A Study to Evaluate the Safety and Tolerability of ETC-1922159 as a Single Agent and in Combination With Pembrolizumab in Advanced Solid Tumours

Male patient with sexual partner(s) of childbearing potential unwilling to use contraception. Sexually active male patients must use a condom during intercourse during the study and for 12 weeks after the end of treatment. Condom must also be used by vasectomised males.

Female of childbearing potential, unless birth control is used during study and for 12 weeks after end of treatment.

Pregnant or nursing (lactating) female.

Dose Escalation: Current or anti-cancer therapy within 4 weeks pre-study or with Grade ≤1 side effects not resolved within 4 weeks pre-study.

Dose Expansion segment: Has received previous treatment with pembrolizumab or immunotherapy treatment within 4 weeks (28 days) prior to starting the study drug is permitted

* Dose Expansion (Groups 1, 2a, 2b and 2d): Immunotherapy within 4 weeks (28 days) prior to starting study.

* Dose Expansion (Group 2c MSS endometrial cancer only): Immunotherapy either alone or in combination with lenvatinib within 4 weeks (28 days) prior starting study drug.

Is receiving any concomitant anti-cancer therapy.

Has used other investigational products within 4 weeks or 5 half-lives (whichever is longer) prior to first dose of study drug.

Has evidence of other malignancy not in remission or history of other malignancy within last 3 yrs (exceptions: treated basal or skin squamous cell carcinoma or in situ cancer of cervix)

Has central nervous system metastases, unless treated with surgery, whole brain radiation or stereotactic radiosurgery, and stable disease ≥8 weeks without steroid use for ≥4 weeks prior to first dose of study drug.

Has received prior radiation therapy within 4 weeks, or limited field radiation within 2 weeks, prior to study drug, or with unresolved Grade ≤1 side effects.

Has history of radiation to spine/pelvis bone or chemoradiation to pelvic organs in the last 6 months prior to starting study drug, or the side effects of such therapy have not resolved to Grade ≤1 (NOTE: Such patients can be enrolled as long as they do not have osteoporosis (for details of calculating T-score for eligibility see Inclusion Criterion 9). Patients should initiate concurrent bone protective treatment prophylaxis if any radiation therapy has been given in the last 2 years or they are at high risk of bone related AEs.

Has had major surgical procedure within 4 weeks of starting study drug. Or patient has not fully recovered from all surgery-related complications to Grade ≤1.

Has a history of interstitial lung disease, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, or pulmonary hypersensitivity pneumonitis.

Has received bisphosphonate therapy for osteoporosis or symptomatic hypercalcaemia, or denosumab for osteoporosis prior to starting study drug.

Has osteoporosis (T-score of \< -2.5 at left or right total hip, left or right femoral neck, or lumbar spine \[L1-L4\] as determined by DEXA scan at Screening).

Has a history of symptomatic vertebral fragility fractures or fragility fracture of hip, pelvis, wrist, or other location (fragility fracture - any fracture without trauma or as a result of a fall from ≤standing height).

Has moderate (25%-40% decrease vertebral height) or severe (\>40% decrease vertebral height) morphometric vertebral fractures.

Has thyrotropin level less than lower limit of normal (LLN).

Has 25-hydroxy vitamin D levels less than 25 mmol/L (10 ng/mL).

Has bone metastases.

Has a history of long QT or prolonged QTc (\>460 ms).

Is receiving, or has received thiazolidinedione peroxisome proliferator-activated receptor gamma agonist (e.g. Actos® \[pioglitazone\] and Avandia® \[rosiglitazone\]) w/in 4 wks prior to starting study drug.

Has metabolic bone disease such as hyperparathyroidism, Paget's disease or osteomalacia.

Has a known clinically significant bleeding disorder or coagulopathy.

Is receiving or has received within 4 weeks prior to starting study drug, heparin, warfarin or similar anti-coagulants except for patients on low molecular weight heparin or Direct-Acting Oral Anticoagulants (DOACs: factor Xa or direct thrombin inhibitors) for treatment or prophylaxis.

Has severe or unstable medical conditions such as heart failure, ischemic heart disease, uncontrolled hypertension, uncontrolled diabetes mellitus, psychiatric condition, ongoing cardiac arrhythmia requiring medication (Grade ≥2, by National Cancer Institute \[NCI\] CTCAE v. 4.03).

Has a known history of human immunodeficiency virus (HIV) or active bacterial, viral or fungal infections.

Has a history of gastric bypass surgery.

Has received prior treatment with an inhibitor of the Wnt-B-catenin pathway.

Is unwilling or unable to comply with the protocol.

Cannot start treatment with the bone protective treatment with denosumab and/or zoledronic acid. Cannot start treatment with the bone protective treatment with denosumab SC, in patients requiring this treatment at the start of the study.

Dose Expansion: Patient is unable to provide tumour tissue (from archival tissue or a fresh biopsy or tumour RNA).

Has received prophylactic administration of hematopoietic colony stimulating factors within 4 weeks prior to starting study drug.

Is receiving active treatment with an oral or IV glucocorticoid for ≥4 weeks at a daily dose equivalent to ≥10 mg of oral prednisone within the 12 weeks prior to starting the study drug.

Has recent or current active infectious disease requiring systemic antibiotics or antifungal or antiviral treatment within 2 weeks prior to the start of the study drug. Subjects receiving prophylactic antibiotics (e.g. for prevention of urinary tract infection or chronic obstructive pulmonary disease) are eligible.

Has a serious non-healing wound.

Has a history of vasculitis.

Has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic treatment.

Has received a live vaccine within 28 days prior to the start of study drug or anticipate that such live vaccine will be required during the study. Anti-SARS-CoV-2 live virus vaccines developed that utilised a replication-deficient simian adenoviral vector (ChAdOx1) should be avoided.

What this study is about