BRAF V600 Mutant Metastatic Melanoma MedDRA version: 20.0 Level: LLT Classification code 10027481 Term: Metastatic melanoma System Organ Class: 100000004864
Conditions
Interventions
Product Name: APR-246
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: APR-246
Other descriptive name: APR-246
Concentration unit: mg/ml milligram(s)/millilitre
Concentr
Sponsors
APREA THERAPEUTICS AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients must meet all of the following criteria in order to be eligible for this study: 1. Age = 18 years 2. 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 3. 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 4. Measurable disease according to RECIST 1.1 criteria. For phase II only, metabolic measurable disease (according to PERCIST) 5. 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. 6. ECOG Performance Status of 0 or 1 7. Patients able to swallow and retain oral medication 8. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form 9. 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 such as described in section 6.3 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 10. Adequate organ system function 11. Signed informed consent before any study specific procedure and/or treatment happens Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 50 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Patients meeting one of the following criteria are not eligible for this study: 1. Presence of Uveal melanoma and/or other non-cutaneous melanomas 2. Current use of a prohibited medication (see section 6.4.2) or need for any of these medications during treatment with study drug and within 28 days before the first administration of APR-246 3. Unresolved toxicity greater than NCI-CTCAE(v4) Grade 1 from previous anti-cancer therapy except alopecia 4. Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs. 5. Known HIV, active hepatitis B or hepatitis C infection 6. Primary malignancy of the central nervous system 7. 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 ( 1 month or off corticosteroids for 2 weeks can be enrolled 9. History of acute coronary syndromes (including unstable angina), coronary angioplasty, stenting or thrombo-embolic event within the past 24 weeks from signature of ICF. 10. Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system. 11. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drugs, or excipients 12. Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity 13. Pregnant or lactating woman
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I: Dose Safety Cohort To determine the safety and tolerability of APR-246 given weekly in combination with dabrafenib in patients with BRAFV600 mutant unresectable and/or metastatic cutaneous melanoma resistant to the dabrafenib/trametinib combination. To determine the recommended phase II dose (RP2D) of the combination of dabrafenib and APR-246. Phase IIa: Expansion Cohort: To evaluate antitumor activity of APR-246 in combination with dabrafenib in patients with BRAFV600 mutant unresectable and/or metastatic cutaneous melanoma resistant to the dabrafenib/trametinib combination. . ;Secondary Objective: Phase Ib and II To further determine the safety of APR-246 and dabrafenib in patients with BRAFV600 mutant unresectable and/or metastatic cutaneous melanoma resistant to a dabrafenib /trametinib combination. To describe pharmacokinetics of APR-246 given weekly in combination with dabrafenib. To further describe the anti-tumour activity of the combination of APR-246 and dabrafenib. To determine the value of early FDG PET/CT-based metabolic response assessment in patients with BRAFV600 mutant unresectable and/or metastatic cutaneous melanoma resistant to the dabrafenib /trametinib combination treated with APR-246 and dabrafenib. ;Primary end point(s): Phase Ib: Adverse Events (AEs) and Dose Limiting Toxicities (DLTs) Phase II: Objective response rate by RECIST1.1 as calculated as the proportion of patients with a best objective response of confirmed CR or PR. ;Timepoint(s) of evaluation of this end point: Please refer to the protocol | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase Ib and II: - To determine clinical benefit rate (defined as the proportion of patients with a CR, PR or SD = 4 months) of APR-246 and dabrafenib in patients with BRAFV600 mutant unresectable and/or metastatic cutaneous melanoma resistant to the dabrafenib/trametinib combination - To determine duration of response (defined as time from documentation of tumor response to disease progression) of APR-246 and dabrafenib in patients with BRAFV600 mutant unresectable and/or metastatic cutaneous melanoma resistant to the dabrafenib/trametinib combination. - To determine the progression free survival (PFS) (defined as the time from registration to the time of disease progression or relapse or death, or the date of last tumor assessment without any such event) of APR-246 and dabrafenib in patients with BRAFV600 mutant unresectable and/or metastatic cutaneous melanoma resistant to the dabrafenib /trametinib combination. - PK parameters including area under plasma concentration-time curve (AUC (0-t)), plasma drug concentration at a specified time t (Ct), Maximum plasma drug concentration (Cmax), and time to reach maximum plasma concentration following drug administration (tmax). - Assessment of metabolic response according to classical PERCIST criteria (30%) modified PERCIST criteria (15%) and the consistency classification ;Timepoint(s) of evaluation of this end point: Please refer to the protocol | — |
Countries
Belgium
Contacts
Public ContactMaria Klockare
APREA THERAPEUTICS AB
Outcome results
None listed