Unresectable Stage III/Metastatic Stage IV Cutaneous Melanoma MedDRA version: 20.0 Level: LLT Classification code 10027152 Term: Melanoma of skin (malignant) System Organ Class: 100000004864
Conditions
Interventions
Product Name: 4SC-202
Product Code: [BYK456992]
Pharmaceutical Form: Tablet
INN or Proposed INN: 4SC-202
Current Sponsor code: BYK456992
Other descriptive name: 4SC-202 - DOMATINOSTAT TOSILATE
Concent
Sponsors
4SC AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Signed informed consent must be obtained prior to any study specific procedure. 1. Male or female patients, age = 18 years (at screening) 2. ECOG PS 0-1 3. Patients with unresectable stage III or stage IV cutaneous melanoma, as per AJCC staging system (Version 8) (must have been histologically confirmed at least once during course of disease) 4. Patients with metastatic tumor of unknown primary site and histology of melanoma are eligible 5. Patients must be primary refractory or non-responding to the last prior anti-PD-1 therapy (either as monotherapy or in combination with Ipilimumab) The following definitions apply: i. Primary refractory: Patients not achieving a response of CR, PR or SD (i.e. not achieving disease control) ii. Non-responding: Patients not having achieved a response of CR or PR but having achieved SD 6. Patients must have progressed during last prior anti-PD-1 mono therapy or Ipilimumab/anti-PD-1 combination therapy, and within 6 months after the last dose of either Nivolumab or Pembrolizumab 7. Patients must have had anti-PD-1 mono therapy or Ipilimumab/anti-PD-1 combination therapy as the last systemic cancer directed treatment consisting of at least two administrations of either Nivolumab or Pembrolizumab and must have received the last anti-PD-1 administration within 6 months prior to ICF signature 8. Patients must have been tested for BRAF V600 mutation status 9. Patients with BRAF-mutated melanoma must have had a BRAF-mutation directed therapy, unless they were not considered eligible (e.g. due to contraindications) for such treatment 10. Measurable disease by CT or MRI per irRECIST 1.1 criteria, with longest diameter for non-nodal lesions = 10 mm and = 15 mm in short axis for nodal lesions 11. At least one tumor site (either primary site or metastasis) must be accessible for sequential biopsies and the patient must consent to 2 mandatory biopsies. This requirement is not applicable for continuous dosing schedules and may be waived by the sponsor in other individual cases 12. Females of Childbearing Potential must agree to use highly effective contraception from screening to at least four months after the last dose of Pembrolizumab or 4SC-202 (whatever is later) 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 18 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 18
Exclusion criteria
Exclusion criteria: 1. Patients not consenting to use adequate contraception as required per protocol 2. Patients currently participating or who have participated in a study of an investigational agent, or who are using an investigational device or have done so within 28 days of the first dose of study drug. 3.Patients who achieved a CR or PR, during or after last prior anti-PD-1 mono- or anti-CTLA-4/anti-PD-1 combination therapy 4. Life expectancy below 3 months 5. Patients with uveal or mucosal melanoma 6. Patients with symptomatic brain metastases/CNS involvement 7. Patients with inadequate organ function, defined as: a) Absolute neutrophil count (ANC) 1.5 x ULN or eGFR 2.5 x ULN g) Serum total bilirubin > 1.5 x ULN h) LDH > 5 x ULN 8. Remaining relevant toxicity (excluding alopecia, fatigue) to previous therapy has not resolved to Grade 1 9. Patients with a history of anti-PD-1 / immune-related adverse drug reactions of Grade 4 or Grade 3 and a high risk of re-occurrence 10. Prior treatment with a HDAC or LSD1 inhibitor or both 11. Prior treatment with anti-PD-L1 or anti-PD-L2 agents 12. Patients with precedent systemic anti-cancer therapy including chemotherapy, endocrine therapy, immunotherapy or who use other investigational agents prior to first study drug administration if no wash-out period of 5 half-lives or 4 weeks has been respected before first study drug administration. 13. Therapy with agents known to prolong the QT interval and increase the risk of Torsade des pointes, such as certain antibiotics, antidepressants or neuroleptics 14. Patients who have received a live vaccine within 28 days prior to anticipated first dose of study drug 15. Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other systemic immunosuppressive medications within 14 days of study drug administration. 16. Patients with any immunodeficiency disorder 17. Patients with any active, known or suspected autoimmune disease that might deteriorate when receiving an immunostimulatory agent as judged by the investigator 18. Patients with a marked baseline prolongation of QT/QTc interval; Long-QTSyndrome 19. Patients with any active gastrointestinal disorder that could interfere with the absorption of 4SC-202 (as per judgement of the investigator), such as ulcerative colitis, Crohn’s disease, diabetic gastroparesis, or other syndromes characterized by malabsorption 20. Patients who are unable to take oral medication 21. Patients with a history of or concurrent other malignancies that require active systemic treatment. 22. Patients with any other medical, psychiatric or social condition, which in the opinion of the investigator would preclude participation in the trial, pose an undue medical hazard, interfere with the conduct of the trial or interfere with interpretation of the trial results 23. Women who are pregnant or lactating or who are planning on becoming pregnant during the trial or for 90 days after completion of the trial 24. Patients with known HIV, acute or chronic active hepatitis B or hepatitis C 25. Patients with an active systemic infection 26. Patients with major surgery within the last 4 weeks 27. Patients with history or current evidence of clinically relevant allergies or hypersen
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the study is to determine safety and tolerability of combination treatment with 4SC-202 and Pembrolizumab in patients with advanced cutaneous malignant melanoma who are primary refractory or non-responding to anti-PD-1 therapy.;Secondary Objective: • Examine preliminary efficacy of combination treatment with 4SC-202 and Pembrolizumab • Determine non-tolerated dose (NTD), maximum tolerated dose (MTD) and recommended phase 2 dose (RPTD) of combination treatment with 4SC-202 and Pembrolizumab •Characterize pharmacokinetics (PK) of formulation I and formulation II of 4SC-202 •Characterize the food effect on PK of formulation II of 4SC-202;Primary end point(s): Safety and tolerability of the combination of 4SC-202 and Pembrolizumab will be assessed from adverse events, laboratory tests, vital signs, ECGs, ECOG PS, physical examination and assessment of concomitant medications.;Timepoint(s) of evaluation of this end point: In addition, after completion of enrollment of dose level 2a, formulation II of 4SC-202 will be explored at selected sites in the following dose levels: •DL 2b: 200 mg QD 4SC-202 p.o. (continuous dosing for 21 days) + 2 mg/kg Pembrolizumab i.v. (from Cycle 1 Day 1 onwards, once every 3 weeks). Note: In dose level 2b, there is a PK run-in in the week prior to C1D1 with two single dose administrations of 4SC-202 on Day -7 and Day 0. •DL 4: 300 mg TDD 4SC-202 p.o. (continuous dosing for 21 days) + 2 mg/kg Pembrolizumab i.v. (from Cycle 1 Day 1 onwards, once every 3 weeks). | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Preliminary anti-tumor efficacy of treatment with 4SC-202 and Pembrolizumab in terms of response rates and survival when administered in combination will be determined using irRECIST. Anti-tumor efficacy will be assessed by calculating the following parameters: • Objective Response Rate (ORR) • Best Overall Response (BOR) • Disease Control Rate (DCR) • Duration of Response (DOR) • Progression Free Survival (PFS) • Time to Progression (TTP) • Overall Survival (OS) Bioavailability of formulation I, formulation II and impact of food on the bioavailability of formulation II will be evaluated in the PK run-in of dose level 2b . Pharmacokinetic analysis will be summarized in a separate report which will be included in the Clinical Study Report.;Timepoint(s) of evaluation of this end point: At the end of each 4th cycle, within ± 7days of D1 of C5, C9, C13, C17, etc., and in case of suspected PD (as per local practice) | — |
Countries
Germany, Italy
Contacts
Public ContactMARTIN ORLOVIUS
4SC AG
Outcome results
None listed