A Phase II Single Arm Open Label Study of Pembrolizumab and Lenvatinib in Patients With High Risk Locally Advanced Cervix Cancer: an EMBRACE High Risk Study Initiative
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 87
- 试验地点
- 1
- 主要终点
- Progression Free Survival
研究概览
简要总结
The goal of this clinical trial is to learn if the combination of Pembrolizumab and Lenvatinib works to treat locally advanced cervical cancer in adults that will undergo primary chemoradiation and brachytherapy. It will also learn about the safety of the combination of Pembrolizumab and Lenvatinib. The main questions it aims to answer are:
- Does the combination of Pembrolizumab and Lenvatinib improve progression free survival at two years after treatment?
- What side effects do participants have when taking the combination of Pembrolizumab and Lenvatinib? Researchers will compare the combination of Pembrolizumab and Lenvatinib to existing results with primary chemoradiatoin and brachytherapy to see if the combination of Pembrolizumab and Lenvatinib works to treat locally advanced cervical cancer.
Participants will:
- Visit the clinic to receive Pembrolizumab intra venously once every 3 weeks for 5 cycles and then once very 6 weeks for a maximum of 2-years
- Take Lenvatinib orally every day starting at the earliest 8 weeks after the last brachytherapy to a maximum of 1 year
- Visit the clinic for checkups and tests during scheduled visits
详细描述
Rationale Chemoradiation (CRT: combined external beam radiotherapy with weekly cisplatin) followed by brachytherapy has remained the standard first line treatment for locally advanced cervical (LACC) patients. Over the last decades, major improvements in radiotherapy have been pioneered through the EMBRACE studies. Most recently the outcome data of 1318 patients undergoing response adapted advanced MRI image guided intracavitary +/-interstitial brachytherapy (MR-IGABT) over and above CRT have been reported. This dose escalated approach resulted in 5-year local control of 92%, pelvic control of 87% and disease-free survival (DFS) of 68%. In this cohort, a 5-year OS of 64% was observed for stage IIIB and 67% for node positive patients. These results essentially confirm both the effectiveness of MR-IGABT for pelvic control but also the need of more effective systemic therapy approaches. Patients most at risk for recurrence and reduced 3-year DFS include patients with presence of multiple nodes in pelvic and paraaortic region or adeno/adenosquamous carcinoma histological type and those with a poor response to CRT.
Considering that both anti-angiogenesis and immune checkpoint blockade work independently in cervix cancer, a combination approach may be associated with synergy and improved outcomes. Recently, the phase III randomized placebo-controlled KEYNOTE A-18 trial investigated the combination of CRT with anti-PD-1 Pembrolizumab in patients with high-risk locally advanced cervical cancer defined as FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA regardless of nodal status. With a median follow-up of 17·9 months a 11% progression free survival (PFS) benefit at 2-years was demonstrated (68% vs 57%). Timing immunotherapy during radiotherapy and close to brachytherapy (where high dose per fraction is utilised) may allow to maximally synchronize "immunotherapy response" by taking advantage of the "inflamed" tumour microenvironment and a high radiotherapy dose fraction that is administered using brachytherapy. Lenvatinib will be initiated not earlier than 8 weeks after the last CRT and brachytherapy, to allow for sufficient healing of acute side effects of CRT.
The study hypothesizes that over and above concurrent and Pembrolizumab monotherapy, the addition of Lenvatinib administered after CRT and brachytherapy will lead to improved outcomes in this high-risk population of patients with locally advanced cervical cancer.
Objective The primary objective of the trial is to evaluate progression free survival (PFS) at 24 months (by investigator assessed RECIST 1.1) in women with high-risk locally advanced cervical cancer treated with chemoradiotherapy and Pembrolizumab followed by Pembrolizumab and Lenvatinib. Secondary Objectives include overall survival (OS), local and regional control; physician reported toxicity (CTCAE v5.0) and patient reported outcomes (EORTC QLQ-C30 and CX-24); and associated tissue, blood and imaging based translational research.
Interventions Patients will undergo standard of care chemoradiation (CRT: combined external beam radiotherapy with weekly cisplatin). Initial tumor imaging at pre-screening must have been performed within 28 days prior to the date of registration. The site study team must review pre-treatment images to confirm the participant has measurable disease per RECIST 1.1 at diagnosis. Target definition and dose reporting follow ICRU-89 and are detailed in the protocol. The elective node target volume is risk based and follows EMBRACE-II, that includes elective para-aortic radiotherapy up to the crossing of the renal vessels in patients with: ≥ 1 pathologic node at common iliac or above OR ≥ 3 pathologic nodes. With regard to organs at risk (OAR) for bowel the outer loops are contoured including the mesenteric, and for bones the whole bone from ischial tuberosity to 25mm superior of the PTV is contoured.
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
- Female
- 接受健康志愿者
- 否
入选标准
- •Age >18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •High risk defined by either of the criteria:
- •Squamous cell carcinoma FIGO 2018 stage IIIA, IIIB, IIIC1-IIIC2 OR
- •Adenocarcinoma or adeno-squamous carcinoma Stage IB3-IIIC
- •Have adequate haematological parameters and organ function as defined in the protocol Table
- •Have adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mm Hg.
- •Have measurable disease based on RECIST 1.1 on imaging at diagnosis.
- •The participant provides written informed consent for the trial.
- •Patients should have been planned for radical chemoradiation and MR guided adaptive brachytherapy with intended treatment completion within 50 days.
- •Patients should be deemed suitable for start of Pembrolizumab during chemoradiation and brachytherapy, and for start of Lenvatinib/Pembrolizumab 8 weeks after last brachytherapy as per local investigators assessment.
- •Criteria for known Hepatitis B and C positive subjects:
- •Hepatitis B and C screening tests are not required unless:
- •Known history of HBV or HCV infection
- •As mandated by local health authority
- •Hepatitis B positive subjects:
- •Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to inclusion.
- •Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention.
- •Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening.
- •Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization.
排除标准
- •Patients with locally advanced cervical cancer and signs of organ wall involvement on MRI or non-gastrointestinal fistula.
- •Major surgery within 3 weeks prior to first dose of study interventions. Brachytherapy is not considered a major surgery.
- •Urine protein ≥1 g/24 hours. Note: Participants with proteinuria ≥2+ (≥100 mg/dL) on urine dipstick testing (or urinalysis) will undergo 24-hour urine collection for quantitative assessment of proteinuria.
- •If a MUGA or cardiac ultrasound was performed (on clinical indication): having a LVEF below the institutional (or local laboratory) normal range.
- •Radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation NOTE: the degree of proximity to major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following Lenvatinib therapy.
- •Prolongation of QTcF interval to >480 ms. NOTE: If the QTcF is prolonged to >480 ms in the presence of a pacemaker, contact the Sponsor to determine eligibility.
- •Clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability.
- •Note: Medically controlled arrhythmia would be permitted.
- •Gastrointestinal malabsorption or any other condition that might affect the absorption of Lenvatinib.
- •Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug.
- •WOCBP who has a positive urine pregnancy test within 72 hours prior to adjuvant phase. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Note eligible patients for this trial are not WOCBP due to treatment with CRT.
- •Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
- •Known additional malignancy that is progressing or has required active treatment within the past 3 years.
- •Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded.
- •Severe hypersensitivity (≥Grade 3) to Pembrolizumab or Lenvatinib and/or any of its excipients.
- •Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
- •History of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
- •Active infection requiring systemic therapy.
- •Known history of Human Immunodeficiency Virus (HIV) infection. Note: No HIV testing is required unless mandated by local health authority.
- •Known concurrent active Hepatitis B (defined as HBsAg positive and detectable HBV DNA) and/or Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA [qualitative]) infection. See inclusion criteria 10
- •Note: no testing for Hepatitis B and Hepatitis C screening tests are not required unless:
- •Known history of HBV and HCV infection
- •As mandated by local health authority.
- •Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or such that it is not in the best interest of the participant 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.
- •Has had an allogenic tissue/solid organ transplant.
研究组 & 干预措施
Single arm: Pembrolizumab and Lenvatinib
Single arm open label study of Pembrolizumab and Lenvatinib in patients with high risk locally advanced cervix cancer that will undergo chemoradiation and brachytherapy
干预措施: pembrolizumab and lenvatinib (Drug)
结局指标
主要结局
Progression Free Survival
时间窗: From date of enrollment to 24 months
Actuarial Progression free survival (PFS) rate at 24 months, with a PFS event defined by either progression, using investigator assessed RECIST 1.1, or by death from any cause.
次要结局
- Overall Survival(From date of enrollment to 24 and to 36 months)
- Progression Free Survival(From date of enrollment to 36 months)
- Local Control(From date of enrollment to 24 and to 36 months.)
- Regional Nodal Control(From date of enrollment to 24 and to 36 months.)
- Adverse Events(From date of enrollment to 24 and 36 months.)
- Patient reported symptoms and health related quality of life(At baseline prior to the start of treatment, at 5 weeks after start of treatment, at the first 6 weekly cycle of pembrolizumab, at 3, 6, 9, 12, 24, 36, 48 and 60 months.)
研究者
Prof. Dr. Remi A. Nout
Professor
Erasmus Medical Center