| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| patients with advanced unresectable/metastatic Merkel Cell Carcinoma progressing on anti-PD(L)1 antibody therapy |
| Patienten mit fortgeschrittenem, nicht resezierbaren / metastasierten Merkelzellkarzinom, bei denen unter einer Anti-PD-(L)1-Antikörpertherapie eine Progression aufgetreten ist |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic, unresectable Merkel Cell Carcinoma that continues to grow after trearment with anti-PD-(L)1 antibody therapy |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064025 |
| E.1.2 | Term | Merkel cell carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| to investigate the anti-tumor efficacy of domatinostat in combination with avelumab in advanced unresectable/metastatic MCC patients progressing on anti-PD-(L)1 antibody monotherapy. |
| Untersuchung der gegen den Tumor gerichteten Wirksamkeit von Domatinostat in Kombination mit Avelumab bei Patienten mit fortgeschrittenem, nicht resezierbaren / metastasierten Merkelzellkarzinom (MZK), bei denen unter einer Anti-PD-(L)1-Antikörpertherapie eine Progression aufgetreten ist. |
|
| E.2.2 | Secondary objectives of the trial |
| to investigate safety, tolerability, pharmacokinetics, avelumab anti-drug antibodies (ADA) and health-related quality of life (HrQoL). |
| Untersuchung der Sicherheit, der Verträglichkeit, der Pharmakokinetik, der gegen Avelumab gerichteten Anti-Medikamenten-Antikörper (ADA) und der gesundheitsbezogenen Lebensqualität (HrQoL). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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)
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.
8. Pretreatment with avelumab monotherapy or any antiPD-1 antibody monotherapy 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.
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 receiving the first dose of study medication and they must comply with contraception methods as requested by the study protocol. |
|
| E.4 | Principal exclusion criteria |
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 days before consenting to study participation.
13. Pregnant or breastfeeding.
14. Conditions requiring systemic anti-arrhythmic therapy known to prolong QT/QTc interval, patients with QTcF interval >480 msec on at least 2 separate and consecutive ECGs at screening or a medical history of long-QT-Syndrome.
15. Clinically significant (i.e. active) cardiovascular and/or thromboembolic diseases:
• Cerebral vascular accident or stroke.
• Uncontrolled hypertension.
• Congestive heart failure (New York Heart Association (NYHA) Class III or IV).
• Serious cardiac arrhythmia requiring medication (patients with status post pace maker and/or defibrillator implantation can be included).
• Symptomatic ischemic or severe valvular heart disease.
• Unstable angina pectoris or a myocardial infarction within 6 months prior to signing ICF. 1
16. Patients with known HIV, acute or chronic active hepatitis B (defined as positive titers for HBsAg, anti-HBc-IgM or DNA) or Hepatitis C (HCV RNA if anti-HCV antibody screening test positive)
17. Significant (current or chronic) diseases or other intercurrent illness, psychiatric illness or social situation that would limit compliance with study requirements or would pose an undue medical hazard, interfere with the conduct of the study or interfere with interpretation of the study results as judged by the investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective Response Rate (ORR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Objective Response Rate (ORR), defined as the percentage of patients having a confirmed CR or PR according to RECIST v1.1 based on radiological imaging or for skin lesions not measurable by scan, measurements with a caliper will be allowed. Tumor assessment will be performed every 8 weeks for the first 6 months of study treatment and thereafter every 12 weeks until disease progression (RECIST-PD) or end of treatment period. For patients without confirmed RECIST-PD at the time of treatment discontinuation, tumor assessments should continue in the afore-mentioned intervals until confirmation of RECIST-PD disease progression or start of a new anticancer treatment, whichever occurs earlier. |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
• Durable Response Rate (DRR), defined as the percentage of patients having a RECIST v1.1 response lasting ≥ 6 months.
• Duration of Response (DoR), defined as the time from an initial objective response (CR or PR) according to RECIST v1.1 until disease progression or death due to any cause.
• Disease Control Rate (DCR), defined as the proportion of patients with either an objective response (CR, PR) or stable disease (SD) according to RECIST v1.1.
• Durable Disease Control Rate (dDCR), defined as the percentage of patients having a RECIST v1.1 disease control lasting ≥ 6 months.
• Best Overall response (BOR), defined as the best response (PD, SD, PR, CR) according to RECIST v1.1 over the course of a patient’s participation in the study, assessed up to 2 years.
• Progression Free Survival (PFS), defined as the time from first dosing (Day +1) to the date of PD or death from any cause (whichever comes first).
• PFS Rate, defined as the percentage of patients without PD at 6 and 12 months after first administration of study drug.
• Overall Survival (OS), defined as the time from the first administration of study medication until death due to any cause.
• OS Rate, defined as the percentage of patients alive at 6 and at 12 months after first administration of study drug.
• Safety and Tolerability of the study medication (determined by number, frequency, duration and severity of AEs using CTCAE v5.0, physical examination, laboratory tests, vital signs, and ECGs).
• Health related Quality of Life (HrQoL).
• Pharmacokinetics of domatinostat and avelumab.
• Avelumab anti-drug antibodies (ADA). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy: for the first approximately 6 months imaging will be done every 8 weeks; thereafter the imaging interval will increase to every 12 weeks.
Safety: During the regular study visits safety and tolerability assessments will be done.
A full physical examination will be performed at screening, every 8 weeks until week 25 (i.e. weeks 9, 17, 25), every 12 weeks thereafter (i.e. weeks 37, 49, 61, 73, 85, 97) and at EOS Visit; brief physical examinations will be performed at all other visits.
PK: Blood sampling for PK analysis will be performed on Visit 1,Visit 2, Visit 3, Visit 5, Visit 9, Visit 13, Visit 19 and Visit 25. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| Switzerland |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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