Condition category
Cancer
Date applied
21/10/2020
Date assigned
04/11/2020
Last edited
04/11/2020
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Lay summary under review with external organisation

Background and study aims
This study will investigate if drug treatment makes radiotherapy a more effective treatment for non-small cell lung cancer (NSCLC) that has not spread beyond the chest. This study aims to see which dose of the drug is safe to use.

DNA carries the instructions for making our body. Radiotherapy works by damaging the cancer cells’ DNA to the point where hopefully they can no longer survive. The cancer cell will try to repair the radiotherapy damage, so blocking these repair systems may make radiotherapy more effective.

The drugs being evaluated in this study are called DNA damage response inhibitors (DDRis), they limit the body’s ability to repair damaged DNA. It is believed that this will cause the radiotherapy to kill more cancer cells. However, radiotherapy can also damage the DNA of the normal non-cancer cells surrounding the tumour. It is important to work out whether using DDRi with radiotherapy leads to increased side-effects or not. DDRis have been given with radiotherapy and chemotherapy in a number of tumour types, including lung cancer.

The main purpose of the study is to find the most suitable dose of the DDRi that can be safely combined with radiotherapy. This will enable us to test this dose in larger clinical studies. This study will also be looking at whether the DDRis might improve the effectiveness of the radiotherapy in treating the cancer. Samples from participant’s tumour and blood will be tested to see if patients who might benefit from the DDRi can be identified. Several DDRis are being examined in the study, each in a separate study-arm. Participants will only be enrolled into one study arm.

Who can participate?
All study participants will have been diagnosed with non small cell lung cancer that is confined to the chest and is suitable for treatment with radiotherapy. Each participant is carefully assessed using tests to check that they are suitable for inclusion in the study. These include: blood tests, an assessment of medical history, a physical examination, lung function tests, pregnancy tests (where appropriate), chest x-ray, heart scan, CT scan and CT or MRI scan of the brain. Some of these tests would need to have been done irrespective assessment of study eligibility.All study participants will have been diagnosed with non small cell lung cancer that is confined to the chest and is suitable for treatment with radiotherapy. Each participant is carefully assessed using tests to check that they are suitable for inclusion in the study. These include: blood tests, an assessment of medical history, a physical examination, lung function tests, pregnancy tests (where appropriate), chest x-ray, heart scan, CT scan and CT or MRI scan of the brain. Some of these tests would need to have been done irrespective assessment of study eligibility.

What does the study involve?
Participants are allocated to either DDRi (study drug) and radiotherapy or radiotherapy alone. All participants will attend hospital for radiotherapy Monday to Friday for 6 weeks. Participants allocated to study drug will also take this throughout radiotherapy. Once treatment has been completed participants will attend hospital every 6 weeks for 6 months and then every 3 months until 2 years after the end of treatment. Assessments will be carried out during treatment and follow up to monitor for adverse effects and to measure the effect of treatment.

What are the possible benefits and risks of participating?
There is no guarantee that participants will benefit from the treatment given in this study, but this is the same as any treatment they would have even if they did not take part in the study. Although radiotherapy is effective in treating lung cancer, as with other cancer treatments, there is no certainty that they will be effective for the participant. Nor can it be certain that the addition of the DDRi will produce any benefit. Therefore, study participation may not be of direct benefit to participants personally, but it is possible that it may be of benefit to future cancer patients. Information from this study will help doctors to learn more about the DDRi when it is used with radiotherapy, and whether this may be a step forward for the treatment of lung cancer in the future. Without research of this sort, improvements in cancer treatments are not possible. All study participants could benefit from more close monitoring than would be possible outside of the study.

Radiotherapy is a tried and tested cancer treatment. The kind of side effects that participants may have whilst being given this treatment are well known and are listed in the participant information. However, as the type of radiotherapy has only been used with a DDRi in a small numbers of patients, there is a chance that there may be side effects that are new or which differ from those which doctors would usually expect to see with radiotherapy alone. Potential adverse effects are described in the participant information provided prior to study enrolment.

Where is the study run from?
Clinical Trials Research Unit (CTRU) at the University of Leeds (UK)

When is the study starting and how long is it expected to run for?
From November 2019 to September 2026

Who is funding the study?
The National Institute for Health Research (NIHR) (UK), AstraZeneca Ltd (UK) and Cancer Research UK (UK)

Who is the main contact?
Mr Jamie Oughton
ctru_concorde@leeds.ac.uk

Trial website

Contact information

Type

Public

Primary contact

Mr Jamie Oughton

ORCID ID

http://orcid.org/0000-0002-2047-804X

Contact details

Clinical Trials Research Unit
Leeds Institute of Clinical Trials Research
University of Leeds
Leeds
LS2 9JT
United Kingdom
+44 (0)113 3431494
Ctru_concorde@leeds.ac.uk

Type

Scientific

Additional contact

Prof Sarah Brown

ORCID ID

Contact details

Clinical Trials Research Unit
Leeds Institute of Clinical Trials Research
University of Leeds
Leeds
LS2 9JT
United Kingdom
+44 (0)113 343 1477
Ctru_concorde@leeds.ac.uk

Additional identifiers

EudraCT number

2020-000206-28

ClinicalTrials.gov number

NCT04550104

Protocol/serial number

CPMS 45504, IRAS 282001

Study information

Scientific title

A platform study of DNA damage response inhibitors in combination with conventional radiotherapy in non small cell lung cancer

Acronym

CONCORDE

Study hypothesis

To find a safe dose for each DNA damage response inhibitors (DDRi) used in combination with radiotherapy in patients with non small cell lung cancer.

Ethics approval

Approved 21/10/2020, Yorkshire and the Humber – Leeds West Research Ethics Committee (Queens Hotel, City Square, Leeds, LS1 1PJ;+44 (0)207 972 2504; leedswest.rec@hra.nhs.uk), ref: 20/YH/0280

Study design

Randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Non small cell lung cancer

Intervention

Participants will initially be allocated to either radiotherapy (RT)-alone, or RT + DNA damage response inhibitors (DDRi), on a 1:1 basis. Once 10 participants have been randomised to RT-alone the allocation ratio will change to 3:1 in favour of RT+DDRi. This is necessary to accrue sufficient RT-alone patients to act as comparators in the early stages of the trial and to assess whether the target toxicity level of 0.25 in each experimental arm is reasonable. Consenting participants will be randomised between DDRi with RT or RT only, initially on a 1:1 basis in order to accumulate sufficient comparator patients in the early stages of the study and to evaluate the pre-defined DLT rate in the calibration arm. The pooling of patients receiving RT across the platform allows us to move to a 3:1 ratio to DDRi and RT combination, maximizing the patients who receive a novel agent in the study whilst developing a robust calibrator cohort to allow interpretation of any toxicities seen on the study. If the calibration arm DLT rate is higher than expected then the target toxicity level in the experimental arms will be adjusted accordingly. Patients are not randomised between experimental arms.

Randomisation will be performed centrally using the CTRU's 9-5 telephone randomisation system. The randomisation is open-label, therefore the patient, clinician and research team will be informed of the treatment allocation.

CONCORDE is a multi-institution, multi-arm, Phase IB study that will determine the safe dose of different DDRis when given in an open label fashion in combination with fixed dose curative intent radiotherapy in patients with locally advanced non small cell lung cancer (NSCLC). The study’s primary objective is to determine the safe dose for each DDRi when given in combination with thoracic radiotherapy of 60 Gy in 30 fractions. This will be evaluated by incorporating the number of observed dose limiting toxicities into a time to event continuous reassessment method (TiTE- CRM) model within each of the experimental arms with a maximum of 30 patients being treated in each experimental arm. TiTE-CRM is used here to take into account longer-term toxicities up to 13.5 months post start of radiotherapy and use these to inform dose escalation decision making.

At the time of patient identification the treating centre will be informed of the allocated study arm by Leeds CTRU following a pre-specified prioritisation schedule. The process of patient allocation will be determined by a number of logistical factors (e.g. which sites are open for which study arm). The speed of recruitment into each arm will be monitored and can be adjusted by the Safety Review Committee (SRC) should additional toxicity data/follow-up be deemed necessary prior to further allocation. The trial information will be provided to the patient and discussed so that the patient can ask questions. Written informed consent will be obtained by a suitably qualified member of the patient's healthcare team at an appropriate clinic visit.

The patients receiving RT alone will be pooled across the arms to provide contemporary data on toxicity in up to 50-60 patients, accounting for recent improvements in RT techniques and quality assurance. All patients will receive external beam RT with a planned dose of 60 Gy in 30 daily fractions. This calibration arm will aid with attribution of toxicities to the addition of DDRi to RT and will therefore aid interpretation rather than permitting formal comparison between arms. Each DDRi will be administered orally in an open-label fashion alongside the RT. The schedule and starting dose for dose escalation will be based on single agent experience in the clinic and pre-clinical safety. This is fully outlined for each agent in the relevant study arm protocol.

Toxicity will be assessed continuously throughout treatment according to Common Toxicity Criteria for Adverse Events (CTCAE) with weekly assessments until grade 2 or higher toxicities have resolved to ≤ grade 1 in severity. Subsequently, the participants will be followed up at 4, 6, 12, 18, and 24 weeks after the completion of RT, and 3 monthly thereafter until 2 years after the completion of RT. Response to treatment, and progression-free survival will be assessed by CT scans performed at 1 month following the completion of RT and subsequently at 3, 6, 12, 18 and 24 months.

Dose limiting toxicities (DLTs) will be monitored from start of treatment up to 13.5 months post start of RT in order to capture both the acute and long term toxicities related to the drug RT combination; and participants will then be followed-up for a maximum of 2 years for safety and efficacy, as described above. DLTs will also be collected for participants randomised to RT-alone. The DLT period will be split into two stages:
1. Short DLT period which will be during DDRi and/or radiotherapy treatment and up to 4.5 months from day 1 of radiotherapy (weighted for 90% of TiTE-CRM)
2. Long DLT period which will be 4.5-13.5 months from day 1 of radiotherapy (weighted for 10% of TiTE-CRM)
Full follow-up of DLTs to 13.5 months post-start of radiotherapy (RT) will allow capture of all DLTs related to the DDRi and RT combination. Full DLT follow-up of all evaluable participants at the highest tolerable dose level will be required to confirm the recommended phase II dose (RP2D) within each DDRi treatment arm. Patients at the highest tolerable dose level may need to be replaced. The end of the DLT period aligns with the 12-month post end of RT study visit.

Dose Escalation
A separate TiTE-CRM model will be used for each DDRi independently, with dose escalation decisions driven by the occurrence of DLTs and reviewed by a SRC. Dose escalation may consist of both changes in dose and schedule to increase exposure as outlined in the relevant study arm protocols.

Each patient’s dose is decided individually based on the available data at the time of recruitment, i.e. using cohorts of size 1 within the TiTE-CRM model.The dose with probability of toxicity closest to the target of 0.25, in the first instance, will be selected. This target toxicity level is based on expert clinical opinion and target DLT rates in phase I studies of novel systemic therapies. It may, however, be adjusted by the SRC following the assessment of the first 10 calibration arm patients and in light of emerging data from the patients treated with radiotherapy alone. Due to the novelty of agents used in this study, untried dose levels will not be skipped.

At least 1 patient is required to have completed the short DLT period (i.e. around 4.5 months’ worth of data) from a dose level before the next dose level can be opened up and the SRC will decide whether enough follow-up has been observed in the previous patients in order to dose escalate. The RP2D will be defined as the dose level at which the toxicity probability is closest to the target DLT probability, 0.25.

During dose escalation, if the dose under assessment for any arm is reduced to dose level -1, recruitment will be restricted to approximately 1 patient per month for that arm, for at least the first three patients recruited at this dose, and additional pauses will be implemented prior to dose re-escalation, as discussed and agreed with the SRC.

If the lower limit of the credible interval for the estimated probability of unacceptable toxicity is higher than 0.3 at dose level -1, or more than 3 DLTs are observed at this dose level, then that arm will be closed to further recruitment and dose escalation.

If no DLTs are seen at any dose level, then that trial arm will close to recruitment once 10 participants have completed the late DLT assessment period at the highest dose level, and that dose level will be deemed the RP2D. The SRC can, however, override this stopping rule if more data is deemed necessary for deciding the RP2D.

Intervention type

Other

Phase

Phase I

Drug names

Primary outcome measure

1. Dose-limiting toxicities (DLTs), within 13.5 months of starting radiotherapy, in order to establish the Recommended Phase II Dose (RP2D) of each DDR-RT combination between baseline and 13.5 months

Secondary outcome measures

1. Safety and toxicity reported based on the occurrence of Serious Adverse Events (SAEs), Serious Adverse Reactions (SARs) and Suspected Unexpected Serious Adverse Reactions (SUSARs). Toxicity will be reported based on adverse events, as graded by Common Toxicity Criteria for Adverse Events (CTCAE v5.0), and determined by routine clinical assessments at each centre.between baseline and 2 years after the end of radiotherapy (RT)
2. Treatment compliance measured by overall radiotherapy treatment time and delays, omissions and reductions to treatment doses (both DDRi and RT) between baseline and the end of trial treatment
3. Best overall response measured as the best response (complete response, partial response or stable disease) recorded until disease progression, using Response Evaluation Criteria In Solid Tumors (RECIST v1.1), by 2 years post-RT
4. Disease control assessed using the Green Criteria by 2 years post-RT. Disease Control includes either the complete disappearance of all evidence of malignant disease or residual radiographic abnormalities assessed by chest CT scan at 3 and 6 months after completion of RT, which then remains stable for an additional 6 months or more and which then qualifies as controlled local disease.
5. Progression-free survival measured using CT scans at 1, 3, 6, 12, 18, and 24 months after the end of RT. Participants who have not progressed at the time of analysis will be censored at the last date they were known to be alive and progression-free.
6. Overall survival measured from patient notes between baseline and 2 years. Participants who have not died at the time of analysis will be censored at the last date they were known to be alive.
7. Changes from baseline in Health Related Quality of Life measured using European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30), IL-73 and IL-74 at baseline, end of RT, 3, 6, 12, 18 and 24 months after the end of RT
8. Objective response rate (ORR) measured using CT scans at 1, 3, 6, 12, 18, and 24 months after the end of RT. ORR is defined as the proportion of patients who have a partial or complete response to therapy. The proportion of patients with evaluable scans that achieve at least a partial response, as defined by RECIST v1.1, will be presented with 95% confidence intervals.
9. Changes in tumour size during and following treatment with DDRi-RT compared to RT alone measured using .. at baseline and 2 years after the end of RT

Exploratory outcomes:
1. Assessment of mutations in components of DDR pathway in archival tumour and cfDNA prior to therapy assessed using using medical tests during treatment and follow up to 2 years after the end of RT
2. Assessment of T cells within the archival tumour specimens assessed using medical tests at baseline and disease progression
3. Changes in cfDNA during and following treatment with DDRi-RT compared to RT alone measured using medical tests during treatment and follow up to 2 years after the end of RT
4. Changes in circulating biomarkers of cardiac and respiratory toxicity measured during and following treatment with DDRi-RT compared to RT alone measured using medical tests during treatment and follow up to during treatment and follow up to 3 months after the end of RT
5. Changes in circulating peripheral T cell sub-sets during and following treatment with DDRi-RT compared to RT alone measured using medical tests at baseline, during treatment and follow up to disease progression
6. Changes in lung parenchyma during and following treatment with DDRi-RT compared to RT alone measured using using medical tests at baseline and 2 years after the end of RT

Overall trial start date

01/11/2019

Overall trial end date

01/09/2026

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Histologically or cytologically confirmed non small cell lung cancer
2. Not suitable for concurrent chemoradiotherapy/surgery due to tumour or patient factors
3. Stage IIB and IIIA/IIIB (TNM 8th Edition) planned to receive radiotherapy (RT) at curative intent doses (i.e. 60 Gy) as part of treatment plan (either with or without induction chemotherapy)
4. Patient considered suitable for radical RT by the local lung cancer multidisciplinary team and a clinical oncologist
5. If chemotherapy has been given previously, the maximum interval between the last day of chemotherapy and the start of RT <8 weeks
6. Age ≥18
7. Life expectancy estimated to be greater than 6 months
8. Performance status (ECOG) 0 or 1
9. MRC dyspnoea score <3
10. Forced expiratory volume in one second (FEV1) ≥40% predicted and diffusing capacity of the lungs for carbon monoxide (DLCO) ≥40% predicted
11. Patient must be fully informed about the study and have signed the informed consent form
12. Patient must be willing and able to comply with the protocol, have mental capacity, and (if relevant) use effective contraception throughout treatment and for 4 months after treatment completion (or comply with more stringent contraceptive requirements if prescribed in the relevant study-arm protocol)
13. Adequate organ function within 28 days prior to confirmation of eligibility and 7 days of study treatment

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 210; UK Sample Size: 210

Participant exclusion criteria

1. Mixed non-small cell and small cell tumours
2. Confirmed progressive disease during induction chemotherapy
3. Participation in a study of an investigational agent or using an investigational device within 4 weeks prior to the anticipated start of treatment
4. Current or previous malignant disease which may impact on a patient’s estimated life expectancy (other than NSCLC)
5. History of interstitial pneumonitis
6. Prior thoracic radiotherapy (excluding patients that have had RT for breast cancer providing that the overlap is minimal as per local investigators discretion or as discussed and agreed by CI as required)
7. Prior treatment with pneumotoxic drugs, e.g. busulfan, bleomycin, within the past year. If prior therapy in lifetime, then exclude if history of pulmonary toxicities from administration. Patients who have received treatment with nitrosoureas (e.g., carmustine, lomustine) in the year before study entry without experiencing lung toxicity are allowed on study.
8. Mean resting corrected QT interval (QTcF) >470 msec obtained from 3 electrocardiograms (ECGs).
9. Received a prior autologous or allogeneic organ or tissue transplantation
10. Patients unable to swallow orally administered medications or chronic gastrointestinal (GI) disease likely to interfere with absorption of IMP in the opinion of the treating investigator (e.g. malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease etc)
11. Grade 2 or higher peripheral sensory neuropathy
12. Known positive test for human immunodeficiency virus (HIV), active hepatitis B or C infection (new test not mandated for trial entry)
13. Positive pregnancy test (at eligibility assessment for women of childbearing potential) or breast-feeding women
14. Patients with persistent toxicities (> CTCAE grade 2) caused by previous cancer therapy, excluding alopecia
15. Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML
16. Major surgery within 2 weeks of confirmation of eligibility
17. Patients considered a poor medical risk by the investigator due to a serious, uncontrolled medical disorder, non-malignant system disease or active uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, uncontrolled hypertension, uncontrolled atrial fibrillation, active bleeding, recent (within 3 months) myocardial infarction, major seizure, active COVID-19, any psychiatric disorder that prohibits obtaining informed consent.
14. Gemcitabine treatment (within 6 months of assessment of eligibility
15. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease (eg, ulcerative colitis or Crohn’s disease), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc)). The following are exceptions to this criterion:
15.1. Patients with vitiligo or alopecia
15.2. Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
15.3. Any chronic skin condition that does not require systemic therapy
15.4. Patients without active disease in the last 5 years at enrolment may be included but only after consultation with the CI/Study arm-lead
15.5. Patients with coeliac disease controlled by diet alone
16. Exclusions as described in the relevant study arm protocol

Recruitment start date

02/11/2020

Recruitment end date

01/11/2024

Locations

Countries of recruitment

United Kingdom

Trial participating centre

The Newcastle Upon Tyne Hospitals NHS Foundation Trust
Freeman Hospital Freeman Road High Heaton
Newcastle Upon Tyne
NE7 7DN
United Kingdom

Trial participating centre

The Christie NHS Foundation Trust
550 Wilmslow Road Withington
Manchester
M20 4BX
United Kingdom

Trial participating centre

Leeds Teaching Hospitals NHS Trust
St. James's University Hospital Beckett Street
Leeds
LS9 7TF
United Kingdom

Trial participating centre

NHS Greater Glasgow and Clyde
J B Russell House Gartnavel Royal Hospital 1055 Great Western Road
Glasgow
G12 0XH
United Kingdom

Trial participating centre

Velindre NHS Trust
Unit 2 Charnwood Court Heol Billingsley
Cardiff
CF15 7QZ
United Kingdom

Trial participating centre

Sheffield Teaching Hospitals NHS Foundation Trust
Northern General Hospital Herries Road
Sheffield
S5 7AU
United Kingdom

Trial participating centre

The Royal Marsden NHS Foundation Trust
Fulham Road
London
SW3 6JJ
United Kingdom

Trial participating centre

University Hospital Southampton NHS Foundation Trust
Southampton General Hospital Tremona Road
Southampton
SO16 6YD
United Kingdom

Trial participating centre

University College London Hospitals NHS Foundation Trust
250 Euston Road
London
NW1 2PG
United Kingdom

Trial participating centre

The Clatterbridge Cancer Centre NHS Foundation Trust
Clatterbridge Hospital Clatterbridge Road Bebington
Wirral
CH63 4JY
United Kingdom

Sponsor information

Organisation

University of Leeds

Sponsor details

-
Leeds
LS2 9JT
United Kingdom
+44 (0)1133434897
c.e.skinner@leeds.ac.uk

Sponsor type

University/education

Website

http://www.leeds.ac.uk/

Funders

Funder type

Government

Funder name

Cancer Research UK

Alternative name(s)

CRUK

Funding Body Type

private sector organisation

Funding Body Subtype

Other non-profit organizations

Location

United Kingdom

Funder name

National Institute for Health Research (NIHR) (UK)

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Funder name

AstraZeneca

Alternative name(s)

AstraZeneca PLC

Funding Body Type

private sector organisation

Funding Body Subtype

For-profit companies (industry)

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Planned publications in a high-impact peer reviewed journal as data emerges, the earliest of which is expected 2025.

IPD sharing statement:
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

31/12/2025

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

2020 protocol in https://pubmed.ncbi.nlm.nih.gov/33072895/

Publication citations

Additional files

Editorial Notes

21/10/2020: Trial’s existence confirmed by the National Institute for Health Research (NIHR).