Rigosertib for Skin Cancer in Dystrophic Epidermolysis Bullosa
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase < 1
Recruiting
Sponsor: Thomas Jefferson University
Disqualifiers: Uncontrolled illness, Active infection, HIV, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial studies how rigosertib sodium, a drug taken orally or through IV, can help treat patients with a rare skin condition and advanced skin cancer who haven't responded to other treatments. The drug targets and kills cancer cells while leaving healthy cells alone. Rigosertib has shown potential as a therapeutic option for nonresectable cholangiocarcinoma, demonstrating antitumoral and radiosensitizing effects.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but you cannot be on any other cancer therapy while participating.
Is Rigosertib safe for use in humans?
There is no specific safety data for Rigosertib in the provided research articles, but it is important to note that targeted cancer therapies, in general, can have skin-related side effects. These side effects are often manageable, but they can sometimes be severe enough to limit the dose or stop the treatment.
12345How is the drug Rigosertib unique for treating skin cancer in dystrophic epidermolysis bullosa?
Rigosertib is unique because it targets specific pathways involved in cancer cell growth, potentially offering a more targeted approach compared to traditional chemotherapy, which can cause severe skin toxicity in patients with dystrophic epidermolysis bullosa.
36789Eligibility Criteria
This trial is for adults aged 18-79 with Recessive Dystrophic Epidermolysis Bullosa (RDEB) who have Squamous Cell Carcinoma (SCC) that hasn't improved after standard treatments. Participants must not be on other cancer therapies, should understand the study and agree to participate, and need measurable SCC based on certain criteria. Pregnant women, those with active infections like HIV or hepatitis, uncontrolled health issues, or abnormal lab results can't join.Inclusion Criteria
You have a tumor that can be measured according to specific guidelines.
Patient (or patient's legally authorized representative) must have signed an informed consent document indicating understanding and willingness to participate in the study
I have been diagnosed with a specific type of skin cancer that cannot be surgically removed.
+3 more
Exclusion Criteria
Your blood test results show abnormal levels of bilirubin, liver enzymes, creatinine, white blood cells, neutrophils, platelets, or hemoglobin.
Unlikely to comply with the study protocol or unable to understand the nature and scope of the study
I am not pregnant or breastfeeding and use reliable birth control.
+12 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive rigosertib sodium either orally or via IV infusion over a 52-week period. Oral administration is three weeks on, one week off per cycle. IV administration is a 72-hour continuous infusion on Days 1-3 of a 2-week cycle for the first eight cycles, then on Days 1-3 of a 4-week cycle thereafter.
52 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment completion, with periodic follow-ups every 3 months over a 12-month period.
12 months
Participant Groups
The trial is testing how well rigosertib sodium works in treating patients with advanced skin cancer associated with RDEB. The goal is to see if rigosertib targets cancer cells without harming normal cells. Patients' quality of life will also be assessed during the study.
1Treatment groups
Experimental Treatment
Group I: Treatment (rigosertib sodium)Experimental Treatment2 Interventions
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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Sidney Kimmel Cancer Center at Thomas Jefferson UniversityPhiladelphia, PA
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Who Is Running the Clinical Trial?
Thomas Jefferson UniversityLead Sponsor
Traws Pharma, Inc.Industry Sponsor
Onconova Therapeutics, Inc.Industry Sponsor
References
Blockade of RAS-Binding Domain Interactions Inhibits RAS Signaling. [2017]Rigosertib acts as a RAS mimetic, binding to the RAS-binding domain of multiple RAS effector proteins.
Fas/Fas ligand mediates keratinocyte death in sunitinib-induced hand-foot skin reaction. [2021]Sunitinib, a multitargeted receptor Y kinase inhibitor (TKI) used for the treatment of renal cell carcinoma and gastrointestinal stromal tumor (GIST), is notorious for cutaneous adverse effects, such as hand-foot skin reaction (HFSR). To explore the underlying mechanism of HFSR, we enrolled 53 sunitinib-treated GIST patients, including 23 HFSR cases, and 30 tolerant controls. Among the 29 biomarkers examined, soluble FasL (sFasL) showed significant increase in the plasma, blister fluids, and skin lesions of HFSR patients. The plasma levels of sFasL were significantly correlated with those of sunitinib in HFSR patients. In addition to FasL, augmented expression of Fas and active caspase 3 was also detected in the epidermis of HFSR patients. The increased FasL caused keratinocyte death, as the use of anti-FasL antibody specifically blocked cell apoptosis. Oral administration of sunitinib to mice increased skin susceptibility to mechanical injuries in a dose/time-dependent manner. The administration of sunitinib (40 mg kg(-1) per day) for 4 weeks to mice caused the maximally affected skin area with an erosion-to-ulceration response to tape-stripping. The skin biopsies of mice administered sunitinib exhibited increased expression of Fas and FasL in the apoptotic keratinocytes in the epidermis. Our data revealed that Fas/FasL interaction mediates keratinocyte death in sunitinib-induced HFSR.
Cetuximab therapy of metastasizing cutaneous squamous cell carcinoma in a patient with severe recessive dystrophic epidermolysis bullosa. [2018]Dystrophic epidermolysis bullosa (EB) is a genetic skin fragility condition with propensity to skin cancer. The severest subtype is the generalized recessive dystrophic EB (RDEB), in which mechanically induced skin blisters and erosions heal with severe scarring. A common and potentially life-threatening complication in RDEB is cutaneous squamous cell carcinoma (SCC). In spite of generally good differentiation of SCC associated with RDEB (RDEB-SCC), the tumours behave in an aggressive manner and metastasize early. Despite the high prevalence of RDEB-SCC, systematic studies on therapeutic options have not been reported. Wide surgical excision is recommended, and unresectable cases have been treated with radiotherapy. Here we report the first treatment of metastasized RDEB-SCC with the epidermal growth factor receptor antagonist cetuximab (Erbitux). The response was favourable, and adverse events were similar to those in patients without EB. Notably, no additional negative cutaneous effects, such as severer skin or mucosal blistering, occurred.
Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management. [2022]Mutations in genes encoding for proteins along the RAS-RAF-MEK-ERK pathway have been detected in a variety of tumor entities, including malignant melanoma, thyroid, colonic and ovarian carcinomas, and some sarcomas. Thus, a number of inhibitors of this pathway have been developed, whose antitumor potential is currently being assessed in different clinical trials. Up to now one drug of this category (vemurafenib) has been approved by the FDA and the European Commission for late-stage melanoma. Although these new targeted anticancer therapies are generally considered to be safe and well tolerated, certain toxicities have been attributed to them, with cutaneous side effects being perhaps the most frequent amongst them. Based on results of clinical trials and on case series, a distinct profile of cutaneous toxicity has been observed, which is similar to that of EGFR and multikinase inhibitors. As exanthema, palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, xerosis, pruritus, photosensitivity, and paronychia, can be controlled in most cases with common conservative modalities, special attention should be given to the early detection of epithelial skin tumors (mainly keratoakanthomas) that can be induced during therapy with these agents. This report reviews all current published data on cutaneous side effects of RAS-RAF-MEK-ERK pathway inhibitors, and attempts to provide the clinician with clear hints for their management.
Skin Manifestations of Targeted Antineoplastic Therapy. [2018]The management of oncology patients has changed significantly over recent years, with the development of new targeted anticancer therapies. Cutaneous adverse effects are among the most frequently observed toxicities with many targeted agents; their intensity can be dose-limiting or lead to the discontinuation of therapy. Tyrosine kinase inhibitors can cause maculopapular rash and hand-foot reaction, whereas papulopustular rash, paronychia, regulatory changes in hair, and dryness are caused by epidermal growth factor receptor inhibitors. SMO inhibitors, vismodegib and sonidegib, may result in muscle spasms and alopecia.
Omaveloxolone attenuates squamous cell carcinoma growth and disease severity in an Epidermolysis Bullosa mouse model. [2022]Patients with epidermolysis bullosa (EB) are susceptible to development of squamous cell carcinomas (SCC) at sites of chronic inflammation and fibrosis. While triterpenoids such as RTA 408 (Omaveloxolone) have been shown to reduce inflammation and inhibit tumour growth in various cancer models, the utility of this class of drugs in the treatment of SCC has not been investigated. Given the dual anti-inflammatory and anti-neoplastic properties of triterpenoids, we hypothesized RTA 408 would be an effective treatment for SCCs that arise in the chronic inflammatory setting in EB. We tested the effects of topical RTA 408 on a mouse model of non-Herlitz, junctional EB. RTA 408 significantly reduced phenotypic severity in the affected ears of Lamc2jeb mice. In cultures, RTA 408 reduced cell viability in EB-associated SCC cell lines and normal human epidermal keratinocytes. When administered in vivo, RTA 408 inhibited SCC tumour growth in mice without cutaneous or systemic toxicity. These results suggest that RTA 408 can be a promising new therapy to reduce inflammation and inhibit SCC growth in patients with EB.
Evaluating a Targeted Cancer Therapy Approach Mediated by RNA trans-Splicing In Vitro and in a Xenograft Model for Epidermolysis Bullosa-Associated Skin Cancer. [2022]Conventional anti-cancer therapies based on chemo- and/or radiotherapy represent highly effective means to kill cancer cells but lack tumor specificity and, therefore, result in a wide range of iatrogenic effects. A promising approach to overcome this obstacle is spliceosome-mediated RNA trans-splicing (SMaRT), which can be leveraged to target tumor cells while leaving normal cells unharmed. Notably, a previously established RNA trans-splicing molecule (RTM44) showed efficacy and specificity in exchanging the coding sequence of a cancer target gene (Ct-SLCO1B3) with the suicide gene HSV1-thymidine kinase in a colorectal cancer model, thereby rendering tumor cells sensitive to the prodrug ganciclovir (GCV). In the present work, we expand the application of this approach, using the same RTM44 in aggressive skin cancer arising in the rare genetic skin disease recessive dystrophic epidermolysis bullosa (RDEB). Stable expression of RTM44, but not a splicing-deficient control (NC), in RDEB-SCC cells resulted in expression of the expected fusion product at the mRNA and protein level. Importantly, systemic GCV treatment of mice bearing RTM44-expressing cancer cells resulted in a significant reduction in tumor volume and weight compared with controls. Thus, our results demonstrate the applicability of RTM44-mediated targeting of the cancer gene Ct-SLCO1B3 in a different malignancy.
EGFR inhibition for metastasized cutaneous squamous cell carcinoma in dystrophic epidermolysis bullosa. [2020]Dystrophic epidermolysis bullosa (DEB) is a hereditary skin fragility disorder, characterized by trauma-induced blistering followed by soft tissue fibrosis. One of the most feared complications is the early development of aggressive cutaneous squamous cell carcinomas (SCC). For patients with locally advanced or metastasized SCCs treatment with cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), has been proposed and so far, treatment of five DEB patients with cetuximab has been published. With this report, we extend the spectrum of EB patients treated with cetuximab by adding two additional patients. Taking together all DEB cases treated with cetuximab, we propose that cetuximab should be administered as early as possible, since it seems to be more efficient and is accompanied by rather mild adverse effects. We also show that EGFR is frequently expressed in DEB-associated SCCs, although there were noticeable differences in the level of expression, which may influence responsiveness to EGFR-targeting therapies. Although only limited experiences with targeted cancer treatments in EB exist, such reports highlight the treatments' effects in this specific cohort and assist our therapeutic decisions.
Squamous cell carcinoma in epidermolysis bullosa. Treatment with systemic chemotherapy. [2019]Dystrophic epidermolysis bullosa is associated with a high incidence of cutaneous squamous cell carcinoma. Despite aggressive surgical treatment, metastases occur frequently, and survival is generally poor. Chemotherapy for advanced disease has usually been avoided because of the potential for severe cutaneous toxicity. Two patients with autosomal recessive dystrophic epidermolysis bullosa and advanced squamous cell carcinoma are described. Both received cisplatin-based systemic chemotherapy without significant toxicity.