Doxycycline Use in Lung CancEr (DULCE)

INTERVENTION: Doxycycline 100 mg tablet, 100 mg oral twice a day on the first day followed by 100 mg oral once a day for the next 27 days. Treatment period is 28 days total. Participants will receive doxycycline alongside their standard of care lung cancer treatment which will be determined prior to commencing on the study by their treating oncologist according to the local cancer treatment protocols and must include targeted therapy. Adherence to the study intervention will be monitored through the completion of weekly patient diaries to record doses taken as well as final accountability of tablets returned. CONDITION: Cancer ‐ Lung ‐ Non small cell Lung cancer; ; Lung cancer PRIMARY OUTCOME: To determine the efficacy of doxycycline or placebo in conjunction with standard of care in participants with adenocarcinoma[The primary endpoint is a hierarchical composite endpoint of the ‘loser’ working through 5 comparisons sequentially. The 5 comparisons are:; Death, (or the earlier time to death if both participants in that comparison die). Vital status will be collected from the medical records or other linked data sources.; Response (or the earlier time to progression if response is the same for both participants in the comparison) assessed by clinical assessment based on routine test results (including imaging and blood tests), ; Toxicity (equal to Grade 4, or first person to experience that toxicity if both participants in the comparison have the same level of toxicity) assessed through adverse events and serious adverse events reported by the investigator and symptoms of interest reported by the participants in the weekly diaries.; Hospitalisation (and longer duration of hospitalisations if both participants in that comparison experience hospitalisations) assessed using participant‐reported outcomes tool (electronic, by phone, or by paper diary).; Delay to scheduled targeted therapy (or the earlier the event occurs for both participants in a comparison where both experience it) assessed through review of the medical records.; A ‘tie’ occurs if there are no differences after the fifth comparison. 12 months after randomisation (+/‐ 28 days)] SECONDARY OUTCOME: To describe medical resource utilisation of participants treated with doxycycline or placebo in conjunction with standard of care[Hospitalisation and unplanned health care contact collected using participant‐reported outcomes tool (electronic, by phone, or by paper diary) at weekly intervals until day 28, then at monthly intervals thereafter up to 12 months post‐randomisation. Day 28 (+/‐ 2 days), 3 months and then 12 months after randomisation (+/‐ 28 days)] To describe the safety and tolerability of doxycycline or placebo in conjunction with standard of care[Assessment of adverse events using National Cancer Institute (NCI) common Terminology Criteria for Adverse Events (CTC AE) criteria Day 1, day 28 (+/‐ 2 days), 3 months and then 12 months after randomisation (+/‐ 28 days)] To determine progression free survival of participants treated with doxycycline or placebo in conjunction with standard of care[Response to treatment measured by clinical assessment based on routine test results (including imaging and blood tests), this also includes death from any cause ; Day 35 (+/‐ 3 days), 3 months and then 12 months after randomisation (+/‐ 28 days)] To determine response to treatment for participants treated with doxycycline or placebo in conjunction with standard of care[Response to cancer treatment as assessed by the treating clinical oncology team. Treatment response will be assessed as per local guidelines using imaging (such as CT, MRI and/or FDG‐PET scans) and blood tests. Day 28 (+/‐ 2 days), 3 months and then 12 months after randomisation (+/‐ 28 days)] To determine the effects of doxycycline or placebo in conjunction with standard of care on the gut microbiome[Microbiome analysis from stool sample Day 1, day 28 (+/‐ 2 days), 3 months after randomisation] To determine the effects of doxycycline or placebo in conjunction with standard of care on the oral microbiome[Microbiome analysis from buccal sweep Day 1, day 28 (+/‐ 2 days), 3 months after randomisation] INCLUSION CRITERIA: Signed informed consent Participant must be 18 years of age or over, at the time of signing the informed consent Participants who have a diagnosis of adenocarcinoma of the lung. The adenocarcinoma is metastatic. The participant has commenced targeted therapy (± chemotherapy) within the previous 7 to 35 days and is continuing on that therapy at the time of commencement of the trial medication. Willing to use (or the participant’s partner is willing to use) contraception as per local regulations for methods of contraception in people undergoing targeted anticancer therapies. A woman of childbearing potential must be willing to undergo a highly sensitive pregnancy test urine or serum (as required by local regulations) within 24 hours before the first dose of study intervention Able to complete the patient diary