A Platform Study of DNA Damage Response Inhibitors in Combination With Conventional Radiotherapy in Non Small Cell Lung Cancer

Who is this study for? Patients with non small cell lung cancer
Status: Recruiting
Location: See all (11) locations...
Intervention Type: Drug, Radiation
Study Type: Interventional
Study Phase: Phase 1
SUMMARY

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, followed by up to 12 months of consolidation durvalumab immunotherapy in selected study arms. 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
Participation Requirements
Sex: All
Minimum Age: 18
Healthy Volunteers: f
View:

• 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).

• Not suitable for concurrent chemoradiotherapy/surgery due to tumour or patient factors

• Stage IIB and III (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).

• Patient considered suitable for radical RT by the local lung cancer multidisciplinary team and a clinical oncologist.

• If chemotherapy has been given previously, the maximum interval between the last day of chemotherapy and the start of RT \<10 weeks.

• Age ≥18

• Life expectancy estimated to be greater than 6 months.

• Karnofsky Performance status ≥70.

⁃ MRC dyspnoea score \<3.

⁃ Forced expiratory volume in one second (FEV1) ≥35% predicted and diffusing capacity of the lungs for carbon monoxide (DLCO or TLCO) ≥35% predicted.

⁃ Patient must be fully informed about the study and have signed the informed consent form.

⁃ 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, and 6 months for men after treatment completion. Treatment is defined as including the last dose of durvalumab or DDRi in the consolidation phase.

⁃ Adequate organ function as defined in master protocol.

⁃ Patient has a body weight of \>30kg.

‣ Core Exclusion Criteria (Radiation Phase)

• Mixed non-small cell and small cell tumours.

• Confirmed progressive disease during induction chemotherapy.

• Participation in a study of an investigational agent or using an investigational device within 4 weeks prior to the anticipated start of treatment.

• Current or previous malignant disease which may impact on a patient's estimated life expectancy (other than NSCLC).

• History of interstitial pneumonitis.

• Prior thoracic radiotherapy.

• 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.

• Mean resting corrected QT interval (QTcF) \>470 msec obtained from 3 electrocardiograms.

• Received a prior autologous or allogeneic organ or tissue transplantation.

⁃ 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.).

⁃ Grade 2 or higher peripheral sensory neuropathy.

⁃ Known positive test for human immunodeficiency virus, active hepatitis B or C infection.

⁃ Positive pregnancy test (at eligibility assessment for women of childbearing potential) or breast-feeding women.

⁃ Patients with persistent toxicities (\>CTCAE grade 2) caused by previous cancer therapy, excluding alopecia.

⁃ Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML.

⁃ Major surgery within 2 weeks of confirmation of eligibility.

⁃ 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.

⁃ Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.

• A minimum of 4 and a maximum of 8 weeks\* have elapsed following completion of RT

• Any toxicities from RT have resolved to grade 1. If patient has pneumonitis following RT treatment, this must be asymptomatic (grade 1). If pneumonitis is ≥2 or requiring steroids, then participant is not eligible

• Karnofsky Performance status ≥70

• The laboratory requirements set out in Table 1 of the master protocol are met

• Patient has no known hypersensitivity to the excipients of durvalumab

• Patient has body weight of \>30kg \*Investigators should ideally aim to start consolidation treatment within 6 weeks, following the receipt of the CT scan results to rule out progression.

‣ Core Exclusion Criteria (Consolidation Phase)

• Progressive disease during RT or at the end of RT treatment response assessment.

• Participant declines treatment in the consolidation phase.

• Patients who have received prior anti-PD-1 or anti PD-L1 treatment.

• Major surgery within 4 weeks of confirmation of eligibility for consolidation phase.

• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab.

• Patients considered a poor medical risk by the investigator due to a serious, uncontrolled medical disorder, non-malignant system disease, active GI infection or active uncontrolled infection.

• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease e.g., colitis or Crohn's disease), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc).

Locations
Other Locations
United Kingdom
Belfast City Hospital
RECRUITING
Belfast
Addenbrooke's Hospital
RECRUITING
Cambridge
Velindre Cancer Centre
RECRUITING
Cardiff
The Royal Marsden Hospital Chelsea
RECRUITING
Chelsea
Western General Hospital
RECRUITING
Edinburgh
St James's University Hospital
RECRUITING
Leeds
University College Hospital London
RECRUITING
London
The Christie NHS Foundation Trust
RECRUITING
Manchester
Freeman Hospital, Newcastle upon Tyne Hospitals NHS Trust
RECRUITING
Newcastle Upon Tyne
Weston Park Hospital
RECRUITING
Sheffield
The Royal Marsden Sutton
RECRUITING
Sutton
Contact Information
Primary
Jamie B Oughton, MPhil
CTRU_CONCORDE@Leeds.ac.uk
0113 343 1494
Time Frame
Start Date: 2021-03-17
Estimated Completion Date: 2028-03
Participants
Target number of participants: 200
Treatments
Active_comparator: Radiotherapy only
Experimental: Olaparib + radiotherapy
Experimental: AZD1390 + radiotherapy
Experimental: Ceralasertib (AZD6738) + radiotherapy + Consolidation durvalumab
This study arm will include up to 12 months of consolidation durvalumab for eligible participants following the completion of radiotherapy +/- DDRi.
Experimental: AZD5305 + radiotherapy + Consolidation durvalumab
This study arm will include up to 12 months of consolidation durvalumab for eligible participants following the completion of radiotherapy +/- DDRi.
Active_comparator: RT + consolidation durvalumab
Experimental: Arm D - did not proceed
Arm D - did not proceed
Sponsors
Collaborators: Velindre NHS Trust, Newcastle University, The Leeds Teaching Hospitals NHS Trust, Beatson West of Scotland Cancer Centre, University of Sheffield, University of Glasgow, University of Manchester, University College London Hospitals, Queen's University, Belfast, University of Oxford
Leads: University of Leeds

This content was sourced from clinicaltrials.gov

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