Phase II Non-Randomised Controlled Trial Of Concomitant Immune Check Point Inhibitor With Radiotherapy And Chemotherapy Or Cetuximab In Advanced Non Metastatic Head And Neck Cancer
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Response Rate
研究概览
简要总结
Background: Locally advanced head and neck cancer (HNC) is a challenge as, in spite of initial good control with chemoradiation, the majority of patients fails systemically. In the last 2 years, immune check points inhibitors (mainly Programmed Death (PD)-1 inhibitors) were approved for metastatic/recurrent HNC. The favorable toxicity profile and durable responses was the main benefit of these drugs along the scope of cancers they were approved for.
Aim of the study and methods: This will be a phase II non-randomized trial to define safety and efficacy of combining the PD-1 inhibitor pembrolizumab given concomitantly with the usual standard of care chemoradiation/bioradiation for locally advanced non-nasopharyngeal HNC. Primary end point will be assessment of toxicity and tolerability while the secondary end points will be response rates (RR) and progression free survival (PFS)
详细描述
Among the Gulf Countries Collaboration Council (GCCC) states, HNC account for 11.5 per 100,000 population. The incidence of HNC in Kuwait is 3.8 per 100,000 population. This, as an example, accounts for about 12.7% of all cancer cases during the period from 1993 to 1999.
Rationale of Immunotherapy in Head and Neck Cancers Cancer immunotherapy principle is functional restoration of certain signaling pathways of the immune system. These pathways help to counteract different tumour evasion strategies. These may include reduced antigen processing and presentation, increased tumour-permissive cytokine profiles, creating an immunosuppressive microenvironment, cellular immune escape, and induction of non-functioning T-cells either by an increase of co-inhibitory receptors; e.g. cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or PD-1 or decreased co-stimulatory receptors. , Immune checkpoints pathway is the most studied so far. It works by regulating the duration and extent of immune system activity through negative feedback signals. These include CTLA-4, PD-1 and PD-L1/PD-L2.
Head and neck cancers use different immune evasion mechanisms. Immune dysfunction has been implicated in carcinogenesis of human papillomavirus (HPV)-positive oropharyngeal cancer as well as cases linked to smoking.
PD-1 and PD-L1 interplay is extremely interesting. A French group from Sorbonne attempted to explain the better prognosis of HPV-positive tumours of the oropharynx. They examined PD-1 and PD-L1 expression in 64 cases, mostly of oropharyngeal origin. Infiltration of PD-1+ T-lymphocytes was a favourable prognostic factor in HPV-related disease. This also was confirmed by others, where expression of PD-L1 is common regardless of HPV status.
Safety Issues At the University of Pennsylvania, safety of ipilimumab with hypofractionated palliative radiotherapy (RT) was tested in a phase I study. There was no grade 4 or higher toxicities in the cohort of 21 patients. The most common grade 3 toxicity was anemia, that is unlikely to be related to the RT.
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
- 16 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The patient has pathologically proven squamous cell carcinoma arising in the oropharynx, hypopharynx, oral cavity, or larynx
- •The patient has stage III or IVA disease with an expected survival of 12 months.
- •The patient is medically suitable to withstand a course of definitive radiation therapy & chemotherapy.
- •Karnofsky performance status is >
- •The patient must have achieved lawful age to provide informed consent according to local or national law .
- •Laboratory values performed within 14 days prior to concurrent chemotherapy should be as follows:
- •i) Absolute neutrophil count (ANC) ≥ 2000/mm ii) Platelet count ≥ 100.000/mm iii) Hemoglobin ≥ 10g/dl or 100g/L iv) Urea and serum creatinine ≤ 1.5 mg/dl. (for cisplatin) v) Creatinine clearance ≥ 50 ml/min. (for cisplatin) vi) serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) ≤ 2 × upper limit of laboratory normal vii) Serum calcium within normal limits.
- •Has provided tissue for Programmed Cell Death Receptor Ligand 1 (PD-L1) biomarker analysis from a core or excisional biopsy
- •Has evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography scan or magnetic resonance imaging, based on RECIST version 1.1
- •Is eligible for definitive chemoradiation (CRT) and not considered for primary surgery based on investigator decision
- •Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study therapy
- •Female and male participants of reproductive potential must agree to use adequate contraception throughout the study period and for up to 180 days after the last dose of study therapy
排除标准
- •The patient has evidence of distant metastatic disease.
- •The patient has received prior systemic chemotherapy within the last three years.
- •The patient has undergone previous surgery for the tumor, other than biopsy.
- •The patient has received prior radiation therapy to the H&N.
- •The patient's radiation therapy is considered to be a part of a postoperative regimen following primary surgical resection.
- •The patient is pregnant or breast feeding.
- •The patient has a medical (e.g. renal impairment) or psychological condition that would not permit the patient to complete the trial or sign informed consent.
- •Has received prior therapy with an anti-Programmed Cell Death Receptor 1 (PD-1), anti-PD-L1, anti-Programmed Cell Death Receptor Ligand 2 (PD-L2) agent or with an agent directed to another co-inhibitory T-cell receptor or has previously participated in clinical studies with immunotherapy
- •Has received a live vaccine within 30 days prior to the first dose of study therapy
- •Has not recovered from major surgery prior to starting study therapy
- •Has known active Hepatitis B or C
- •Has known history of Human Immunodeficiency Virus (HIV)
- •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study therapy
- •Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
- •Has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic treatment.
- •Has history of a diagnosed and/or treated hematologic or primary solid tumor malignancy, unless in remission for at least 5 years prior to randomization
- •Has had previous allogeneic tissue/solid organ transplant
- •Has active infection requiring systemic therapy
- •Has a history of severe hypersensitivity reaction to Pembrolizumab, Cisplatin, cetuximab or radiotherapy or their analogs
研究组 & 干预措施
Investigational Arm
All patients will receive radical chemoradiation in addition to the investigational concomitant check point inhibitor CHEMOTHERAPY: Cisplatin: 100 mg/m2 Q21d D1, D22, D43. OR Cetuximab Loading dose 400 mg/m², one week before radiation then maintenance dose 250 mg/m² weekly, D8, D15, D22, D29, D36, D43.
PD-1 inhibitor: Pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks 21 days prior to radiation, then Day 1 of radiation and then every 21 days for total 6 doses
Intensity modulated radiotherapy (IMRT) techniques will be used. A total dose of 66-70 Gy/ 30-35 Fr over 6-7 weeks will be delivered to the primary site and draining lymphatics using simultaneous Integrated Boost (SIB).
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Response Rate
时间窗: 3 years
Response rates according to irRECIST criteria
Dose Limiting Toxicity (DLT)
时间窗: From the first dose of pembrolizumab to 28 days after the completion of radiation therapy
A pembrolizumab attributable, dose-limiting toxicity (DLT) will be defined as follows: 1) Any ≥ grade 3 adverse event (CTCAE, v. 4) that is related to pembrolizumab that does not resolve to grade 1 or less within 28 days; 2) A delay in radiotherapy of \> 2 weeks due to toxicity related to pembrolizumab; 3) Inability to complete radiotherapy due to toxicity related to pembrolizumab; 4) Inability to receive an adequate dose (≥ 70%) of cisplatin or cetuximab due to toxicity definitely related to pembrolizumab.
次要结局
- Progression free survival(5 years)
- Overall survival(5 years initially (longer follow up will be done))
- Locoregional control rates(5 years)