A Study to Evaluate the Safety and Tolerability of ETC-1922159 in Advanced Solid Tumours

Inclusion Criteria:

- 18+ yrs (US), 21+ yrs (Singapore)

- Histologically/cytologically confirmed advanced/metastatic or unresectable solid
tumors, no treatment options

- Radiologically confirmed disease progression

- Evaluable/measurable disease by RECIST

- ECOG 0-2

- Life expectancy ≥3 mos

- Organ function:

- Absolute neutrophil count ≥1.0×109/L

- Platelets ≥100×109/L (w/o transfusions w/in 21 days)

- Hemoglobin ≥9 g/dL

- PT and PTT w/in ≤1.5× ULN

- INR ≤1.5× ULN

- Total bilirubin ≤1.5× ULN

- AST and/or ALT ≤2.5× ULN, <5× ULN w/liver metastases

- Creatinine clearance ≥60 mL/min

- Total Ca (corrected for serum albumin) w/in normal limits

- Mg ≥ lower limit of normal

- Normal urinalysis

- Pts w/ osteopenia (T-score of -1 to -2.5 at L/R total hip, L/R femoral neck or lumbar
spine [L1-L4]) eligible

- Neg pregnancy test

Part A extension only:

• Has a primary tumor or a metastatic site that is accessible for pre- and post-dose biopsy
without subjecting patient to high level of risk

Part B only:

- Tumor tissue available if biopsy consent not provided, if no archival tumor tissue
available and pt provides consent, pre-dose biopsy will be done

- Tumor tissue receptive to Wnt signalling in biopsy

Exclusion Criteria:

- Male w/partner(s) (childbearing) unwilling to use contraception

- Female of childbearing potential, unless birth control used on study and 12 wks
post-treatment.

- Pregnant/nursing female

- Current or anti-cancer therapy w/in 4 wks pre-study or w/Grade ≤1 side effects not
resolved w/in 4 wks pre-study

- Other IPs w/in 4 wks or 5 half-lives (whichever is longer) prior to study drug

- Malignancy not in remission or w/in last 3 yrs (exceptions: basal or skin squamous
cell carcinoma or in situ cervix cancer)

- CNS metastases, unless treated w/ surgery, whole brain radiation or stereotactic
radiosurgery, and stable disease ≥8 wks w/o steroid use for ≥4 wks prior to study drug

- Radiation w/in 4 wks, or limited field radiation w/in 2 wks, prior to study drug, or
w/unresolved Grade ≤1 side effects

- Radiation to spine/pelvis bone or chemoradiation to pelvic organs

- Surgical procedure w/in 4 wks of starting study drug. Or pt has surgery-related
complications to Grade ≤1

- Interstitial lung disease, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, or
pulmonary hypersensitivity pneumonitis

- Bisphosphonate therapy (osteoporosis or symptomatic hypercalcaemia) or denosumab
(osteoporosis) prior to study drug

- Osteoporosis (T-score of <−2.5 at L/R total hip, L/R femoral neck, or lumbar spine
[L1-L4] by DEXA scan)

- Symptomatic vertebral fragility fractures or fragility fracture of hip, pelvis, wrist,
or other location (fragility fracture - any fracture w/out trauma or as a result of a
fall from ≤standing height)

- Moderate (25%-40% decrease vertebral ht.) or severe (>40% decrease vertebral ht.)
morphometric vertebral fractures

- β-CTX serum level >1000 pg/mL (morning after ≥10hrs fasting)

- Thyrotropin/25-hydroxyvitamin D levels < lower limit of normal

- Bone metastases

- Long QT or prolonged QTc (>460 ms)

- Thiazolidinedione peroxisome proliferator-activated receptor gamma agonist (e.g.
Actos® [pioglitazone] and Avandia® [rosiglitazone]) w/in 4 wks prior to study drug

- PO or IV glucocorticoid for ≥4 wks at daily dose eq. to ≥7.5 mg of PO prednisone w/in
12 wks prior to study drug dosing

- Hyperparathyroidism, Paget's disease or osteomalacia

- Bleeding disorder/coagulopathy

- Heparin, warfarin or similar anti-coagulants (except. low molecular weight heparin for
treatment/prophylaxis) currently or w/in 4 wks of study drug

- Heart failure, ischemic heart disease, uncontrolled hypertension, uncontrolled
diabetes mellitus, psychiatric condition, ongoing cardiac arrhythmia requiring
medication (Grade ≥2, by NCI CTCAE v. 4.03), or significant/unstable concurrent
medical illness by investigator opinion

- HIV or active bacterial, viral or fungal infections

- Gastric bypass

Part A extension and B only:

• Cannot start treatment with the bone protective treatment with denosumab SC

Part B only:

• APC, CTNNB1, WTX [FAM123], AXIN1 and GSK3B in tumor