This trial is a multicenter, open-label, biology driven, phase II study using a sequential Bayesian design, aiming to assess the efficacy and safety of different Matched Targeted Therapy (MTT) in independent and parallel cohorts of treatment.
Patients will be assigned to a treatment cohort based on molecular alterations/characteristics detected on tumor sample from primary tumor or metastatic lesion.
In this protocol, several MTTs treatment cohorts are planned. This study is designed with the flexibility to open new MTTs treatment cohorts and to close existing MTTs treatment cohorts that demonstrate no clinical benefit. Each treatment cohort will be driven separately even though procedures, quality control and reporting, will be common. The protocol will be amended in order to include new treatments or combinations that emerge as being of interest for patients with advanced/metastatic cancers.
All eligible patients will receive study drugs as long as patient experiences clinical benefit in the opinion of the investigator, or until unacceptable toxicity, or until symptomatic deterioration attributed to disease progression as determined by the investigator after an integrated assessment of radiographic data and clinical status, or withdrawal of consent.
Patients will be permitted to continue study treatment after progressive disease according to RECIST v1.1 if they meet all of the following criteria and following validation of the Sponsor:
* Evidence of clinical benefit as assessed by the investigators, * Absence of symptoms and signs (including worsening of laboratory values; e.g., new or worsening hypercalcemia) that indicate unequivocal progression of disease, * No decline in ECOG Performance Status (PS) that can be attributed to disease progression.
Male or female patients aged of at least 18 years on day of signing informed consent.
Patients with histologically confirmed diagnosis of metastatic disease or unresectable locally advanced malignancy 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.
Cohort HDM201-Ribociclib : 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.
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.
Patients amenable to therapy with curative intent.
Patients participating to another clinical trial with a medicinal product.
Patients previously treated with similar MTT meaning any agent targeting the same signaling pathways components.
Patients unable to swallow oral medication.
Parallel
HDM201
DrugHDM201 120mg, Every 3 weeks, Per os
Ribociclib
DrugRibociclib 200mg/day, once daily 2 weeks on/1 week off, Per os
Cabozantinib
DrugCabozantinib, 60 mg /day, continuous, Per os
Alectinib
DrugAlectinib, 600mg twice daily, Per os
Regorafenib
DrugRegorafenib 160mg, once daily, 3 weeks on/1 week off, Per os
Trametinib
DrugTrametinib 2 mg/day, continuous, Per os
Dabrafenib
DrugDabrafenib 150 mg twice daily, Per os
Avapritinib
Drug300 mg/day,continuous, Per os
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Treatment groupsSee each treatment group below.
Progression free rate after 3 months (12 weeks) of treatment
The proportion of patients with a complete response (CR), a partial response (PR) or a stable disease (SD) at 3 months (12 weeks).
Objective response rate after 3 months (12 weeks) of treatment
The proportion of patients with a complete or a partial response (CR or PR) as best overall response at 3 months (12 weeks).
Duration of Response
Duration of response applies only to patients whose best overall response was a complete response or a partial response (CR or PR). It will be defined as the time from the date of first documented response (CR or PR) to the date of the first documented progression or death due to underlying cancer and censored at the date of the last adequate tumor assessment.
Progression Free Survival
The time from the date of the first study drug administration to the first documented progression according to investigator assessment of RECIST version 1.1 or death due to any cause
Overall survival
The time from the date of the first study drug administration to the date of death due to any cause
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