A platform study of DNA damage response inhibitors in combination with conventional radiotherapy in non small cell lung cancer
Non small cell lung cancer
Current intervention as of 12/01/2024: 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 the 'radiation phase' in patients with locally advanced non-small-cell lung cancer (NSCLC). In selected cohorts a second phase of treatment known as the 'consolidation phase' eligible participants will receive up to 12 months of consolidation durvalumab treatment with or without DDRi depending on randomisation and study-
Current inclusion criteria as of 12/01/2024: Core inclusion criteria (radiation phase): 1. Histologically or cytologically confirmed NSCLC (patients where the local MDT agree the diagnosis is NSCLC after review of the available pathology and imaging at MDT can be enrolled after discussion with the CI) 2. Not suitable for concurrent chemoradiotherapy/surgery due to tumour or patient factors 3. Stage IIB and III (TNM 8th Edition) 4. Planned to receive RT at curative intent doses (i.e. 60 Gy) as part of treatment plan (either with or without induction chemotherapy) 5. Patient considered suitable for radical RT by the local lung cancer multidisciplinary team and a clinical oncologist 6. If chemotherapy has been given previously, the maximum interval between the last day of chemotherapy and the start of RT <10 weeks 7. Age ≥18 years 8. Life expectancy estimated to be greater than 6 months 9. Karnofsky Performance status ≥70 10. MRC dyspnoea score <3 11. Forced expiratory volume in one second (FEV1) ≥35% predicted and diffusing capacity of the lungs for carbon monoxide (DLCO or TLCO) ≥35% predicted 12. Patient must be fully informed about the study and have signed the informed consent form 13. 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 for women of childbearing potential (WOCBP)/6 months for men after trial treatment completion. Treatment is defined as including the last dose of durvalumab or DDRi in the consolidation phase (or comply with more stringent contraceptive requirements if prescribed in the relevant study-arm protocol). 14. Adequate organ function within 28 days prior to confirmation of eligibility and 7 days of study treatment 15. Patient has body weight of >30 kg Inclusion criteria (consolidation phase): The following eligibility criteria must be met before participants can receive durvalumab +/- DDRi in the consolidation phase. Part
Current exclusion criteria as of 31/03/2023: Core exclusion criteria (radiation phase): 1. Mixed non-small cell and small cell tumours 2. Confirmed progressive disease according to RECIST 1.1 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 (to include diffuse alveolar damage, non-malignant causes of pneumonitis, acute respiratory distress syndrome, alveolitis, cryptogenic organising pneumonia, obliterative bronchiolitis, non-malignant causes of pulmonary fibrosis, usual interstitial pneumonia, interstitial pulmonary fibrosis and connective tissue disorder (scleroderma, systemic lupus erythematosus)) 6. Prior thoracic radiotherapy (excluding patients that have had RT for breast cancer or lung SABR to the contralateral lung providing that the overlap is minimal as per local investigator's discretion or as discussed and agreed by CI/Study Arm Lead contacted via CTRU 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) (QTc interval will be calculated using Fridericia’s formula). Multiple ECGs are only required if 1st ECG QTcF >470 msec. ECGs should be at least 5 minutes apart. 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