Lung Cancer Clinical Trials

⁃ Part A and B1/2:

⁃ Histologically or cytologically confirmed advanced solid tumours, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient.

⁃ Part B1:

⁃ Histologically or cytologically confirmed advanced solid tumours, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient AND:

‣ Patients with any tumour type that previously responded to a PD-1 or PD-L1 inhibitor and subsequently progressed (defined as secondary resistance to PD-1/PD-L1 inhibitors ie CR or PR by RECIST, or SD by RECIST for 6 months' duration) or/

‣ Patients with microsatellite-instability-high (MSI-High) tumours, provided they have been defined by validated assays or patients with deficient mismatch repair (dMMR) defined by immunohistochemistry, who have previously received and have progressed on a PD-1 or PD-L1 inhibitor (primary resistance to PD-1/PD-L1 inhibitors) or/

‣ Patients with other solid tumour types who could benefit, based on emerging anti-tumour activity data, from combination therapy with a demethylating agent and PD-1 or PD-L1 inhibitors, in consultation with any other relevant preclinical or clinical data, at the Chief Investigator's discretion.

⁃ Part B2:

⁃ Patients with histologically or cytologically confirmed NSCLC previously treated with PD-1 or PD-L1 inhibitor for advanced or metastatic disease.

⁃ Life expectancy of at least 12 weeks.

⁃ Eastern Co-operative Oncology Group (ECOG) performance status of 0-1 with no significant deterioration over the previous 2 weeks (Appendix 1).

⁃ Evaluable or measurable disease as assessed by RECIST 1.1.

⁃ Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -7 to Day 1) prior to administration of any investigational medicinal product.

∙ Haemoglobin (Hb) ≥ 9.0 g/dL

‣ Absolute neutrophil count ≥ 1.5 x 109/L

‣ Platelet count ≥ 100 x 109/L

‣ International normalised ratio (INR) ≤ 1.5x upper limit of normal (ULN)

• Or:

• Prothrombin time ≤ 1.5x upper limit of normal (ULN)

• Serum bilirubin ≤1.5x ULN

• Or:

• Direct bilirubin (for patients with total bilirubin \>1.5x ULN) ≤ 1.5x ULN

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5x ULN (for patients with liver metastases ≤ 5x ULN is permissible)

• Calculated creatinine clearance (per institutional standard) ≥ 50 mL/min 6.18 years or over. 7. Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up.

• 8\. Agree to the use of archival paraffin embedded tissue (if available) for PD-L1 (programmed death-ligand 1) analysis 9. Agree to provide a fresh tumour biopsy at baseline and on Cycle 2 Day 8 of a tumour lesion not previously irradiated (tumours progressing in a prior site of radiation are allowed for PD-L1 characterization, other exceptions may be considered after consultation with the Chief Investigator).

• 10\. Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 14 days prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

• 11\. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 6 months after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \>1 year. Decitabine, a metabolite of Guadecitabine/ASTX727, can affect fertility and so oocyte cryopreservation should be discussed with female patients.

• 12\. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 6 months after the last dose of study therapy. Decitabine, a metabolite of Guadecitabine/ASTX727, can affect fertility and so cryopreservation of sperm should be discussed with male patients.