ASTEROID: A Trial of ASTX660 in Combination With Pembrolizumab

Inclusion Criteria:

• 1. PART A: Patients with histologically or cytologically confirmed malignant advancedsolid tumours, refractory to conventional treatment, or for which no conventional therapyexists or is declined by the patient. PART B1: Patients with histologically or cytologically confirmed malignant advanced solidtumours, refractory to immune checkpoint inhibitors and for which no conventional therapyexists or is declined by the patient. PART B2: Patients with histologically or cytologically confirmed cervical cancer,refractory to conventional treatment, or for which no conventional therapy exists or isdeclined by the patient. PART B3: Patients with histologically or cytologically confirmed triple negative breastcancer, refractory to conventional treatment, or for which no conventional therapy existsor is declined by the patient. For Immune Checkpoint inhibitor refractory tumours, participants must have progressed ontreatment with an anti-PD-1/L1 mAb administered either as monotherapy or in combinationwith other checkpoint inhibitors or other therapies. PD-1 treatment progression is definedby meeting all of the following criteria:

1. Has received at least 2 doses of an approved anti-PD-1/PD-L1 mAb.
2. Has demonstrated disease progression after anti-PD-1/PD-L1 as defined by RECIST v1.1.The initial evidence of PD is to be confirmed by a second assessment no less than 4weeks from the date of the first documented disease progression, in the absence ofrapid clinical progression (as defined in c below).
3. Progressive disease has been documented within 12 weeks from the last dose ofanti-PD-1/PD-L1 mAb. i) Progressive disease is determined according to iRECIST. ii) This determination is madeby the investigator. Once disease progression is confirmed, the initial date of diseaseprogression documentation will be considered the date of disease progression.
4. Parts A, B1, B2 and B3: Measurable disease as assessed by imRECIST. 3. All patients withadvanced solid tumours must be willing and able to have fresh paired tissue biopsies forbiomarker analysis.
5. Life expectancy of at least 12 weeks. 5. World Health Organisation (WHO) performancestatus of 0 or 1. 6. Haematological and biochemical indices within the ranges shown below.These measurements must be performed within one week (Day -7 to Day 1) prior to thepatient's first dose of IMP. Laboratory Test Value required Haemoglobin (Hb)

≥ 9.0 g/dL Absolute neutrophil count

• 1.5 x 109/L Lymphocyte count >0.5 x 109/L Platelet count
• 100 x 109/L Total Serum bilirubin
• 1.5 x upper limit of normal (ULN) Alanine aminotransferase (ALT)
• 2.5 x (ULN) unless raised due to known metastatic liver disease in which case ≤ 5x ULN is permissible Aspartate aminotransferase (AST)
• 2.5 x (ULN) unless raised due to to known metastatic liver disease in which case ≤ 5 x ULN is permissible Either: Calculated creatinine clearance Or: Creatinine ≥ 50 mL/min (uncorrected value) Or < 1.5 x upper limit of normal (ULN) Albumin >28 g/L LDH <3 x ULN Amylase

≤ ULN Lipase

≤ ULN 7. 18 years or over 8. Written (signed and dated) informed consent and be capable ofco-operating with treatment and follow-up 9. Female patients with reproductive potentialmust have a negative urine or serum pregnancy test performed within 72 hours of first dose

Exclusion Criteria:

• 1. Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapyincluding Pembrolizumab or chemotherapy during the previous four weeks (six weeks fornitrosoureas, Mitomycin-C) and four weeks for investigational medicinal products,except for hormonal therapy with luteinizing hormone-releasing hormone (LHRH)analogues for medical castration in patients with castrate resistant prostate canceror ovarian suppression in pre- or peri-menopausal women with endocrine-driven breastcancer, which are permitted, and bisphosphonates or RANK ligand antagonists that arepermitted for the management of bone metastases. Current malignancies of other types, with the exception of adequately treated cone biopsiedin situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin.Cancer survivors, who have undergone potentially curative therapy for a prior malignancy,have no evidence of that disease for five years or more and are deemed at negligible riskfor recurrence, are eligible for the trial.

3. Ongoing Grade 2 or greater toxicities of previous treatments. Exceptions to this arealopecia 4. Ability to become pregnant (or already pregnant or lactating). However, thosefemale patients who have a negative serum or urine pregnancy test before enrolment andagree to use two highly effective forms of contraception (oral, injected or implantedhormonal contraception and condom, have an intra-uterine device and condom, diaphragm withspermicidal gel and condom) for four weeks before entering the trial, during the trial andfor six months afterwards are considered eligible. NB. Abstinence is only considered to bean acceptable method of contraception when this is in line with the preferred and usuallifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,post-ovulation methods) and withdrawal are not acceptable methods of contraception 5. Malepatients with partners of child-bearing potential (unless they agree to take measures notto father children by using one form of highly effective contraception [condom plusspermicide] and not to donate sperm during the trial and for six months afterwards). Menwith pregnant or lactating partners should be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure to the foetus or neonate.

4. Known untreated or active central nervous system (CNS) metastases (progressing or requiringcorticosteroids for symptomatic control). Patients with a history of treated CNS metastasesare eligible, provided they meet all of the following criteria:

• Evaluable or measurable disease outside the CNS is present.
• Radiographic demonstration of improvement upon the completion of CNS-directed therapyat least 4 weeks after completion of CNS directed therapy and no evidence of interimprogression between the completion of CNS-directed therapy and the baseline diseaseassessment.
• Not requiring corticosteroids. 7. Major surgery within four weeks of the first dose ofstudy treatment. 8. History of malabsorption syndrome or other condition that wouldinterfere with enteral absorption. At high medical risk because of non-malignant systemic disease including activeuncontrolled infection.

10. History of (non-infectious) pneumonitis/interstitial lung disease that requiredsteroids, or current pneumonitis/interstitial lung disease.

11. Known to be serologically positive for hepatitis B, hepatitis C or humanimmunodeficiency virus (HIV).

12. Has an active autoimmune disease that has required systemic treatment in past 3 months (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacementtherapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemictreatment. Patients with Sjogren's syndrome will not be excluded from the study. Inaddition, patients that experienced a Grade 3 or higher immune-related AE on treatment withimmunotherapy will be excluded from the study. Patients that have experience a prior G2immune-related AE on treatment will need case-by-case discussion with the CI. Patients withinactive autoimmune disease which has previously required systemic therapy, may beconsidered on a case-by-case basis after discussion with the sponsor.

13. 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 of trialtreatment. The use of physiologic doses of corticosteroids may be approved afterconsultation with the chief Investigator. Stable use (i.e., no change in dose within 1month prior to Day 1 of Cycle 1) of inhaled corticosteroids is allowed.

14. Has received a live vaccine within 30 days of planned start of study therapy. Note: Thekilled virus vaccines used for seasonal influenza vaccines for injection are allowed;however intranasal influenza vaccines (e.g. FluMist®) are live attenuated vaccines and arenot allowed.

15. Any of the following cardiac criteria:

16. Mean resting corrected QT interval (QTcF) > 470 msec obtained from 3 consecutiveelectrocardiograms (ECGs) within 5 minutes of each other. Known congenital QT syndromeor history of torsades de pointes.

17. Left ventricular ejection fraction of <50% on echocardiogram.

18. Any clinically significant abnormalities in rhythm, conduction or morphology ofresting ECG, e.g. complete left bundle branch block, third degree heart block.Controlled atrial fibrillation is allowed.

19. Experience of any of the following procedures or conditions in the preceding 6 months:coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction,angina pectoris, congestive heart failure New York Heart Association [NYHA Grade 2 orabove], severe valvular disease, uncontrolled hypertension despite optimal therapy.

20. Prior bone marrow transplant or have had extensive radiotherapy to greater than 25% of bone marrow within eight weeks.

21. Participates or plans to participate in another interventional clinical trial,whilst taking part in this Phase I study of ASTX660 and Pembrolizumab. Participationin an observational trial would be acceptable.

22. Patients with prior exposure to an IAP antagonist (Smac mimetic) will be excludedfrom this study. Patients with prior exposure to immunotherapy (either CTLA-4,PD-1/PD-L1 inhibitor/cellular therapy) will be permitted to enrol as long as they didnot experience any immune-adverse event toxicity while on their prior immunotherapy asdescribed in exclusion criteria 12.

23. History or current evidence of any condition, therapy, or laboratory abnormalitythat might confound the results of the study, interfere with the patient'sparticipation for the full duration of the study, or is not in the best interest ofthe patient to participate, in the Investigator's opinion.

24. Severe hypersensitivity (≥ Grade 3) to any of the IMPs and/or any of theirexcipients.

25. Known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

26. History of an allogenic tissue/ solid organ transplant. 23. Symptoms of COVID-19and/or documented COVID-19 infection.