Locally Advanced Non-Small Cell Lung Cancer
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGAtovaquone Oral Suspension
Atovaquone, cisplatin and vinorelbine are all considered Investigational Medicinal Products (IMPs) in this trial due to the investigation of these drugs in a novel combination. Patients will be allocated one of four doses of atovaquone: 450 mg, 600 mg, 675 mg or 750 mg (all doses PO BD).
Atovaquone, cisplatin and vinorelbine are all considered Investigational Medicinal Products (IMPs) in this trial due to the investigation of these drugs in a novel combination. Patients will receive two 21-day cycles of cisplatin and vinorelbine chemotherapy, comprising 80 mg/m2 cisplatin on days 1 \& 22 of their CRT treatment and 15 mg/m2 vinorelbine on days 1, 8, 22 \& 29.
RADIATIONStandard of care radiotherapy
Thoracic radiotherapy will commence on day one of chemotherapy and be delivered in 66 Gy in 33 fractions, once daily, 5 days a week (Monday-Friday) for 6.5 weeks.
Sponsors
University of Oxford
Cancer Research UK
National Institute for Health Research, United Kingdom
NHS Lothian
Oxford University Hospitals NHS Trust
NHS Research Scotland
Guy's and St Thomas' NHS Foundation Trust
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Time-to-Event Continual Reassessment Method to determine the maximum tolerated dose (MTD) of atovaquone in combination with concurrent CRT in NSCLC
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
A patient will be eligible for inclusion in this study if all of the following criteria apply: 1. Histologically or cytologically confirmed diagnosis of locally advanced NSCLC and selected for treatment with full dose radical concurrent CRT 2. 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) 3. Male or female, age at least 18 years 4. ECOG performance status 0 or 1 5. Adequate pulmonary function tests for thoracic radiotherapy (FEV1 and TLCO, greater than 40 percent predicted) 6. 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 7. The patient is willing and able to comply with the protocol scheduled follow-up visits and examinations for the duration of the study 8. Written (signed and dated) informed consent and be capable of co-operating with protocol
Exclusion criteria
1. Pregnant or breast-feeding women, or women of childbearing potential unless effective methods of contraception are used 2. Previous systemic chemotherapy or biological therapy within 21 days of commencing atovaquone treatment 3. Treatment with any other investigational agent as part of a clinical trial within 28 days of study enrolment 4. Previous thoracic radiotherapy 5. Known previous adverse reaction to atovaquone or its excipients 6. Active hepatitis, gallbladder disease or pancreatitis 7. Impaired gastrointestinal function that may significantly alter absorption of atovaquone 8. Concurrent administration of warfarin in the 14 days prior to starting atovaquone 9. 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). 10. An additional cancer diagnosis that the treating clinician feels may significantly impact planned CRT treatment tolerability or treatment outcome 11. Established diagnosis of pulmonary fibrosis 12. Established diagnosis of connective tissue disorder (e.g. scleroderma or systemic lupus erythematosus) 13. Cardiac morbidity such as angina, myocardial infarction in the previous six months, unstable angina or uncontrolled hypertension, left ventricular failure or severe valvular disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Dose Limiting Toxicities in Patients Taking Atovaquone in Combination With Radical Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer. | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Toxicity profile when atovaquone administered in combination with radical concurrent chemotherapy for NSCLC. Worst grade adverse event for each patient by dose schedule (according to the Common Terminology Criteria for Adverse Events, Version 4.03). Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe or medically significant, but not immediately life-threatening); Grade 4 (life-threatening); Grade 5 (death). |
| 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) | To confirm feasibility of measuring hypoxia metagene signature using 3'RNA-Seq on genetic material extracted from diagnostic non-small cell lung tumour samples. The score method was derived by Buffa et al (Buffa et al. Large meta-analysis of multiple cancers reveals a common, compact and highly prognostic hypoxia metagene. Br J Cancer. 2010 Jan 19;102(2):428-35. doi: 10.1038/sj.bjc.6605450). |
| Mean Baseline Tumour Hypoxia Level (TBRvol) Assessed by F18-FMISO PET-CT | At baseline (prior to atovaquone treatment) | The level of hypoxia in patient tumours was calculated using the Tumour-to-Blood Ratio volume (TBRvol) assessed from the patient's baseline PET scan. This scan was conducted with 18F-labelled fluoromisonidazole (F18-FMISO) which has been shown to selectively bind to hypoxic cells and can be quantified with PET imaging (Koh, et al. Imaging of hypoxia in human tumours with \[F-18\]fluoromisonidazole. Int J Radiat Oncol Biol Phys. 1992;22(1)). Tumour outlining of the region of interest on each axial slice was conducted centrally for all patients in consultation with an experienced consultant radiologist and combined to give a volume of interest (VOI). The number of voxels in the VOI with a threshold regional tumor:plasma F18-FMISO ratio of greater than or equal to 1.4 were combined to give the TBRvol (above reference). Patients with a TBRvol at baseline of \<1.5mL were regarded as unevaluable for later endpoints, so are excluded from the report. |
| Mean Baseline Plasma miR-210 Level Assessed Via TaqMan Quantitative PCR | At baseline (prior to atovaquone treatment) | MicroRNA-210 (miR-210) has been found to be upregulated in response to hypoxia-inducing factors (Dang and Myers, The Role of Hypoxia-Induced miR-210 in Cancer Progression, Int. J. Mol. Sci., vol 16, 2015). Additionally, elevated serum levels of miR-210 are indicative of poor clinical outcomes in non-small cell lung cancer (He, et al. Clinical Significance of miR-210 and its Prospective Signaling Pathways in Non-Small Cell Lung Cancer. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol., vol. 46, 2018). RNA was isolated from blood plasma and miR210 level detected using a two-step TaqMan quantitative PCR, using TaqMan probes for miR-210. An endogenous control miRNA (miR-16), plus an exogenous synthetic miRNA (cel-miR-39) were used for normalisation of miR210 counts. This endpoint was assessed in order to investigate a possible alternative to 18F-FMISO PET-CT scan for assessment of patients' tumour hypoxia level. |
| 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) | The level of hypoxia (Tumour-to-Blood Ratio volume, TBRvol) in patient tumours was calculated at baseline and following two weeks (+/- 7 days) of atovaquone treatment according to the details given in outcome measure 4. The mean percentage difference in TBRvol between the two timepoints at each dose level of atovaquone was calculated and is reported, below. Patients with a TBRvol at baseline of \<1.5mL were regarded as unevaluable as it would not be possible to evaluate a reduction in hypoxic volume between this timepoint and the later timepoint. These patients were excluded from the report. |
| 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) | The miR-210 in participant plasma samples was calculated at baseline and following two weeks (+/- 7 days) of atovaquone treatment according to the details given in outcome measure 5. The mean percentage difference in miR210 count between the two timepoints for each dose level of atovaquone was calculated and is reported, below. This endpoint was assessed in order to investigate a possible alternative to 18F-FMISO PET-CT scan for assessment of patients' tumour hypoxia level. |
| 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) | Efficacy of the combination (atovaquone and chemoradiotherapy), measured by objective tumour response via RECIST 1.1 (Eisenhauer, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247). Scale of response assessed as Progressive Disease (PD) (worst outcome), Stable Disease (SD), Partial Response (PR), Complete Response (CR) (best outcome). |
Countries
United Kingdom
Contacts
PRINCIPAL_INVESTIGATORGeoffrey Higgins
University of Oxford
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT 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. | 3 |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT 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. | 2 |
| Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT 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. | 1 |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT 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. | 15 |
| Total | 21 |
Baseline characteristics
| Characteristic | Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | Total | Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT |
|---|---|---|---|---|---|
| Age, Continuous | 67.3 Years STANDARD_DEVIATION 17.7 | 63.9 Years STANDARD_DEVIATION 10.7 | 65.2 Years STANDARD_DEVIATION 16.4 | 65.0 Years | 48.0 Years STANDARD_DEVIATION 9.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 15 Participants | 9 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 6 Participants | 6 Participants | 0 Participants | 0 Participants |
| Non-small cell lung cancer sub-type Adenocarcinoma | 3 Participants | 8 Participants | 4 Participants | 0 Participants | 1 Participants |
| Non-small cell lung cancer sub-type Squamous cell carcinoma | 0 Participants | 13 Participants | 11 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 0 Participants | 7 Participants | 6 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 14 Participants | 9 Participants | 1 Participants | 1 Participants |
| Smoking status Current smoker | 0 Participants | 3 Participants | 2 Participants | 0 Participants | 1 Participants |
| Smoking status Ex-smoker | 2 Participants | 16 Participants | 13 Participants | 1 Participants | 0 Participants |
| Smoking status Never smoked | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 2 | 0 / 1 | 2 / 15 |
| other Total, other adverse events | 3 / 3 | 2 / 2 | 1 / 1 | 15 / 15 |
| serious Total, serious adverse events | 2 / 3 | 1 / 2 | 0 / 1 | 7 / 15 |
Outcome results
Primary
Number of Dose Limiting Toxicities in Patients Taking Atovaquone in Combination With Radical Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer.
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).
Time frame: From first dose of atovaquone to 3-month follow up visit (up to 25 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | Number of Dose Limiting Toxicities in Patients Taking Atovaquone in Combination With Radical Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer. | 0 Dose Limiting Toxicities (DLTs) |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | Number of Dose Limiting Toxicities in Patients Taking Atovaquone in Combination With Radical Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer. | 0 Dose Limiting Toxicities (DLTs) |
| Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | Number of Dose Limiting Toxicities in Patients Taking Atovaquone in Combination With Radical Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer. | 0 Dose Limiting Toxicities (DLTs) |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | Number of Dose Limiting Toxicities in Patients Taking Atovaquone in Combination With Radical Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer. | 2 Dose Limiting Toxicities (DLTs) |
Comparison: The primary analysis is performed using the Time-To-Event Continual Reassessment Method (TiTE-CRM). Giving posterior estimates for the probability of toxicity (DLT) at each dose level.95% CI: [0.032, 0.26]
Secondary
Mean Baseline Plasma miR-210 Level Assessed Via TaqMan Quantitative PCR
MicroRNA-210 (miR-210) has been found to be upregulated in response to hypoxia-inducing factors (Dang and Myers, The Role of Hypoxia-Induced miR-210 in Cancer Progression, Int. J. Mol. Sci., vol 16, 2015). Additionally, elevated serum levels of miR-210 are indicative of poor clinical outcomes in non-small cell lung cancer (He, et al. Clinical Significance of miR-210 and its Prospective Signaling Pathways in Non-Small Cell Lung Cancer. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol., vol. 46, 2018). RNA was isolated from blood plasma and miR210 level detected using a two-step TaqMan quantitative PCR, using TaqMan probes for miR-210. An endogenous control miRNA (miR-16), plus an exogenous synthetic miRNA (cel-miR-39) were used for normalisation of miR210 counts. This endpoint was assessed in order to investigate a possible alternative to 18F-FMISO PET-CT scan for assessment of patients' tumour hypoxia level.
Time frame: At baseline (prior to atovaquone treatment)
Population: Eight of 21 participant samples are not reported either because the samples showed evidence of haemolysis (n=7) or because the participant withdrew consent (n=1).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | Mean Baseline Plasma miR-210 Level Assessed Via TaqMan Quantitative PCR | 0.00146 miR210 count (x10^3) |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | Mean Baseline Plasma miR-210 Level Assessed Via TaqMan Quantitative PCR | 0.00219 miR210 count (x10^3) |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | Mean Baseline Plasma miR-210 Level Assessed Via TaqMan Quantitative PCR | 0.00195 miR210 count (x10^3) |
Secondary
Mean Baseline Tumour Hypoxia Level (TBRvol) Assessed by F18-FMISO PET-CT
The level of hypoxia in patient tumours was calculated using the Tumour-to-Blood Ratio volume (TBRvol) assessed from the patient's baseline PET scan. This scan was conducted with 18F-labelled fluoromisonidazole (F18-FMISO) which has been shown to selectively bind to hypoxic cells and can be quantified with PET imaging (Koh, et al. Imaging of hypoxia in human tumours with \[F-18\]fluoromisonidazole. Int J Radiat Oncol Biol Phys. 1992;22(1)). Tumour outlining of the region of interest on each axial slice was conducted centrally for all patients in consultation with an experienced consultant radiologist and combined to give a volume of interest (VOI). The number of voxels in the VOI with a threshold regional tumor:plasma F18-FMISO ratio of greater than or equal to 1.4 were combined to give the TBRvol (above reference). Patients with a TBRvol at baseline of \<1.5mL were regarded as unevaluable for later endpoints, so are excluded from the report.
Time frame: At baseline (prior to atovaquone treatment)
Population: Nine of 21 patients results were excluded from the report because they did not have F18-FMISO PET-CT scans at two of two timepoints in the trial (e.g. due to having a TBRvol considered too low to be evaluable on the first scan (n=6), or for logistical reasons (n=3)).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | Mean Baseline Tumour Hypoxia Level (TBRvol) Assessed by F18-FMISO PET-CT | 282.4 TBRvol (mL) |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | Mean Baseline Tumour Hypoxia Level (TBRvol) Assessed by F18-FMISO PET-CT | 21.4 TBRvol (mL) |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | Mean Baseline Tumour Hypoxia Level (TBRvol) Assessed by F18-FMISO PET-CT | 58.7 TBRvol (mL) |
Secondary
Mean Percentage Change in Plasma miR-210 Level Between Baseline and After Two Weeks (+/- 7 Days) of Atovaquone Treatment, Assessed Via TaqMan Quantitative PCR
The miR-210 in participant plasma samples was calculated at baseline and following two weeks (+/- 7 days) of atovaquone treatment according to the details given in outcome measure 5. The mean percentage difference in miR210 count between the two timepoints for each dose level of atovaquone was calculated and is reported, below. This endpoint was assessed in order to investigate a possible alternative to 18F-FMISO PET-CT scan for assessment of patients' tumour hypoxia level.
Time frame: Between baseline (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment (up to 21 days)
Population: Eight of 21 participant samples are not reported either because the samples showed evidence of haemolysis (n=7) or because the participant withdrew consent (n=1).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | Mean Percentage Change in Plasma miR-210 Level Between Baseline and After Two Weeks (+/- 7 Days) of Atovaquone Treatment, Assessed Via TaqMan Quantitative PCR | 53.0 Percentage change in miR210 count |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | Mean Percentage Change in Plasma miR-210 Level Between Baseline and After Two Weeks (+/- 7 Days) of Atovaquone Treatment, Assessed Via TaqMan Quantitative PCR | -42.5 Percentage change in miR210 count |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | Mean Percentage Change in Plasma miR-210 Level Between Baseline and After Two Weeks (+/- 7 Days) of Atovaquone Treatment, Assessed Via TaqMan Quantitative PCR | 15.1 Percentage change in miR210 count |
Secondary
Mean Percentage Change in Tumour Hypoxia Level Between Baseline and After Two Weeks (+/- 7 Days) of Atovaquone Treatment
The level of hypoxia (Tumour-to-Blood Ratio volume, TBRvol) in patient tumours was calculated at baseline and following two weeks (+/- 7 days) of atovaquone treatment according to the details given in outcome measure 4. The mean percentage difference in TBRvol between the two timepoints at each dose level of atovaquone was calculated and is reported, below. Patients with a TBRvol at baseline of \<1.5mL were regarded as unevaluable as it would not be possible to evaluate a reduction in hypoxic volume between this timepoint and the later timepoint. These patients were excluded from the report.
Time frame: Between baseline (prior to atovaquone treatment) and following two weeks (+/- 7 days) of atovaquone treatment (up to 21 days)
Population: Nine of 21 patients results were excluded from the report because they did not have F18-FMISO PET-CT scans at two of two timepoints in the trial (e.g. due to having a TBRvol considered too low to be evaluable on the first scan (n=6), or for logistical reasons (n=3)).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | Mean Percentage Change in Tumour Hypoxia Level Between Baseline and After Two Weeks (+/- 7 Days) of Atovaquone Treatment | -8 Percentage change in TBRvol |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | Mean Percentage Change in Tumour Hypoxia Level Between Baseline and After Two Weeks (+/- 7 Days) of Atovaquone Treatment | -15 Percentage change in TBRvol |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | Mean Percentage Change in Tumour Hypoxia Level Between Baseline and After Two Weeks (+/- 7 Days) of Atovaquone Treatment | -25 Percentage change in TBRvol |
Secondary
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
To confirm feasibility of measuring hypoxia metagene signature using 3'RNA-Seq on genetic material extracted from diagnostic non-small cell lung tumour samples. The score method was derived by Buffa et al (Buffa et al. Large meta-analysis of multiple cancers reveals a common, compact and highly prognostic hypoxia metagene. Br J Cancer. 2010 Jan 19;102(2):428-35. doi: 10.1038/sj.bjc.6605450).
Time frame: At baseline (diagnosis)
Population: Five of 21 participants did not have a hypoxia metagene signature score derived due to the quality of extracted RNA being of insufficient quality to sequence (n=3), no archival tumour sample being available (n=1), or participant withdrew consent (n=1).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | 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 | 3 Participants |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | 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 | 2 Participants |
| Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | 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 | 0 Participants |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | 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 | 11 Participants |
Secondary
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
Efficacy of the combination (atovaquone and chemoradiotherapy), measured by objective tumour response via RECIST 1.1 (Eisenhauer, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247). Scale of response assessed as Progressive Disease (PD) (worst outcome), Stable Disease (SD), Partial Response (PR), Complete Response (CR) (best outcome).
Time frame: At 3 months post completion of chemoradiotherapy (up to 25 weeks after first dose of atovaquone)
Population: Two of 21 participants were non-evaluable because they did not have a follow up scan at 3 months post-chemoradiotherapy treatment on which RECIST assessment could be performed. .
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | 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 | Complete Response (CR) | 0 Participants |
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | 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 | Partial Response (PR) | 2 Participants |
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | 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 | Stable Disease (SD) | 1 Participants |
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | 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 | Progressive Disease (PD) | 0 Participants |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | 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 | Partial Response (PR) | 2 Participants |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | 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 | Stable Disease (SD) | 0 Participants |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | 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 | Progressive Disease (PD) | 0 Participants |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | 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 | Complete Response (CR) | 0 Participants |
| Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | 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 | Stable Disease (SD) | 0 Participants |
| Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | 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 | Partial Response (PR) | 1 Participants |
| Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | 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 | Progressive Disease (PD) | 0 Participants |
| Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | 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 | Complete Response (CR) | 0 Participants |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | 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 | Progressive Disease (PD) | 2 Participants |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | 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 | Partial Response (PR) | 8 Participants |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | 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 | Complete Response (CR) | 1 Participants |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | 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 | Stable Disease (SD) | 2 Participants |
Secondary
Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03
Toxicity profile when atovaquone administered in combination with radical concurrent chemotherapy for NSCLC. Worst grade adverse event for each patient by dose schedule (according to the Common Terminology Criteria for Adverse Events, Version 4.03). Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe or medically significant, but not immediately life-threatening); Grade 4 (life-threatening); Grade 5 (death).
Time frame: From first dose of atovaquone until last follow up visit at 6 months post completion of CRT (up to 38 weeks)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 4 | 0 Participants |
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 2 | 1 Participants |
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 5 | 0 Participants |
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 3 | 2 Participants |
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 1 | 0 Participants |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 3 | 1 Participants |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 4 | 0 Participants |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 5 | 0 Participants |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 2 | 1 Participants |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 1 | 0 Participants |
| Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 3 | 0 Participants |
| Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 1 | 1 Participants |
| Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 2 | 0 Participants |
| Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 4 | 0 Participants |
| Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 5 | 0 Participants |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 4 | 1 Participants |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 2 | 6 Participants |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 1 | 0 Participants |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 3 | 6 Participants |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | Severity of Worst Adverse Events Per Dose Level of Atovaquone Administered in Combination With Radical Concurrent Chemotherapy for NSCLC According to CTCAE V4.03 | Worst AE: Grade 5 | 2 Participants |