Patient case: 32-year-old male with dilated cardiomyopathy; genetic feature: LMNA

Clinical trial: Rigosertib for RDEB-SCC

Summary: Epidermolysis bullosa (EB) is a heritable skin disease characterized by marked fragility of epithelialized tissue with blistering in skin and mucous membranes following the slightest mechanical trauma. Eighty percent of all patients suffering from recessive dystrophic EB (RDEB), a subtype originating from mutations in the COL7A1 gene, develop squamous cell carcinoma (SCC). In RDEB patients SCC presents early (most patients are in their 20s or 30s) and shows a highly aggressive metastatic course which often leads to premature death at this young age.
  In light of scarce data on the efficacy and safety of systemic treatment regimens for advanced SCC, the investigators propose to perform a small, "first in EB " trial of an experimental drug called rigosertib for the treatment of EB cancer. The trial will be conducted in two study centres, in London and Salzburg, and will last approximately 2.5 years with each patient recruited being in the study for 1 year. The drug is a polo-like kinase inhibitor interfering with different molecular pathways that are essential for cancer cell growth. Rigosertib was developed by Onconova Therapeutics and is currently tested in several clinical trials for a number of other cancers including myelodysplastic syndrome (a cancer of the blood). The investigators have identified that rigosertib most selectively kills EB cancer cells in vitro while leaving normal EB skin cells unaffected. This project will evaluate whether rigosertib is capable of inducing an anti-cancer response in EB patients and whether the drug is well-tolerated. Mechanisms of molecular targeting of squamous cancer cells by rigosertib will further be investigated in EB patients, also aiming at the identification of biomarkers that may allow the predictive identification of best responders.


Eligibility: Inclusion Criteria:
  1. 18-79 years of age;
  2. Diagnosis of unresectable, locally advanced or metastatic SCC confirmed prior to the screening visit.
  3. 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. For recent guidelines on standard of care for RDEB SCC and non EB-SCC please see Mellerio 2016 and Stratigos 2015.
  4. Is not currently receiving any other cancer therapy.
  5. Measurable disease based on Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1).
  6. Patient (or patient's legally authorized representative) must have signed an informed consent document indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study.
  Exclusion Criteria:
  1. Response to standard of care;
  2. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure or unstable angina pectoris;
  3. Active systemic infection not adequately responding to appropriate therapy;
  4. Total bilirubin ≥ 1.5 mg/dL not related to hemolysis or Gilbert's disease;
  5. Alanine transaminase (ALT)/aspartate transaminase (AST) ≥ 2.5 x upper limit of normal (ULN);
  6. Serum creatinine ≥2 .0 mg/dL or eGFR (estimated Glomerular Filtration Rate) <60 mL/min;
  7. White blood cell count ≤ 2000/μl, Neutrophils ≤ 1500/μL, Platelets ≤ 100 x103/μL, Hemoglobin ≤ 7.9 g/dL;
  8. 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;
  9. Uncorrected hyponatremia (defined as serum sodium value of <125 mmol/L);
  10. Female patients of child-bearing potential and male patients with partners of child-bearing potential who are unwilling to follow strict contraception requirements throughout the study, up to and including the 30-day non-treatment follow-up period;
  11. 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 reliable methods of contraception with a Pearl index ≤1. Reliable contraception should be maintained throughout the study. A pregnancy test in urine will be performed at screening in all women of childbearing potential, and repeated before biopsy treatment and 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.
  12. Uncontrolled hypertension;
  13. 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.
  14. Psychiatric illness or social situation that would limit the patient's ability to tolerate and/or comply with study requirements.
  15. Patients (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.
  16. Participation in another clinical trial where investigational drug was received less than 6 months prior to Screening Visit.
  17. 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.
  18. Known hypersensitivity reaction to any of the components of study treatment.

Relevance to patient case: not relevant