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

NCT04116541

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: ET19-073 (MegaMOST)
  • SECONDARY ID: 2019-001494-88
  • NCT ID: NCT04116541

Conditions

  • Malignant Solid Tumor

Interventions

DrugSynonymsArms
HDM201HDM201 + Ribociclib
RibociclibHDM201 + Ribociclib
CabozantinibCabozantinib

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
HDM201 + RibociclibExperimentalPatient 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.
  • HDM201
  • Ribociclib
CabozantinibExperimentalPatient 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.
  • Cabozantinib

Eligibility 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: 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.

          -  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, all screening laboratory tests should be performed within 7
             days prior to Cycle 1 Day 1 (C1D1) :

               -  Hematological (without transfusion within 14 days prior to screening lab tests) :

               -  Absolute neutrophil count (ANC) ≥ 1.5 G/L,

               -  Platelets ≥ 100 G/L,

               -  Hemoglobin ≥ 9 g/dL,

               -  Lymphocyte count ≥ 0.8 G/L,

               -  White blood cell count ≥ 3 G/L.

               -  Renal and Hepatic function :

               -  Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 3 × Upper
                  Limit of Normal (ULN) in the absence of liver metastases (or ≤ 5 × ULN in case of
                  liver metastasis or hepatic infiltration),

               -  Serum total bilirubin ≤ 1.5 × ULN (except for patients with Gilbert disease for
                  whom a total serum bilirubin ≤ 3 x ULN is acceptable),

               -  Serum creatinine ≤ 1.5 × ULN or Creatinine clearance ≥ 50 mL/min/1.73m2
                  calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).

               -  Adequate ionic balance: potassium, calcium, magnesium and phosphorus within
                  normal limits (supplementation is authorized)

          -  Adequate cardiovascular function :

               -  corrected QT interval by Fredericia (QTcF) ≤ 450 ms,

               -  Resting blood pressure systolic < 160 mmHg and diastolic < 90 mmHg,

               -  Heart rate > 50 bpm at rest,

               -  Left Ventricular Ejection Fraction (LVEF) ≥ 50% as determined by Multi Gated
                  Acquisition scan (MUGA Scan) or transthoracic echocardiogram.

          -  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 documented infertility, men must agree to use effective contraception from C1D1
             until 21 days after the last dose of study drugs.

          -  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 to up to 21 days after the last dose of study drugs.

          -  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 Ribociclib excipients: hypersensitivity to
             peanut or soy.

          -  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 listed below:

               -  Any approved anti-cancer treatment Or Any investigational therapy other than the
                  specified therapies in present protocol (4 weeks)

               -  Chemotherapy 4 weeks (6 weeks for nitrosoureas and mitomycin C).

               -  Radiotherapy 4 weeks

               -  Surgery : Major surgical procedure, open biopsy, or significant traumatic injury
                  4 weeks

               -  Live vaccines 4 weeks

               -  Growth factors targeting the myeloid lineage 2 weeks

               -  Medicinal products known to prolong the QT interval and/ or to induce "Torsades
                  de Pointes" 1 week

               -  Strong and moderate inducers or inhibitors of CYP3A4/5, CYP3A4/5 substrates with
                  a narrow therapeutic index 1 week

               -  Substrates of CYP2C19 with a narrow therapeutic index and Substrates of OATP1B1
                  prohibited 24 hours prior and 1 week after HDM201 administration

               -  Substrates of P-gp prohibited 4 hours before and after HDM201 and Ribociclib
                  administration

          -  Patients with history of thromboembolic or cerebrovascular events within the last 3
             months, including transient ischemic attack, cerebrovascular accident, deep vein
             thrombosis, or pulmonary embolism.

          -  Patients with clinically significant, uncontrolled heart disease and/or recent events
             including any of the following:

               -  History of acute coronary syndromes or symptomatic pericarditis within 12 months
                  prior to C1D1,

               -  History of documented congestive heart failure,

               -  Documented cardiomyopathy,

               -  History of any cardiac arrhythmias, e.g. ventricular, supraventricular, nodal
                  arrhythmias, or conduction abnormality within 12 months prior to C1D1,

               -  Congenital long QT syndrome or family history of long QT syndrome,

               -  Patients with drug eluting stents for cardiovascular purposes.

          -  Patients with a diagnosis of acute or chronic pancreatitis.

          -  Impairment of gastrointestinal function or GI disease that may significantly alter
             drug absorption of oral drugs

          -  Known Human Immunodeficiency Virus (HIV) infection and/or active Hepatitis B (HBV) or
             Hepatitis C (HCV) infection.

          -  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 21 days after the last dose of trial treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free rate after 3 months of treatment
Time Frame:3 months
Safety Issue:
Description:The proportion of patients with a complete response (CR), a partial response (PR) or a stable disease (SD) at 3 months.

Secondary Outcome Measures

Measure:Objective response rate after 3 months of treatment
Time Frame:3 months
Safety Issue:
Description:The proportion of patients with a complete or a partial response (CR or PR) as best overall response at 3 months.
Measure:Duration of Response
Time Frame:Up to 3 years
Safety Issue:
Description: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.
Measure:Progression Free Survival
Time Frame:Up to 3 years
Safety Issue:
Description: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
Measure:Overall survival
Time Frame:Up to 3 years
Safety Issue:
Description:The time from the date of the first study drug administration to the date of death due to any cause
Measure:Percentage of long-term responders (> 6 months)
Time Frame:6 months
Safety Issue:
Description:The proportion of long term responders (> 6 months)
Measure:Assessment of the safety profile of the study drugs for each cohort
Time Frame:Up to 3 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Centre Leon Berard

Trial Keywords

  • Metastatic Solid Neoplasm
  • Advanced Solid Tumor
  • Genomic alteration
  • Targeted therapy
  • Cabozantinib
  • Ribociclib
  • HDM201

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