Clinical trial NCT03391050 (phase 1/phase 2, status: terminated)
Conditions: melanoma
ICD codes: C43.0, C43.31, D03.9, C43.51, C43.9, D03.0, C43.4
Drugs: apr-246, dabrafenib
SMILES: COCC1(CO)N2CCC(CC2)C1=O, CC(C)(C)C1=NC(=C(S1)C1=NC(N)=NC=C1)C1=C(F)C(NS(=O)(=O)C2=C(F)C=CC=C2F)=CC=C1
Reason stopped: 
    target patient population - difficult to find patientes
  
Eligibility criteria:

        Inclusion Criteria:

          -  Patients with confirmed BRAF V600 mutation-positive unresectable and/or metastatic
             malignant cutaneous melanoma, as determined locally by a validated test and treated
             with dabrafenib/trametinib first line combination therapy or second line after first
             line immunotherapy.

          -  Patients that have progressed according to RECIST 1.1 after at least 4 weeks of
             treatment with dabrafenib/trametinib and remained on dabrafenib full dose (150mg bid)
             treatment for the study.

          -  Measurable disease according to RECIST 1.1 criteria. For phase II only, metabolic
             measurable disease (according to PERCIST).

          -  Availability of tissue from a metastatic lesion. A new biopsy is required unless
             inaccessible. An archival sample is accepted in that case after discussion with the
             sponsor.

          -  ECOG Performance Status of 0 or 1.

          -  Patients able to swallow and retain oral medication.

          -  Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form.

          -  For female patients of childbearing potential, a pregnancy test (serum) will be
             performed within 7 days before inclusion. Woman of childbearing potential must be
             willing to use one highly effective form of contraception during anticancer treatment
             and for at least six months thereafter. Men must agree to use condom during the course
             of this study and at least six months after the last administration of the study
             treatment and contraception should be considered for partner of childbearing
             potential.

          -  Adequate organ system function.

          -  Signed informed consent before any study specific procedure and/or treatment happens.

        Exclusion Criteria:

          -  Presence of uveal melanoma and/or other non-cutaneous melanomas.

          -  Current use of a prohibited medication or need for any of these medications during
             treatment with study drug and within 28 days before the first administration of
             APR-246. I.e., no anti-cancer other than that given in this clinical trial, no
             immunotherapy, no hormonal cancer therapy, no radiation therapy (except palliative)
             and no experimental medications are permitted during the trial. All alternative
             therapies must first be approved by the sponsor. Supportive care therapies are
             allowed.

          -  Unresolved toxicity greater than NCI-CTCAE(v4) Grade 1 from previous anti-cancer
             therapy except alopecia.

          -  Presence of active gastrointestinal disease or other condition that will interfere
             significantly with the absorption, distribution, metabolism, or excretion of drugs.

          -  Known HIV, active hepatitis B or hepatitis C infection.

          -  Primary malignancy of the central nervous system.

          -  History of familial long QT, serious ventricular arrhythmia (no VT > 130 bpm and > 5
             extra beats per minute), no QTc ≥ 480 msec calculated from a single ECG reading or a
             mean of 3 ECG readings using Fridericia's correction (QTcF = QT/RR0.33) or bradycardia
             (< 45 bpm).

          -  Untreated or symptomatic brain metastasis, leptomeningeal disease or spinal cord
             compression. Patients who are on a stable dose of corticosteroids > 1 month or off
             corticosteroids for 2 weeks can be enrolled.

          -  History of acute coronary syndromes (including unstable angina), coronary angioplasty,
             or stenting, or thrombo-embolic event within the past 24 weeks from signature of ICF.

          -  Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA)
             functional classification system.

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to the study drugs, or excipients.

          -  Uncontrolled diabetes, hypertension or other medical conditions that may interfere
             with assessment of toxicity.

          -  Pregnant or lactating woman.