A Platform Study of Novel Agents in Combination With Radiotherapy in NSCLC

Non Small Cell Lung Cancer Clinical Trial

— CONCORDE  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04550104
• Other study ID #: MO20/118073
• Secondary ID: 2020-000206-2828
• Status: Recruiting
• Phase: Phase 1
• Start date: March 17, 2021
• Est. completion date: March 2028

Study information

• Verified date: February 2024
• Source: University of Leeds
• Contact: Jamie B Oughton, MPhil
• Phone: 0113 343 1494
• Email: CTRU_CONCORDE[@]Leeds.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: March 2028
• Est. primary completion date: April 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 exclusion criteria for that arm. This will need to be discussed with CTRU and the patient will be required to reconsent using the appropriate study arm PIS/ICF. Core Inclusion Criteria (Consolidation Phase)

1. A minimum of 4 and a maximum of 8 weeks* have elapsed following completion of RT

2. 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

3. Karnofsky Performance status =70

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

5. Patient has no known hypersensitivity to the excipients of durvalumab

6. 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)

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

2. Participant declines treatment in the consolidation phase.

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

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

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

6. 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.

7. 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).

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non Small Cell Lung Cancer

Intervention

Radiation:
• Radiotherapy
Administered as 30 fractions of 2Gy. Total 60 60Gy. Administered once daily monday to friday.

Drug:
• Olaparib Oral Tablet [Lynparza]
Oral tablet
• AZD1390
Oral tablet
• Ceralasertib
Oral Tablet
• AZD5305
Oral Tablet
• Durvalumab
1500mg iv infusion

Locations

Country	Name	City	State
United Kingdom	Belfast City Hospital	Belfast
United Kingdom	Addenbrooke's Hospital	Cambridge
United Kingdom	Velindre Cancer Centre	Cardiff
United Kingdom	The Royal Marsden Hospital Chelsea	Chelsea
United Kingdom	Western General Hospital	Edinburgh
United Kingdom	St James's University Hospital	Leeds
United Kingdom	University College Hospital London	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Freeman Hospital, Newcastle upon Tyne Hospitals NHS Trust	Newcastle Upon Tyne
United Kingdom	Weston Park Hospital	Sheffield
United Kingdom	The Royal Marsden Sutton	Sutton

Sponsors (11)

Lead Sponsor	Collaborator
University of Leeds	Beatson West of Scotland Cancer Centre, Newcastle University, Queen's University, Belfast, The Leeds Teaching Hospitals NHS Trust, University College London Hospitals, University of Glasgow, University of Manchester, University of Oxford, University of Sheffield, Velindre NHS Trust

Country where clinical trial is conducted

United Kingdom, 

References & Publications (2)

Faivre-Finn C, Brown S, Ryan A, Greystoke A; CONCORDE Investigators. The UK at the Forefront of Innovative Drug-Radiotherapy Combination Clinical Trials: Introducing the CONCORDE Platform. Clin Oncol (R Coll Radiol). 2020 Jun;32(6):358-362. doi: 10.1016/j.clon.2020.02.003. Epub 2020 Feb 24. No abstract available. — View Citation

Walls GM, Oughton JB, Chalmers AJ, Brown S, Collinson F, Forster MD, Franks KN, Gilbert A, Hanna GG, Hannaway N, Harrow S, Haswell T, Hiley CT, Hinsley S, Krebs M, Murden G, Phillip R, Ryan AJ, Salem A, Sebag-Montefoire D, Shaw P, Twelves CJ, Walker K, Young RJ, Faivre-Finn C, Greystoke A. CONCORDE: A phase I platform study of novel agents in combination with conventional radiotherapy in non-small-cell lung cancer. Clin Transl Radiat Oncol. 2020 Sep 22;25:61-66. doi: 10.1016/j.ctro.2020.09.006. eCollection 2020 Nov. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Assessment of mutations in components of DDR pathway in archival tumour and cfDNA prior to therapy	Exploratory endpoint	2 years after end of RT
Other	Assessment of T cells within the archival tumour specimens	Exploratory endpoint	2 years after end of RT
Other	Changes in cfDNA during and following treatment with DDRi-RT compared to RT alone.	Exploratory endpoint	2 years after end of RT
Other	Changes in circulating biomarkers of cardiac and respiratory toxicity during and following treatment with DDRi-RT compared to RT alone.	Exploratory endpoint	3 months post end of RT
Other	Changes in circulating peripheral T cell sub-sets during and following treatment with DDRi-RT compared to RT alone.	Exploratory endpoint	2 years after end of RT
Other	Changes in lung parenchyma during and following treatment with DDRi-RT compared to RT alone.	Exploratory endpoint	2 years after end of RT
Primary	Dose limiting Toxicities	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.	13.5 months after start of radiotherapy
Secondary	Safety and toxicity	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.	2 years after end of RT
Secondary	Treatment compliance	Treatment compliance will be measured by overall radiotherapy treatment time and delays, omissions and reductions to treatment doses (both DDRi and RT).	End of trial treatment (DDRi and RT)
Secondary	Best overall response	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	2 years after end of RT
Secondary	Disease control	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.	2 years after end of RT
Secondary	Progression-free survival	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	2 years post-RT
Secondary	Overall survival	Participants who have not died at the time of analysis will be censored at the last date they were known to be alive	2 years post-RT
Secondary	Changes in Health Related Quality of Life	Health Related Quality of Life will be determined using EORTC QLQ-C30, IL-73 and IL-74	2 years after end of RT
Secondary	Objective response rate	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.	2 years after end of RT
Secondary	Changes in tumour size during and following treatment with DDRi-RT compared to RT alone.		2 years after end of RT