Immunotherapy Followed By EGFR Inhibitor In Locally Advanced Or Metastatic Squamous Cell Cancer Of The Skin: Tackling Primary And Secondary Resistance
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 43
- 试验地点
- 7
- 主要终点
- Cumulative response rate
研究概览
简要总结
Cutaneous Squamous Cell Cancer (Cscc, 25%) and basal cell carcinoma (BCC; 75%) are the major subtypes of non-melanoma skin cancer. Most cSCC arise in the head and neck region because it is frequently exposed to sunlight and its ensuing UV radiation-induced DNA damage, which is the major etiologic factor.
There is an urgent need to identify new therapeutic targets for patients with locally advanced or metastatic squamous Cell Cancer of the skin.
Substantial progress has recently been made in the development of immunotherapy for the treatment of cancer. In particular, the treatment with pembrolizumab alone or in conjunction with an anti epidermal growth factor receptor (EGFR) agent may reverse this condition, so performing radical surgery. Finally, the adjunct of an anti EGFR agent as cetuximab could reverse the primary and secondary resistance to pembrolizumab, with a synergistic effect able to counteract pathway redundancy (i.e. the presence of several concurrent pathways which need to be addressed together) and boosting T cell priming.
Hence, there is rationale to combine cetuximab with pembrolizumab in order to increase its effectiveness.
详细描述
Cutaneous squamous cell cancers (cSCC) increase in incidence in recent years. Prognosis of these tumors is generally favorable, with most of the patients cured with local therapies, except from a small percentage (less than 10% of the cases) with recurrence not amenable to surgery or radiation or with distant metastasis. There are only limited clinical risk factors able to discriminate an aggressive lesion at its presentation (size > 2cm, perineural invasion (PNI) or beyond subcutaneous tissues). The American Joint Committee on Cancer (AJCC) added aggressive features of cSCC that lead to upstaging the disease and are associated with increased risk of recurrence or metastasis, including invasion of bone, or presence of at least two high-risk factors such as poor differentiation, PNI, invasion greater than 2 mm, occurrence at a high-risk site (i.e., ear or lip), or Clark level greater than or equal to 4.
Untreatable recurrences are most frequently localized in the head and neck area (80% of cases) and they are often disfiguring, while metastasis may involve lymph nodes, lungs, liver or bone. The probability of metastasis in SCC of the skin varies between 2% and 10% depending on the series and on the risk factors considered. Chemotherapy is reserved to cases of recurrence or distant metastasis, with palliative intent. The most commonly used drug combinations are cisplatin-based, in combination with bleomycin, methotrexate, 5-fluorouracil, anthracycline or with cis-retinoic acid and interferon alfa.
However, clinical responses are limited, so underlining the medical need existing with recurrent SCCs of the skin not amenable to local therapy or with metastatic disease.
The role of immunosuppression is well-known in the pathogenesis of skin SCCs; however, only limited evidence exists about the possibility to treat this disease through the restoration of an immune activity against cancer cells. In this regard, there is the need to acquire more information about the expression and the role of the PD-L1:PD1 pathway in skin SCCs, being one of the most attractive in cancer treatment.
In fact, immuno-oncologic agents targeting checkpoint inhibitors such as programmed death receptor-1 (PD-1) or its ligand PD-L1 are very promising new anti-cancer drugs, while efficacy correlates with PD-L1 expression in various tumor types. In order to provide a translational basis for the possible use of PD1/PD-L1 inhibitors in cSCC, Sharper et al examined the expression pattern of PD-L1 in tumor cells and tumor infiltrating leukocytes (TILs) as well as the proportion of CD8+ T- cells and correlated these findings with clinic-pathological characteristics of patients. Utilizing a cut-off ≥ 5%, 10.3% tumors and 42.7% of TILs were PD-L1 positive. The severity of inflammation was positively correlated with PD-L1 expression in both tumor and TILs and PD-L1 expression in tumor cells was associated with the presence of intratumoral CD8+ cells. Additionally, the location of the tumor had an impact on PD- L1 expression: cSCC located in sun-exposed areas (66.2%) showed a higher expression of PD-L1 in TILs compared to cSCC excised in no sun-exposed areas of the body.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Willing and able to provide written informed consent/assent for the trial.
- •18 years of age.
- •Histological diagnosis of squamous cell carcinoma of the skin not amenable to surgical treatment and to radiation with curative purposes or with clinical contraindication to surgery and radiation.
- •Have metastatic disease
- •Have measurable disease based on RECIST 1.
- •Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion.
- •Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
- •Demonstrate adequate hematological, renal and hepatic organ function as defined in the study protocol.
- •Women of childbearing potential should have a negative pregnancy within 72 hours prior to receiving the first dose of study medication.
- •Women of childbearing potential must be willing to use an adequate method of contraception as outlined in the study protocol4
- •Men of childbearing potential must be willing to use an adequate method of contraception as outlined in the study protocol
排除标准
- •Current or past participation participating and receiving study 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.
- •Previous treatment with anti-EGFR agent
- •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (prednisone equivalent dose > 10 mg per day) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
- •Has a known history of active TB (Bacillus Tuberculosis)
- •Hypersensitivity to the trials drugs or their excipients.
- •Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
- •Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (≤ Grade 1 or at baseline) from adverse events.
- •Has a known additional malignancy that is progressing or requires active treatment.
- •Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
- •Has active autoimmune disease that has required systemic treatment in the past 2 years.
- •Has known history of, or any evidence of active, non-infectious pneumonitis.
- •Has an active infection requiring systemic therapy.
- •Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with participation, or is not in the best interest of the subject.
- •Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- •Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial.
- •Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
- •Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- •Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
- •Has previously received an organ transplant
- •Has previously received bone marrow transplantation
- •Has received a live vaccine within 30 days of planned start of study therapy.
研究组 & 干预措施
Pembrolizumab
Pembrolizumab 200 mg, IV infusion on Day 1 of each 3 week cycle. After 3 cycles patient will be evaluated. In case of disease control (SD, PR, CR) the patient will continue to receive pembrolizumab. In case of progression the patient will receive also Cetuximab (250 mg/m2 after loading dose of 400mg/m2 IV infusion every week.
干预措施: Pembrolizumab (Drug)
Pembrolizumab
Pembrolizumab 200 mg, IV infusion on Day 1 of each 3 week cycle. After 3 cycles patient will be evaluated. In case of disease control (SD, PR, CR) the patient will continue to receive pembrolizumab. In case of progression the patient will receive also Cetuximab (250 mg/m2 after loading dose of 400mg/m2 IV infusion every week.
干预措施: Cetuximab (Drug)
结局指标
主要结局
Cumulative response rate
时间窗: 15 patients will be enrolled. The first evaluation will take place when the last completes three 21-day cycles of Pembrolizumab+/-cetuximab. If we don't observe at least 5 responses (PR/CR), we will stop the recruitment and reject the hypothesis.
Increase in cumulative response rate (PR + CR) obtained by single agent or by combination strategy (pembrolizumab alone or with pembrolizumab + EGFR inhibiting agent) in respect to monotherapy with anti-EGFR agent.
次要结局
- Compliance and safety(Treatment emergent adverse events will be measured throughout the study treatment (at each 21-days cycle.).)
- OS(through study completion, an average of 4 years. OS, calculated for each patient as the time from the date of treatment start to the date of death.)
- percentage of responding patients(Through study completion, an average of 4 years)
- PFS(through study completion, an average of 4 years. PFS calculated in each patient as the time from the date of treatment start to the date of first progression or death, whichever comes first)
- Best response(After first evaluation (after 9 weeks), every restaging will be performed every 6 weeks)
- Proportion of patients undergoing surgery(Through study completion an average of 4 years)