Unresectable Stage III/Metastatic Stage IV Cutaneous Melanoma
Conditions
Interventions
Product Name: 4SC-202
Product Code: BYK456992
Pharmaceutical Form: Tablet
INN or Proposed INN: Domatinostat
CAS Number: 1186222-89-8
Other descriptive name: 4SC-202
Concentration unit: mg milligram(s)
Sponsors
4SC AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: All inclusion criteria must be met during screening, unless otherwise stated. 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 (Version 7 or 8) staging system (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 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 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) to 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 patient must consent to the 2 mandatory biopsies. This requirement may be waived by the sponsor in individual cases. [Note: Applicable in dose levels 1, 2a, 3 and 4; biopsies in dose level 2b were only optional] 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 20 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 20
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. A patient in the Survival Follow-up phase of an investigational agent where no further treatment is expected is eligible 3. Patients who achieved a CR or PR, during or after 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 (applicable at screening) 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 (as judged by the investigator) 10. Prior treatment with a HDAC or LSD1 inhibitor or both 11. Prior treatment with anti-PD-L1 or anti-PD-L2 agents (prior treatment with anti-CTLA-4 agents is allowed) 12. Patients with precedent systemic anti-cancer therapy including chemotherapy, endocrine therapy, immunotherapy or use of other investigational agents prior first study drug administration. 13. Therapy with agents known to prolong the QT interval and increase the risk for Torsades de Pointes, such as certain antibiotics (i.e. erythromycin, clarithromycin), antidepressants (i.e. doxepin, amitryptilin) or neuroleptics (i.e. haloperidol, clozapin) 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 (e.g. methotrexate, azathioprine, mTOR inhibitors, Interferons, mycophenolate, anti-TNF agents, and other) 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, e.g., repeated demonstration of a QTc interval >450 msec (Grade 1 NCI-CTCAE); Long-QT-Syndrome (QTcF is applicable) 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 anti-cancer treatment. Note: Patients with ongoing hormonal treatment of prostate, breast or others cancers are excluded even if the cancer has been removed in a curative extent. 22. Patients with any other medical, psychiatric or social condition, which i
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: The secondary objectives of the study are to: • 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 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: Dose limiting toxicities will be evaluated during the DLT period: For dose Levels 1, 2a, 3: The DLT period encompasses the first 3 cycles, i.e. the initial 4SC-202 monotherapy cycle (Cycle 1) and the following 2 cycles of 4SC-202 and Pembrolizumab combination treatment (Cycle 2 and 3). For dose Levels 2b, 4: The DLT period encompasses the first 2 combination therapy cycles, i.e. extends from Cycle 1 Day 1 to Cycle 2 Day 21. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Preliminary anti-tumor efficacy of combination treatment with 4SC-202 and Pembrolizumab as response rates and survival will be determined using irRECIST 1.1 criteria. 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) Pharmacokinetic analysis will be summarized in a separate report which will be included in the CSR.;Timepoint(s) of evaluation of this end point: At the end of each 4th cycle, within ± 7 days of D1 of C5, C9, C13, C17, etc., and in case of suspected PD (as per local practice) | — |
Countries
Germany, Italy
Contacts
Public ContactBabett Krauss
4SC AG
Outcome results
None listed