NCT04648033已完成1 期
A Phase I Trial of the Hypoxia Modifier Atovaquone in Combination With Radical Concurrent Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 21
- 试验地点
- 3
- 主要终点
- Number of Dose Limiting Toxicities in Patients Taking Atovaquone in Combination With Radical Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer.
研究概览
简要总结
This is a phase I, open-label trial that will utilise a Time To Event Continual Reassessment Method (TiTE-CRM) to determine the maximum tolerated dose (MTD) of atovaquone in combination with concurrent CRT in NSCLC. Twenty evaluable participants will be recruited at three centres.
详细描述
Twice daily oral atovaquone will be added to standard concurrent chemoradiotherapy (CRT): 66 Gy in 33 fractions, once daily, 5 days a week (Monday-Friday), with cisplatin (80 mg/m2 IV on days 1 and 22 of CRT) and vinorelbine (15 mg/m2 IV on days 1, 8, 22 and 29 of CRT). Whilst awaiting CRT to start, patients will receive two weeks (+/- 7 days) of oral atovaquone to ensure steady state is reached (after seven days). Patients will be allocated one of four dose levels: 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD). Atovaquone dose will be assigned as per the TiTE-CRM statistical model. The first two trial participants will receive 450 mg BD. In the absence of unacceptable toxicity, subsequent patients will be assigned doses up to and including 750 mg BD.
Hypoxia biomarker data will be collected at baseline (start of atovaquone run-in) and following two weeks (+/- 7 days) of atovaquone treatment. Atovaquone will then be continued without break for the duration of CRT, with the CRT schedule remaining constant for all patients at both centres. Assessment for Dose Limiting Toxicities (DLTs) will be from the first scheduled dose of atovaquone until three months after completion of CRT. The CT scan performed at the three-month follow up visit will be reviewed to collect tumour response data.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- •A patient will be eligible for inclusion in this study if all of the following criteria apply:
- •Histologically or cytologically confirmed diagnosis of locally advanced NSCLC and selected for treatment with full dose radical concurrent CRT
- •At least one measurable lesion greater than 2 cm maximal length in any direction on routine imaging (CT or PET-CT scan performed in the 60 days prior to consent)
- •Male or female, age at least 18 years
- •ECOG performance status 0 or 1
- •Adequate pulmonary function tests for thoracic radiotherapy (FEV1 and TLCO, greater than 40 percent predicted)
- •Haematological and biochemical indices within the ranges shown below:
- •Bilirubin ≤ 1.5 x upper limit of normal (ULN); ALT and/or AST ≤ 2.5 x ULN; Creatinine clearance ≥ 60 mL/min; Absolute Neutrophil Count ≥ 1.5 x 10*9/L; Platelets ≥ 100 x 10*9/L; Haemoglobin ≥ 90 g/L; INR ≤ 1.5
- •The patient is willing and able to comply with the protocol scheduled follow-up visits and examinations for the duration of the study
- •Written (signed and dated) informed consent and be capable of co-operating with protocol
排除标准
- •Pregnant or breast-feeding women, or women of childbearing potential unless effective methods of contraception are used
- •Previous systemic chemotherapy or biological therapy within 21 days of commencing atovaquone treatment
- •Treatment with any other investigational agent as part of a clinical trial within 28 days of study enrolment
- •Previous thoracic radiotherapy
- •Known previous adverse reaction to atovaquone or its excipients
- •Active hepatitis, gallbladder disease or pancreatitis
- •Impaired gastrointestinal function that may significantly alter absorption of atovaquone
- •Concurrent administration of warfarin in the 14 days prior to starting atovaquone
- •Concurrent administration of known electron transport chain inhibitors (e.g. metformin). A wash-out period prior to administration of atovaquone is required (e.g. 4 days for metformin).
- •An additional cancer diagnosis that the treating clinician feels may significantly impact planned CRT treatment tolerability or treatment outcome
- •Established diagnosis of pulmonary fibrosis
- •Established diagnosis of connective tissue disorder (e.g. scleroderma or systemic lupus erythematosus)
- •Cardiac morbidity such as angina, myocardial infarction in the previous six months, unstable angina or uncontrolled hypertension, left ventricular failure or severe valvular disease
研究组 & 干预措施
Dose level 1 - 450 mg BD atovaquone + concurrent CRT
Experimental
Atovaquone:
- Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.
- One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.
- Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).
- Last dose atovaquone taken on the last day of radiotherapy.
- Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason.
Chemotherapy:
- 2 x 21-day cycles.
- 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.
- 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy.
Radiotherapy:
- 66 Gy in 33 fractions.
- Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.
干预措施: Atovaquone Oral Suspension (Drug)
Dose level 1 - 450 mg BD atovaquone + concurrent CRT
Experimental
Atovaquone:
- Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.
- One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.
- Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).
- Last dose atovaquone taken on the last day of radiotherapy.
- Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason.
Chemotherapy:
- 2 x 21-day cycles.
- 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.
- 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy.
Radiotherapy:
- 66 Gy in 33 fractions.
- Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.
干预措施: Standard of care chemotherapy (Drug)
Dose level 1 - 450 mg BD atovaquone + concurrent CRT
Experimental
Atovaquone:
- Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.
- One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.
- Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).
- Last dose atovaquone taken on the last day of radiotherapy.
- Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason.
Chemotherapy:
- 2 x 21-day cycles.
- 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.
- 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy.
Radiotherapy:
- 66 Gy in 33 fractions.
- Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.
干预措施: Standard of care radiotherapy (Radiation)
Dose level 2 - 600 mg BD atovaquone + concurrent CRT
Experimental
Atovaquone:
- Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.
- One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.
- Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).
- Last dose atovaquone taken on the last day of radiotherapy.
- Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason.
Chemotherapy:
- 2 x 21-day cycles.
- 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.
- 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy.
Radiotherapy:
- 66 Gy in 33 fractions.
- Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.
干预措施: Atovaquone Oral Suspension (Drug)
Dose level 2 - 600 mg BD atovaquone + concurrent CRT
Experimental
Atovaquone:
- Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.
- One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.
- Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).
- Last dose atovaquone taken on the last day of radiotherapy.
- Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason.
Chemotherapy:
- 2 x 21-day cycles.
- 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.
- 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy.
Radiotherapy:
- 66 Gy in 33 fractions.
- Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.
干预措施: Standard of care chemotherapy (Drug)
Dose level 2 - 600 mg BD atovaquone + concurrent CRT
Experimental
Atovaquone:
- Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.
- One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.
- Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).
- Last dose atovaquone taken on the last day of radiotherapy.
- Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason.
Chemotherapy:
- 2 x 21-day cycles.
- 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.
- 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy.
Radiotherapy:
- 66 Gy in 33 fractions.
- Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.
干预措施: Standard of care radiotherapy (Radiation)
Dose level 3 - 675 mg BD atovaquone + concurrent CRT
Experimental
Atovaquone:
- Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.
- One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.
- Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).
- Last dose atovaquone taken on the last day of radiotherapy.
- Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason.
Chemotherapy:
- 2 x 21-day cycles.
- 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.
- 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy.
Radiotherapy:
- 66 Gy in 33 fractions.
- Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.
干预措施: Atovaquone Oral Suspension (Drug)
Dose level 3 - 675 mg BD atovaquone + concurrent CRT
Experimental
Atovaquone:
- Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.
- One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.
- Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).
- Last dose atovaquone taken on the last day of radiotherapy.
- Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason.
Chemotherapy:
- 2 x 21-day cycles.
- 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.
- 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy.
Radiotherapy:
- 66 Gy in 33 fractions.
- Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.
干预措施: Standard of care chemotherapy (Drug)
Dose level 3 - 675 mg BD atovaquone + concurrent CRT
Experimental
Atovaquone:
- Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.
- One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.
- Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).
- Last dose atovaquone taken on the last day of radiotherapy.
- Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason.
Chemotherapy:
- 2 x 21-day cycles.
- 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.
- 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy.
Radiotherapy:
- 66 Gy in 33 fractions.
- Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.
干预措施: Standard of care radiotherapy (Radiation)
Dose level 4 - 750 mg BD atovaquone + concurrent CRT
Experimental
Atovaquone:
- Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.
- One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.
- Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).
- Last dose atovaquone taken on the last day of radiotherapy.
- Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason.
Chemotherapy:
- 2 x 21-day cycles.
- 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.
- 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy.
Radiotherapy:
- 66 Gy in 33 fractions.
- Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.
干预措施: Atovaquone Oral Suspension (Drug)
Dose level 4 - 750 mg BD atovaquone + concurrent CRT
Experimental
Atovaquone:
- Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.
- One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.
- Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).
- Last dose atovaquone taken on the last day of radiotherapy.
- Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason.
Chemotherapy:
- 2 x 21-day cycles.
- 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.
- 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy.
Radiotherapy:
- 66 Gy in 33 fractions.
- Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.
干预措施: Standard of care chemotherapy (Drug)
Dose level 4 - 750 mg BD atovaquone + concurrent CRT
Experimental
Atovaquone:
- Taken during an initial run in period (2 weeks +/- 7 days), then continued during standard of care chemoradiotherapy.
- One of 4 dose levels is allocated to each patient by a TiTE-CRM statistical model which takes into account all toxicity data to date.
- Dose levels - 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).
- Last dose atovaquone taken on the last day of radiotherapy.
- Total duration of atovaquone treatment is 59 days (+/- 7 days), unless stopped earlier for toxicity or any other reason.
Chemotherapy:
- 2 x 21-day cycles.
- 80 mg/m2 cisplatin on day 1 and 22 of chemoradiotherapy.
- 15 mg/m2 vinorelbine on days 1,8, 22 and 29 of chemoradiotherapy.
Radiotherapy:
- 66 Gy in 33 fractions.
- Delivered once daily, 5 days a week (Monday-Friday) for 6.5 weeks.
干预措施: Standard of care radiotherapy (Radiation)
结局指标
主要结局
Number of Dose Limiting Toxicities in Patients Taking Atovaquone in Combination With Radical Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer.
时间窗: From first dose of atovaquone to 3-month follow up visit (up to 25 weeks)
To determine the maximum tolerated dose level (and therefore recommended phase II dose) of atovaquone when administered concomitantly with radical concurrent chemoradiotherapy (CRT) in patients with non-small cell lung cancer (NSCLC). This is the dose of atovaquone associated with no more than 48% dose limiting toxicity (DLT) rate (target toxicity level).
次要结局
- Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03(From first dose of atovaquone until last follow up visit at 6 months post completion of CRT (up to 38 weeks))
- Number of Patients for Whom it Was Possible to Derive a Hypoxia Metagene Signature Score From 3'RNA-Seq of Genetic Material From Archival Tumour Samples(At baseline (diagnosis))
- Mean Baseline Tumour Hypoxia Level (TBRvol) Assessed by F18-FMISO PET-CT(At baseline (prior to atovaquone treatment))
- Mean Baseline Plasma miR-210 Level Assessed Via TaqMan Quantitative PCR(At baseline (prior to atovaquone treatment))
- Mean Percentage Change in Tumour Hypoxia Level Between Baseline and After Two Weeks (+/- 7 Days) of Atovaquone Treatment(Between baseline (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment (up to 21 days))
- Mean Percentage Change in Plasma miR-210 Level Between Baseline and After Two Weeks (+/- 7 Days) of Atovaquone Treatment, Assessed Via TaqMan Quantitative PCR(Between baseline (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment (up to 21 days))
- Objective Tumour Response to Treatment With Atovaquone in Combination With Chemoradiotherapy, as Evaluated by CT or PET-CT Scan and Quantified by RECIST 1.1(At 3 months post completion of chemoradiotherapy (up to 25 weeks after first dose of atovaquone))
研究者
研究点 (3)
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