A Phase 2 Study Evaluating INCB099280 in Participants With Advanced Cutaneous Squamous Cell Carcinoma

Trial ID: 2022-502476-23-00
Protocol: INCB 99280-212
Sponsor: Incyte Corp.

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Diseases & Conditions

Skin squamous cell carcinoma metastatic Skin squamous cell carcinoma recurrent

Objectives

The primary objective of this Phase 2 study is to determine the **safety**, tolerability, and preliminary efficacy of INCB099280 administered at doses of 400 mg BID, 600 mg BID, and 800 mg BID in participants with advanced cutaneous squamous cell carcinoma (cSCC). This is clinically relevant as it aims to establish a foundational understanding of the drug's safety profile and its potential therapeutic benefits in a population with limited treatment options, particularly those who are immunotherapy-naive and have previously untreated or recurrent locally advanced or metastatic cSCC not amenable to curative surgery and/or radiotherapy.

Secondary objectives include:

Determining the efficacy of INCB099280 at the specified doses in participants with advanced cSCC.
Characterizing the pharmacokinetics (PK) of INCB099280 in plasma in this patient population.

These objectives are crucial for understanding the drug's therapeutic potential and its behavior within the body, which can inform dosing strategies and further clinical development.

Participants

The clinical trial involves a total of **144 participants** who are immunotherapy-naive patients with previously untreated or recurrent locally advanced or metastatic cutaneous squamous cell carcinoma (**cSCC**) that is not amenable to curative surgery and/or radiotherapy. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their ability to comprehend and sign a written informed consent form, a histopathological diagnosis of cSCC, and measurable disease as per specific criteria. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a life expectancy of more than three months. Participants are required to have a baseline archival tumor specimen available or be willing to undergo a pretreatment tumor biopsy. The trial population is characterized by a willingness to adhere to specific reproductive precautions to avoid pregnancy or fathering children during and after the study period. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, indicating that additional ethical considerations are in place to protect these participants.

Plans and Procedures

The clinical trial is designed to evaluate the **safety**, tolerability, and preliminary efficacy of the investigational drug INCB099280 in participants with advanced cutaneous squamous cell carcinoma (cSCC). This is a Phase II, randomized, double-blind, controlled study. The trial will assess three different dosages of INCB099280: 400 mg, 600 mg, and 800 mg, administered orally twice daily. The study is expected to run until July 31, 2025, with recruitment having commenced on July 3, 2023. Participants will be involved in the study for a maximum treatment period of 24 weeks, with the possibility of early termination if adverse events occur or if the participant withdraws consent.

The sequence of study visits includes an initial screening visit to confirm eligibility based on inclusion criteria such as age, diagnosis of cSCC, and measurable disease. Following successful screening, participants will undergo baseline assessments before the initiation of treatment. Regular follow-up visits will be scheduled to monitor the participants' response to the treatment and to assess any treatment-emergent adverse events (TEAEs). These visits will include physical examinations, vital signs monitoring, ECGs, and laboratory tests. The primary endpoints of the study are the objective response rate and the incidence of TEAEs. Secondary endpoints include disease control, duration of response, time to response, progression-free survival, overall survival, and plasma concentration of INCB099280.

The end-of-study visit will occur after the completion of the treatment period or upon early termination. This visit will involve a comprehensive assessment to evaluate the overall health status of the participant and to document any final outcomes related to the study drug. Participants may be withdrawn from the study if they experience significant adverse effects, if the disease progresses, or if they choose to discontinue participation. The study aims to provide valuable insights into the potential benefits and risks of INCB099280 for patients with advanced cSCC who are not candidates for curative surgery or radiotherapy.

Treatment

The clinical trial involves the administration of **INCB099280**, an experimental medication developed by Incyte Corporation. **INCB099280** is formulated as a **film-coated tablet** and is intended for **oral use**. The active substance, also named **INCB099280**, is of chemical origin. The trial aims to evaluate the safety, tolerability, and preliminary efficacy of this compound in participants with advanced cutaneous squamous cell carcinoma (cSCC). The dosing regimen includes three different dosages: 400 mg, 600 mg, and 800 mg, administered twice daily (BID). The maximum daily dose is set at 1600 mg, with a total treatment period not exceeding 24 weeks. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, as deemed necessary by the study protocol. These treatments will be administered according to standard medical practice and will serve as a control to evaluate the effects of **INCB099280**. The administration of any non-experimental treatments will be documented, and participant adherence will be monitored to maintain the integrity of the trial data.

Efficacy

Efficacy in the clinical trial evaluating INCB099280 for participants with advanced **cutaneous squamous cell carcinoma** (cSCC) will be assessed using both primary and secondary endpoints. The primary endpoints include the objective response, defined as a best overall response of confirmed complete response (CR) or partial response (PR) by blinded independent central review (BICR) per RECIST v1.1 or composite criteria for metastatic cSCC, and per WHO criteria for locally advanced cSCC. Additionally, the incidence of treatment-emergent adverse events (TEAEs) will be assessed through physical examinations, changes in vital signs and ECGs, and analysis of clinical laboratory samples, including those leading to dose interruption, reduction, or discontinuation.

Secondary endpoints will further evaluate efficacy by measuring disease control, defined as a best overall response of confirmed CR, PR, or stable disease (SD) after a minimum of 15 weeks following the initiation of study treatment. Duration of response (DOR) will be calculated from the earliest date of confirmed CR or PR to the earliest date of disease progression or death. Time to response (TTR) will be determined from the date of the first dose to the earliest date of confirmed CR or PR. Progression-free survival (PFS) will be assessed from the date of the first dose to the earliest date of disease progression or death. Overall survival (OS) will be measured from the date of the first dose to death due to any cause. Additionally, the concentration of INCB099280 in plasma will be monitored.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Ability to comprehend and willingness to sign a written ICF for the study.
Age 18 years or older inclusive at the time of signing the ICF.
Histopathological diagnosis of cSCC. Note: Tumors arising on the cutaneous hair-bearing portion of the lip with extension to the dry red lip (vermilion) are eligible if the origin of the primary tumor is known and clearly documented as the cutaneous hair-bearing portion of the lip. Participants with mixed histology are eligible if the predominant histology is cSCC.
Previously untreated or recurrent locally advanced (without nodal metastases) or metastatic (distant or regional metastasis) cSCC not amenable to curative surgery and/or radiotherapy following consultation with a surgeon and/or radiation oncologist, respectively.
Measurable disease based on either radiographic imaging per RECIST 1.1 with at least 1 baseline lesion ≥ 10 mm in maximal diameter for metastatic disease or digital medical photography per WHO criteria with at least 1 baseline lesion in which both the longest diameter and the perpendicular diameter are ≥ 10 mm for externally visible disease.
ECOG performance status of 0 or 1 (see Section 8.3.4 of the protocol)
Baseline archival tumor specimen available or willingness to undergo a pretreatment tumor biopsy to obtain a specimen for retrospective biomarker analysis. Must be a tumor block or 15 unstained slides (6 slides minimum) from biopsy or resection of primary tumor or metastasis that are ≤ 1 year old (≤ 6 months for slides). It is preferred that the archival sample is from tissue obtained after completion of last treatment. Fine-needle aspirate and bone metastases samples are not acceptable
Life expectancy of > 3 months, in the opinion of the investigator.
Willingness to avoid pregnancy or fathering children based on the criteria below. a. Men must agree to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through 100 days after the last dose of study drug (or longer as appropriate based on country-specific requirements) and must refrain from donating sperm during this period. Permitted methods that are at least 99% effective in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed. b. WOCBP must meet the following criteria: − Have a negative serum pregnancy test at screening and agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through 190 days after the last dose of study treatment. Permitted methods that are at least 99% effective in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed. − Refrain from donating oocytes from 30 days before the first dose of study drug until 90 days after the last dose.

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Exclusion Criteria

cSCC arising in the following locations: • Primary tumors of the vermilion only • Primary site of cancer on the penis, scrotum, and perianal region
Known history of an additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of disease recurrence for 3 years since initiation of that therapy.
CNS metastases requiring treatment and/or leptomeningeal disease. Note: Participants with untreated CNS metastases are excluded if any of the following apply: are symptomatic, require increasing steroids and/or a steroid dose of more than 1 mg of dexamethasone daily (or equivalent), or have lesions with significant edema. Note: Participants with treated CNS metastases are excluded if any of the following apply: CNS metastatic disease that is progressing, not clinically stable within 2 weeks of C1D1, or require increasing steroids and/or a steroid dose of more than 1 mg of dexamethasone daily (or equivalent).
Toxicity from prior therapy that has not recovered to ≤ Grade 1 or baseline (with the exception of anemia not requiring transfusion support and any grade of alopecia).
Prior receipt of an anti–PD-1, anti–PD-L1, or anti–PD-L2 agent; treatment with an immune modulator (eg, CTLA-4, GITR, LAG3, TIM3, OX40, ICOS, IL-2, 4-1BB, CAR-T cell); or treatment with a BRAF inhibitor.
Received thoracic radiation of > 30 Gy within 6 months of the first dose of study treatment. Note: Participants must have recovered from all radiation-related toxicities to ≤ Grade 1 and not require corticosteroids.
Participation in another interventional clinical study while receiving INCB099280.
Treatment with anticancer medications or investigational drugs within the following intervals before the first administration of study drug: • At least 14 days for chemotherapy or targeted small-molecule therapy • At least 28 days for a prior monoclonal antibody used for anticancer therapy • At least 28 days or 5 half-lives (whichever is longer) before the first dose for all other investigational study drugs or devices Note: Participants receiving bisphosphonates and/or denosumab are eligible for enrollment.
Impaired cardiac function or clinically significant cardiac disease: • New York Heart Association Class III or IV cardiac disease, including preexisting clinically significant ventricular arrhythmia, congestive heart failure, or cardiomyopathy • Unstable angina pectoris • Acute myocardial infarction ≤ 6 months before study participation • Other clinically significant heart disease (ie, uncontrolled ≥ Grade 3 hypertension)
History or evidence of interstitial lung disease, including noninfectious pneumonitis.
Presence of gastrointestinal conditions that may affect drug absorption, as well as those that interfere with gastrointestinal transit, including gastric bypass surgery, gastric sleeve, or gastric band
Any autoimmune disease requiring systemic treatment in the past 5 years, including corticosteroids of a daily dose exceeding 10 mg of prednisone or equivalent.
Diagnosis of primary immunodeficiency or receiving chronic systemic steroid therapy at a daily dose exceeding 10 mg of prednisone or equivalent.
HIV infection and any one or more of the following: CD4+ T-cell count < 200 cells/µL, detectable viral load, or antiretroviral therapy regimen containing moderate or potent CYP3A4/CYP3A5 inhibitors or inducers. Note: Participants modifying their HIV regimen to include only drugs without CYP3A4/5 inhibitors or inducers must be on a stable regimen for > 28 days.
Active infection requiring systemic therapy, with the exception of HIV and hepatitis as noted.
History of organ transplantation, including allogeneic stem cell transplantation
Known hypersensitivity or severe reaction to any component of study drug or formulation components.
Postoperative complications preventing the participant from adhering to protocol assessments and procedures.
Receipt of systemic antibiotics within 28 days of first dose of study treatment.
Probiotic usage within 28 days of first dose of study treatment and while on study is prohibited.
Received a live vaccine within 28 days of the planned start of study drug.
Treatment with moderate and potent CYP3A4/CYP3A5 inhibitors or inducers (see Appendix E). Note: A washout period ≥ 10 days before the first dose of INCB099280 is required for prior treatment with CYP3A4/CYP3A5 inhibitors/inducers.
Unable to be weaned off of a prohibited medication as described in Section 6.6.3 before the initiation of study treatment
Laboratory values at screening as defined in Table 5.
Clinically significant ECG abnormality, including QTcF interval > 480 milliseconds. Note: If a single ECG tracing at screening is > 480 milliseconds, the average of a triplicate ECG may be used.
Active HBV or HCV infection defined as follows (testing must be performed to determine eligibility): a. Detectable HBV DNA and HBsAg positive. b. A positive HCV antibody and quantitative HCV RNA result greater than the lower limit of detection for the assay.
Pregnant, expecting to conceive, or breastfeeding starting with the screening visit through 190 days after the last dose of study treatment or expecting to father children starting with the screening visit through 100 days after the last dose of study treatment.
Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits, pose a significant risk to the participant, or interfere with interpretation of study data
The following participants are excluded in France: vulnerable populations according to article L.1121-6 of the French Public Health Code and adults under legal protection, or who are unable to express their consent per article L.1121-8 of the French Public Health Code, not affiliated to a social security per article L.1121-8-1 of the French Public Health Code

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Croatia	Not Recruiting	03 Jul 2023	6
Finland	Not Recruiting	03 Jul 2023	4
France	Not Recruiting	03 Jul 2023	36
Hungary	Not Recruiting	03 Jul 2023	9
The Netherlands	Not Yet Recruiting	03 Jul 2023	—
Romania	Not Recruiting	03 Jul 2023	18
Spain	Not Recruiting	03 Jul 2023	21
Netherlands	—	—	3