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

NCT02521844

Description:

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).

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

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

Title

  • Brief Title: A Study to Evaluate the Safety and Tolerability of ETC-1922159 in Advanced Solid Tumours
  • Official Title: A Phase 1A/B Study to Evaluate the Safety and Tolerability of ETC-1922159 in Advanced Solid Tumours
  • Clinical Trial IDs

    NCT ID: NCT02521844

    ORG ID: D3-002

    Trial Conditions

    Solid Tumors

    Trial Interventions

    Drug Synonyms Arms
    ETC-1922159 ETC-1922159

    Trial Purpose

    This is a Phase 1A/B study consisting of two parts. Part A is a non-randomised, open-label,
    sequential evaluation of the safety, pharmacokinetics, MTD, and 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, will be guided by an oCRM model with a cohort size of one
    patient.

    Part B will be a non-randomised, non-comparative, open-label evaluation of the safety and
    tolerability of the 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, with a molecular phenotype that is expected to make them sensitive to PORCN
    inhibitor treatment.

    It is anticipated that the study will take approximately 30 months to complete
    (approximately 18 months for Part A and approximately 12 months for Part B).

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    ETC-1922159 Experimental Single-arm open label ETC-1922159

    Eligibility Criteria

    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 1.0109/L

    - Platelets 100109/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 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

    - -CTX >1000 pg/mL (morning after 10hrs fasting)

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

    - Bone metastases and 1 of the following:

    - Pathologic fracture

    - Lytic lesion requiring orthopedic intervention

    - 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 B only:

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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    MTD and Recommended Dose

    Safety Measured by monitoring of adverse events (AEs), 12-lead electrocardiogram readings, Eastern Cooperative Oncology Group performance status, clinical laboratory test results, and vital sign measurements of patients

    Tolerability Measured by monitoring of fatigue and gastrointestinal-related side effects in patients

    Secondary Outcome Measures

    Safety Measured by monitoring of adverse events (AEs), 12-lead electrocardiogram readings, Eastern Cooperative Oncology Group performance status, clinical laboratory test results, and vital sign measurements of patients

    Tolerability Measured by monitoring of fatigue and gastrointestinal-related side effects in patients

    Pharmacokinetics Peak Plasma Concentration (Cmax)

    Pharmacokinetics Area under the plasma concentration versus time curve (AUC)

    Pharmacokinetics Measured by t1/2

    Clinical Activity Measured by RECIST and molecular phenotype

    Trial Keywords

    solid tumors

    responsive to Wnt signalling regulation