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 conventionaltherapy exists or is declined by the patient. PART B1: Patients with histologically or cytologically confirmed malignant advancedsolid tumours (including melanoma, renal cell cancer, non-small cell lung cancer andhead and neck squamous cell cancer), refractory to immune checkpoint inhibitors andfor which no conventional therapy exists or is declined by the patient. Patientswith other tumour types where immune checkpoint inhibitors are licensed can beconsidered upon discussion with the Chief Investigator. PART B2: Patients with histologically or cytologically confirmed cervical cancer,refractory to conventional treatment, or for which no conventional therapy exists oris declined by the patient. PART B3: Patients with histologically or cytologically confirmed triple negativebreast cancer, refractory to conventional treatment, or for which no conventionaltherapy exists or is declined by the patient. PART B4 (no longer recruiting): Patients with histologically confirmed relapsedglioblastoma (GBM). Diagnosis of GBM will be based on WHO classification of CNStumours, 5th edition (2021): IDH wild type diffuse astrocytic glioma with microvascular proliferation, ORnecrosis, OR one or more of the following molecular features of GBM:

• TERT promoter mutation,

• EGFR gene amplification,

• 7 gain/10 loss chromosome copy number changes. PART B5: Patients with histologically or cytologically confirmed ER positive HER2negative breast cancer who have progressed on CDK4/6 inhibitor therapy. For Immune Checkpoint inhibitor refractory tumours, participants must haveprogressed on treatment with an anti-PD-1/L1 mAb administered either as monotherapyor in combination with other checkpoint inhibitors or other therapies. PD-1treatment progression is defined by 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 RECISTv1.1. The initial evidence of PD is to be confirmed by a second assessment noless than 4 weeks from the date of the first documented disease progression, inthe absence of rapid clinical progression (as defined in c below).

3. Progressive disease has been documented within 24 weeks from commencinganti-PD-1/PD-L1 and no later than 12 weeks from the last dose ofanti-PD-1/PD-L1 mAb. i) Progressive disease is determined according to iRECIST. ii) This determination ismade by the investigator. Once disease progression is confirmed, the initial date ofdisease progression documentation will be considered the date of diseaseprogression.

4. Parts A, B1, and B2: Measurable disease as assessed by imRECIST. Parts B3 and B5 :Measurable disease as assessed by imRECIST OR Evaluable disease as assessed by wholebody MRI. Part B4: Measurable disease as assessed by RANO.

5. Patients in the ER positive HER2 negative cohort (cohort B5 ) must not have had morethan two prior systemic lines of chemotherapy in the metastatic setting. There is nolimitation on number of prior lines of hormonal or targeted therapies.

6. All patients with advanced solid tumours enrolled onto Part A must be willing andable to have fresh paired tissue biopsies for biomarker analysis.

7. Life expectancy of at least 12 weeks.

8. World Health Organisation (WHO) performance status of 0 or 1.

9. Haematological and biochemical indices within the ranges shown below. Thesemeasurements 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 Serumbilirubin ≤ 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 ≤ 5 x ULN ispermissible Aspartate aminotransferase (AST) ≤ 2.5 x (ULN) unless raised due to toknown 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 ≤ ULNLipase ≤ ULN Coagulation INR <1.5 APTT <1.5 x ULN

8. 18 years or over

9. Written (signed and dated) informed consent and be capable of co-operating withtreatment and follow-up

10. Female patients with reproductive potential must have a negative urine or serumpregnancy 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 weeksfor nitrosoureas, Mitomycin-C) and four weeks for investigational medicinalproducts, except for hormonal therapy with luteinizing hormone-releasing hormone (LHRH) analogues for medical castration in patients with castrate resistant prostatecancer or ovarian suppression in pre- or peri-menopausal women with endocrine-drivenbreast cancer, which are permitted, and bisphosphonates or RANK ligand antagoniststhat are permitted for the management of bone metastases.

2. Current malignancies of other types, with the exception of adequately treated conebiopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinomaof the skin. Cancer survivors, who have undergone potentially curative therapy for aprior malignancy, have no evidence of that disease for five years or more and aredeemed at negligible risk for recurrence, are eligible for the trial.

3. Ongoing Grade 2 or greater toxicities from pre-existing conditions or previoustreatments. Exceptions to this are alopecia and ongoing anticoagulation therapy dueto prior thromboembolic episodes.

4. Ability to become pregnant (or already pregnant or lactating). However, those femalepatients who have a negative serum or urine pregnancy test before enrolment andagree to use two highly effective forms of contraception (oral, injected orimplanted hormonal contraception and condom, have an intra-uterine device andcondom, diaphragm with spermicidal gel and condom) for four weeks before enteringthe trial, during the trial and for six months afterwards are considered eligible.NB. Abstinence is only considered to be an acceptable method of contraception whenthis is in line with the preferred and usual lifestyle of the subject. Periodicabstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) andwithdrawal are not acceptable methods of contraception

5. Male patients with partners of child-bearing potential (unless they agree to takemeasures not to father children by using one form of highly effective contraception [condom plus spermicide] and not to donate sperm during the trial and for six monthsafterwards). Men with pregnant or lactating partners should be advised to usebarrier method contraception (for example, condom plus spermicidal gel) to preventexposure to the foetus or neonate.

6. For cohorts A, B1, B2, B3 and B5 only - Known untreated or active central nervoussystem (CNS) metastases (progressing or requiring corticosteroids for symptomaticcontrol). Patients with a history of treated CNS metastases are eligible, providedthey meet all of the following criteria:

• Evaluable or measurable disease outside the CNS is present.

• Radiographic demonstration of improvement or stability upon the completion ofCNS-directed therapy at least 4 weeks after completion of CNS directed therapyand no evidence of interim progression between the completion of CNS-directedtherapy and the baseline disease assessment.

• Not requiring corticosteroids.

7. For Cohort B4 only (no longer recruiting):

• Participants with infratentorial tumors and tumors primarily located in orclose to critical structures (e.g., brain stem). Patients with leptomeningealdisease.

• Patients with evidence of raised intracranial pressure or mass effect onimaging

• Patients unable to tolerate contrast enhanced MRI.

8. Major surgery within four weeks of the first dose of study treatment.

9. History of malabsorption syndrome or other condition that would interfere withenteral absorption.

10. At high medical risk because of non-malignant systemic disease including activeuncontrolled infection.

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

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

13. 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 3 or higher immune-related AE on treatment with immunotherapywill 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 with inactive autoimmune disease which has previously required systemictherapy, may be considered on a case-by-case basis after discussion with thesponsor.

14. 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. Stable use (i.e., no change in dosewithin 1 month prior to Day 1 of Cycle 1) of inhaled corticosteroids is allowed.Patients for cohort B4 who are on a stable dose of corticosteroids not exceeding 2mgDexamethasone for tumour associated oedema or symptoms will be permitted to enrol onthe study.

15. 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.

16. Any of the following cardiac criteria:

17. Mean resting corrected QT interval (QTcF) > 470 msec obtained from anelectrocardiogram (ECG). Known congenital QT syndrome or history of torsades depointes.

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

19. 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.

20. 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 or above], severe valvular disease, uncontrolledhypertension despite optimal therapy.

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

22. 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.

23. 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 theydid not experience any immune-adverse event toxicity while on their priorimmunotherapy as described in exclusion criteria 12.

24. 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.

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

26. Known psychiatric or substance abuse disorders that would interfere with cooperationwith the requirements of the trial.

27. History of an allogenic tissue/ solid organ transplant.

28. Symptoms of COVID-19 and/or documented COVID-19 infection.