Cemiplimab for Kidney Transplant Recipients With Advanced Cutaneous Squamous Cell Carcinoma

Официальное название

A Phase 2 Study of Cemiplimab for Kidney Transplant Recipients With Advanced Cutaneous Squamous Cell Carcinoma (CONTRAC-2)

Обзор

This is a phase II, multicenter, open label, single arm, non-randomized trial using Simon's optimal two-stage design to evaluate the efficacy of cemiplimab in kidney transplant recipients with advanced cutaneous squamous cell carcinoma. The hypothesis being tested is that cemiplimab alongside standardized immune suppression will generate anti-tumor activity without triggering allograft rejection.

Вмешательства

• Препарат Cemiplimab
  Cemiplimab is administered intravenously (IV) at a dose of 350mg over 30 minutes on Day 1 of each 21-day cycle.
• Препарат Prednisone
  Prednisone is administered orally and taken about the same time each day. Prednisone will be pulsed for Cycles 1-6 and continued to be pulsed or dose reduced for Cycles 7+. For Cycles 1-6: 40 mg dose will be administered the day before each cycle (Day -1 or Day 21) and Days 1-3, 20mg dose Days 4-6, and 10mg dose Days 7-20. For Cycles 7+: Dose will be administered pulsed as Cycles 1-6 or 10mg daily
• Препарат Sirolimus
  Sirolimus will be taken orally once daily at dose prescribed to achieve a goal trough level of 4-6 ng/mL. It should be taken around the same time daily. Sirolimus will be administered daily throughout each cycle.
• Препарат Cetuximab (EGFR inhibitor)
  Cetuximab may be administered according to standard of care (SOC).

Первичные конечные точки

• Overall response rate (ORR) [Срок оценки: From start of cemiplimab treatment through completion of follow-up (total estimated time 36 months)]

Вторичные конечные точки (9)

• Incidence of adverse events as assessed by CTCAE v6.0 [Срок оценки: Start of lead-in treatment through 90 days after discontinuation of cemiplimab (total estimated time 27 months and 2 weeks)]
• Discontinuation of treatment due to treatment-related adverse events (AEs) [Срок оценки: Start of lead-in treatment through completion of treatment (total estimated time 24 months and 2 weeks)]
• Kidney allograft rejection rate [Срок оценки: From start of cemiplimab treatment through completion of follow-up (total estimated time 36 months)]
• Allograft loss rate [Срок оценки: Start of cemiplimab treatment through completion of follow-up (total estimated time 36 months)]
• Overall Survival (OS) [Срок оценки: Start of cemiplimab treatment to death, whichever comes first (estimated time frame 36 months)]
• Progression-free survival (PFS) [Срок оценки: Start of cemiplimab treatment to time of progression or completion of follow-up, whichever occurs first (estimated total time 36 months)]
• Duration of response (DoR) [Срок оценки: Time of CR or PR response to time of progression or death for any reason, whichever comes first (total estimated time 36 months)]
• Overall response rate (ORR2) at 9 weeks [Срок оценки: Start of cetuximab treatment to 9 weeks after start of cetuximab treatment (total time 9 weeks)]
• Progression-free survival (PFS2) at 9 weeks [Срок оценки: Start of cetuximab treatment to 9 weeks after start of cetuximab treatment (total time 9 weeks)]

Критерии участия

Критерии включения

• Histologically confirmed locoregionally advanced and unresectable or recurrent/metastatic cutaneous squamous cell carcinoma (CSCC). Definitions that encompass unresectable disease include any of the following, after discussion at the multidisciplinary meeting:

• Anatomically unresectable disease to include carotid artery encasement; invasion into the skull base, cavernous sinus, sagittal sinus; pre-vertebral fascia/vertebral body/vertebral artery; disseminated distant metastatic disease
• Functionally unresectable disease resulting in the loss of sight, oral competency/speech/swallowing, or limb
• Biologically unresectable disease to include satellitosis, in-transit/dermal metastasis, or disease which has failed 2 or more prior surgeries (by an experienced CSCC surgeon) or failed curative intent radiation therapy
• Measurable disease per RECIST 1.1.
• Received a kidney transplant. Must have a functioning allograft, be at least 6 months from last allograft transplantation, and have had no evidence of biopsy-proven allograft rejection (Banff 1A or above, requiring treatment) at any time. In order to be considered a functioning allograft, the following criteria must be met:

• Estimated glomerular filtration rate (GFR) ≥ 30 mL/min (using the CKD-EPI equation either by Cr or Cystatin C based measurement) (Inker LA et al, 2021)
• Baseline proteinuria < 0.5 g/day (by spot urine protein-creatinine ratio or 24-hr urine collection, if available)
• Not receiving antiproliferative immunosuppressive medications. If patients are on antiproliferative immunosuppressive medications, they must be discontinued for at least 7 days before initiation of C1D1 (i.e. at the screening visit and/or during the lead-in period)
• At least 18 years of age.
• ECOG performance status ≤ 2
• Adequate bone marrow and organ function as defined below:

• Leukocytes ≥ 2.2 K/cumm
• Absolute neutrophil count ≥ 1.0 K/cumm
• Platelets ≥ 90 K/cumm
• Total bilirubin within normal institutional limits (except in cases where Gilbert syndrome is known or suspected, where total bilirubin should be < 3 mg/dL)
• AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN
• The effects of cemiplimab on the developing human fetus are unknown. For this reason, people of childbearing potential and people able to father a child must agree to use highly effective contraception prior to study entry, for the duration of study participation, and for 4 months after last dose of cemiplimab.
• Able to switch immunosuppression regimen to sirolimus and prednisone if not already receiving sirolimus and prednisone as SOC.
• Able to understand and willing to sign an IRB approved written informed consent document and willing and able to comply with clinic visits and study-related procedures. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Критерии исключения

• Received chemotherapy or radiotherapy within 2 weeks prior to C1D1. Note: prior cetuximab exposure is permitted, but it must have been discontinued at least 2 weeks prior to the start of cemiplimab.
• Received prior anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CLTA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways (including chimeric antigen receptor \[CAR\] T-cell therapies).

Note: prior topical or intralesional immunotherapies (e.g., imiquimod, talimogene laherparepvec) are permitted.

• Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial
• Currently receiving any other investigational agents.
• Unable to swallow pills.
• Currently receiving any medications or substances that are strong inhibitors or inducers of CYP3A4.
• Receipt of a live vaccine within 28 days of C1D1.
• Receipt of COVID-19 vaccination within 7 days of C1D1 or for which the planned COVID-19 vaccinations would not be completed 7 days prior to C1D1.
• Patients with untreated brain metastases. Patients with treated brain metastases are allowed if post-treatment brain-imaging after CNS-directed therapy shows no evidence of progression and if they are at least 4 weeks out from treatment. They must also be asymptomatic and on stable doses of anti-epileptic drugs (AEDs) and oral corticosteroids at the time of enrollment
• A history of allergic reactions attributed to or known hypersensitivity to cemiplimab or any of its components or other agents used in the study.
• Ongoing or recent evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments. Note: the following are not exclusionary: vitiligo, childhood asthma that has resolved, endocrinopathies (such as hypothyroidism or type 1 diabetes) that require only hormone replacement, or psoriasis that does not require systemic treatment. Patients with a history of Hashimoto thyroiditis who are stable on replacement hormone therapy are not excluded.
• Any condition that requires ongoing/continuous corticosteroid therapy (> 10 mg prednisone/day or anti-inflammatory equivalent) within 7 days prior to C1D1. Patients who require a brief course of steroids (up to 2 days in the week before C1D1) or physiologic replacement are not excluded.
• Uncontrolled intercurrent illness including but not limited to ongoing or active infection requiring hospitalization or treatment with IV anti-infectives within 14 days prior to C1D1; NYHA heart failure classifications of Class II, III, or IV; myocardial infarction or acute coronary syndrome within 12 months prior to C1D1; unstable angina pectoris; cardiac arrhythmia; transient ischemic attack or stroke within 12 months prior to C1D1.
• Known non-infectious pneumonitis or any history of interstitial lung disease.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test within 14 days of study entry.
• Uncontrolled infection with HIV, hepatitis B or C infection, diagnosis of immunodeficiency, and/or tuberculosis (active or latent).

• Participants with known controlled HIV infection (undetectable viral load on HIV RNA PCR) and CD4 count > 350 either spontaneously or on a stable antiviral regiment are eligible. For these participants, monitoring will be performed as per local standards.
• Participants with HBsAg positive who have controlled infection (serum HBV DNA PCR that is below the limit of detection and receiving anti-viral therapy for hepatitis B) are eligible. Participants with controlled infections must undergo periodic monitoring of HBV DNA. Participants must remain on anti-viral therapy for at least 6 months beyond the last dose of cemiplimab.
• Participants with HBsAg negative but total HBcAb positive are permitted with the following requirements: if serum HBV DNA is above the limit of detection at screening, initiate HBV antiviral therapy before study entry. If serum HBV DNA PCR is below the limit of detection, periodic monitoring of HBsAg must be performed.
• Participants who are HCV Ab+ who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are eligible.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Washington University School of Medicine — St Louis

Идентификаторы

NCT: NCT07715734 · 26-x257

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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