A Study Evaluating the Activity of Anti-cancer Treatments Targeting Tumor Molecular Alterations/Characteristics in Advanced / Metastatic Tumors.

NCT04116541 | Recruiting Phase 2 DMC

• 3 other identifiers: ET19-073 (MegaMOST)2023-510567-35-002019-001494-88
• Study Type: interventional
• Target: 455
• Locations: 1 country
• Sites: 10

Brief Summary

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.

Conditions

Malignant Solid Tumor

Keywords

Metastatic Solid Neoplasm; Advanced Solid Tumor; Genomic alteration; Targeted therapy; Cabozantinib; Ribociclib; HDM201; Alectinib; Trametinib; Dabrafenib; Avapritinib

Outcome Measures

Primary Outcomes (1)

• 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).

  3 months (12 weeks)

Secondary Outcomes (6)

• Objective response rate after 3 months (12 weeks) of treatment

  3 months (12 weeks)

• Duration of Response

  Up to 3 years

• Progression Free Survival

  Up to 3 years

• Overall survival

  Up to 3 years

• Percentage of long-term responders (> 6 months)

  6 months

Study Arms (7)

HDM201 + Ribociclib

EXPERIMENTAL

Patient with documented amplification of Cyclin-dependent kinase 6 (CDK6) and/or Cyclin-dependent kinase 4 (CDK4), and/or cyclin dependent kinase inhibitor 2A (CDKN2A) homozygous deletion, and/or amplification of Cyclin D1 (CCND1) and/or Cyclin D3 (CCND3) with no deletion/losses more than single copy of retinoblastoma 1 (RB1) by copy number and P53 wild-type detected on tumor sample from primary tumor or metastatic lesion.

Drug: HDM201; Drug: Ribociclib

Cabozantinib

EXPERIMENTAL

Patient with AXL, MET, vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor (VEGF), RET, ROS1, MER, Tropomyosin receptor kinase B (TRKB),TIE-2 and/or Tyro3 activating mutations and/or amplification, and/or NTRK translocation and/or ROS1 translocation, and/or MET translocation detected on tumor sample from primary tumor or metastatic lesion.

Drug: Cabozantinib

Alectinib

EXPERIMENTAL

Activating ALK alterations: translocation, or selected mutations,), or activating rearrangements following validation by central molecular tumor board of Centre Léon Bérard.

Drug: Alectinib

Regorafenib

EXPERIMENTAL

Patient with 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 CSF1R, and/or amplification of the ligands, and/or biallelic inactivation of SMAD4, following validation by central molecular tumor board of Centre Léon Bérard.

Drug: Regorafenib

Trametinib

EXPERIMENTAL

Patient with activating mutation and/or amplification of KRAS (except all KRAS G12 mutations), NRAS, HRAS and/or Mitogen-Activated Protein Kinase Kinase (MAP2K); and/or biallelic inactivation of Neurofibromin 1 (NF1); and/or activating mutation Protein Tyrosine Phosphatase Non-Receptor Type 11 (PTPN11); and/or amplification or translocation of BRAF ; and/or translocation RAF1

Drug: Trametinib

Trametinib + Dabrafenib

EXPERIMENTAL

Patient with BRAF V600 mutation

Drug: Trametinib; Drug: Dabrafenib

Avapritinib

EXPERIMENTAL

Activating mutations of KIT exon 17 or PDGFRA exon 18 associated or not to mutation on KIT exon 11 or PDGFRA exon 12/14

Drug: Avapritinib

Interventions

HDM201 DRUG

HDM201 120mg, Every 3 weeks, Per os

Also known as: Closed cohort

HDM201 + Ribociclib

Ribociclib DRUG

Ribociclib 200mg/day, once daily 2 weeks on/1 week off, Per os

Also known as: Closed cohort

HDM201 + Ribociclib

Cabozantinib DRUG

Cabozantinib, 60 mg /day, continuous, Per os

Also known as: Open cohort

Cabozantinib

Alectinib DRUG

Alectinib, 600mg twice daily, Per os

Also known as: Open cohort

Alectinib

Regorafenib DRUG

Regorafenib 160mg, once daily, 3 weeks on/1 week off, Per os

Also known as: Closed cohort

Regorafenib

Trametinib DRUG

Trametinib 2 mg/day, continuous, Per os

Also known as: Closed cohort

Trametinib; Trametinib + Dabrafenib

Dabrafenib DRUG

Dabrafenib 150 mg twice daily, Per os

Also known as: Open cohort

Trametinib + Dabrafenib

Avapritinib DRUG

300 mg/day,continuous, Per os

Also known as: Open cohort

Avapritinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• A multidisciplinary molecular board must have recommended the specific MTT based on the following documented actionable alterations:
• 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.
• Cohort Alectinib : Activating ALK alterations: translocation, or selected mutations, or activating rearrangements following validation by central molecular tumor board of Centre Léon Bérard.
• Cohort Regoranib : 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 RAF1
• Cohort Trametinib + Dabrafenib : BRAF V600 mutation.
• 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
• Previously treated by at least one prior line of treatment in the advanced/metastatic setting except for specific tumor type with no standard treatment approved and reimbursed in France following sponsor approval.
• 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.
• Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale.
• Adequate organ function
• Adequate cardiovascular function

You may not qualify if:

• 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.
• Patients with known hypersensitivity to excipients
• 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.
• 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.
• Patients using, or requirement to use while on the study, or not respecting the minimal wash-out period of medications
• 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.
• Patients with known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Patients who are pregnant or breastfeeding women or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through after the last dose of trial treatment (depanding on cohort).

Sponsors & Collaborators

• Centre Leon Berard: lead

Study Sites (10)

Institut Bergonié

Bordeaux, 33076, France

RECRUITING

Centre François Baclesse

Caen, 14076, France

RECRUITING

Centre Léon Bérard

Lyon, 69373, France

RECRUITING

Institut Paoli Calmettes

Marseille, 13273, France

RECRUITING

Centre Antoine LACASSAGNE

Nice, 06189, France

RECRUITING

Institut Curie

Paris, 75248, France

NOT YET RECRUITING

Institut de Cancérologie de Strasbourg

Strasbourg, 67033, France

TERMINATED

CHU Strasbourg - Hôpital de Hautepierre

Strasbourg, 67098, France

RECRUITING

Institut Claudius Regaud

Toulouse, 31059, France

RECRUITING

Institut Gustave Roussy

Villejuif, 94805, France

RECRUITING

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

siremadlin; Cohort Studies; ribociclib; cabozantinib; alectinib; regorafenib; trametinib; dabrafenib; avapritinib

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Epidemiologic Studies; Epidemiologic Study Characteristics; Epidemiologic Methods; Investigative Techniques; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health

Study Officials

• Jean-Yves BLAY, MD

  Centre Leon Berard

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jean-Yves BLAY, MD

CONTACT

+33478785126; jean-yves.blay@lyon.unicancer.fr

Olivier TREDAN, MD

CONTACT

+33478782828; olivier.tredan@lyon.unicancer.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 1, 2019
• First Posted: October 4, 2019
• Study Start: January 28, 2020
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2027
• Last Updated: April 24, 2026

Record last verified: 2026-04

Locations

FR (10)