet, with a maximum daily dose of 20 mg and a total dose of 420 mg over a treatment period of 21 days. The administration route is oral. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**IMFINZI** (durvalumab) is administered as a 50 mg/mL concentrate for solution for infusion. The maximum daily and total dose is 1500 mg, administered intravenously over a single day. This treatment is monitored for infusion-related reactions and participant adherence to the protocol.

**Lynparza** (olaparib) is available in two dosages: 150 mg and 100 mg film-coated tablets. The maximum daily dose is 600 mg, with a total dose of 16.8 g over a 28-day period. The administration route is oral, and participant compliance is tracked through pill counts and patient diaries.

**Mekinist** (trametinib) is provided as film-coated tablets in dosages of 0.5 mg and 2 mg. The maximum daily dose is 2 mg, with a total dose of 56 mg over 28 days. The administration route is oral, and adherence is monitored through regular follow-ups and pill counts.

**IBRANCE** (palbociclib) is available in hard capsules of 125 mg, 100 mg, and 75 mg. The maximum daily dose is 125 mg, with a total dose of 2625 mg over a 4-week period. The administration route is oral, and compliance is ensured through patient logs and regular check-ins.

**Daurismo** (glasdegib) is administered as film-coated tablets in dosages of 100 mg and 25 mg. The maximum daily dose is 300 mg, with a total dose of 8.4 g over 28 days. The administration route is oral, and adherence is monitored through patient diaries and pill counts.

**Tabrecta** (capmatinib) is provided as film-coated tablets in dosages of 150 mg and 200 mg. The maximum daily dose is 800 mg, with a total dose of 22.4 g over 28 days. The administration route is oral, and participant compliance is tracked through regular assessments and pill counts.

**Tafinlar** (dabrafenib) is available in hard capsules of 75 mg and 50 mg. The maximum daily dose is 300 mg, with a total dose of 8.4 g over 28 days. The administration route is oral, and adherence is monitored through patient logs and regular follow-ups.

**Tasigna** (nilotinib) is administered as 200 mg hard capsules. The maximum daily dose is 800 mg, with a total dose of 22.4 g over 28 days. The administration route is oral, and compliance is ensured through patient diaries and regular check-ins.

**Tyverb** (lapatinib) is provided as 250 mg film-coated tablets. The maximum daily dose is 1500 mg, with a total dose of 42,000 mg over 28 days. The administration route is oral, and participant adherence is monitored through pill counts and patient logs.

**Zykadia** (ceritinib) is administered as 150 mg hard capsules. The maximum daily dose is 450 mg, with a total dose of 12.6 g over 28 days. The administration route is oral, and compliance is tracked through regular assessments and patient diaries.

All medications are part of an anti-cancer treatment regimen, and participant compliance is a critical component of the study, monitored through various methods such as pill counts, patient diaries, and regular follow-ups. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Each medication is administered according to its specific dosing schedule, and participant adherence is closely monitored to ensure the integrity of the trial data.

The efficacy of the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint focuses on the feasibility of high throughput molecular analysis using next-generation sequencing (NGS) exome. This will be considered feasible if the NGS results are available and interpretable, and a report of exome sequencing, including a clinical recommendation from a molecular tumor board, is provided to investigators within 7 weeks from the reception of blood and tumor samples.

Secondary endpoints include several measures of efficacy. **Overall survival (OS)** is defined as the time from randomization to death, and for the assessment of first-line and targeted treatments, it is defined from the onset of treatment to death. **Progression-free survival (PFS)** is measured from randomization to progression or death, and similarly, from the onset of treatment to progression or death for first-line and targeted treatments. The presence of targetable genomic alterations will be evaluated, with participants considered to have at least one targetable alteration if the molecular tumor board identifies a match with available drugs in the study.

Additional secondary endpoints include the best overall response and objective response under treatment, defined as complete or partial response according to RECIST v1.1 criteria. Non-progression at 6 months is assessed as complete or partial response or stable disease at 6 months. Changes in tumor size will be measured as the percentage difference from baseline to assessment. Immunosequencing will correlate TCR-sequencing data with objective response, PFS, and OS. Economic evaluations will include the real cost of NGS, utility data, and quality-adjusted life years, assessed through the EuroQol-5D-5L questionnaire, and the incremental cost-utility ratio comparing NGS and non-NGS strategies.