A phase II, open label study to investigate the efficacy and safety of domatinostat in combination with avelumab in patients with advanced unresectable/metastatic Merkel Cell Carcinoma progressing on anti-PD(L)1 antibody therapy – the MERKLIN 2 study

4SC AG0 个研究点目标入组 40 人开始时间: 2020年5月29日最近更新: 2023年12月19日

试验速览

阶段: 1 期
状态: 进行中（未招募）
发起方: 4SC AG
入组人数: 40

研究概览入排标准研究者记录与标识符相似试验

研究概览

简要总结

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研究设计

研究类型: Interventional clinical trial of medicinal product

入排标准

性别: All

入选标准

•1. Age = 18 years (at signature of ICF), mentally and physically able and willing to provide informed consent for study participation.
•2. Histologically confirmed Merkel Cell Carcinoma (MCC).
•3. ECOG performance status = 1.
•4. MCC in an advanced, unresectable stage III or metastatic stage IV (includes patients who refused surgical resection or are not eligible for such surgical resection) [Note: patients with PD post-R0 surgical resection and adjuvant anti-PD-(L)1 antibody monotherapy of at least 12 weeks will be eligible as long as Inclusion Criterion #6 is fulfilled]
•5. RECIST v1.1 evaluable disease.
•6. Progressing on previous anti-PD-(L)1 antibody monotherapy within the last 12 weeks before planned first administration of study medication fulfilling at least one of the following criteria:
•Radiology Criteria: - Detection of new lesion(s) or - At least a 20% increase in the sum of diameters; in addition, the sum must also demonstrate an absolute increase of at least 5 mm.
•In case of unresectable locoregional tumor not measurable by scan, assessment with a caliper will be allowed: a single, unirradiated/ untreated lesion must have a diameter of > 10 mm, at least a 20% increase in the diameter and an absolute increase of at least 5 mm.
•Biopsy of new lesion(s) and histological confirmation of PD in case of progression during adjuvant anti-PD-(L)1 treatment.
•7. Confirmation of PD not earlier than 4 weeks after initial assessment of PD on previous anti-PD-(L)1 monotherapy. [Note: Confirmatory scan can be the baseline scan for this study, if evaluable for RECIST v1.1 and can be performed during screening phase]
•8. Pretreatment with avelumab monotherapy (cohort 1) or any antiPD-1 antibody monotherapy (cohort 2) fulfilling the following minimum exposure criteria:
•Anti-PD-(L)1 antibody given every 2 weeks Q2W: at least 6 administrations within the last 6 months, last dose within 3 months before planned first administration of study medication.
•Anti-PD-(L)1 antibody given every 3 weeks Q3W: at least 4 administrations within the last 6 months, last dose within 3 months before planned first administration of study medication. • Anti-PD-(L)1 antibody given every 4 weeks Q4W: at least 3 administrations within the last 6 months, last dose within 3 months before planned first administration of study medication.
•9. Patients must have been treated with anti-PD-(L)1 antibody therapy as the most recent systemic anti-neoplastic therapy
•10. Patients must have been treated with approved doses and schedules of avelumab or anti-PD-1 antibodies. For investigational anti-PD-1 antibodies, patients must have been treated with the recommended phase 2 dose and schedule.
•11. Patients with brain or central nervous system metastases will be eligible, if asymptomatic, treated with surgery, whole brain or stereotactic radiotherapy, clinically stable (at least for a period of 2 months prior to signing ICF) and do not require continued steroid therapy. [Note: patients with known leptomeningeal carcinomatosis must be excluded]
•12. Locally advanced/unresectable MCC must not be eligible for radiation therapy due to prior cumulative radiation treatment, judgment of radiation oncologist that the tumor is unlikely to respond to therapy or because radiation treatment is contraindicated for other reasons (e.g. tumor location).
•13. Female patients of childbearing potential must have a negative urine or serum pregnancy test before receiv

排除标准

•1. History of serious anti-PD-(L)1 therapy-related adverse reactions prohibiting further avelumab treatment:
•- Pneumonitis: Grade 3 or 4 or recurrent Grade 2
•- Hepatitis: AST or ALT more than 5 times the upper limit of normal or total bilirubin more than 3 times the upper limit of normal
•- Colitis/diarrhea: Grade 4 or recurrent Grade 3
•- Nephritis and renal dysfunction: serum creatinine more than 6 times the upper limit of normal
•- Any other immune-mediated adverse reactions which resulted in a life-threatening situation for the patient (excluding endocrinopathies) or infusion-related reactions Grade 3 or 4.
•2. More than one line of previous systemic anti-neoplastic therapy other than anti-PD-(L)1 antibody monotherapy.
•3. Palliative radiation therapy of single lesions within 2 weeks before planned administration of study medication.
•4. Patients currently participating or having participated in a clinical study in which the last administration of the investigational medicinal product was within 2 weeks before consenting to study participation (i.e. signing ICF).
•5. Not recovered adequately (= Grade 1) from toxicities and/or complications from surgical intervention or from previous anticancer therapies (excluding alopecia, fatigue or endocrine dysfunction on replacement therapy) as judged by the investigator.
•6. History or current evidence of clinically relevant allergies or hypersensitivity, which includes known or suspected intolerabilities attributed to domatinostat or avelumab or to constituents of the domatinostat tablets or avelumab infusion including known severe hypersensitivity reactions (Grade = 3) to monoclonal antibodies.
•7. Inadequate organ function defined by the following laboratory parameters:
•Absolute Neutrophil Count (ANC) < 1500/µl.
•Hemoglobin (Hb) < 9 g/dl (< Hb 5.6 mmol/L), may have been transfused.
•Platelet count < 100.000/µl.
•Serum creatinine > 1.5 x ULN or eGFR < 60 mL/min (as per Cockroft-Gault formula).
•ALT or AST > 1.5 x ULN.
•Serum total bilirubin > 1.5 x ULN.
•8. Any medical condition requiring continuous systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other systemic immunosuppressive medications (e.g. methotrexate, azathioprine, interferons, mycophenolate, anti-TNF agents and other) within 2 weeks before consenting to study participation (i.e. signing ICF) except for the following: intranasal, inhaled, topical, local steroid applications/injection (e.g., intra-articular injection) or single doses of systemic corticosteroids as premedication/prevention for hypersensitivity reactions (e.g., CT scan premedication).
•9. Any active gastrointestinal disorder that could interfere with the absorption of domatinostat characterized by malabsorption or inability to swallow tablets as per judgment of the investigator.
•10. Any known or suspected, current or chronic infection, immunodeficiency disorder or autoimmune disease requiring systemic treatment and/or that might deteriorate when receiving an immunostimulatory agent (e.g. chronic lymphocytic leukemia (CLL) or allogeneic stem-cell transplantation).
•11. History of other hematologic or primary solid malignancies which received or require any form of active systemic anti-cancer treatment (such as, but not limited to, hormone anti-cancer therapy, immunotherapy or targeted therapy) during the last 12 months before consenting to study participation.
•12. Received a live vaccine within 30 da

研究者

发起方

4SC AG

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The purpose of the research study is to determine if domatinostat in combination with avelumab will be able to delay or prevent worsening of the disease in patients with advanced unresectable/metastatic Merkel Cell Carcinoma that is continuing to grow after previous anti-PD-(L)1 antibody therapy. Furthermore, safety of the combination during the study conduct will be assessed.patients with advanced unresectable/metastatic Merkel Cell Carcinoma progressing on anti-PD(L)1 antibody therapyMedDRA version: 21.1Level: LLTClassification code 10064025Term: Merkel cell carcinomaSystem Organ Class: 100000004864

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