Phase 1:~A first-in-human, single-centre, accelerated, dose de-escalation design with a modified Bayesian continual reassessment method (mCRM) to estimate the recommended Phase II dose (RP2D) of MSCTRAIL in combination with pemetrexed/cisplatin chemotherapy.~The first cohort of three patients will receive cisplatin 75mg/m2 and pemetrexed 500mg/m2 on day 1 followed by the highest dose of MSCTRAIL, 4x10^8 cells, on day 2. This schedule will be repeated every 21 days until 3 cycles of treatment have been delivered. It is expected that patients will receive 4-6 cycles of cisplatin/pemetrexed in total and may continue with maintenance pemetrexed thereafter.~If there are no DLTs within the first cohort then a subsequent expansion cohort will receive the same regimen of cisplatin/pemetrexed and MSCTRAIL and data from this expansion cohort will be used to determine the recommended phase 2 dose (RP2D). Between 6 and 12 patients will be enrolled into phase I of the trial depending on the number of cohorts assessed.~Phase 2:~A multicentre, randomised, placebo controlled trial comparing MSCTRAIL at the RP2D and pemetrexed/cisplatin chemotherapy versus pemetrexed/cisplatin chemotherapy alone.~Patients will be randomised 1:1 between the intervention and control arm. Patients entering the intervention arm will receive cisplatin 75mg/m2 and pemetrexed 500mg/m2 on day 1 followed by MSCTRAIL at the RP2D on day 2. This schedule will be repeated after 21 days for 3 cycles.~Patients in the control arm with receive cisplatin 75mg/m2 and pemetrexed 500mg/m2 on day 1 and placebo on day 2. This will be repeated after 21 days for up to 3 cycles.~At this point patients will receive a further 1-3 cycles of pemetrexed/ cisplatin alone. They may then be eligible for maintenance pemetrexed according to clinical response as directed by their Oncologist in line with local standard of care.
The aim of the study is to evaluate the safety and anti-tumour activity of MSCTRAIL in addition to chemotherapy in metastatic Non-small cell lung cancer (NSCLC) patients in a Phase I/II clinical trial.~In the phase I study, patients will receive cisplatin and pemetrexed on day one followed by MSCTRAIL cells on day 2. This constitutes one cycle of treatment. Each patient will receive 3 cycles of treatment at 21 day intervals. The aim of phase 1 is to estimate the recommended Phase II dose (RP2D) of MSCTRAIL in combination with pemetrexed/cisplatin chemotherapy.~During the phase II study patients will be randomised to either the intervention or the control arm of the study. All patients in both arms will receive cisplatin and pemetrexed on day one of treatment. Patients randomised to the intervention arm will receive the recommended dose of MSCTRAIL from Phase I on day 2 whilst those in the control arm will receive a placebo. As this is a double blind trial both patients and the clinical team will not know whether they are receiving MSCTRAIL or a placebo product. The aim of phase 2 is to assess tolerability and preliminary efficacy of MSCTRAIL in combination with pemetrexed/cisplatin chemotherapy.