TT-702 in Patients With Advanced Solid Tumours.

Inclusion criteria:

1. Be able to provide informed consent and be capable of co-operating with IMPadministration, procedures and follow-up.

2. Be willing to provide samples (blood and tissue) as required.

3. Consent to access any available archival tissue.

4. Consent for fresh tumour biopsy samples at baseline and on trial (may beInvestigator mandated for patients in the dose escalation phase; mandatory for aminimum of eight patients in each expansion cohort). Investigators will considerwhether a biopsy is feasible for the patient in the dose escalation phase and thiswill not impede participation in the trial if biopsy is not a suitable option.

5. Life expectancy estimated by the Investigator to be at least 12 weeks.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

7. Cohort 1M/2M (TT-702 monotherapy) - Aged 16 years or over at the time consent isgiven.

8. Cohort 1A/2A (TT-702 & darolutamide combination cohorts) - Aged 18 years or over atthe time consent is given.

9. Haematological and biochemical indices within the protocol specified ranges.

10. Objectively or measurable evaluable disease, radiologically according to RECISTVersion 1.1 (and/or, in mCRPC patients, according to PCWG3 criteria). Hasradiological disease progression (and/or, in mCRPC patients, PSA progressionaccording to PCWG3 criteria) at the time of study enrolment.

11. Castrate levels of testosterone (<1.7 nmol/L [50 ng/dL]) (mCRPC patients only).

Phase I, dose escalation phase

Histologically or cytologically proven advanced solid tumours refractory to conventional treatment, or for which no conventional therapy is considered appropriate by the Investigator or is declined by the patient. Phase I dose escalation cohorts are:

• Phase I, Cohort 1M (TT-702 monotherapy cohort): Any solid tumour for which standardof care has been exhausted or, is considered inappropriate for or, declined by thepatient.

• Phase I, Cohort 1A (TT-702 & darolutamide combination cohort): mCRPC previouslytreated with a next generation AR antagonist (including enzalutamide, apalutamide ordarolutamide) or abiraterone.

• Phase I, Cohort 1P (TT-702 & PD-1/PD-L1 combination cohort): Patients withPD-1/PD-L1 resistant tumours (i.e. disease progression after a prior PD-1/PD-L1inhibitor with at least 12 weeks treatment).

Phase II (expansion phase)

Histologically or cytologically proven advanced solid tumour of particular interest based on preclinical and clinical data, refractory to conventional treatment or, for which no conventional therapy is considered appropriate by the Investigator or, is declined by the patient. Phase II expansion cohorts are:

• Cohort 2M (TT-702 Monotherapy expansion cohorts) - mCRPC,TNBC and MMR/MSI defective tumours:

MMR/MSI defective tumours:

• Prior treatment with an anti-PD-1 or anti-PD-L1 agent, either as monotherapy or incombination with other agent(s). This should be the preceding treatment prior totrial entry.

• Patients must have progressed on an anti-PD-1/anti-PD-L1 agent.

• Patients must have experienced Investigator-assessed initial clinical benefit fromthe most recent anti-PD-1/anti-PD-L1 treatment (either as monotherapy or incombination with other compounds) for at least 10 weeks. Initial benefit is definedas SD or better with an anti-PD 1/anti-PD-L1 therapy.

• Diagnosis of metastatic MSI-H (defined as MSI polymerase chain reaction test withinstability shown in ≥2 or ≥30% of microsatellite markers) or metastatic MMRd (defined as loss of MLH1, MSH2, MSH6, and/or PMS2 expression is detected) throughlocal testing in NHS lab within UKAS/ISO 15198 scope of accreditation.

mCRPC:

• Prior treatment with a next generation hormonal agent.

• Adenocarcinoma without predominant neuroendocrine or small cell features.

TNBC:

• Human epidermal growth factor receptor 2 negativity (negative immunohistochemistry [IHC] staining [score 0 or 1] or negative fluorescence in situ hybridisation basedon the American Society of Clinical Oncology/College of American Pathologistsguidelines and recommendations) and determined through local testing in NHS labwithin UKAS/ISO 15198 scope of accreditation. Note: patients initially diagnosedwith hormone receptor-positive and/ or HER2-positive breast cancer OR de novometastatic patients with a primary tumour hormone receptor-positive (weak positivityor ER negativity and progesterone receptor positivity) considered as nonclinicallyrelevant are eligible if the tumour biopsy obtained from a local recurrence ordistant metastasis site confirms the TNBC disease.

• ER and progesterone receptor negativity (<1% positive staining cells in the invasivetumour) determined locally using IHC per American Society of ClinicalOncology/College of American Pathologists criteria.

• Patients who have received prior anti-PD-1/anti-PD-L1 agent must have experiencedInvestigator-assessed initial clinical benefit from the most recentanti-PD-1/anti-PD-L1 treatment (either as monotherapy or in combination with othercompounds) for at least 10 weeks, followed by subsequent progression. Initialbenefit is defined as SD or better with an anti-PD-1/anti-PD-L1 therapy.

Cohort 2A (TT-702 & darolutamide combination cohort): mCRPC.

• Patients with mCRPC must have progressive disease according to PCWG3 criteria.

• Previously irradiated lesions cannot be counted as target lesions unless clearlyprogressed after radiotherapy.

• Patients undergoing biopsy should have at least two lesions, one to be used as atarget lesion and one to be biopsied.

• Cohort 2P (TT-702 & PD-1/PD-L1 combination cohort): MMR/MSI defective tumours, TNBCor mCRPC.

Exclusion criteria:

1. Radiotherapy (except single fractions for palliative reasons), endocrine therapyduring the previous four weeks, immunotherapy and chemotherapy during the previousfour weeks(previous six weeks for nitrosoureas, Mitomycin-C) before receivingTT-702. A washout period of eight weeks is required for enzalutamide and apalutamidebefore the patient receives their first dose of TT-702. A washout period of 4 weeksor 5 half-lives whichever is shorter for any other previous preceding IMPs isrequired before the patient receives their first dose of TT-702 (in the combinationcohorts no washout is needed from PD-1/PD-L1 and darolutamide, respectively).

2. Patients with ongoing toxic manifestations of previous treatments greater than NCICTCAE Version 5.0 Grade 1. Exceptions to this are alopecia and any ongoing toxicmanifestation which in the opinion of the Investigator should not exclude thepatient.

3. Patients with symptomatic brain or leptomeningeal metastases should be excluded.Asymptomatic patients with previously treated and stable brain metastases (inprevious four weeks to study entry) and not requiring any steroids are eligible forthe trial. Patients who are stable on anticonvulsants are also eligible.

4. Cohort 1M/2M (monotherapy) - Women of childbearing potential (or are alreadypregnant or lactating). However, those patients who meet the following points areconsidered eligible:

• Have a negative highly sensitive pregnancy test of a serum sample within 7 daysprior to trial inclusion; and

• Agree to use two forms of medically approved contraception: i. one highlyeffective form including but not limited to: oral, injected,implanted, transdermalor intravaginal hormonal contraception associated with inhibition of ovulation;intrauterine device; intrauterine hormonereleasing system, bilateral tubal occlusionor vasectomised partner; ii. plus a barrier method (for example, condom plusspermicide); iii. or agree to sexual abstinence. Effective from the firstadministration of TT-702, throughout the trial and for six months after the lastadministration of IMP.

5. Male patients with partners of childbearing potential. However, those patients whomeet the following points are considered eligible:

• Agree to take measures not to father children by using a barrier method ofcontraception [condom plus spermicide] or sexual abstinence12 effective fromthe first administration of IMP throughout the trial and for six months afterthe last administration of IMP.

• Male patients with pregnant or lactating partners must be advised to usebarrier method contraception (for example, condom plus spermicide) to preventexposure of the foetus or neonate.

• Non-vasectomised male patients must also be willing to ensure that any partnerof childbearing potential uses a highly effective method of contraception (forexample, oral, injected, implanted, transdermal or intravaginal hormonalcontraception associated with inhibition of ovulation, intrauterine device,intrauterine hormone-releasing system or bilateral tubal occlusion) or agree tosexual abstinence for the same duration.

6. Major thoracic or abdominal surgery from which the patient has not yet recovered.

7. At high medical risk because of non-malignant systemic disease including activeuncontrolled infection. Patients with previous Hepatitis C exposure but no currentinfection are eligible to participate.

8. Known to be serologically positive for Hepatitis B, Hepatitis C or HumanImmunodeficiency Virus (HIV).

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

10. Concurrent congestive heart failure, prior history of class II-IV cardiac disease (New York Heart Association [NYHA]), prior history of clinically significant cardiacischaemia or prior history of clinically significant cardiac arrhythmia. Patientswith significant cardiovascular disease are excluded as defined by:

11. History of congestive heart failure requiring therapy (NYHA III or IV);

12. History of unstable angina pectoris or myocardial infarction up to six monthsprior to trial entry (patients with previous cardiac or thrombotic events whoare now stable and or recovered are eligible);

13. Presence of severe valvular heart disease;

14. Presence of a ventricular arrhythmia requiring treatment;

15. Left ventricular ejection fraction < 50%;

16. Has a QTcF prolongation to >470 milliseconds (ms) based on a 12-lead ECG intriplicate;

17. Previous stroke or transient ischaemic attack within 6 months of trial entry;

18. History of clinically significant peripheral vasculardisease/vasculitis/vasculopathy;

19. Cohort 1A/2A - A history of QTcF prolongation or Torsade de pointes.

20. Is a participant or plans to participate in another interventional clinical trial,whilst taking part in this Phase I/II trial of TT-702. Participation in anobservational trial or interventional clinical trial which does not involveadministration of an IMP and which would not place an unacceptable burden on thepatient in the opinion of the Investigator would be acceptable.

21. Previous malignancies of other types, apart from adequately treated in situcarcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin.Cancer survivors, who have undergone potentially curative therapy for a priormalignancy, have no evidence of that disease for five years or more and are deemedat negligible risk for recurrence, are eligible for the trial.

22. A concomitant significant other illness that might in the opinion of theInvestigator affect compliance with the protocol or interpretation of results,examples include but are not limited to autoimmune diseases or immune deficiency, orother disease with ongoing fibrosis (such as scleroderma, pulmonary fibrosis,emphysema, neurofibromatosis, palmar/plantar fibromatosis), alcoholic hepatitis,cirrhosis, and inherited liver disease, previous organ transplantation, uncontrolledor poorly controlled diabetes mellitus (for example HbA1c >10%) and patients withnon-alcoholic steatohepatitis.

23. History of an immune-mediated adverse event of Grade 3 or above attributed to priorcancer immunotherapy that resulted in permanent discontinuation of the priorimmunotherapeutic agent. Immune-mediated adverse events related to priorimmunomodulatory therapy (other than endocrinopathy managed with replacement therapyor stable vitiligo) that have not either resolved completely to baseline or areGrade ≤2 in severity.

24. Patients on systemic corticosteroids (apart from replacement doses forendocrinopathy up to an equivalent of 10 mg QD prednisolone). Topical or inhaledsteroids for pre-existent diseases are allowed.

25. Patients who received a live vaccine within 30 days before trial enrolment areexcluded.

26. Patients with a known or suspected history of hypersensitivity or allergy to TT-702,or any of its excipients (for any strength) are excluded:

• TT-702 10 mg strength, excipients: hydroxypropyl cellulose, sodium laurylsulfate, lactose monohydrate, microcrystalline cellulose, croscarmellose sodiumand magnesium stearate;

• TT-702 40 mg strength, excipients: hydroxypropyl cellulose, sodium laurylsulfate, mannitol, croscarmellose sodium and magnesium stearate;

• TT-702 120 mg strength, excipients: poloxamer-188, sodium lauryl sulfate,mannitol, croscarmellose sodium and magnesium stearate in hydroxypropylmethylcellulose (HPMC) capsules;

• TT-478 (also known as GS-6201 or CVT-6883).

18. Cohort 1A/2A (TT-702 & darolutamide) - Patients with a known or suspected history ofhypersensitivity or allergy to darolutamide or any of its excipients: calciumhydrogen phosphate, croscarmellose sodium, lactose monohydrate, magnesium stearate,povidone, hypromellose, lactose monohydrate, macrogol, and titanium dioxide.

19. Patients who take therapies that inhibit or induce CYP3A must be excluded.

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

If a patient is taking any dietary supplements or complementary medicines/botanicals, the Sponsor's Centre for Drug Development (CDD) must be informed at the earliest opportunity both prior to enrolment and during the patient's time on trial.