A Study to Evaluate the Safety and Tolerability of ETC-1922159 as a Single Agent and in Combination With Pembrolizumab in Advanced Solid Tumours
Study Details
Study Description
Brief Summary
This is a Phase 1A/B study consisting of four parts.
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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.
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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.
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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.
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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 |
|---|---|---|
| Phase 1 |
Study Design
Arms and Interventions
| 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
|
Outcome Measures
Primary Outcome Measures
- Maximum Tolerated Dose (MTD) of ETC-1922159 when administered with pembrolizumab (Part B Dose Escalation) [For 2 cycles (42 days)]
- Recommended Dose (RD) of ETC-1922159 when administered with pembrolizumab (Part B Dose Escalation) [For 2 cycles (42 days)]
- Number of participants with adverse events (AEs) (Part B Dose Expansion) [From date of enrolment until end of treatment]
- Number of participants with adverse bone density imaging assessments via DEXA scan (Part B Dose Expansion) [From date of enrolment until end of treatment]
- Number of participants with abnormal 12-lead electrocardiogram (ECG) readings (Part B Dose Expansion) [From date of enrolment until end of treatment]
- Change in Eastern Cooperative Oncology Group performance status (Part B Dose Expansion) [From date of enrolment until end of treatment]
- Number of participants with abnormal clinical laboratory test results (Part B Dose Expansion) [From date of enrolment until end of treatment]
- Number of participants with abnormal vital sign measurements (Part B Dose Expansion) [From date of enrolment until end of treatment]
- Tolerability measured by monitoring of fatigue and gastrointestinal-related side effects and when applicable, immune-related side effects in patients (Part B Dose Expansion) [From date of enrolment until end of treatment]
Secondary Outcome Measures
- Number of participants with adverse events (AEs) (Part B Dose Escalation) [From date of enrolment until end of treatment]
- Number of participants with adverse bone density imaging assessments via DEXA scan (Part B Dose Escalation) [From date of enrolment until end of treatment]
- Number of participants with abnormal 12-lead electrocardiogram (ECG) readings (Part B Dose Escalation) [From date of enrolment until end of treatment]
- Change in Eastern Cooperative Oncology Group performance status (Part B Dose Escalation) [From date of enrolment until end of treatment]
- Number of participants with abnormal clinical laboratory test results (Part B Dose Escalation) [From date of enrolment until end of treatment]
- Number of participants with abnormal vital sign measurements (Part B Dose Escalation) [From date of enrolment until end of treatment]
- Tolerability measured by monitoring of fatigue and gastrointestinal-related side effects and when applicable, immune-related side effects in patients (Part B Dose Escalation) [From date of enrolment until end of treatment]
- 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) [From date of enrolment until end of treatment]
- 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 Escalation) [From date of enrolment until end of treatment]
- ETC-1922159 Maximum plasma concentration (Cmax) (Part B) [From date of enrolment until end of treatment]
- ETC-1922159 Area under the curve (AUC) (Part B) [From date of enrolment until end of treatment]
- Retrospective evaluation of plasma/serum concentration of pembrolizumab (Part B) [From date of enrolment to Cycle 2 for Dose Escalation and Cycle 1 of combination therapy for Dose Expansion]
- Retrospective evaluation of plasma/serum concentration of bone protective agents, if administered (Part B) [Before and after the first administration only]
Eligibility Criteria
Criteria
Inclusion Criteria (Part B):
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18+ yrs (US), 21+ yrs (Singapore)
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Ability to give informed consent
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Histologically/cytologically confirmed advanced or metastatic tumors, that are unresectable solid malignancies, and that are are refractory, intolerant or not suitable to available treatment
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Objective and radiologically confirmed disease progression at screening
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Measurable disease by RECIST v1.1
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ECOG (Eastern Cooperative Oncology Group) 0-2
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Life expectancy ≥3 months
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Organ function:
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Absolute neutrophil count ≥1.0×10^9/L
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Platelets ≥100×10^9/L (w/o transfusions w/in 21 days)
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Hemoglobin ≥9 g/dL
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PT (prothrombin time) and PTT (partial thromboplastin time) w/in ≤1.5× ULN
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International normalised ration (INR) ≤1.5× ULN
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Total bilirubin ≤1.5× ULN
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Transaminases (AST and/or alanine aminotransferase) ≤2.5× ULN (<5× ULN with liver metastases)
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Creatinine clearance ≥60 mL/min
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Total calcium (corrected for serum albumin) within normal limits
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Magnesium ≥ lower limit of normal (LLN)
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Normal urinalysis
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Patients must have a T-score greater than -1 to be eligible, however, patients with osteopenia (T-score of -1 to -2.5 at L/R total hip, L/R femoral neck or lumbar spine [L1-L4]) are eligible to participate and will receive calcium and vitamin D supplements during the study. Patients with osteoporosis (T-score of < -2.5) must be excluded.
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Capable of swallowing study medication or has caregiver responsible for administering study drug
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Negative serum pregnancy test
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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.
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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).
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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).
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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).
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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.
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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):
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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.
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Female of childbearing potential, unless birth control is used during study and for 12 weeks after end of treatment.
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Pregnant or nursing (lactating) female.
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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.
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Dose Expansion: Has received previous treatment with pembrolizumab or other immune checkpoint inhibitors.
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Is receiving any concomitant anti-cancer therapy.
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Has used other investigational products within 4 weeks or 5 half-lives (whichever is longer) prior to first dose of study drug.
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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)
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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.
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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 .
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Has history of radiation to spine/pelvis bone or chemoradiation to pelvic organs.
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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.
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Has a history of interstitial lung disease, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, or pulmonary hypersensitivity pneumonitis.
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Has received bisphosphonate therapy for osteoporosis or symptomatic hypercalcaemia, or denosumab for osteoporosis prior to starting study drug.
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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).
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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).
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Has moderate (25%-40% decrease vertebral height) or severe (>40% decrease vertebral height) morphometric vertebral fractures.
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Has ß-CTX serum level >600 pg/mL in the morning after at least 10 hours of fasting at Screening. Note: If patients meet the sole exclusion criteria of ß-CTX serum level
600 pg/mL in the morning after at least 10 hours of fasting at screening, patient can begin their treatment with the bone protective treatment (denosumab with a starting dose of 120 mg, administered SC) as long as the patient has a ß-CTX serum level ≤1000 pg/mL.
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Has thyrotropin level less than lower limit of normal (LLN).
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Has 25-hydroxy vitamin D levels less than 50 mmol/L (20 ng/mL).
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Has bone metastases.
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Has a history of long QT or prolonged QTc (>460 ms).
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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.
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Has metabolic bone disease such as hyperparathyroidism, Paget's disease or osteomalacia.
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Has a known clinically significant bleeding disorder or coagulopathy.
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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).
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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).
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Has a known history of human immunodeficiency virus (HIV) or active bacterial, viral or fungal infections.
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Has a history of gastric bypass surgery.
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Has received prior treatment with an inhibitor of the Wnt-B-catenin pathway.
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Is unwilling or unable to comply with the protocol.
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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.
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Dose Expansion: Patient is unable to provide tumour tissue (from archival tissue or a fresh biopsy or tumour RNA).
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Has received prophylactic administration of hematopoietic colony stimulating factors within 4 weeks prior to starting study drug.
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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.
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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.
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Has a serious non-healing wound.
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Has a history of vasculitis.
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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.
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Anti-SARS-CoV-2 live virus vaccines developed that utilised a replication-deficient simian adenoviral vector (ChAdOx1) should be avoided.
Other protocol-defined inclusion and exclusion criteria may apply.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Arizona Cancer Center, 3838 N. Campbell Avenue | Tucson | Arizona | United States | 85719 |
| 2 | Chao Family Comprehensive Cancer Center,Stern Center for Cancer Clinical Trials and Research, 101 City Drive South | Orange | California | United States | 92668 |
| 3 | University of Colorado Hospital Anschutz Cancer Pavilion, 1665 Aurora Court | Aurora | Colorado | United States | 80045 |
| 4 | Washington University School of Medicine, Siteman Cancer Center, 4921 Parkview Place | Saint Louis | Missouri | United States | 63110 |
| 5 | Duke University Medical Center, Duke Cancer Center, 20 Duke Medicine Circle | Durham | North Carolina | United States | 27710 |
| 6 | Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Mail Code Cr 9-4 | Portland | Oregon | United States | 97239 |
| 7 | The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 455 | Houston | Texas | United States | 77030 |
| 8 | National University Hospital, 1E Kent Ridge Road, NUHS Tower Block, Level 7 | Singapore | Singapore | 119228 | |
| 9 | National Cancer Centre Singapore, 11 Hospital Drive | Singapore | Singapore | 169610 |
Sponsors and Collaborators
- EDDC (Experimental Drug Development Centre), A*STAR Research Entities
- PPD
Investigators
- Study Director: Venkateshan Srirangam Prativadibhayankara, EDDC, Medical Director
- Study Director: Karuppan C Palaniappan, PPD, Medical Director
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- D3-002