| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genodermatose caused by mutations in COL7A1, characterized by generalized skin blistering and involvement of mucous membranes. Aggressive metastasizing squamous cell carcinomas (SCCs) are a common complication, which reduce patients’ average life expectancy to less than 40 years. The aim of this study is to evaluate anti-tumor activity of oral Rigosertib, a PLK1 inhibitor, in RDEB patients diagnosed with SCCs. |
| Rezessiv dystrophe Epidermolysis bullosa (RDEB) ist eine Genodermatose, die durch COL7A1 Mutationen entsteht und durch generalisierte Blasenbildung und Beteiligung von Schleimhäuten charakterisiert ist. Die Patienten leiden an chronischen Wunden in denen sich oft agressive methastasierend Plattenepithelkarzinome bilden, die die Lebenserwartung auf unter 40 Jahre senken. Ziel der Studie ist die Anti-Tumor Wirkung von oralem Rigosertib in RDEB- Patienten mit Plattenepithelkarzinomen zu bewerten. |
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| E.1.1.1 | Medical condition in easily understood language |
| Metastasizing non-melanoma skin cancer is a severe complication of recessive dystrophic epidermolysis bullosa. A new drug against this form of cancer shall be tested in this trial. |
| Eine schwerwiegende Komplikationen von rezessiv dystropher Epidermolysis bullosa ist metastasierender weißer Hautkrebs. In der Studie soll ein neues Medikament gegen diesen Krebs getestet werden |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 estimate the anti-tumor activity of rigosertib in RDEB patients with advanced SCC that has failed prior standard of care.
Overall response rate (ORR) is defined as the proportion of patients who achieve either a CR or a PR.
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| Bewertung der Anti-Tumor Wirkung von Rigosertib in RDEB Patienten mit fortgeschrittenen SCCs, die nicht auf den Standard of Care angesprochen haben. Die "Overall Response Rate" wird aus der Zahl der Patienten die entweder "Complete oder Partial Response" gezeigt haben ermittelt. |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of oral rigosertib administered daily for three weeks on, one week off.
To evaluate safety and tolerability of rigosertib applied via a 72-hr continous intravenous infusion on days 1, 2, and 3 of a 2-week cycle for the first eight 2-week cycles, then on days 1, 2, and 3 of a 4-week cycle thereafter.
Assess impact on quality of life (QoL).
Biomarker analysis (to include markers of PI3K/Akt and PLK1 pathways) performed on all archival tissue from all patients.
Exome sequencing of patient tumors before, during and after treatment.
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Bewertung von Sicherheit und Verträglichkeit von oralem Rigosertib, täglich angewendet für jeweils 3Wochen und darauffolgend 1 Woche Pause.
Bewertung von Sicherheit und Verträglichkeit von Rigosertib als 72h intravenöse Infusion verabreicht, jeweils an Tag 1-3 von 8 2-wöchigen Zyklen und darauffolgend an Tag 1-3 von von 4-wöchigen Zyklen.
Auswirkungen auf die Lebensqualität.
Biomarker Analyse aus entnommenen Gewebeproben der Patienten.
Exom Sequenzierung der Tumoren vor, während und nach der Behandlung.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
a) Diagnosis of RDEB confirmed by genetic testing or by a skin biopsy with immunofluorescence mapping (IFM).
b) 18-79 years of age;
c) Diagnosis of unresectable, locally advanced or metastatic SCC confirmed prior to the Screening Visit.
d) Failure to respond to RDEB SCC standard of care, such as surgical excision, radiotherapy or conventional cytotoxic chemotherapy with e.g. platin derivates (i.e. cisplatin or carboplatin), 5-fluorouracil, bleomycin, methotrexate, adriamycin, taxanes, gemcitabine or ifosfamide alone or in combination or failure to respond to previous alternative biologic treatments such as epidermal growth factor inhibitors
(like cetuximab and panitumumab) or immune checkpoint (programmed cell death 1) inhibitors (such as nivolumab, pembrolizumab, cemiplimab). For recent Guidelines on standard of care for RDEB SCC and non EB-SCC please see Mellerio et al., 2016; Stratigos et al., 2015 and Kim et al., 2018.
e) Is not currently receiving any other cancer therapy.
f) Measurable disease based on Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
g) Patient (or patient’s legally authorized representative) must have signed an informed consent indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study. |
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| E.4 | Principal exclusion criteria |
a) Response to standard of care.
b) Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure or unstable angina pectoris.
c) Active systemic infection not adequately responding to appropriate therapy.
d) Total bilirubin ≥ 1.5 mg/dL (≥5.3 mg/dL in patients if related to hemolysis or Gilbert’s disease).
e) Alanine transaminase (ALT)/aspartate transaminase (AST) ≥ 2.5 x upper limit of normal (ULN).
f) Serum creatinine ≥2 .0 mg/dL or eGFR (estimated Glomerular Filtration Rate) <60 mL/min.
g) White blood cell count ≤ 2000/μl, neutrophils ≤ 1500/μL, platelets ≤ 100 x103/μL, hemoglobin ≤ 7.9 g/dL.
h) Known active HIV, hepatitis B or hepatitis C, where active is defined as follows: a. HIV or Hepatitis C – presence of viral load; b. Hepatitis B – antigen positive
i) Uncorrected hyponatremia (defined as serum sodium value of <125 mmol/L).
j) Male patients with partners of child-bearing potential who are unwilling to use male contraception (condom) throughout the study, up to and including the 30-day nontreatment follow-up period.
k) Female subjects: pregnant or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential) UNLESS they are willing to use one or more highly effective and reliable methods of contraception with a Pearl index ≤1 including combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral or intravaginal or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral or injectable or implantable); an intrauterine device (IUD); an intrauterine hormone-releasing system ( IUS); bilateral tubal occlusion; vasectomised Partner (provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical success) or sexual abstinence (The reliability of sexuality abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject). Reliable contraception should be maintained throughout the study. A pregnancy test in serum will be performed at screening in all women of childbearing potential, and in urine at all visits. Any postmenopausal women (physiologic menopause defined as “12 consecutive months of amenorrhea”) or women permanently sterilized (e.g. tubal occlusion, hysterectomy or bilateral salpingectomy) will not be required to undergo pregnancy test.
l) Uncontrolled hypertension. (i.e.. systolic blood pressure greater than or equal to 140mmHg and diastolic blood pressure greater than or equal to 90mmHg despite intake of ≥ 3 antihypertensive medications with complementary mechanisms of action (a diuretic should be 1 component); (Whelton et al., 2018).
m) Patient is currently participating and receiving study therapy or systemic therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
n) Psychiatric illness or social situation that would limit the patient’s ability to tolerate and/or comply with study requirements.
o) Patiens (or parents in case of paediatric subject) unlikely to comply with the study protocol or unable to understand the nature and scope of the study or the possible benefits or unwanted effects of the study procedures and treatments.
p) History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator.
q) Known hypersensitivity reaction to any of the components of study treatment.
r) Presence of clinically significant ECG abnormalities based on the inverstigator´s criteria. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The anti-tumor activity of rigosertib in RDEB patients with advanced SCC evaluated by overall response rate (ORR) which is defined as the proportion of patients who achieve either a CR or a PR.
Safety and tolerability of rigosertib.
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Die Anti-Tumor Wirkung von Rigosertib in RDEB Patienten mit fortgeschrittenen SCCs wird mit der "Overall Response Rate" , die aus der Zahl der Patienten die entweder "Complete oder Partial Response" gezeigt haben, ermittelt wird, bewertet.
Sicherheit und Verträglichkeit von Rigosertib.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Anti-tumor activitiy: 12 weekly; final analysis after 52 weeks or when treatment stopped for whatever reason.
Safety and Tolerability: weekly; final analysis after 52 weeks or when Treatment stopped for whatever reason.
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Anti-Tumor Wirkung: 12 wöchentlich; finale Analyse nach 52 Wochen oder bei Behandlungsende (aus welchen Gründen auch immer)
Sicherheit und Verträglichkeit: wöchentlich; finale Analyse nach 52 Wochen oder bei Behandlungsende (aus welchen Gründen auch immer)
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| E.5.2 | Secondary end point(s) |
Quality of life
Biomarker Analysis |
Lebensqualität
Biomarkeranalyse |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Quality of life: weekly; final Analysis after 52 weeks or when treatment stopped for whatever reason.
Biomarker Analysis: after week 25; final Analysis after 52 weeks or when treatment stopped for whatever reason. |
Lebensqualität: wöchentlich; finale Analyse nach 52 Wochen oder bei Behandlungsende (aus welchen Gründen auch immer)
Biomarkernalyse: nach 25 Wochen; finale Analyse nach 52 Wochen oder bei Behandlungsende (aus welchen Gründen auch immer)
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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 | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| 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 | 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
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| When all included patients have completed 17 cycles (IV Treatment) or 13 cycles (oral Treatment) of treatment or have ceased treatment for whatever reason. |
| Wenn alle eingeschlossenen Patienten 17 Behandlungszyklen (IV Behandlung) oder 13 Behandlungszyklen (orale Behandlung) beendet haben oder die Behandlung aus welchen Gründen auch immer beendet wurde. |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| 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 | 9 |
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