Overview

CONCORDE is a multi-institution, multi-arm, Phase IB study that will determine the recommended phase II dose (RP2D) and safety profiles of different DNA damage repair inhibitors (DDRis) when given in an open label fashion in combination with fixed dose curative intent radiotherapy (RT) in patients with stage IIB/IIIA/IIIB NSCLC. The RP2D will be evaluated by incorporating the number of observed dose limiting toxicities (DLTs) into a time to event continuous reassessment method (TiTE- CRM) model within each of the experimental arms. 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.

Eligibility

Inclusion Criteria:

1. Histologically or cytologically confirmed NSCLC
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 RT at curative intent doses (i.e. 60Gy) 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 28 days after treatment completion (for women) and 3 months after treatment completion (for men) (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 as defined in master protocol

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
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) (QTc interval will be calculated using Fridericia's formula).
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.
18. 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:
    1. Patients with vitiligo or alopecia.
    2. Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
    3. Any chronic skin condition that does not require systemic therapy.
    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.
    5. Patients with coeliac disease controlled by diet alone.
19. Exclusions as described in the relevant study arm protocol