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
- Conditions
- Merkel Cell Carcinoma (MCC)10040900
- Registration Number
- NL-OMON49071
- Lead Sponsor
- 4SC AG
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 4
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 t
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
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Primary Objective: to investigate the anti-tumor efficacy of domatinostat in<br /><br>combination with avelumab in advanced unresectable/metastatic MCC patients<br /><br>progressing on anti-PD-(L)1 antibody monotherapy.</p><br>
- Secondary Outcome Measures
Name Time Method <p>Secondary Objectives: to investigate safety, tolerability, pharmacokinetics,<br /><br>avelumab anti-drug antibodies (ADA) and health-related quality of life (HrQoL).<br /><br>Exploratory Objective: to investigate tumor tissue for molecular<br /><br>characteristics correlating with clinical parameters/clinical outcome.</p><br>