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Rigosertib in Patients With Recessive Dystrophic Epidermolysis Bullosa Associated SCC

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ClinicalTrials.gov Identifier: NCT04177498
Recruitment Status : Not yet recruiting
First Posted : November 26, 2019
Last Update Posted : February 11, 2021
Sponsor:
Collaborator:
Onconova Therapeutics, Inc.
Information provided by (Responsible Party):
Thomas Jefferson University

Brief Summary:
This pilot trial studies how rigsertib sodium works in treating patients with Recessive Dystrophic Epidermolysis bullosa (RDEB) with locally advanced Squamous Cell Carcinoma (SCC). Rigosertib may selectively target Epidermolysis bullosa (EB) cancer cells while leaving normal EB cells unaffected.

Condition or disease Intervention/treatment Phase
Recessive Dystrophic Epidermolysis Bullosa Drug: Rigosertib Sodium Other: Quality-of-Life Assessment Early Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To estimate the anti-tumor activity of oral or IV rigosertib in RDEB patients with advanced SCC that have failed prior standard of care, by determining the overall response rate (ORR) which is defined as the proportion of patients who achieve either a CR or a PR by RECIST v1.1 II. To evaluate the safety and tolerability of oral rigosertib administered either orally daily three weeks on, one week off or as 72h CIV infusions on day 1-3 of a two week-cycle for 8 cycles and then on day 1-3 of a 4 week cycle thereafter

SECONDARY OBJECTIVES:

I. Assess impact on quality of life (QoL) II. Biomarker analysis (to include markers of PI3K/Akt and PLK1 pathways) performed on all archival tissue from all patients

EXPLORATORY OBJECTIVE:

I. Exome sequencing of patient tumors before, during, and after treatment

OUTLINE: Patients will receive rigosertib sodium as either oral capsules or IV infusion. Mode of application is determined by the responsible investigator depending on participant's needs, general condition, and possibility of ambulatory treatment or need of hospitalization.

Patients will take oral rigosertib continuously for a total of three weeks of a four-week cycle (three weeks on, one week off drug).

For IV treatment, patients will receive rigosertib IV administered as a 72-hr continuous 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.

Patients will receive treatment over a 52 week period. After completion of study treatment, patients are followed periodically every 3 months over a 12 month period.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 6 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot, Open Study to Assess Efficacy and Safety of Rigosertib in Patients With Recessive Dystrophic Epidermolysis Bullosa Associated Locally Advanced/Metastatic Squamous Cell Carcinoma
Estimated Study Start Date : March 1, 2021
Estimated Primary Completion Date : June 2023
Estimated Study Completion Date : June 2023


Arm Intervention/treatment
Experimental: Treatment (rigosertib sodium)
Patients receive rigosertib sodium either oral or IV over a 52 week period. Patients will take oral rigosertib continuously for a total of three weeks, every four-week cycle (three weeks on, one week off drug). For IV, rigosertib is administered as a 72-hr continuous 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.
Drug: Rigosertib Sodium
given PO or 72 hour continuous infusion
Other Name: ON 01910.Na

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment




Primary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: baseline up to12 months post treatment ]
    Defined as the proportion of patients who achieve either a complete response (CR) or partial response (PR)

  2. Incidence of treatment-related adverse events [ Time Frame: baseline up to12 months post treatment ]
    Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, physical examinations, and clinical laboratory tests. Results will be reported as an aggregate of the adverse events using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 terminology and grading.


Secondary Outcome Measures :
  1. Quality of Life Epidermolysis Bullosa (QOLEB) questionnaire [ Time Frame: baseline up to12 months post treatment ]
    Descriptive methods used to analyze scores from QOLEB questionnaire. It consists of 17 questions with four response choices from "not at all" to "constant"

  2. Biomarker Analysis [ Time Frame: baseline up to12 months post treatment ]
    Fixed tissue will be assessed using immuno-histochemistry with antibodies raised against phosphorylated AKT (p473 Akt), phosphorylated C-RAF (p-S338 RAF), phosphorylated ERK and cleaved caspase.

  3. Efficacy of rigosertib sodium treatment: The Objective Response Rate [ Time Frame: baseline to end of treatment (52 weeks) ]
    The Objective Response Rate (ORR) will be computed with the corresponding exact binomial 90% confidence interval.


Other Outcome Measures:
  1. Exosome sequencing [ Time Frame: baseline up to12 months post treatment ]
    whole exosome sequencing will be done on frozen tumor tissue. The investigators will catalogue somatic mutations identified in each tumor and compare these data with patient response and ex-vivo tumor responses.



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Ages Eligible for Study:   18 Years to 79 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 18-79 years of age;
  2. Diagnosis of RDEB associated unresectable, locally advanced or metastatic SCC of the skin confirmed prior to the Screening Visit.
  3. Failure to respond to SCC standard of care as follows; surgical excision, radiotherapy and conventional chemotherapy with e.g. platin derivates (i.e., cisplatin carboplatin) or cetuximab, 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, cempilimab). For recent guidelines on standard of care for RDEB SCC and non EB-SCC
  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 a. Surgical excision, radiotherapy and or conventional chemotherapy with e.g. platin derivates (i.e., cisplatin, carboplatin) or cetuximab, 5-fluorouracil, bleomycin, methotrexate, adriamycin, taxanes, gemcitabine or ifosfamide alone or in combination; or 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, cempilimab). For recent guidelines on standard of care for RDEB SCC and non EB-SCC
  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, ≥5.3 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) <60 mL/min.
  7. White blood cell count ≤ 2000/μl OR Neutrophils ≤ 1500/μL OR Platelets ≤ 100 x103/μL OR 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 childbearing 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 including combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (either oral or intravaginal or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (either oral or injectable or implantable); an intrauterine device (IUD); an intrauterine hormone-releasing system ( IUS); bilateral tubal occlusion; vasectomised partner or sexual abstinence. 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 a. (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)
  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 patient's legally authorized representative) 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. Any patient with a known medical condition leading to abnormal vital signs that is not correctable or a patient whose vital sign is within abnormal range upon arrival in clinic will not be receiving the medication. If this abnormal vital signs are not medically controlled and addressed that patient will be excluded at anytime (regardless of it is at arrival or in the middle of the study).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04177498


Contacts
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Contact: Bahar Dasgeb, MD 215-955-6680 bahar.dasgeb@jefferson.edu

Locations
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United States, Pennsylvania
Sidney Kimmel Cancer Center at Thomas Jefferson University
Philadelphia, Pennsylvania, United States, 19107
Contact: Bahar Dasgeb, MD    215-955-6680    bahar.dasgeb@jefferson.edu   
Sponsors and Collaborators
Thomas Jefferson University
Onconova Therapeutics, Inc.
Investigators
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Principal Investigator: Bahar Dasgeb, MD Sidney Kimmel Cancer Center at Thomas Jefferson University
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Responsible Party: Thomas Jefferson University
ClinicalTrials.gov Identifier: NCT04177498    
Other Study ID Numbers: 19G.527
First Posted: November 26, 2019    Key Record Dates
Last Update Posted: February 11, 2021
Last Verified: February 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Epidermolysis Bullosa
Epidermolysis Bullosa Dystrophica
Skin Abnormalities
Congenital Abnormalities
Skin Diseases, Genetic
Genetic Diseases, Inborn
Skin Diseases
Skin Diseases, Vesiculobullous
Collagen Diseases
Connective Tissue Diseases
ON 01910
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action