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    Summary
    EudraCT Number:2019-001399-13
    Sponsor's Protocol Code Number:69HCL19_0115
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-04-05
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2019-001399-13
    A.3Full title of the trial
    MEK and Autophagy Inhibition in Metastatic/Locally Advanced, Unresectable NRAS Melanoma: A Phase Ib/II Trial of Trametinib plus Hydroxychloroquine in Patients with NRAS Melanoma. CHLORO TRAM MEL
    Etude de phase I/II évaluant la tolérance d’un traitement par hydroxychloroquine associé au tramétinib dans le mélanome NRAS muté métastatique ou localement avancé non résécable après échec d’une immunothérapie. CHLORO TRAM MEL
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    MEK and Autophagy Inhibition in Metastatic/Locally Advanced, Unresectable NRAS Melanoma: A Phase Ib/II Trial of Trametinib plus Hydroxychloroquine in Patients with NRAS Melanoma. CHLORO TRAM MEL
    Etude de phase I/II évaluant la tolérance d’un traitement par hydroxychloroquine associé au tramétinib dans le mélanome NRAS muté métastatique ou localement avancé non résécable après échec d’une immunothérapie. CHLORO TRAM MEL
    A.3.2Name or abbreviated title of the trial where available
    CHLORO TRAM MEL
    A.4.1Sponsor's protocol code number69HCL19_0115
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorHospices Civils de Lyon
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportHealth ministry
    B.4.2CountryFrance
    B.4.1Name of organisation providing supportNovartis
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHospices Civils de Lyon
    B.5.2Functional name of contact pointAnnie IUNG
    B.5.3 Address:
    B.5.3.1Street Address3 Quai des Célestins
    B.5.3.2Town/ cityLYON
    B.5.3.3Post code69002
    B.5.3.4CountryFrance
    B.5.4Telephone number330472406824
    B.5.5Fax number330472115190
    B.5.6E-maildrci_promo@chu-lyon.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Mekinist
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTrametinib
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Plaquenil
    D.2.1.1.2Name of the Marketing Authorisation holderSANOFI-AVENTIS FRANCE
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSulfate d'hydroxychloroquine
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with metastatic NRAS melanoma
    E.1.1.1Medical condition in easily understood language
    Patients with metastatic NRAS melanoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10027481
    E.1.2Term Metastatic melanoma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • Phase Ib: To assess the safety and tolerability of escalating doses of hydroxychloroquine (HCQ) in combination with a fixed dose of trametinib in subjects with metastatic or locally advanced, unresectable NRAS mutated melanoma and determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of the combination.
    • Phase II: To assess the efficacy of trametinib and hydroxychloroquine in the study population, when used at the RP2D.
    E.2.2Secondary objectives of the trial
    To evaluate toxicity and safety of the combination trametinib and hydroxychloroquine and evaluate long term antitumor activity
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histologically confirmed metastatic or locally advanced unresectable malignant melanoma with an activating NRAS mutation.
    2. Available archival tissue OR if not the patient is willing to provide a baseline tumor biopsy
    3. Patient must have progressed during or after a first line treatment by immunotherapy (ipilimumab, pembrolizumab, nivolumab).
    - Progression will be confirmed by two consecutive CT assessements separated by 4 weeks.
    - Inclusion is possible if patients progress during an adjuvant treatment by immunotherapy or if they progress less than six months after adjuvant treatment discontinuation.
    - If patients progress six months after adjuvant treatment discontinuation, they have to be treated by a second line of immunotherapy before they can be included in the trial.
    4. Patient age ≥18
    5. Patient Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.
    6. Patient able to provide informed consent and sign approved consent forms to participate in the study and provide tumor samples
    7. Patient willing and able to comply with all study procedures and able to take oral medications.
    8. Patients must be willing and able to undergo skin or tumor biopsies according to the institute’s own guidelines, the study protocol and requirements for such procedures.
    9. Patients must have measurable disease as defined by RECIST v1.1 criteria
    10. Adequate bone marrow, renal and liver function determined biologically:
    - Hematologic: absolute neutrophil count (ANC) ≥1.5x10e9/L, platelet count ≥100 x10e9/L, and hemoglobin ≥9g/dL
    - Hepatic: total bilirubin level ≤1.5 x the upper limit of the normal (ULN) range ((except subjects with Gilbert’s Syndrome who must have normal direct bilirubin) and ASAT and ALAT levels ≤3 ULN. For patients with metastatic disease to the liver allow levels ≤5 ULN
    - Renal: estimated creatinine clearance ≥50ml/min according to the Cockcroft-Gault formula (or local institutional standard method).
    - Albumin ≥ 27 g/l
    11. Adequate cardiac function determined by a pre-treatment EKG and cardiac ultra-sound.
    - QTc interval ≤ 480 ms
    - Left ventricular ejection fraction (LVEF) ≥50%
    12. Women of childbearing potential must have a negative serum or urine pregnancy test at screening.
    13. Both male and female patients must agree to the use of 2 methods of contraception, with one method being highly effective and the other being either highly effective or less effective as listed in annexe 1 throughout the study and for at least 4 months after last study treatment administration if the risk of conception exists.
    14. Women of childbearing potential who are continuously not heterosexually active are exempt from contraceptive requirements. However, women of childbearing who abstain from heterosexual activity on a continuous basis must still undergo pregnancy testing as described in this protocol.
    E.4Principal exclusion criteria
    1. Prior to the first dose of study treatment patient who received systemic antineoplastic therapy (including unconjugated therapeutic antibodies and toxin immunoconjugates) or any investigational therapy within 4 weeks (6 weeks for nitrosurea or mitomycin-C, antibodies like ipilimumab, pembrolizumab and nivolumab) or within 7-half lives of the investigational therapy prior to starting study treatment, whichever is longer.
    2. Patient received radiotherapy within 2 weeks prior to the first dose of study treatment except localized radiation therapy for symptomatic bone metastasis
    3. Patients with multiple primary malignancies may be enrolled if non-melanoma tumor(s) are determined stable by treating investigator and do not require active treatment.
    4. Patients with symptomatic brain metastases or cranial epidural disease. Asymptomatic patients with brain metastases can be included.
    5. Has retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of uveitis, or history of retinal vein occlusion (RVO) or any eye condition that would be considered a risk factor for RVO (e.g., uncontrolled glaucoma or ocular hypertension).
    6. Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:
    - Cardio-vascular disorders: Congestive heart failure NYHA class 3 or 4, unstable angina, serious cardiac arrythmias. Stroke, myocardial infarction or other ischemic event within 3 months before first dose.
    - History of G6PD deficiency
    - Patients who have neuromuscular disorders that are associated with elevated CK
    - Impairment of gastrointestinal function or gastrointestinal disease (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection that under the judgement of the PI may impair absorption of study drugs)
    - Any other condition that would, in the Investigator’s judgment, contraindicate the patient’s participation in the clinical study due to safety concerns or compliance with clinical study procedures.
    7. Known positive serology for HIV, active Hepatitis B, and/or active Hepatitis C infection.
    8. Patients who have undergone major surgery ≤ 3 weeks prior to starting study drug or who have not recovered from side effects of such procedure.
    9. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
    10. Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study
    11. Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5.0 Grade≥3)
    E.5 End points
    E.5.1Primary end point(s)
    • Phase Ib: Incidence of dose-limiting toxicities (DLTs) to choose the optimal dose for the phase II (RP2D).
    • Phase II: Evaluate the Overall Response Rate (ORR) by comparing target lesions on a CTscan performed after two cycles of treatment (56 days) to those present on the base line CT prior to treatment initiation, to determinate the percentage of patients with a partial or complete response according to RECIST v1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase I : DLTs will be determined weekly during the first cycle of treatment (28 days).
    Phase II : 56 days
    E.5.2Secondary end point(s)
    o Median progression Free survival and Overall Survival will be determined in the cohort treated by the RP2D
    o AEs and SAEs according to CTCAE v 5.0 will be reported
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the study
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    3+3 dose escalation design to determine the maximum tolerated dose (MTD) or recommended phase 2 dose
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months30
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 29
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 29
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state29
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Expected treatment following patients' condition
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-05-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial StatusOngoing
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