A Platform Study of Novel Agents in Combination With Radiotherapy in NSCLC (CONCORDE)

• ClinicalTrials.gov Identifier: NCT04550104
• Recruitment Status: Not yet recruiting
• First Posted: September 16, 2020
• Last Update Posted: September 16, 2020
• Sponsor: University of Leeds
• Collaborators: 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
• Information provided by (Responsible Party): University of Leeds

Tracking Information

• First Submitted Date: June 24, 2020
• First Posted Date: September 16, 2020
• Last Update Posted Date: September 16, 2020
• Estimated Study Start Date: September 2020
• Estimated Primary Completion Date: March 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 8, 2020)

Dose limiting Toxicities [ Time Frame: 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.

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: September 8, 2020)

• Safety and toxicity [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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. [ Time Frame: 2 years after end of RT ]

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: September 8, 2020)

• Assessment of mutations in components of DDR pathway in archival tumour and cfDNA prior to therapy [ Time Frame: 2 years after end of RT ]
  Exploratory endpoint
• Assessment of T cells within the archival tumour specimens [ Time Frame: 2 years after end of RT ]
  Exploratory endpoint
• Changes in cfDNA during and following treatment with DDRi-RT compared to RT alone. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 2 years after end of RT ]
  Exploratory endpoint
• Changes in lung parenchyma during and following treatment with DDRi-RT compared to RT alone. [ Time Frame: 2 years after end of RT ]
  Exploratory endpoint

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: A Platform Study of Novel Agents in Combination With Radiotherapy in NSCLC
• Official Title: A Platform Study of DNA Damage Response Inhibitors in Combination With Conventional Radiotherapy in Non Small Cell Lung Cancer
• 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. 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. The study will try to find out the most effective and safe dose of this combination treatment. There 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.

• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
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.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: 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
• Drug: AZD1390
  Oral tablet
• Drug: TBD Compound 1
• Drug: TBD Compound 2
• Drug: TBD Compound 3

Study Arms

• Active Comparator: Radiotherapy only
  Intervention: Radiation: Radiotherapy
• Experimental: Olaparib + radiotherapy
  Interventions:

  • Radiation: Radiotherapy
  • Drug: Olaparib Oral Tablet [Lynparza]
• Experimental: AZD1390 + radiotherapy
  Interventions:

  • Radiation: Radiotherapy
  • Drug: AZD1390
• Experimental: TBD1 + radiotherapy
  DDRi to be decided
  Interventions:

  • Radiation: Radiotherapy
  • Drug: TBD Compound 1
• Experimental: TBD2 + radiotherapy
  DDRi to be decided
  Interventions:

  • Radiation: Radiotherapy
  • Drug: TBD Compound 2
• Experimental: TBD3 + radiotherapy
  DDRi to be decided
  Interventions:

  • Radiation: Radiotherapy
  • Drug: TBD Compound 3

• Publications *: 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.

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: September 8, 2020): 200
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 2027
• Estimated Primary Completion Date: March 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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. Gemcitabine treatment (within 6 months of assessment of eligibility)

19. 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.
20. Exclusions as described in the relevant study arm protocol

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Jamie B Oughton, MPhil; 0113 343 1494; CTRU_CONCORDE@Leeds.ac.uk

• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT04550104
• Other Study ID Numbers: MO20/118073; 2020-000206-28 ( EudraCT Number ); 282001 ( Other Identifier: IRAS ); A28890 ( Other Grant/Funding Number: Cancer Research UK )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: University of Leeds
• Study Sponsor: University of Leeds

Collaborators

• 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

Investigators

• Principal Investigator: Alastair Greystoke, MB ChB, MSc, PhD; Newcastle University
• Principal Investigator: Corinne Faivre-Finn, MD, PhD; University of Manchester

• PRS Account: University of Leeds
• Verification Date: September 2020