A Platform Study of Novel Agents in Combination With Radiotherapy in NSCLC
- Conditions
- Non Small Cell Lung Cancer
- Interventions
- Registration Number
- NCT04550104
- Lead Sponsor
- University of Leeds
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 200
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Olaparib + radiotherapy Radiotherapy - Olaparib + radiotherapy Olaparib Oral Tablet [Lynparza] - Radiotherapy only Radiotherapy - AZD1390 + radiotherapy Radiotherapy - AZD1390 + radiotherapy AZD1390 - Ceralasertib (AZD6738) + radiotherapy + Consolidation durvalumab Radiotherapy This study arm will include up to 12 months of consolidation durvalumab for eligible participants following the completion of radiotherapy +/- DDRi. Ceralasertib (AZD6738) + radiotherapy + Consolidation durvalumab Ceralasertib This study arm will include up to 12 months of consolidation durvalumab for eligible participants following the completion of radiotherapy +/- DDRi. Ceralasertib (AZD6738) + radiotherapy + Consolidation durvalumab Durvalumab This study arm will include up to 12 months of consolidation durvalumab for eligible participants following the completion of radiotherapy +/- DDRi. AZD5305 + radiotherapy + Consolidation durvalumab Radiotherapy This study arm will include up to 12 months of consolidation durvalumab for eligible participants following the completion of radiotherapy +/- DDRi. AZD5305 + radiotherapy + Consolidation durvalumab Durvalumab This study arm will include up to 12 months of consolidation durvalumab for eligible participants following the completion of radiotherapy +/- DDRi. RT + consolidation durvalumab Radiotherapy - RT + consolidation durvalumab Durvalumab - Arm D - did not proceed Radiotherapy Arm D - did not proceed AZD5305 + radiotherapy + Consolidation durvalumab AZD5305 This study arm will include up to 12 months of consolidation durvalumab for eligible participants following the completion of radiotherapy +/- DDRi.
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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
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.
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.
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).
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
Changes in tumour size during and following treatment with DDRi-RT compared to RT alone. 2 years after end of RT
Trial Locations
- Locations (11)
Addenbrooke's Hospital
🇬🇧Cambridge, United Kingdom
Belfast City Hospital
🇬🇧Belfast, United Kingdom
Freeman Hospital, Newcastle upon Tyne Hospitals NHS Trust
🇬🇧Newcastle Upon Tyne, United Kingdom
Velindre Cancer Centre
🇬🇧Cardiff, United Kingdom
The Royal Marsden Hospital Chelsea
🇬🇧Chelsea, United Kingdom
St James's University Hospital
🇬🇧Leeds, United Kingdom
Western General Hospital
🇬🇧Edinburgh, United Kingdom
University College Hospital London
🇬🇧London, United Kingdom
The Christie NHS Foundation Trust
🇬🇧Manchester, United Kingdom
The Royal Marsden Sutton
🇬🇧Sutton, United Kingdom
Weston Park Hospital
🇬🇧Sheffield, United Kingdom