Combination Study of Guadecitabine/ASTX727 and Pembrolizumab

Inclusion Criteria:

1. Part A and B1/2: Histologically or cytologically confirmed advanced solid tumours, refractory toconventional treatment, or for which no conventional therapy exists or is declinedby the patient. Part B1: Histologically or cytologically confirmed advanced solid tumours, refractory toconventional treatment, or for which no conventional therapy exists or is declinedby the patient AND:

• Patients with any tumour type that previously responded to a PD-1 or PD-L1inhibitor and subsequently progressed (defined as secondary resistance toPD-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 theyhave been defined by validated assays or patients with deficient mismatchrepair (dMMR) defined by immunohistochemistry, who have previously received andhave progressed on a PD-1 or PD-L1 inhibitor (primary resistance to PD-1/PD-L1inhibitors) or/

• Patients with other solid tumour types who could benefit, based on emerginganti-tumour activity data, from combination therapy with a demethylating agentand PD-1 or PD-L1 inhibitors, in consultation with any other relevantpreclinical or clinical data, at the Chief Investigator's discretion. Part B2: Patients with histologically or cytologically confirmed NSCLC previously treatedwith PD-1 or PD-L1 inhibitor for advanced or metastatic disease.

2. Life expectancy of at least 12 weeks.

3. Eastern Co-operative Oncology Group (ECOG) performance status of 0-1 with nosignificant deterioration over the previous 2 weeks (Appendix 1).

4. Evaluable or measurable disease as assessed by RECIST 1.1.

5. Haematological and biochemical indices within the ranges shown below. Thesemeasurements must be performed within one week (Day -7 to Day 1) prior toadministration 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 (forpatients with liver metastases ≤ 5x ULN is permissible)

• Calculated creatinine clearance (per institutional standard) ≥ 50 mL/min 6.18 yearsor over. 7. Written (signed and dated) informed consent and be capable ofco-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 biopsyat 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-L1characterization, other exceptions may be considered after consultation withthe Chief Investigator).

9. Female subjects of childbearing potential should have a negative urine or serumpregnancy test within 14 days prior to receiving the first dose of studymedication. If the urine test is positive or cannot be confirmed as negative, aserum pregnancy test will be required.

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

11. Male subjects should agree to use an adequate method of contraception startingwith the first dose of study therapy through 6 months after the last dose ofstudy therapy. Decitabine, a metabolite of Guadecitabine/ASTX727, can affectfertility and so cryopreservation of sperm should be discussed with malepatients.

Exclusion Criteria:

1. Radiotherapy (except brief course for palliative reasons), endocrine therapy,immunotherapy or chemotherapy during the previous four weeks (six weeks fornitrosoureas, Mitomycin-C and 4 weeks for investigational medicinal products) beforetreatment, except for hormonal therapy with luteinizing hormone-releasing hormone (LHRH) analogues for medical castration in patients with CRPC, which are permitted.

2. Patient has a known additional malignancy that is progressing or requires activetreatment. Exceptions include basal cell carcinoma of the skin, squamous cellcarcinoma of the skin, or in situ bladder or cervical cancer that has undergonepotentially curative therapy.

3. Spinal cord compression or brain metastases unless asymptomatic, treated and stableand not requiring steroids for at least 4 weeks prior to start of study treatment.

4. Ongoing toxic manifestations of previous treatments. Exceptions to this are:

• Grade 1 toxicities, which in the opinion of the investigator should not excludethe patient

• Alopecia of any grade

5. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or anyother form of immunosuppressive therapy within 14 days prior to the first dose oftrial treatment. The use of physiologic doses of corticosteroids may be approvedafter consultation with the chief Investigator.

6. Has an active autoimmune disease that has required systemic treatment in past 3months (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment. Patients withSjogren's syndrome will not be excluded from the study. In addition patients thatexperienced a Grade 2 or higher immune-related AE's on treatment with immunotherapywill be excluded from the study.

7. Has evidence of interstitial lung disease.

8. Has a history of (non-infectious) pneumonitis that required steroid treatment or hasactive pneumonitis. Pneumonitis includes acute interstitial pneumonitis, pneumonitisand idiopathic pneumonia syndrome.

9. Active infection, requiring systemic therapy.

10. Has received a live vaccine within 30 days of planned start of study therapy. Note:The killed virus vaccines used for seasonal influenza vaccines for injection areallowed; however intranasal influenza vaccines (e.g. FluMist®) are live attenuatedvaccines and are not allowed.

11. Major surgery (excluding minor procedures, e.g. placement of vascular access) fromwhich the patient has not yet recovered.

12. At high medical risk because of severe or uncontrolled non-malignant systemicdisease including active uncontrolled infection, active bleeding diathesis.

13. Known to be serologically positive for hepatitis B, hepatitis C or humanimmunodeficiency virus (HIV). Screening for chronic conditions is not required.

14. Any of the following cardiac criteria:

• Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 consecutiveelectrocardiograms (ECGs) within 5 minutes of each other.

• Any clinically significant abnormalities in rhythm, conduction or morphology ofresting ECG, e.g. complete left bundle branch block, third degree heart block.

• Any factors that increase the risk of QTc prolongation or risk of arrhythmicevents, such as heart failure, hypokalaemia, congenital long QT syndrome,family history of long QT syndrome or unexplained sudden death under 40 yearsof age or any concomitant medication known to prolong the QT interval

• Experience of any of the following procedures or conditions in the preceding 6months: coronary artery bypass graft, angioplasty, vascular stent, myocardialinfarction, angina pectoris, congestive heart failure New York HeartAssociation [NYHA Grade 2 (refer to Appendix 4)]

• Uncontrolled hypertension - Systolic BP >160mmHg and/or diastolic BP >100mmHg

• Left ventricular ejection fraction (LVEF) below institutional lower limit ofnormal.

15. History of hypersensitivity to active or inactive excipients of guadecitabine orpembrolizumab or drugs with a similar chemical structure or class to either agent.

16. Is a participant or plans to participate in another interventional clinical trial,whilst taking part in this Phase I study of guadecitabine and pembrolizumab.Participation in an observational trial would be acceptable.

17. Any other condition which in the Investigator's opinion would not make the patient agood candidate for the clinical trial.