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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04116541
Recruitment Status : Recruiting
First Posted : October 4, 2019
Last Update Posted : May 20, 2022
Sponsor:
Information provided by (Responsible Party):
Centre Leon Berard

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.

Condition or disease Intervention/treatment Phase
Malignant Solid Tumor Drug: HDM201 Drug: Ribociclib Drug: Cabozantinib Drug: Alectinib Drug: Regorafenib Drug: Trametinib Drug: Dabrafenib Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 375 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: MegaMOST - A Multicenter, Open-label, Biology Driven, Phase II Study Evaluating the Activity of Anti-cancer Treatments Targeting Tumor Molecular Alterations /Characteristics in Advanced / Metastatic Tumors.
Actual Study Start Date : January 28, 2020
Estimated Primary Completion Date : February 2024
Estimated Study Completion Date : November 2024

Arm Intervention/treatment
Experimental: HDM201 + Ribociclib
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
HDM201 120mg, Every 3 weeks, Per os

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

Experimental: Cabozantinib
Patient with AXL, MET, vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor (VEGF), KIT, RET, ROS1, MER, Tropomyosin receptor kinase B (TRKB), Fms-like tyrosine kinase 3 (FLT3), TIE-2 and/or Tyro3 activating mutations and/or amplification, and/or NTRK translocation detected on tumor sample from primary tumor or metastatic lesion.
Drug: Cabozantinib
Cabozantinib, 60 mg /day, continuous, Per os

Experimental: Alectinib
Patient with ALK alterations: translocation, mutation or amplification
Drug: Alectinib
Alectinib, 600mg twice daily, Per os

Experimental: Regorafenib
Patient with activating mutation and/or amplification of VEGFR1-3, TIE-2, KIT, RET, RAF1, BRAF (other than V600 mutations), CRAF, HRAS, KRAS, Platelet Derived Growth Factor Receptor (PDGFR), Fibroblast Growth Factor Receptor 1-2 (FGFR1-2), FLT3 and/or Colony Stimulating Factor 1 Receptor (CSF1R), and/or amplification of the ligands, and/or biallelic inactivation of SMAD4
Drug: Regorafenib
Regorafenib 160mg, once daily, 3 weeks on/1 week off, Per os

Experimental: Trametinib
Patient with activating mutation and/or amplification of KRAS, 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
Drug: Trametinib
Trametinib 2 mg/day, continuous, Per os

Experimental: Trametinib + Dabrafenib
Patient with BRAF V600 mutation
Drug: Trametinib
Trametinib 2 mg/day, continuous, Per os

Drug: Dabrafenib
Dabrafenib 150 mg twice daily, Per os




Primary Outcome Measures :
  1. Progression free rate after 3 months of treatment [ Time Frame: 3 months ]
    The proportion of patients with a complete response (CR), a partial response (PR) or a stable disease (SD) at 3 months.


Secondary Outcome Measures :
  1. Objective response rate after 3 months of treatment [ Time Frame: 3 months ]
    The proportion of patients with a complete or a partial response (CR or PR) as best overall response at 3 months.

  2. Duration of Response [ Time Frame: Up to 3 years ]
    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.

  3. Progression Free Survival [ Time Frame: Up to 3 years ]
    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

  4. Overall survival [ Time Frame: Up to 3 years ]
    The time from the date of the first study drug administration to the date of death due to any cause

  5. Percentage of long-term responders (> 6 months) [ Time Frame: 6 months ]
    The proportion of long term responders (> 6 months)

  6. Adverse Events [ Time Frame: Up to 3 years ]
    Nature, frequency and severity of Adverse Events (AEs), Serious Adverse Events (SAEs) and Suspected Unexpected Serious Adverse Reactions (SUSARs) graded using Common Terminology Criteria for Adverse Events (CTCAE) V5.0.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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, KIT, RET, ROS1, MER, TRKB, FLT3, TIE-2 and/or Tyro3 activating mutations and/or amplification, and/or NTRK translocation
    • Cohort Alectinib : Activating ALK alterations: translocation, mutation or amplification
    • Cohort Regoranib : Activating mutation and/or amplification of VEGFR1-3, TIE-2, KIT, RET, RAF1, BRAF (other than V600 mutations), CRAF, HRAS, KRAS, PDGFR, FGFR1-2, FLT3 and/or CSFR1, and/or amplification of the ligands, and/or biallelic inactivation of SMAD4
    • Cohort Trametinib : Activating mutation and/or amplification of KRAS, NRAS, HRAS and/or MAP2K; and/or biallelic inactivation of NF1; and/or activating mutation PTPN11; and/or amplification or translocation of BRAF.
    • Cohort Trametinib + Dabrafenib : BRAF V600 mutation.
  • Previously treated by at least one prior line of treatment in the advanced/metastatic setting.
  • 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
  • Specific toxicities related to any prior anti-cancer therapy must have resolved to grade ≤1 , except for alopecia (all grades), grade 2 neuropathy or anemia.
  • Unless infertility is proven, men must agree to use effective contraception
  • Women of child-bearing potential must have a negative serum pregnancy test within 7 days of first dose of study drug and agree to use effective contraception
  • 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.
  • Patient must be covered by a medical insurance.

Exclusion Criteria:

  • 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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04116541


Contacts
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Contact: Jean-Yves BLAY, MD +33478785126 jean-yves.blay@lyon.unicancer.fr
Contact: Olivier TREDAN, MD +33478782828 olivier.tredan@lyon.unicancer.fr

Locations
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France
Institut Bergonié Recruiting
Bordeaux, France, 33076
Contact: Antoine ITALIANO, PHD    05 56 33 32 44    a.italiano@bordeaux.unicancer.fr   
Sub-Investigator: Kevin BOURCIER         
Sub-Investigator: Sophie COUSIN         
Sub-Investigator: Thomas GRELLETY         
Sub-Investigator: Simon PERNOT         
Sub-Investigator: Camille MAZZA         
Sub-Investigator: Diego TEYSSONNEAU         
Sub-Investigator: Maud TOULMONDE         
Centre Léon Bérard Recruiting
Lyon, France, 69373
Contact: Jean-Yves BLAY, MD    04 78 78 27 57    jean-yves.blay@lyon.unicancer.fr   
Principal Investigator: Jean-Yves BLAY, MD         
Sub-Investigator: Philippe CASSIER, MD         
Sub-Investigator: Olivier TREDAN, MD         
Institut Paoli Calmettes Recruiting
Marseille, France, 13273
Contact: François BERTUCCI, MD    04 91 22 35 37    bertuccif@ipc.unicancer.fr   
Contact: Anthony GONCALVES, MD    04 91 22 37 89    goncalvesa@ipc.unicancer.fr   
Principal Investigator: François BERTUCCI, MD         
Sub-Investigator: Anthony GONCALVES, MD         
Centre Antoine LACASSAGNE Recruiting
Nice, France, 06189
Contact: Esma SAADA-BOUZID, MD    04 92 03 15 14    esma.saada-bouzid@nice.unicancer.fr   
Principal Investigator: Esma SAADA-BOUZID, MD         
Sub-Investigator: Agnès DUCOULOMBIER         
Sub-Investigator: Joël GUIGAY         
Sub-Investigator: Nicolas MARTIN         
Sub-Investigator: Magalie Pascale TARDY         
Institut Curie Not yet recruiting
Paris, France, 75248
Contact: Christophe LE TOURNEAU, MD    01 44 32 46 75    christophe.letourneau@curie.fr   
Contact: Delphine LOIRAT, MD    01 44 32 46 75    delphine.loirat@curie.fr   
Principal Investigator: Christophe LE TOURNEAU, MD         
Sub-Investigator: Delphine LOIRAT, MD         
Sub-Investigator: Marie-Paule SABLIN, MD         
Institut Claudius Regaud Recruiting
Toulouse, France, 31059
Contact: Carlos-Alberto GOMEZ-ROCA, MD    05 31 15 51 01    gomez-roca.carlos@iuct-oncopole.fr   
Contact: Jean-Pierre DELORD, MD    05 31 15 51 01    delord.jean-pierre@iuct-oncopole.fr   
Principal Investigator: Carlos-Alberto GOMEZ-ROCA, MD         
Sub-Investigator: Jean-Pierre DELORD, MD         
Sub-Investigator: Iphigénie KORAKIS, MD         
Sponsors and Collaborators
Centre Leon Berard
Investigators
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Principal Investigator: Jean-Yves BLAY, MD Centre Leon Berard
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Responsible Party: Centre Leon Berard
ClinicalTrials.gov Identifier: NCT04116541    
Other Study ID Numbers: ET19-073 (MegaMOST)
2019-001494-88 ( EudraCT Number )
First Posted: October 4, 2019    Key Record Dates
Last Update Posted: May 20, 2022
Last Verified: May 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Centre Leon Berard:
Metastatic Solid Neoplasm
Advanced Solid Tumor
Genomic alteration
Targeted therapy
Cabozantinib
Ribociclib
HDM201
Alectinib
Trametinib
Dabrafenib
Additional relevant MeSH terms:
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Neoplasm Metastasis
Neoplasms
Neoplastic Processes
Pathologic Processes
Trametinib
Dabrafenib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action