Clinical trial NCT04550104: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Non Small Cell Lung Cancer
Lead sponsor: University of Leeds
Sponsor class: OTHER
Collaborators: name: University of Manchester
name: Newcastle University
name: University of Oxford
name: The Leeds Teaching Hospitals NHS Trust
name: Beatson West of Scotland Cancer Centre
name: University of Glasgow
name: Velindre NHS Trust
name: University College London Hospitals
name: Queen's University, Belfast
name: University of Sheffield
First posted: 2020-09-16
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

Eligibility 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 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).

Primary outcomes:
measure: Dose limiting Toxicities
timeFrame: 13.5 months after start of radiotherapy
Secondary outcomes:
measure: Safety and toxicity
timeFrame: 2 years after end of RT
measure: Treatment compliance
timeFrame: End of trial treatment (DDRi and RT)
measure: Best overall response
timeFrame: 2 years after end of RT
measure: Disease control
timeFrame: 2 years after end of RT
measure: Progression-free survival
timeFrame: 2 years post-RT
measure: Overall survival
timeFrame: 2 years post-RT
measure: Changes in Health Related Quality of Life
timeFrame: 2 years after end of RT
measure: Objective response rate
timeFrame: 2 years after end of RT
measure: Changes in tumour size during and following treatment with DDRi-RT compared to RT alone.
timeFrame: 2 years after end of RT
Other outcomes:
measure: Assessment of mutations in components of DDR pathway in archival tumour and cfDNA prior to therapy
timeFrame: 2 years after end of RT
measure: Assessment of T cells within the archival tumour specimens
timeFrame: 2 years after end of RT
measure: Changes in cfDNA during and following treatment with DDRi-RT compared to RT alone.
timeFrame: 2 years after end of RT
measure: Changes in circulating biomarkers of cardiac and respiratory toxicity during and following treatment with DDRi-RT compared to RT alone.
timeFrame: 3 months post end of RT
measure: Changes in circulating peripheral T cell sub-sets during and following treatment with DDRi-RT compared to RT alone.
timeFrame: 2 years after end of RT
measure: Changes in lung parenchyma during and following treatment with DDRi-RT compared to RT alone.
timeFrame: 2 years after end of RT
Locations:
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Centre
city: Chelsea
country: United Kingdom
facility: The Royal Marsden Hospital Chelsea
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Leeds
country: United Kingdom
facility: St James's University Hospital
city: London
country: United Kingdom
facility: University College Hospital London
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Newcastle Upon Tyne
country: United Kingdom
facility: Freeman Hospital, Newcastle upon Tyne Hospitals NHS Trust
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
city: Sutton
country: United Kingdom
facility: The Royal Marsden Sutton
Study officials:
affiliation: Newcastle University
name: Alastair Greystoke, MB ChB, MSc, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Manchester
name: Corinne Faivre-Finn, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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.