Rigosertib for RDEB-SCC

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Brief Title

Rigosertib for RDEB-SCC

Official Title

A Phase II, Open Study to Assess Efficacy and Safety of Rigosertib in Patients With Recessive Dystrophic Epidermolysis Bullosa Associated Locally Advanced/Metastatic Squamous Cell Carcinoma

Brief 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.
    


Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Efficacy: Objective Response Rate (ORR)

Secondary Outcome

 Evaluation of quality of life using the "Quality of life in Epidermolysis bullosa questionnaire (QOLEB)"

Condition

Epidermolysis Bullosa Dystrophica

Intervention

Rigosertib Oral Capsules / Rigosertib Intravenous

Study Arms / Comparison Groups

 Treatment Oral Capsules / Intravenous
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

12

Start Date

April 12, 2021

Completion Date

June 2023

Primary Completion Date

December 2022

Eligibility Criteria

        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 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.

          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

        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 (≥5.3 mg/dL in patients if 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) <60mL/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. 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.

         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 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.

         12. 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).

         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. 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.

         17. Known hypersensitivity reaction to any of the components of study treatment.

         18. Presence of clinically significant ECG abnormalities based on the inverstigator´s
             criteria.
      

Gender

All

Ages

18 Years - 79 Years

Accepts Healthy Volunteers

No

Contacts

Johann W Bauer, Prof., MD, +43 5 7255, [email protected]

Location Countries

Austria

Location Countries

Austria

Administrative Informations


NCT ID

NCT03786237

Organization ID

Rigosertib 3.4


Responsible Party

Sponsor-Investigator

Study Sponsor

Prof. Johann Bauer


Study Sponsor

Johann W Bauer, Prof., MD, Principal Investigator, Department of Dermatology, Paracelsus Medical University, Salzburger Landeskliniken


Verification Date

September 2021