Phase I Study of the Anti-PD1 Immune Checkpoint Inhibitor Pembrolizumab And Platinum in Combination With Radical radiotherApY in Cervix cAncer.
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 1
- 试验地点
- 2
- 主要终点
- Maximum Tolerated Dose (MTD)
研究概览
简要总结
Locally advanced cervix cancers (stage 1B-IV) are usually treated with radiotherapy, concomitant cisplatin chemotherapy and brachytherapy. Failure to achieve locoregional control (LRC) remains a problem, especially in the setting of stage III/IV disease. More importantly, however, the dominant unresolved problem remains the occurrence of distant metastatic relapse. With the knowledge that 99% of all cervix cancer is associated with human papillomavirus (HPV) infection, there is a strong rationale to consider immunomodulatory strategies in the radical management of this disease. Therefore, in this research protocol the investigator will treat patients with stage 1B-IVA carcinoma of the cervix planned to receive radical radiotherapy with concomitant cisplatin and brachytherapy. The research involves adding a new therapy in the form of an antiPD1 monoclonal antibody (pembrolizumab) to the standard treatment of radiotherapy combined with cisplatin chemotherapy and brachytherapy. This treatment seeks to activate the patient's own immune system to attack the cancer cells - and the investigator believes that adding this treatment during standard treatment may be particularly effective. Patients will receive an initial dose of pembrolizumab 2 weeks before starting a course of chemoradiotherapy and brachytherapy. In the first instance, patients will receive 100 mg of pembrolizumab and, if this is safe and tolerable in the first 3 patients, the dose will be increased to 200 mg for all other patients. Radiation will be delivered on 28 occasions with chemotherapy given intravenously in weeks 0, 1, 2 and 3. Brachytherapy will be given on 3 occasions after completion of the radiation. Additional doses of pembrolizumab will be given every 3 weeks for a further 7 doses. The investigator will assess the feasibility and safety of the combination of pembrolizumab with radiotherapy and cisplatin.
详细描述
The study is designed to determine the safest dosage of pembrolizumab to be given in combination with chemoradiotherapy and brachytherapy for patients with locally advanced cervix cancer. The study will be run at the Royal Marsden Hospital only and is open label so both patient and doctor will know what treatment patients are receiving. Patients will receive pembrolizumab in combination with chemoradiotherapy and brachytherapy. Patients will be tested against 2 dose escalation levels (Dose Level 1/2). An initial dose of 100mg of pembrolizumab will be implemented. If dose limiting toxicity is not observed at this dose, pembrolizumab will be escalated to 200mg. A minimum of 3 patients will be required at each dose level. A minimum gap of 1 week should be left between the recruitment of the first and second patient in a new dosing level to mitigate against multiple patients suffering from any acute toxicity.
- If no dose limiting toxicity is observed at a dose level, pembrolizumab will be escalated to the next dosing level.
- If 1 in 3patients experience a dose limiting toxicity then the cohort will be expanded to 6 patients.
- If 1 in 6 patients experience a DLT then the dose will be escalated to the next dosing level.
- However if ≥ 2 in 6 patients experience a DLT then the maximum administered dose (MAD)will have been reached and the previous dosing level should be used for the expansion phase. If the MAD is reached at dose level 1 the combination therapy of pembrolizumab, cisplatin and radiotherapy will not be considered possible and the trial discontinued. Once the MTD has been determined the trial enters the expansion cohort whereby a further 14 patients are treated with the determined dosage of pembrolizumab in combination with radiotherapy, brachytherapy and cisplatin. For this study the dose limiting toxicities will be assessed by the presence of:
- >=Grade 3 gastrointestinal toxicity
o Excluding grade 3 toxicity which resolves to grade 2 within 48 hours of medical management
-
Haematological toxicity including:
-
Grade 3 thrombocytopenia with bleeding
-
Grade 4 thrombocytopenia
-
Grade 4 neutropenia lasting >7 days in the absence of growth factor support
-
Grade 4 neutropenia of any duration accompanied by fever ≥ 38.5°C and/or systemic infection
-
Any other grade ≥4 haematological toxicity
-
Immune system toxicity
-
Grade 4 immune toxicity requiring treatment with corticosteroids
-
Grade 3 immune toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks. (For patients requiring corticosteroids at week 12 toxicity assessment, the observation period will be continued to monitor for this DLT)
-
Radiotherapy treatment interruption > 5 days or failure to complete external beam radiotherapy and brachytherapy due to toxicity
-
any other ≥Grade 3 non-hematologic toxicity (except nausea and vomiting) which in the opinion of the investigator is considered dose-limiting.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed FIGO stage 1B - IVA carcinoma of the cervix planned to receive radical radiotherapy with concomitant cisplatin and brachytherapy. Pelvic lymph node but not para-aortic lymph node involvement is permitted.
- •ECOG PS 0-1
- •Be willing and able to provide written informed consent for the trial.
- •Be >= 18 years of age on day of signing informed consent.
- •Have measurable disease based on RECIST 1.
- •Demonstrate adequate organ function (as defined in Table 1 of the trial protocol) all screening tests should be performed within 10 days prior to confirmation of study eligibility.
- •Female patient of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to confirmation of study eligibility. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- •Female patients of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
- •For Concomitant cisplatin GFR>50ml/min, no contraindications to cisplatin (pre-existing tinnitus or neuropathy)
排除标准
- •Requires para-aortic radiotherapy
- •Has had previous pelvic radiotherapy
- •Has had bowel resection, history of inflammatory bowel disease or autoimmune condition
- •Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
- •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 trial treatment.
- •Has had a prior monoclonal antibody, chemotherapy, targeted small molecule therapy, or radiation therapy. Note: If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
- •Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
- •Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study.
- •Has a history of (non-infectious) pneumonitis that required steroids or current 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 the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
- •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 children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
- •Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD
- •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 received a live vaccine within 30 days prior to the first dose of trial treatment.
研究组 & 干预措施
Part A - Escalation dose
Escalation of dose to 200mg of pembrolizumab in a further n=3 patients provided no more than 1/6 patients at starting dose experience a DLT. Increase in cohort by three patients to n=6 patients provided no more than 1/3 patients experience a Dose Limiting Toxicity (DLT).
干预措施: Pembrolizumab (Combination Product)
Part A - Starting dose
100mg of pembrolizumab in n=3 patients, administered in 8 cycles every 3 weeks for a total of 18 weeks commencing two weeks prior to first fraction of radiotherapy and given in combination with Radical Radiotherapy, Brachytherapy and Cisplatin Chemotherapy. Increase in cohort by three patients to n=6 patients provided no more than 1/3 patients experience a Dose Limiting Toxicity (DLT).
干预措施: Pembrolizumab (Combination Product)
Part B - Expansion phase
Recruitment of expansion cohort of n=14 patients using Maximum Tolerated Dose (MTD) of Pembrolizumab as determined in the dose escalation phase. MTD to be administered in 8 cycles every 3 weeks for a total of 18 weeks commencing two weeks prior to first fraction of radiotherapy and given in combination with Radical Radiotherapy, Brachytherapy and Cisplatin Chemotherapy.
干预措施: Pembrolizumab (Combination Product)
结局指标
主要结局
Maximum Tolerated Dose (MTD)
时间窗: 2 years from patients commencement
To establish the maximum tolerated dose (MTD) of pembrolizumab that can be safely combined with radiotherapy, brachytherapy and cisplatin in the absence of dose limiting toxicities (DLTs)
Efficacy
时间窗: 2 years from patients commencement
Establish its efficacy on progression-free survival.
次要结局
- Presence / Absence of HPV(12 weeks following radiation therapy (Week 18))
- Overall survival (OS)(Up to 2 years post treatment.)
- Late Radiotherapy Toxicity(12 weeks (study week 18), 6 months, 1 year and 2 years following radiation therapy)
- Evaluate Toxicities of Treatment(Through study completion, up to 19 weeks after last dose of Pembrolizumab)
- Response Rates(12 weeks (week 18), 6 months, 1 year and 2 following radiation treatment)
- Progression Free survival (PFS)(Up to 2 years post treatment.)