Study of Ruxolitinib in Solid Organ Transplant Recipients With Advanced Cutaneous Squamous Cell Carcinoma

Study Overview
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Brief Summary
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In this open-label, multicenter, Phase II study, the investigators propose to evaluate the efficacy of ruxolitinib, an orally administered inhibitor of JAK1/2, in solid organ transplant recipients with advanced cSCC. In a safety lead-in of 6 patients, subjects will receive ruxolitinib 15mg twice daily (BID). After 4 weeks, if dose-limiting toxicities (DLT) are observed in 1 or fewer patients, the study will enter stage 1 of the Simon two-stage design where all subsequent patients will receive a starting dose of ruxolitinib 15mg BID. If more than 1 DLTs are observed, another cohort of 6 patients will be treated at a dose of 10mg BID. If less than 2 DLTs are observed at the new dose of 10mg, then the study will proceed to stage I using this dose; otherwise the study will stop.

Detailed Description
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Approximately 5.4 million individuals in the United States are diagnosed with non-melanoma skin cancers (NMSC) annually, with the incidence increasing over time. Twenty-five percent are cutaneous squamous cell carcinomas (cSCC), which affect up to 1,350,000 individuals and result in up to 12,000 deaths annually in the US alone. Immunosuppressed patients are particularly vulnerable to the development of highly aggressive or catastrophic cSCC. Patients receiving immunosuppressive therapy, such as solid organ transplant recipients (SOTRs), and HIV/AIDS patients have an estimated 60 to 250-fold increased risk of cSCC development. In renal SOTRs, cSCC represents over 70% of all malignancies that develop, with an incidence up to 200 times that of the general population. Post-transplant cSCC occurs at a younger age and is more aggressive than in non-transplant cohorts, with 30% of cSCC recurring within 1 year and up to 8% of disease associated with metastasis. The median survival from diagnosis of metastasis is 3 years.5 Cemiplimab, an anti-PD1 antibody, recently became the first agent to achieve regulatory approval for the treatment of advanced cSCC; however, due to the risk of graft rejection, the role of immunological checkpoint blockade in the SOTR population is extremely limited. Thus, although surgical excision is effective for sporadic cSCC, there remains a large unmet medical need for novel strategies for treatment and/or prevention of multiply recurrent, locally advanced, and metastatic cSCC, particularly in immunosuppressed patients.

Official Title
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A Multi-Center Phase II Study of Ruxolitinib in Solid Organ Transplant Recipients With Advanced Cutaneous Squamous Cell Carcinoma

Conditions
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Advanced Cutaneous Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathologically confirmed diagnosis of metastatic advanced cutaneous squamous cell carcinoma. History of solid-organ transplant requiring immunosuppression Age ≥ 18 yrs Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Karnofsky Performance Status Scale (KPS) ≥60%, Eastern Cooperative Oncology Group (ECOG) ≤2 No prior Janus kinase (JAK) Inhibitor therapy Adequate organ function All clinically significant toxicities from prior systemic therapy must be ≤ Grade 1 (with the exception of alopecia, and peripheral neuropathy, which may be ≤ grade 2). Subjects must agree to undergo tumor biopsies until biopsies have been obtained from 10 subjects (i.e., biopsies are required in at least the first 10 enrolled subjects, or until a goal of 10 study biopsies are obtained). Subjects in whom a biopsy is technically not feasible or in whom would result in unacceptable risk in the opinion of the investigator, may be exempted from the biopsy requirement with discussion with the principal investigator. Negative pregnancy test for women of child bearing potential Ability to take oral medications Adequate marrow function: Absolute neutrophil count (ANC) ≥1000 /mm3 Platelet count ≥50,000/mm3 Hemoglobin ≥8.0g/dL (not requiring transfusion in the past 2 weeks) Exclusion Criteria: At least 21 days must have elapsed since the last dose of systemic chemotherapy or immunotherapy and the first dose of study drug. At least 14 days must have elapsed since the last dose of radiation therapy and the first dose of study drug. Patients who have previously been treated with a JAK inhibitor. Patients who are receiving any other investigational agents concurrently. Patients who have had recent major surgery within a minimum 4 weeks prior to starting study treatment, with the exception of surgical placement for vascular access. Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ruxolitinib. Patients with symptomatic or growing brain metastases. Patients with brain metastases that have been treated and have remained stable for at least one month prior to initiation of study therapy are eligible. Concurrent use of strong CYP3A4 or CYP3A4 substrate drugs with a narrow therapeutic range within 14 days or 5 drug half-lives, whichever is longer, before start of study drug. A list of strong CYP3A4 and 2C8 inhibitors and inducers can be found in Appendix A. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with ruxolitinib. In addition, these patients are at increased risk of lethal infections when treated with marrow- suppressive therapy. Subjects with known active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patients being actively treated for a second malignancy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ruxolitinib<br>In a safety lead-in of 6 patients, subjects will receive 15mg of ruxolitinib twice daily (BID). After 4 weeks, if dose-limiting toxicities (DLT) are observed in 1 or fewer patients, the study will enter stage 1 of the Simon two-stage design where all subsequent patients will receive a starting dose of ruxolitinib 15mg BID. Subjects will have regularly scheduled study visits at the clinical site on Day 1 and Day 15 (± 3 days) of the first 2 cycles, then on Day 1 (± 3 days) of every subsequent cycle (starting cycle 3), where safety assessments, including laboratory assessments, vital signs, and physical examinations will be performed. | Drug: Ruxolitinib<br>* Ruxolitinib will be administered orally twice daily during the entirety of each 28-day cycle.<br>* Other names: JAKAVI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | The primary endpoint is the overall response rate as defined as the best response, confirmed at ≥4 weeks, within the first 24 weeks of the start of study therapy, using RECIST v1.1 criteria. | within the first 24 weeks of the start of study therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | Progression-free survival (PFS) (time alive without advanced cutaneous squamous cell carcinoma (cSCC) probabilities will be estimated | Up to 36 months | 
| Overall Survival (OS) | The length of time from the start of treatment that subjects with the disease are still alive. | Up to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ruxolitinib, Solid Organ Transplant