Phase 1/2 Trial Evaluating the Effectiveness and Safety of Dose-adapted HYpofractionated Pelvic Radiotherapy for Advanced Cervical Cancers INeligible for ChemoTherapy
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 55
- 主要终点
- Maximum tolerated dose (for phase 1)
研究概览
简要总结
BACKGROUND: For patients with locally advanced cervical cancer (LACC) ineligible for concurrent chemotherapy, radiotherapy (RT) alone achieves complete response rate (CRR) <70% and long-term locoregional control (LRC) <62%. Hypofractionated (HF-)RT using older techniques results in comparable CRR and disease control, and low late toxicity rates (4-8%). Dose-adapted HF-RT using intensity-modulated radiotherapy (IMRT) with nodal simultaneous integrated boost (nSIB) could improve tumor control and toxicity.
GENERAL OBJECTIVE: To determine the effectiveness and safety of HF-RT with (or without) nSIB in LACC among patients who are chemo-ineligible.
PRIMARY OBJECTIVES:
Phase 1: To determine the maximum tolerated dose (MTD) for nSIB used in combination with pelvic HF-RT (2.67 Gray (Gy) x 15 fractions), using IMRT Phase 2: To assess the efficacy of HF-RT ± nSIB in terms of complete response rates at 3 months
SECONDARY OBJECTIVES:
To assess the efficacy of HF-RT ± nSIB in terms of progression free survival (PFS), locoregional PFS, distant metastasis free survival (DMFS), cervical cancer specific survival (CCSS), overall survival (OS)
To assess the acute and late toxicity of HF-RT ± nSIB, and patient-reported quality of life outcomes
EXPLORATORY OBJECTIVES:
To evaluate the predictive utility of clinical and dosimetric variables for tumor response/control and toxicity. Variables: age, performance status, T- and N-stage, T-score, histology, baseline hemoglobin, clinical target volume and organs-at-risk doses, overall treatment time
STUDY DESIGN:
Phase 1: Dose-escalation study (standard 3+3 design) Phase 2: Single-arm clinical trial (Simon's two-stage design)
STUDY TREATMENTS:
Pelvic HF-RT ± nSIB to 40 Gy in 15 fractions using IMRT, followed by brachytherapy (BRT) 6.5-7.5 Gy x 4 fractions using 2D or image-guided techniques
SAMPLE SIZE:
One-sided hypothesis testing. H0: CRR p0 ≤64%; H1: CRR p1 ≥84%. Simon 2 stage: First stage, n1=28 will be enrolled. If response (r1) ≤18, the study will be stopped for futility. Otherwise, second stage: n2=22, for a total of 50.
H0 will be rejected if r1+r2 ≥38, in 50 patients. This yields a type I error rate of 5% and power of 95% when the true response rate is ≥84%.
Accrual: Accounting for 10% attrition, a n=55 will be targeted. At a rate of 4-5 patients quarterly, accrual may take 33-42 months. The trial may be opened to other centers to accelerate accrual.
详细描述
SAMPLE SIZE CALCULATION:
CRR with chemoradiotherapy based on a meta-analysis in 2017 is about 80%; with advanced RT techniques, based on a multi-center, prospective study, local control rate >90% could be achieved.
Based on retrospective studies, CRR with HF-RT without concurrent chemotherapy (ChT) followed by BRT, using 2D techniques, is about 70%. This is comparable to CRR for conventionally fractionated RT without concurrent ChT in the above meta-analysis. Given the retrospective nature of HF-RT data, a low CRR of 64% could be projected (p0). Given that in the current study, the investigators propose to do dose-adapted radiation by using more advanced RT and BRT, a high CRR of 84% could be projected (p1).
In the first stage, 28 patients will be accrued, including the 3 or 6 patients enrolled in the MTD level from phase 1. If there are ≤18 responses in these 28 patients, the study will be stopped. Otherwise, 22 additional patients will be accrued in the second stage, for a total of 50.
The null hypothesis will be rejected if >38 responses are observed in 50 patients. This design yields a type I error rate of 5% and power of 95% when the true response rate is ≥84%.
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
- •Females aged ≥18 years
- •Histologically confirmed cervical squamous, adeno-, or adenosquamous carcinoma
- •2018 Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) Stage IIIA-IIIC1, IVA
- •Pelvic nodal metastases (for the phase 1 cohorts)
- •Contraindication to chemotherapy
- •Brachytherapy candidate
- •World Health Organization (WHO)/ECOG performance status of ≤2
- •Life expectancy of at least 12 weeks
- •Adequate bone marrow function: Absolute neutrophil count ≥1,500 cell/mm3; Platelets ≥100,000 cell/mm3; Hemoglobin ≥10.0 g/dL; Leukocyte count ≥4,000 cell/mm3
排除标准
- •Other histology (small cell, neuroendocrine, lymphoma, sarcoma, etc.)
- •2018 FIGO Stage IIIC2 (para-aortic nodal metastases)
- •Clinical and/or radiologic evidence of metastatic disease
- •History of another malignancy except for the following: malignancy treated with curative intent and with no known active disease ≥5 years and of low potential risk for recurrence; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; adequately treated carcinoma-in-situ without evidence of disease
- •Uncontrolled concurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease, serious chronic GI conditions associated with diarrhea (including Crohn's disease or ulcerative colitis), or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse events or compromise the ability of the patient to give written informed consent
- •Presence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse
- •Prior hysterectomy
- •Prior treatment for cervical cancer
- •Prior pelvic radiotherapy
- •Concomitant anti-cancer therapy
结局指标
主要结局
Maximum tolerated dose (for phase 1)
时间窗: 4 months
The highest dose studied for which the incidence of dose-limiting toxicity was less than 33%
Complete response rate (for phase 2)
时间窗: 3 months
Proportion of treated patients with disappearance of all lesions on clinical and radiologic examination
次要结局
- Late toxicity(5 years)
- Progression-free survival(5 years)
- European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Cervix 24 Scores(5 years)
- Cervical cancer-specific survival(5 years)
- Overall survival(5 years)
- Acute and subacute toxicity(4 months)
- European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 Scores(5 years)
- Patient's Global Impression of Change (PGIC)(5 years)
- Locoregional progression-free survival(5 years)
- Expanded Prostate Index Composite - Bowel Domain Scores(5 years)
- Metastasis-free survival(5 years)
- Expanded Prostate Index Composite - Urinary Domain Scores(5 years)
研究者
Warren Bacorro
Doctor
University of Santo Tomas Hospital, Philippines