SHIVA02 - Evaluation of the Efficacy of Targeted Therapy Based on Tumor Molecular Profiling in Patients With Advanced Cancer Using Each Patient as Its Own Control (SHIVA02)

Study Overview
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Brief Summary
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The study will evaluate the efficacy of targeted therapy based on tumor molecular profiling versus conventional chemotherapy in patients with advanced cancer using each patient as its own control. This study is a study involving patients with advanced cancer. All types of solid tumors will be allowed in the study.

Official Title
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SHIVA02 - Evaluation of the Efficacy of Targeted Therapy Based on Tumor Molecular Profiling in Patients With Advanced Cancer Using Each Patient as Its Own Control

Conditions
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Cancer, Solid Tumor, Adult

Intervention / Treatment
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* Diagnostic Test: research of druggable molecular alterations on tumor biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Inclusion will proceed in 2 steps. First step for molecular analyses and second step in order to be included in the efficacy analysis. Inclusion criteria for Step 1: Patient with recurrent/metastatic solid tumor who failed or are not candidate for treatments usually proposed in first intention and for whom a prospective clinical trial has been indicated in a tumor board Patient with a documented progression before the start of conventional therapy according to RECIST 1.1. Patient ≥18 years old 3) Disease amenable to biopsy 5) ECOG performance status of 0 or 1 6) Measurable disease 7) Adequate renal function defined by a serum creatinine <1.5xUNL (upper normal limit) 8) Adequate liver function test defined by SGOT & SGPT <3xUNL (5xUNL in case of liver metastases), and bilirubin level <1.5xUNL 9) Adequate bone marrow function defined by platelets >100,000/mm3, hemoglobin >9 g/dL, and neutrophils >1,000/mm3 10) Patient must be affiliated to the French Social Security System 11) Signed informed consent 12 For female of child-bearing potential: a negative pregnancy test <72 hours before starting study treatment is required. If sexually active, female of childbearing potential must use highly effective methods of contraception for the study duration and for 3 months following the last treatment 13) For male of reproductive potential: any sexually active male patient must use a condom while on study treatment and for 3 months following the last treatment Inclusion criteria for Step 2: Patient for whom the Molecular Biology Board (MBB) has identified a druggable molecular alteration of the RAF/MEK signaling pathway and a treatment recommendation has been established by the MBB. Patient with a documented progression during the conventional therapy according to RECIST 1.1. Patient with imaging performed within 28 days prior to the planned start date of treatment Exclusion criteria: Patients below 18 years old Patients with CNS involvement that has not been controlled for >3 months Patients planned to receive a molecularly targeted agent Patients who are candidate to receive a molecularly targeted agent that is approved for their disease Patients with other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study, including uncontrolled diabetes, cardiac disease, uncontrolled hypertension, congestive cardiac failure, ventricular arrhythmias, active ischemic heart disease, myocardial infection within one year, chronic liver or renal disease, active gastrointestinal tract ulceration, severely impaired lung function Pregnant and/or breastfeeding women Patients individually deprived of liberty or placed under the authority of a tutor Patients with any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule Known HIV, HBV, or HCV infection

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: Screening
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: research of druggable molecular alterations on tumor biopsy<br> | Diagnostic Test: research of druggable molecular alterations on tumor biopsy<br>* The study will run in 2 steps. Before starting a new treatment, patients with advanced cancer will undergo a tumor biopsy of a metastatic site in order to perform molecular analyses seeking for druggable molecular alterations<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with a PFS2 to PFS1 ratio superior to 1.5. | PFS1 is defined as the time to a documented progression under conventional therapy according to RECIST 1.1. PFS2 is defined as the time to a documented progression or death when patients are treated by targeted therapy according to RECIST 1.1 | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) on both treatments | Evaluation of the best objective response rate (ORR) for each treatment according to RECIST 1.1 The best ORR is the best response reached during treatment according to RECIST 1.1 criteria. | 3 years | 
| Overall survival (OS) | Evaluation of overall survival (OS) defined as the time between inclusion and death, whatever the cause is. Alive patients will be censored at their last known contact date. | 3 years | 
| number of grade 3 or 4 adverse events and grade 1 or 2 adverse events that lead to dose modification or interruption | Evaluation of toxicities related to treatments according to CTCAE v4.03. Only grade 3 or 4 adverse events and grade 1 or 2 adverse events that lead to dose modification or interruption | 3 years | 
| Ability of ctDNA to detect molecular alterations identified on tumor biopsies | Percentage of patients for whom all druggable molecular alterations detected on the tumor biopsy are also detected on ctDNA. | at baseline | 
| Ability of fine-needle aspiration cytology to detect molecular alterations identified on tumor biopsies | Percentage of patients for whom all druggable molecular alterations detected on the tumor biopsy are also detected on fine-needle aspiration cytology | at baseline | 
| Ability of sequential ctDNA sampling to predict response/resistance to treatment | Changes in ctDNA levels and molecular alterations observed at different time points. | through study completion, every 2 months | 
| Proportion of patients with a PFS2 to PFS1 ratio superior to 1.5, including patients who were treated with matched therapy based on a molecular alteration outside of RAF/MEK pathway | PFS1 is defined as the time to a documented progression under conventional therapy according to RECIST 1.1. PFS2 is defined as the time to a documented progression or death when patients are treated by targeted therapy according to RECIST 1.1 | 3 years |