Combining new drugs with radiotherapy for non-small cell lung cancer

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

This study is testing if new drugs that help repair DNA damage can make radiotherapy more effective for people with advanced non-small cell lung cancer.

Quick facts

• Phase: PHASE1
• Study type: Interventional
• Enrollment: 200 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University of Leeds (other)
• Drugs / interventions: durvalumab, chemotherapy, Radiation, immunotherapy
• Locations: 14 sites (Belfast and 13 other locations)
• Trial ID: NCT04550104 on ClinicalTrials.gov

What this trial studies

This study evaluates the safety and effectiveness of novel DNA damage repair inhibitors (DDRi) in combination with radiotherapy for patients with stage IIB/IIIA/IIIB non-small cell lung cancer (NSCLC). It aims to determine the recommended phase II dose (RP2D) of these agents when administered alongside curative intent radiotherapy, followed by up to 12 months of durvalumab immunotherapy in selected arms. The study employs a continuous reassessment method to inform dose escalation decisions based on observed toxicities. Patients will receive radiotherapy, with a subset also receiving a DDRi, and will be closely monitored for side effects and treatment outcomes.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with histologically confirmed stage IIB or III NSCLC who are not suitable for concurrent chemoradiotherapy or surgery.

Not a fit: Patients with advanced NSCLC beyond stage III or those who are not candidates for radical radiotherapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could enhance the effectiveness of radiotherapy, potentially leading to better treatment outcomes and prolonged survival for patients with NSCLC.

How similar studies have performed: Other studies have shown promise in using DNA damage repair inhibitors in conjunction with radiotherapy, suggesting potential for success in this novel approach.

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).

Where this trial is running

Belfast and 13 other locations

• Belfast City Hospital — Belfast, United Kingdom (RECRUITING)
• Birmingham Heartlands Hospital — Birmingham, United Kingdom (RECRUITING)
• Addenbrooke's Hospital — Cambridge, United Kingdom (RECRUITING)
• Velindre Cancer Centre — Cardiff, United Kingdom (RECRUITING)
• The Royal Marsden Hospital Chelsea — Chelsea, United Kingdom (RECRUITING)
• Western General Hospital — Edinburgh, United Kingdom (RECRUITING)
• St James's University Hospital — Leeds, United Kingdom (RECRUITING)
• The Clatterbridge Cancer Centre — Liverpool, United Kingdom (RECRUITING)
• St Bartholomew's Hospitals — London, United Kingdom (RECRUITING)
• University College Hospital London — London, United Kingdom (RECRUITING)
• The Christie NHS Foundation Trust — Manchester, United Kingdom (RECRUITING)
• Freeman Hospital, Newcastle upon Tyne Hospitals NHS Trust — Newcastle upon Tyne, United Kingdom (RECRUITING)
• Weston Park Hospital — Sheffield, United Kingdom (RECRUITING)
• The Royal Marsden Sutton — Sutton, United Kingdom (RECRUITING)

Study contacts

• Principal investigator: Alastair Greystoke, MB ChB, MSc, PhD — Newcastle University
• Study coordinator: Jamie B Oughton, MPhil

Conditions: Non Small Cell Lung Cancer