| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| treatment-naïve metastatic Merkel Cell Carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| metastatic Merkel Cell Carinoma in patients who have not received any treatment of their disease |
|
| 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 |
| Evaluation of the clinical efficacy of domatinostat in combination with avelumab in treatment-naïve metastatic or distally recurrent MCC patients as determined by the Objective Response Rate (ORR) according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) by independent review. |
|
| E.2.2 | Secondary objectives of the trial |
Evaluation of additional parameters for the clinical efficacy of avelumab in combination with domatinostat, correlation of clinical data to biomarker expression, safety profile of the study treatment, Anti-Drug Antibodies (ADAs) to avelumab and pharmacokinetics (PK) of avelumab and domatinostat, Health-related Quality of Life (HrQoL)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed written informed consent.
2. Age ≥ 18 years at signature of Informed Consent Form (ICF).
3. Histologically proven MCC.
• Confirmation of the diagnosis by immune-histochemistry as per standard at the institution, including (but not limited to) CK20 and TTF-1.
• Patients must have metastatic or distally recurrent disease; M1 status must be confirmed at entry.
• Patients must not have received any prior systemic treatment for metastatic MCC. Prior treatment in the adjuvant setting (no clinically detectable disease; no metastatic disease) will be allowed, if the end of the treatment occurred at least 6 months prior to study entry, i.e. signing ICF.
4. Fresh biopsy or archival tumor tissue (not older than 3 months) from an unirradiated lesion.
5. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at study entry.
6. Estimated life expectancy of more than 12 weeks.
7. Disease must be measurable with at least one unidimensional measurable lesion by RECIST v1.1 (including skin lesions).
8. Adequate hematological and organ function defined by the following parameters:
Adequate hematological function defined by
• White blood cell count (WBC) ≥ 3000/µl
• Absolute Neutrophil Count (ANC) ≥ 1500/µl
• Lymphocyte count ≥ 500/µl
• Hemoglobin (Hb) ≥ 9 g/dl (or > 5.6 mmol/L), may have been transfused
• Platelet count ≥ 100.000/µl
Adequate hepatic function defined by
• Serum total bilirubin ≤ 1.5 x ULN
• ALT and/or AST ≤ 1.5 x ULN
Adequate renal function defined by
• eGFR > 60 ml/min (as per Cockcroft-Gault formula)
9. Highly effective contraception for both male and female subjects if the risk of conception exists. Female patients of childbearing potential must have a negative urine or serum pregnancy test before receiving the first dose of study medication and must comply with contraception methods as requested by the study protocol.
|
|
| E.4 | Principal exclusion criteria |
1. Participation in another interventional clinical study within the past 30 days (participation in observational studies is permitted)
2. Concurrent treatment with a non-permitted drug.
3. Prior therapy with any histone deacetylase (HDAC) inhibitor or antibody/drug targeting T cell coregulatory proteins (immune checkpoints) such as anti-programmed death 1 (PD-1), anti-programmed death-ligand 1 (PD-L1) or anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody.
4. Concurrent anti-cancer treatment (for example, cytoreductive therapy, radiotherapy, immune therapy, or cytokine therapy except for erythropoietin). Radiotherapy administered to superficial lesions is not allowed if such lesions are considered target lesions in the efficacy evaluation or may influence the efficacy evaluation of the study treatment.
5. Major surgery for any reason, except diagnostic biopsy, within 4 weeks and/or if the subject has not fully recovered from surgery.
6. Concurrent systemic therapy with steroids or other immunosuppressive agents (e.g. methotrexate, azathioprine, interferons, mycophenolate, anti-TNF agents and other), or the use of any investigational drug within 28 days before the start of study treatment. Short-term administration of systemic steroids e.g. for allergic reactions or the management of immune-related adverse events [irAE] while on study is allowed. Also, patients requiring hormone replacement with corticosteroids for adrenal insufficiency are eligible if the steroids are administered only for purpose of hormonal replacement and at doses < 10 mg or equivalent prednisone per day.
7. 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.
8. Patients with active central nervous system (CNS) metastases are excluded and a brain CT/MRI will be required during screening if not performed within 6 weeks prior to the planned start of the study treatment. Subjects with a history of treated CNS metastases (by surgery or radiation therapy) are not eligible unless they have fully recovered from treatment, demonstrated no progression for at least 2 months, and do not require continued steroid therapy.
9. History of or concurrent malignancies, except the malignancy is clinically insignificant, no systemic treatment is or has been required for the last 6 months, and the patient is clinically stable
10. Prior organ transplantation (including allogeneic stem-cell transplantation).
11. 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.
12. Positive testing for HIV or known AIDS or HBV or HCV infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening is positive).
13. Active or history of any autoimmune disease (except for patients with vitiligo) or immune-diseases that required treatment with systemic immune modulating drugs.
14. 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 and known severe hypersensitivity reactions (Grade ≥ 3) to monoclonal antibodies.
15. Persisting toxicity related to prior therapy Grade > 1 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0; however, sensory neuropathy Grade ≤ 2 will be acceptable.
16. Pregnancy or lactation period.
17. Known or suspected alcohol or drug abuse.
18. Clinically significant (i.e. active) cardiovascular and/or thromboembolic diseases:
• Cerebral vascular accident or stroke < 6 months prior to enrollment.
• Uncontrolled hypertension
• Congestive heart failure (New York Heart Association (NYHA) Class III or IV)
• Serious cardiac arrhythmia requiring medication (patients with status post pacemaker 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 screening, i.e. signing ICF
19. All other significant diseases (for example, inflammatory bowel disease), which, in the opinion of the Investigator, might impair the patient´s tolerance to the study treatment.
20. Any psychiatric condition that would prohibit the understanding or rendering of informed consent.
21. Legal incapacity or limited legal capacity.
22. Administration of a live vaccine within 28 days prior to study drug administration. Live vaccines are also prohibited during study treatment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Confirmed Objective Response (OR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Confirmed Objective Response (OR) according to RECIST v1.1, determined by independent review. Both Complete Response and Partial Response must be confirmed by a second tumor assessment preferably at the regularly scheduled 6-weeks assessment interval, but no sooner than 4 weeks after the initial diagnosis of CR or PR. |
|
| E.5.2 | Secondary end point(s) |
• Duration of Response (DOR) according to RECIST v1.1 as determined by independent review.
• Durable Response (DR) according to RECIST v1.1, defined as objective response (CR or PR) determined by independent review with duration of at least 6 months.
• Overall Survival (OS) time, defined as the time from the first administration of study treatment until death due to any cause determined by the Investigator.
• Progression Free Survival (PFS) according to RECIST v1.1, defined as the time from first dosing (Day 1) to the date of PD or death from any cause (whichever comes first) as determined by independent review.
• Disease Control (DC) according to RECIST v1.1, defined as the proportion of patients with either an objective response (CR, PR) or stable disease (SD), as determined by independent review.
• RECIST v1.1 responses at 6 and 12 months after start of study treatment as determined by independent review.
• Safety and tolerability of the study treatment determined by number, frequency, duration and severity of AEs using CTCAE v5.0 classification, physical examination, laboratory tests, vital signs and ECGs.
• ORR, DOR, DR, DC and PFS in correlation to biomarker expression.
• Anti-drug-antibodies (ADAs) and pharmacokinetics of study treatments.
• Changes in EQ-5D-5L and FACT-M scores over the treatment period.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy: imaging will be done in study week 7; thereafter the imaging interval will be every 6th week until 12 months, then increase to every 12 weeks.
Safety: During the regular study visits safety and tolerability assessments will be done. Physical examination and weighing will be performed at screening and thereafter every second week and at EOS Visit
Quality of Life: HrQoL questionnaires will be completed on day 1, week 7 and thereafter 6 weekly as well as at EoS.
PK: Blood sampling for PK analysis of avelumab will be performed on Day 1 and weeks 3, 5, 9, 17, 25, 37 and 49. Blood sampling for PK analysis of domatinustat will be performed on Day 1 and weeks 3, 5, 7, 9, 17, 25, 37 and 49. |
|
| 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.8.3 |
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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
| Switzerland |
| United Kingdom |
|
| 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
|
| The end of the study will be defined as the date when the last patient has completed Extended Safety Follow-up or has discontinued the study per protocol. |
|
| 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 | |
| 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 |
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