Patient case: 72-year-old male with lung adenocarcinoma; genetic feature: EZR-ROS1 fusion

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

Summary: This is a Phase 1A/B study consisting of three parts. Part A (completed) is a non-randomised, open-label, sequential evaluation of the safety, pharmacokinetics, maximum tolerated dose (MTD), and recommended dose (RD) of ETC-1922159 in patients with advanced or metastatic, or unresectable solid malignancies, for whom no approved treatment option or standard of care is available. Dose escalation, with the goal of identifying the MTD and RD, is guided by an ordinal continual reassessment method (oCRM) model with a cohort size of one patient.
  Part A extension (completed) is a non-randomised, non-comparative, open-label evaluation of the safety and tolerability of ETC-1922159 together with the bone protective treatment (denosumab) in patients with advanced or metastatic, or unresectable solid malignancies, for whom no approved treatment option or standard of care is available.
  Part B will be a non-randomised, non-comparative, open-label evaluation of the safety and tolerability of the RD of ETC 1922159 as a single agent and in combination with pembrolizumab in patients with advanced or metastatic, or unresectable solid malignancies, that are refractory, intolerant or not suitable for available treatment at screening according to the treating physician. It is anticipated that the study will take approximately 72 months to complete (36 months for Part A and Part A Extension, and approximately 36 months for Part B).


Eligibility: Inclusion Criteria (Part B):
  -  18+ yrs (US), 21+ yrs (Singapore)
  -  Histologically/cytologically confirmed advanced or metastatic tumors, that are unresectable solid malignancies, and that are are refractory, intolerant or not suitable to available treatment
  -  Objective and radiologically confirmed disease progression at screening
  -  Measurable disease by RECIST v1.1
  -  ECOG 0-2
  -  Life expectancy ≥3 months
  -  Organ function:
  -  Absolute neutrophil count ≥1.0×10^9/L
  -  Platelets ≥100×10^9/L (w/o transfusions w/in 21 days)
  -  Hemoglobin ≥9 g/dL
  -  PT and PTT w/in ≤1.5× ULN
  -  International normalised ration (INR) ≤1.5× ULN
  -  Total bilirubin ≤1.5× ULN
  -  Transaminases (AST and/or ALT) ≤2.5× ULN (<5× ULN with liver metastases)
  -  Creatinine clearance ≥60 mL/min
  -  Total Ca (corrected for serum albumin) within normal limits
  -  Mg ≥ lower limit of normal
  -  Normal urinalysis
  -  Patients with osteopenia (T-score of -1 to -2.5 at L/R total hip, L/R femoral neck or lumbar spine [L1-L4]) eligible
  -  Capable of swallowing study medication or has caregiver responsible for administering study drug
  -  Negative serum pregnancy test
  -  For Group 1 and Group 2a only (patients with MSS-colorectal cancer [CRC]): Is refractory, intolerant or not suitable for treatment with fluoropyrimidine, oxaliplatin, or irinotecan.
  -  Group 1 patients: CRC with confirmed presence of at least one of the four different recurrent gene fusions involving RSPO2 or RSP03 (Fusions A-D)
  -  Group 2a patients: Has CRC with confirmed absence of all four different recurrent gene fusions involving RSPO2 or RSPO3 (Fusions A-D)
  -  For Groups 2b and 2c only (patients with ovarian and endometrial cancer): Has advanced or metastatic disease for which further conventional therapy, e.g. platinum-based chemotherapy, is not suitable. Has MSS tumour as determined by IHC, PCR or NGS.
  -  All patients must have sufficient archival tumour tissue available, or if no archival tumour tissue or tumour ribonucleic acid (RNA) sample is available, the patient must have tumour sites that allow conduction of biopsies.
  Exclusion Criteria (Part B):
  -  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.
  -  Current or anti-cancer therapy within 4 weeks pre-study or with Grade ≤1 side effects not resolved within 4 weeks pre-study.
  -  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)
  -  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 study drug.
  -  Radiation w/in 4 weeks, or limited field radiation within 2 weeks, prior to study drug, or with unresolved Grade ≤1 side effects .
  -  Radiation to spine/pelvis bone or chemoradiation to pelvic organs.
  -  Surgical procedure within 4 wks of starting study drug. Or patient has surgery-related complications to Grade ≤1.
  -  History of interstitial lung disease, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, or pulmonary hypersensitivity pneumonitis.
  -  Bisphosphonate therapy for osteoporosis or symptomatic hypercalcaemia, or denosumab for osteoporosis prior to study drug.
  -  Has osteoporosis (T-score of <−2.5 at L/R total hip, L/R femoral neck, or lumbar spine [L1-L4] by DEXA scan).
  -  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).
  -  Moderate (25%-40% decrease vertebral height) or severe (>40% decrease vertebral height) morphometric vertebral fractures.
  -  Thyrotropin/25-hydroxyvitamin D levels < lower limit of normal.
  -  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 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 for treatment/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 NCI CTCAE v. 4.03).
  -  Has a known history of 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.
  -  For CRC patients: Patient is unable to provide tumour tissue (from archival tissue or a fresh biopsy or tumour RNA) to determine presence or absence fo the 4 recurrent RSPO gene fusions (Fusions A-D).
  -  For ovarian and endometrial cancer patients: Patient is unable to provide tumour tissue (from archival tissue or a fresh biopsy).
  -  Has received previous treatment with pembrolizumab or other immune checkpoint inhibitors.
  -  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 21 days prior to the start of the study drug.
  Other protocol-defined inclusion and exclusion criteria may apply.

Relevance to patient case: not relevant