Non Small Cell Lung Cancer
Conditions
Brief 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.
Detailed description
Radiotherapy is an effective treatment for patients with non-small cell lung cancer (NSCLC) that has not spread beyond the chest area. Radiotherapy is used as a curative treatment but unfortunately for most patients the cancer can return. Radiotherapy kills cells by damaging their DNA. Cells have the ability to repair that damage, especially the cells of normal tissue. If DNA repair can be prevented radiotherapy should be more effective causing the cancer cells to die. The study will use new drugs that affect how cells repair DNA damage, called DNA damage response inhibitors (DDRi). These will be given together with radiotherapy to hopefully improve the effectiveness of radiotherapy, followed by up to 12 months of durvalumab immunotherapy in selected study arms to develop the trial in line with the standard of care for NSCLC. The study will try to find out the most effective and safe dose of this combination treatment. This will be a clinical trial where patients due to have radiotherapy, with the hope of successful treatment that could lead to cure from their cancer or extension of life, will be offered entry onto the study. All patients will receive their radiotherapy, with 3 out of every 4 people also receiving a single DDRi drug alongside this. Both patients and study doctors will know prior to the start of the actual treatment whether a DDRi will be given, and if so which one; no placebos will be used. The patients will be followed closely to check for side effects and to assess how their cancer is responding to treatment. Blood samples will be taken to monitor treatment progress and to try to predict which patients are most likely to benefit from this type of combined treatment.
Interventions
Sponsors
University of Manchester
Newcastle University
University of Oxford
The Leeds Teaching Hospitals NHS Trust
Beatson West of Scotland Cancer Centre
University of Glasgow
Velindre NHS Trust
University College London Hospitals
Queen's University, Belfast
University of Sheffield
University of Leeds
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The trial is designed as a randomised Phase I dose escalation platform study, using the TiTE CRM design to find the RP2D of each DDRi with RT combination. At the time of patient identification the treating centre will be informed of the allocated study arm following a pre-specified prioritisation schedule. Consenting participants will be randomised between DDRi with RT or RT only. Patients are not randomised between experimental arms nor will endpoints be compared between experimental arms. RT only participants will be pooled across the platform to provide contemporary data on toxicity.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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., 60Gy) 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 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, and 6 months for men after treatment completion. Treatment is defined as including the last dose of durvalumab or DDRi in the consolidation phase. 14. Adequate organ function as defined in master protocol. 15. Patient has a body weight of \>30kg. Core
Exclusion criteria
(Radiation Phase) 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. 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. 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, active hepatitis B or C infection. 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 (MDS)/acute myeloid leukaemia (AML) 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 (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. 19. Exclusions as described in the relevant study arm protocol. Patients ineligible for a particular study arm may be considered for entry into an alternative study arm if an appropriate slot is available and they meet all the inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose limiting Toxicities | 13.5 months after start of radiotherapy | Dose-limiting toxicities (DLTs), within 13.5 months of starting radiotherapy, in order to establish the Recommended Phase II Dose (RP2D) of each DDRi-RT combination. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment compliance | End of trial treatment (DDRi and RT) | Treatment compliance will be measured by overall radiotherapy treatment time and delays, omissions and reductions to treatment doses (both DDRi and RT). |
| Best overall response | 2 years after end of RT | Best overall response will be measured as the best response (complete response, partial response or stable disease) recorded until disease progression, reported up to 2 years post-RT. This will be assessed using RECIST 1.1 |
| Disease control | 2 years after end of RT | This will be assessed using the Green Criteria. 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. |
| Progression-free survival | 2 years post-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 |
| Overall survival | 2 years post-RT | Participants who have not died at the time of analysis will be censored at the last date they were known to be alive |
| Changes in Health Related Quality of Life | 2 years after end of RT | Health Related Quality of Life will be determined using EORTC QLQ-C30, IL-73 and IL-74 |
| Objective response rate | 2 years after end of RT | Objective response rate (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(31), will be presented with 95% confidence intervals. |
| Changes in tumour size during and following treatment with DDRi-RT compared to RT alone. | 2 years after end of RT | — |
| Safety and toxicity | 2 years after end of RT | Safety will be reported based on the occurrence of SAEs, SARs and SUSARs. Toxicity will be reported based on adverse events, as graded by CTCAE V5.0, and determined by routine clinical assessments at each centre. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Assessment of mutations in components of DDR pathway in archival tumour and cfDNA prior to therapy | 2 years after end of RT | Exploratory endpoint |
| Assessment of T cells within the archival tumour specimens | 2 years after end of RT | Exploratory endpoint |
| Changes in cfDNA during and following treatment with DDRi-RT compared to RT alone. | 2 years after end of RT | Exploratory endpoint |
| Changes in circulating biomarkers of cardiac and respiratory toxicity during and following treatment with DDRi-RT compared to RT alone. | 3 months post end of RT | Exploratory endpoint |
| Changes in circulating peripheral T cell sub-sets during and following treatment with DDRi-RT compared to RT alone. | 2 years after end of RT | Exploratory endpoint |
| Changes in lung parenchyma during and following treatment with DDRi-RT compared to RT alone. | 2 years after end of RT | Exploratory endpoint |
Countries
United Kingdom
Contacts
Primary ContactJamie B Oughton, MPhil
Outcome results
None listed