SIREMADLIN for Advanced/metastatic solid tumours

Inclusion criteria

• {"criterion_text":"- General criteria: - Male or female patients aged of at least 18 years on day of signing informed consent.\n- Unless documented infertility, men must agree to use effective contraception from C1D1 and after the last dose of study drugs (see each specific cohort for the duration).\n- Patient should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study procedures as per protocol.\n- Patient must be covered by a medical insurance.\n- Patients with histologically confirmed diagnosis of metastatic disease or unresectable locally advanced malignancy (solid tumors) that is resistant or refractory to standard therapies or for which standard therapies does not exist or is/are not considered appropriate by the investigator.\n- A multidisciplinary molecular board must have recommended the specific MTT based on the following documented actionable alterations:Cohort Ribociclib + HDM201 = amplification of CDK6 and/or CDK4, and/or CDKN2A homozygous deletion, and/or amplification of CCND1 and/or CCND3, with no deletion/losses more than single copy of RB1 by copy number and P53 wild-type (Closed). Cohort Cabozantinib = AXL, MET, VEGFR, VEGF, RET, ROS1, MER, TRKB, TIE-2 and/or Tyro3 activating mutations and/or amplification, and/or NTRK translocation and/or ROS1 translocation and/or MET translocation Cohort Alectinib = Activating ALK alterations: translocation or selected mutations (for instance R1275Q, F1245C, F1174X) , or activating rearrangements following validation by central molecular tumor board of Centre Léon Bérard. Cohort Regorafenib = Activating mutation and/or amplification and/or rearrangement of VEGFR1-3, TIE-2, KIT, RET, RAF1, BRAF (other than V600 mutations), CRAF, HRAS, PDGFR, FGFR1-2 , FLT3 and/or CSFR1, and/or amplification of the ligands, and/or biallelic inactivation of SMAD4, following validation by central molecular tumor board of Centre Léon Bérard. Cohort Trametinib = Activating mutation and/or amplification of KRAS (except all KRAS G12 mutations), NRAS, HRAS and/or MAP2K; and/or biallelic inactivation of NF1; and/or activating mutation PTPN11; and/or amplification or translocation of BRAF ; and /or translocation of RAF1 (Closed) Cohort Trametinib + Dabrafenib = BRAF V600 mutation.\n- Previously treated by at least one prior line of treatment in the advanced/metastatic setting.\n- Cohort Avapritinib : Activating mutations of KIT exon 17 or PDGFRA exon 18 associated or not to mutation on KIT exon 11 or PDGFRA exon 12/14\n- Documented radiological disease progression as per RECIST v1.1 and presence of at least one measurable lesion according to RECIST 1.1 criteria based on screening tumor assessment.\n- Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale.\n- Adequate organ function, as per laboratory tests performed within 7 days prior to C1D1 (see specific criteria in protocole for each cohort) - Specific toxicities related to any prior anti-cancer therapy must have resolved to grade ≤1 (according to NCI CTCAE v5.0), except for alopecia (all grades), grade 2 neuropathy or anemia.\n- Women of child-bearing potential must have a negative serum pregnancy test within 7 days of first dose of study drugs and agree to use effective contraception from the date of negative pregnancy test and after the last dose of study drugs (see each specific cohort for the duration)."}

Exclusion criteria

• {"criterion_text":"- General criteria: Patients amenable to therapy with curative intent.\n- Patients who are pregnant or breastfeeding women\n- Patients participating to another clinical trial with a medicinal product.\n- Patients previously treated with similar MTT meaning any agent targeting the same signaling pathways components.\n- Patients with known hypersensitivity to excipients of products.\n- Patients with symptomatic central nervous system (CNS) metastasis who are neurologically unstable or require increasing doses of corticosteroids or local CNS-directed therapy to control their CNS disease.\n- Patients with secondary malignancy unless this malignancy is not expected to interfere with the evaluation of study endpoints and is approved by the sponsor. Examples of the latter include: basal or squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, localized prostate cancer, prior malignancy and no evidence of recurrence for ≥ 2 years.\n- Known Human Immunodeficiency Virus (HIV) infection and/or active Hepatitis B (HBV) or Hepatitis C (HCV) infection.\n- Any clinically significant and/or uncontrolled medical disease that could compromise the patient's ability to tolerate study drug or would likely interfere with study procedures or results.\n- Patients with known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial."}

Primary endpoints

• {"endpoint_text":"- Progression free rate after 3 months of treatment (3M-PFR). (12 weeks)","definition_or_measurement_approach":"Assessed at 12 weeks (3 months); progression status determined by radiological assessment (screening/tumor assessments) — RECIST v1.1 is cited in inclusion criteria for measurable disease."}

Secondary endpoints

• {"endpoint_text":"- Objective response rate after 3 months of treatment (3M-ORR)","definition_or_measurement_approach":"Objective response rate at 3 months, assessed by radiological response criteria (RECIST v1.1 referenced in inclusion criteria)."}
• {"endpoint_text":"- Duration of Response (DoR)","definition_or_measurement_approach":"Time from first documented response to disease progression (standard DoR definition; specific protocol definition not provided in JSON)."}
• {"endpoint_text":"- Progression Free Survival (PFS)","definition_or_measurement_approach":"Time from treatment start to radiological/clinical disease progression or death (standard PFS definition; specific protocol text not provided in JSON)."}
• {"endpoint_text":"- Overall survival (OS)","definition_or_measurement_approach":"Time from treatment start to death from any cause (standard OS definition; specific protocol text not provided in JSON)."}
• {"endpoint_text":"- Percentage of long-term responders (> 6 months)","definition_or_measurement_approach":"Proportion of patients with response duration greater than 6 months."}

Other endpoints

• {"endpoint_text":"- Exploratory objective: follow the evolution of the mutations identified in ctDNA and to evaluate the correlation with efficacy endpoints.","definition_or_measurement_approach":"Longitudinal monitoring of tumor-associated mutations in circulating tumor DNA before and after treatment and correlation of mutation dynamics with clinical efficacy endpoints (as stated in protocol secondary/exploratory objectives)."}

France

Earliest CTIS Part Ii Submission Date

09-08-2024

Latest Decision Or Authorization Date

10-11-2025

Processing Time Days

458

Number Of Sites

10

Number Of Participants

455

Primary sponsor

Full Name

Centre Leon Berard

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France

Contract research organisations

Name

Almac Clinical Services Limited

Responsibilities

Listed as third party; contact clinicalservices@almacgroup.com; sponsor duties codes include 14 and 15 (15: Manufacturer and distributor).

Third parties

• {"country":"United Kingdom","full_name":"Almac Clinical Services Limited","duties_or_roles":"Code 14; Code 15 - Manufacturer and distributor","organisation_type":"Industry"}