Targeted Stem Cells Expressing TRAIL as a Therapy for Lung Cancer

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.

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.

Eligibility Criteria:
1. Inoperable stage IIIb/IV histologically/cytologically confirmed lung adenocarcinoma
2. EGFR mutation and EML4-ALK translocation negative
3. Patients with evaluable but unmeasurable disease can be included in the phase I study, but disease must be measurable (CT scan must be within 28 days of randomisation) to be included in the phase II study
4. ECOG performance status of 0 or 1
5. Life expectancy of at least 12 weeks
6. Age at least 18 years
7. Adequate haematological status:

   1. Haemoglobin ≥100g/L
   2. Neutrophil count ≥1.5 x 109/L
   3. Platelets ≥100 x 109 /L
8. Adequate organ function:

   1. Bilirubin ≤1.5 x ULN
   2. ALT or AST ≤3 x ULN (≤5 x ULN is acceptable with liver metastases)
   3. Creatinine clearance ≥ 60 ml/min (C\&G or EDTA)
9. Negative pregnancy test for female patients of child bearing potential.
10. Male subjects and women of child bearing potential must agree to use an acceptable method of birth control for the duration of the trial and for 12 months after the last trial treatment administration.
11. Ability to understand and provide written informed consent
12. Ability to comply with the requirements of the protocol

Exclusion Criteria:

1. Prior chemotherapy, hormonal therapy, radiotherapy (including palliative radiotherapy), immunotherapy or treatment with an investigational drug for advanced NSCLC.
2. Any surgical procedure in the previous 6 weeks prior to registration/ randomisation
3. Known respiratory failure with baseline resting SpO2 \<88%
4. Long term oxygen therapy
5. Severe intercurrent infection
6. Active or infected wounds
7. Yellow fever vaccination within 30 days prior to trial registration/randomisation
8. Subject has known sensitivity to any of the trial drugs to be administered during the trial.
9. Any contraindication to the administration and use of cisplatin, pemetrexed, vitamin B12 or folic acid
10. Prior malignancy other than NSCLC (except if the tumour was a non-melanoma skin tumour that has been completely excised or in situ cervix carcinoma), unless have been treated with curative intent with no evidence of disease for \> 3 years
11. Evidence of symptomatic brain metastases requiring treatment
12. Myocardial infarction, or unstable or uncontrolled disease or condition related to or impacting cardiac function (e.g., unstable angina, congestive heart failure \[New York Heart Association \> class II\]) within 1 year of enrolment
13. Known inflammatory bowel disease
14. Known hepatitis B or C infection, human immunodeficiency virus (HIV)-positive patients
15. Pregnant women or those who are breast feeding
16. Other medications, severe acute/chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with trial participation or trial drug administration, or may interfere with the interpretation of trial results, and in the judgment of the investigator would make the patient inappropriate for entry into this trial