E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Merkel cell carcinoma |
Merkel-Zell-Karzinom |
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E.1.1.1 | Medical condition in easily understood language |
Merkel cell carcinoma (primary small cell carcinoma of the skin) |
Merkel-Zell-Karzinom |
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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 | 14.1 |
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 |
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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 compare the efficacy of F16IL2 in combination with paclitaxel vs. paclitaxel monotherapy, in terms of overall survival rate at 12 months after beginning of study treatments, in patients with metastatic Merkel cell carcinoma, who are not amenable to surgery. |
Therapieansprechen von F16IL2 in Kombination mit Paclitaxel im Vergleich mit Alleingabe von Paclitaxel, in Hinsicht auf Gesamtüberlebenszeitrate 12 Monate nache Beginn der Studienbehandlungen bei Patienten mit nicht operierbarem Merkelzellkarzinom. |
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E.2.2 | Secondary objectives of the trial |
To investigate safety and tolerability of the combination treatment of F16IL2 and paclitaxel. To investigate the treatment efficacy in terms of response to treatment measured as ORR and DCR. |
Bestimmung von Sicherheit und Verträglichkeit von F16IL2 in Kombination mit Paclitaxel. Bestimmung der Objektiven Ansprechrate (ORR) und Krankheits Kontrollrate (DCR). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Patients with advanced or metastatic Merkel cell carcinoma (MCC) not amenable to surgery and who have not received previous systemic therapy with taxanes; diagnosis of MCC must be histologically confirmed (evaluation of primary lesions or advanced disease) and endorsed by the IMMOMEC central dermatopathology center (central review of diagnosis at the Department of General Dermatology, Medical University of Graz). Patients must be amenable for paclitaxel treatment according to the discretion of the principal investigator;
• Patients aged >/= 18 ≤ 75 years;
• ECOG performance status ≤ 1;
• Patients must have measurable disease including cutaneous and subcutaneous metastases as defined by RECIST v.1.1 criteria [23] or immune related response Criteria (irRC) [24] as assessed by CT or MRI and/or ultrasound within 4 weeks before the first study drug administration.
• All acute side effects from any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.03) Grade ≤ 1;.
• Adequate hematologic, liver and renal function:
o Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L, platelets ≥ 100 x 10^9/L, haemoglobin (Hb) ≥ 9.0 g/dl
o Alkaline phosphatase (AP), alanine aminotransferase (ALT) and/or aspartate aminotransferase ≤ 3 x upper limit of reference range (ULN), and total bilirubin ≤ 2.0 mg/gL unless liver involvement by the tumor, in which case the transaminase levels could be ≤ 5 x ULN
o Creatinine ≤ 1.5 ULN or 24 h creatinine clearance ≥ 50 mL/min
• Negative serum pregnancy test for females of childbearing potential within 14 days of starting treatment;
• If of childbearing potential, agreement to use adequate contraceptive methods (e.g., oral contraceptives, condoms, or other adequate barrier controls, intrauterine contraceptive devices, or sterilization) beginning at the screening visit and continuing until 3 months following last treatment with study drug;
• Evidence of a personally signed and dated EC-approved Informed Consent form indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the study;
• Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.
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-Patienten mit fortgeschrittenem metastasiertem nicht operierbarem Merkelzellkarzinom, bislang keine systemische Taxantherapie; histologisch bestätigte Merkelzellkarzinomdiagnose (Bestimmung der Primärlesion oder fortgeschrittener Erkrankung) genehmigt durch zentraldes Dermopathologizentrum IMMUMEC (zentrale Diagnoseüperprüfung). Patienten die nach Meinung des Prüfarztes für eine Paclitaxelbehandlung geeignet sind.
-Alter ≥ 18 und </=75Jahre.
-ECOG Status ≤ 1.
-messbare Erkrankung einschliesslich kutane und subkutane Metastasen definiert nach RECIST Kriterien (Version 1.1) oder immun related Response Criteria (irRC).
- Rückgang sämtlicher toxischer Effekte vorangegangener Therapien auf ≤ Grad 1
- Ausreichende haematologische-, Leber- und Nierenfunktion:
o Gesamt Neutrophilen Zahl (ANC) ≥ 1.5 x 10^9/L,
Thrombozyten ≥ 100 x 10^9/L, Hämoglobin (Hb) ≥ 9.0 g/dL.
o ALT und AST und /oder Aspartat-Aminotransferase ≤ 3 x ULN und Gesamtbilirubin ≤ 2.0 mg/gL (</=5.0 x ULN für Patienten mit Leberinvolvierung).
o Serum Kreatinin ≤ 5 ULN oder 24 Kreatinin- Clearance ≥ 50 ml/min.
- Negativer Blutschwangerschaftstest für Frauen im gebärfähigen Alter innerhalb 14 Tagen vor Behandlungsstart.
- Falls in gebärfähigem Alter, Einverständnis angemessene Verhütungsmittel zu benutzen (z.B. orale Kontrazeptiva, Kondome oder andere angemessene Systeme, Intrataurine Verhütung, oder Sterilisation) beginnen vom Screening bis 3 Monate nach letzter Studienmedikamentgabe.
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E.4 | Principal exclusion criteria |
• Life expectancy of less than 3 months;
• Any previous taxanes therapy;
• Previous or concurrent CLL patients;
• Any other malignancy from which the patient has been disease-free for less than 2 years prior to study entry, with the exception of adequately treated and cured cervical carcinoma in situ, basal or squamous cell carcinoma, superficial bladder cancer, or in situ melanoma;
• Presence of uncontrolled infections or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study;
• Presence of known brain metastases;
• Chronic-active hepatitis B, C, or HIV;
• Severe cardiovascular disease:
o History of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris;
o Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria);
o Irreversible cardiac arrhythmias requiring permanent medication;
o LVEF </= 50% and/or abnormalities observed during baseline 2D-ECHO or 12-lead ECG investigations;
o Uncontrolled hypertension;
o Ischemic peripheral vascular disease (Grade IIb-IV);
• Severe rheumatoid arthritis; or other uncontrolled autoimmune disease;
• Severe diabetic retinopathy;
• History of allograft or stem cell transplantation;
• Major trauma including major surgery (e.g. visceral surgery) within 4 weeks of administration of study treatment;
• Known history of allergy to IL-2, taxanes, cremophor or other intravenously administered human proteins/peptides/antibodies;
• Pregnancy or breast-feeding. Female patient must agree to use effective contraception, or be surgically sterile or postmenopausal. The definition of effective contraception will be based on the European guideline ICH M3 rev 2.
• Treatment with an investigational study drug within four weeks before beginning of treatment with F16IL2;
• Previous treatment with monoclonal antibodies for biological therapy in the four weeks before administration of study treatment;
• Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.
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- Lebenserwartung < 3 Monate.
- Vorangegangene Taxan Therapie.
- Vorangegangene oder gleichzeitige CLL Patienten.
- Jegliche Krebserkrankungen die vor weniger als 2 Jahren vor Studienantritt behandelt wurden, außer Zervikalkarzinom in situ, behandeltes Basalzellkarzinom, Plattenepithelkarzinom, oberflächliche Harnblasentumoren (TA, Tis & Ti) oder Melanom in situ.
- Aktive Infektionen oder andere schwere gleichzeitige Krankheiten, welche nach Meinung des Arztes den Patienten
unnötigem Risiko aussetzen könnten oder mit der Studie
interferieren.
- Presenz von Hirnmetastasen.
- Chronische Hepatitis B, C, oder HIV Infektion.
- Schwere kardiovaskulare Erkrankung:
o Akute oder subakute koronare Syndrome einschließlich Myokardinfarkt, instabiler oder schwerer stabiler Angina pectoris
o Herzinsuffizienz (> Grad II, New York Heart Association (NYHA) Kriterien).
o LVEF ≤ 50% und /oder Abnormalitäten die während der ECHO oder ECG Screeninguntersuchungen aufgefgallen sind.
o Unkontrollierter Bluthochdruck.
o Ischämisch periphere arteriosklerotische Gefäßerkrankung (Grad IIb-IV).
- Schwere rheumatoide Arthritis oder andere unkontrollierte Autoimmunerkrankung.
- Schwere diabetische Retinopathie.
- Allogene Transplantation oder Stammzell Transplantation in der Anamnese.
- Erholung von größeren Verletzungen inkl. Operationen (z.B. viszerale Operation weniger als 4 Wochen vor Verabreichung der Studienmedikation.
- Bekannte Allergie auf IL-2, Taxane oder anderen intravenös verabreichte menschliche Proteine / Peptide / Antikörper .
- Schwangerschaft oder stillende Mütter. Weibliche Patientinnen müssen einwilligen eine wirksame Empfängnisverhütung zu verwenden, oder chirurgisch steril oder postmenopausal sein. Die Definition der effektiven Empfängnisverhütung, wird auf der europäischen Richtlinie ICH M3 rev 2 basieren.
- Behandlung mit einem Prüfmedikament innerhalb 4 Wochen vor Berginn der Behandlung mit F16IL2.
- Vorangehende Behandlung mit monoklonalen Antikörper zur biologischen Behandlung innerhalb 4 Wochen vor Verabreichung der Studienmedikation.
- Jegliche Bedingung, die nach Auffassung des Prüferarztes die Einhaltung des Studienprotokolls behindern könnte.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this study is overall survival rate at 12 months. |
Die Gesamtüberlebenszeitrate nach 12 Monaten |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary endpoints of this study are (1) safety and tolerability assessment of the combination treatment of F16IL2 and paclitaxel in terms of adverse events, clinical laboratory evaluations, vital signs and physical examinations(2) treatment efficacy evaluation in terms of response to treatment measured as ORR and DCR. |
(1) Bestimmung von Sicherheit und Verträglichkeit von F16IL2 in Kombination mit Paclitaxel. Sicherheitsprüfung. (2) Bestimmung der Objektiven Ansprechrate (ORR) und Krankheits Kontrollrate (DCR). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
(1) 24 weeks
(2) 12 months |
(1) 24 Wochen
(2) 12 Monate |
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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 | No |
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 | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |