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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02521844
Recruitment Status : Recruiting
First Posted : August 13, 2015
Last Update Posted : September 22, 2020
Sponsor:
Collaborator:
PPD
Information provided by (Responsible Party):
EDDC (Experimental Drug Development Centre), A*STAR Research Entities

Brief Summary:

This is a Phase 1A/B study consisting of four parts.

  1. Part A (completed) is a non-randomised, open-label, sequential evaluation of the safety, pharmacokinetics (PK), 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.
  2. 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.
  3. Part B dose escalation will be a non-randomised, open-label, sequential evaluation of the MTD, RD, safety, PK, and PD (pharmacodynamics) of ETC 1922159 in combination with pembrolizumab in patients with advanced or metastatic, or unresectable solid malignancies, for whom no approved treatment option or standard of care is available.
  4. Part B dose expansion will be a non-randomised, non-comparative, open-label study evaluation of the safety and tolerability of ETC-1922159 as a single agent until disease progression and then in combination with pembrolizumab at the RD identified in the Part B dose escalation segment, in patients with advanced or metastatic, or unresectable solid malignancies that are refractory, intolerant or not suitable for available treatment according to the treating physician.

It is anticipated that the study will take approximately 78 months to complete (36 months for Part A and Part A Extension, approximately 6 months for Part B dose escalation and approximately 36 months for Part B dose expansion).


Condition or disease Intervention/treatment Phase
Solid Tumors Drug: ETC-1922159 Drug: Pembrolizumab Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 83 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1A/B Study to Evaluate the Safety and Tolerability of ETC-1922159 in Advanced Solid Tumours
Actual Study Start Date : October 2015
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : July 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Dose Escalation
ETC-1922159 + pembrolizumab
Drug: ETC-1922159
Oral administration

Drug: Pembrolizumab
IV administration

Experimental: Dose Expansion
ETC-1922159 as single agent until disease progression, then in combination with pembrolizumab at the recommended dose (RD) identified in the dose escalation segment
Drug: ETC-1922159
Oral administration

Drug: Pembrolizumab
IV administration




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) of ETC-1922159 when administered with pembrolizumab (Part B Dose Escalation) [ Time Frame: For 2 cycles (42 days) ]
  2. Recommended Dose (RD) of ETC-1922159 when administered with pembrolizumab (Part B Dose Escalation) [ Time Frame: For 2 cycles (42 days) ]
  3. Number of participants with adverse events (AEs) (Part B Dose Expansion) [ Time Frame: From date of enrolment until end of treatment ]
  4. Number of participants with adverse bone density imaging assessments via DEXA scan (Part B Dose Expansion) [ Time Frame: From date of enrolment until end of treatment ]
  5. Number of participants with abnormal 12-lead electrocardiogram (ECG) readings (Part B Dose Expansion) [ Time Frame: From date of enrolment until end of treatment ]
  6. Change in Eastern Cooperative Oncology Group performance status (Part B Dose Expansion) [ Time Frame: From date of enrolment until end of treatment ]
  7. Number of participants with abnormal clinical laboratory test results (Part B Dose Expansion) [ Time Frame: From date of enrolment until end of treatment ]
  8. Number of participants with abnormal vital sign measurements (Part B Dose Expansion) [ Time Frame: From date of enrolment until end of treatment ]
  9. Tolerability measured by monitoring of fatigue and gastrointestinal-related side effects and when applicable, immune-related side effects in patients (Part B Dose Expansion) [ Time Frame: From date of enrolment until end of treatment ]

Secondary Outcome Measures :
  1. Number of participants with adverse events (AEs) (Part B Dose Escalation) [ Time Frame: From date of enrolment until end of treatment ]
  2. Number of participants with adverse bone density imaging assessments via DEXA scan (Part B Dose Escalation) [ Time Frame: From date of enrolment until end of treatment ]
  3. Number of participants with abnormal 12-lead electrocardiogram (ECG) readings (Part B Dose Escalation) [ Time Frame: From date of enrolment until end of treatment ]
  4. Change in Eastern Cooperative Oncology Group performance status (Part B Dose Escalation) [ Time Frame: From date of enrolment until end of treatment ]
  5. Number of participants with abnormal clinical laboratory test results (Part B Dose Escalation) [ Time Frame: From date of enrolment until end of treatment ]
  6. Number of participants with abnormal vital sign measurements (Part B Dose Escalation) [ Time Frame: From date of enrolment until end of treatment ]
  7. Tolerability measured by monitoring of fatigue and gastrointestinal-related side effects and when applicable, immune-related side effects in patients (Part B Dose Escalation) [ Time Frame: From date of enrolment until end of treatment ]
  8. Clinical activity measured by RECIST (Response Evaluation Criteria in Solid Tumours) version 1.1 and iRECIST (Response Evaluation Criteria in Solid Tumours modified for immune-based therapeutics) (Part B Dose Expansion) [ Time Frame: From date of enrolment until end of treatment ]
  9. ETC-1922159 Maximum plasma concentration (Cmax) (Part B) [ Time Frame: From date of enrolment until end of treatment ]
  10. ETC-1922159 Area under the curve (AUC) (Part B) [ Time Frame: From date of enrolment until end of treatment ]
  11. Retrospective evaluation of plasma/serum concentration of pembrolizumab (Part B) [ Time Frame: From date of enrolment to Cycle 2 for Dose Escalation and Cycle 1 of combination therapy for Dose Expansion ]
  12. Retrospective evaluation of plasma/serum concentration of bone protective agents, if administered (Part B) [ Time Frame: Before and after the first administration only ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria (Part B):

  • 18+ yrs (US), 21+ yrs (Singapore)
  • Ability to give informed consent
  • 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 (Eastern Cooperative Oncology Group) 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 (prothrombin time) and PTT (partial thromboplastin time) w/in ≤1.5× ULN
    • International normalised ration (INR) ≤1.5× ULN
    • Total bilirubin ≤1.5× ULN
    • Transaminases (AST and/or alanine aminotransferase) ≤2.5× ULN (<5× ULN with liver metastases)
    • Creatinine clearance ≥60 mL/min
    • Total calcium (corrected for serum albumin) within normal limits
    • Magnesium ≥ lower limit of normal (LLN)
    • 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
  • Dose Expansion - Group 1 and Group 2a only (patients with MSS [microsatellite stable]-colorectal cancer [CRC]): Is refractory, intolerant or not suitable for treatment with fluoropyrimidine, oxaliplatin, or irinotecan.
  • Dose Expansion - Group 1 patients: MSS-CRC with confirmed presence of at least one of the four different recurrent gene fusions involving RSPO2 or RSPO3 (Fusions A-D).
  • Dose Expansion - Group 2a patients: Has MSS-CRC with confirmed absence of all four different recurrent gene fusions involving RSPO2 or RSPO3 (Fusions A-D).
  • Dose Expansion - Groups 2b and 2c only (patients with MSS-ovarian and MSS-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 (immunohistochemistry), PCR (polymerase chain reaction) or NGS (next generation sequencing).
  • Dose Expansion: 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.
  • Dose Expansion: Pre-dose and post-dose tumour biopsies are mandatory unless tumour is inaccessible or deemed unsafe for procedure by principal investigator.

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.
  • 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: Has received previous treatment with pembrolizumab or other immune checkpoint inhibitors.
  • 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.
  • 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] by DEXA scan).
  • 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 B-CTX serum level >600 pg/mL in the morning after at least 10 hours of fasting at Screening.
  • Has thyrotropin level less than lower limit of normal (LLN).
  • Has 25-hydroxy vitamin D levels less than 50 mmol/L (20 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 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.
  • 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 the study drug.

Other protocol-defined inclusion and exclusion criteria may apply.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02521844


Contacts
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Contact: Venkateshan Srirangam Prativadibhayankara, MD +65 6407 4213 Venkateshan_Srirangam@eddc.a-star.edu.sg
Contact: Dhananjay Umrani, PhD +65 6407 4149 Dhananjay@eddc.a-star.edu.sg

Locations
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United States, Colorado
University of Colorado Hospital Anschutz Cancer Pavilion, 1665 Aurora Court Recruiting
Aurora, Colorado, United States, 80045
Contact: Nicole Morris    720-848-6876    nicole.c.morris@cuanschutz.edu   
Principal Investigator: Wells Messersmith         
United States, Missouri
Washington University School of Medicine, Siteman Cancer Center, 4921 Parkview Place Not yet recruiting
Saint Louis, Missouri, United States, 63110
Contact: James Jeffrey    314-273-8602    james.jeffrey@wustl.edu   
Principal Investigator: Siddhartha Devarakonda         
United States, North Carolina
Duke University Medical Center, Duke Cancer Center, 20 Duke Medicine Circle Not yet recruiting
Durham, North Carolina, United States, 27710
Contact: Joanne Leicester    919-668-1861    joanne.leicester@duke.edu   
Principal Investigator: John Strickler         
United States, Texas
The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 455 Recruiting
Houston, Texas, United States, 77030
Contact: Holly Liu    713-794-4289    hliu5@mdanderson.org   
Principal Investigator: Vivek Subbiah         
Singapore
National University Hospital, 1E Kent Ridge Road, NUHS Tower Block, Level 7 Recruiting
Singapore, Singapore, 119228
Contact: Priscilla Soh    +65 9710-2772    xueman_priscilla_soh@nuhs.edu.sg   
Principal Investigator: David SP Tan         
National Cancer Centre Singapore, 11 Hospital Drive Recruiting
Singapore, Singapore, 169610
Contact: Miu Leng Goh    +65 6436-8443    goh.mui.leng@nccs.com.sg   
Principal Investigator: Matthew Ng Chau Hsien         
Sponsors and Collaborators
EDDC (Experimental Drug Development Centre), A*STAR Research Entities
PPD
Investigators
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Study Director: Venkateshan Srirangam Prativadibhayankara EDDC, Medical Director
Study Director: Wenyan Li, MBBS, PhD PPD, Associate Medical Director
Additional Information:
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Responsible Party: EDDC (Experimental Drug Development Centre), A*STAR Research Entities
ClinicalTrials.gov Identifier: NCT02521844    
Other Study ID Numbers: D3-002
First Posted: August 13, 2015    Key Record Dates
Last Update Posted: September 22, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by EDDC (Experimental Drug Development Centre), A*STAR Research Entities:
solid tumors
responsive to Wnt signalling regulation
RSPO fusions
Porcupine
PD-1
MSS
CRC
endometrial cancer
ovarian cancer
Additional relevant MeSH terms:
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Neoplasms
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents