A Phase I/II Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of EP0031 in Patients with Advanced RET-Altered Malignancies
- Trial ID
- 2022-501636-42-00
- Protocol
- EP0031-101
- Sponsor
- Ellipses Pharma Limited
Trial statistics
Diseases & Conditions
Objectives
The primary objectives of this study are to evaluate the safety and tolerability of EP0031 administered as monotherapy in patients with advanced RET-altered malignancies. Additionally, the study aims to assess the efficacy of EP0031, as measured by RECIST v1.1, in patients with RET-altered tumors who have either received a first-generation selective RET inhibitor or have no prior exposure to such therapy. In Module B, the evaluation specifically includes patients with RET fusion-positive non-small cell lung cancer.
The secondary objectives involve:
- Characterization of the pharmacokinetics of EP0031 following single and multiple doses to determine steady state levels.
- Continued investigation of safety and tolerability across the study modules.
- Assessment of efficacy within Module B.
Participants
This study involves 269 participants diagnosed with advanced RET-altered malignancies. The population includes both male and female adult patients aged 18 years or older. Eligible individuals present with locally advanced or metastatic medullary thyroid cancer, non-small cell lung cancer, or other solid tumours characterized by RET fusions or mutations as confirmed by DNA- or RNA-based assays. Participants are categorized based on prior exposure to selective RET inhibitors and specific disease characteristics. Key inclusion requirements include an ECOG performance status of 0 or 1 and a life expectancy exceeding 3 months. Certain cohorts require measurable disease according to RECIST v1.1 standards.
Plans and Procedures
This is a modular, open-label, Phase I/II study designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of EP0031 in patients diagnosed with advanced RET-altered malignancies. The research methodology is organized into three modules: Module A focuses on safety and tolerability of EP0031 as a monotherapy, while Modules B and C assess efficacy in specific patient populations, including those with non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC), both with and without prior selective RET inhibitor (SRI) therapy. The study utilizes RECIST v1.1 criteria to measure tumor response, progression-free survival (PFS), and overall survival (OS). Primary endpoints for safety include the incidence of dose-limiting toxicities (DLTs), adverse events (AEs), and serious adverse events (SAEs). Participants must meet specific inclusion criteria, such as having documented RET alterations via DNA or RNA-based assays, an ECOG performance status of 0 or 1, and a life expectancy exceeding 3 months. The study involves multiple cohorts to evaluate different disease states and treatment histories. While a specific total duration for individual participant involvement is not provided, the recruitment period is estimated to occur between December 2022 and December 2026.
Treatment
The experimental treatment consists of EP0031, an orphan drug administered in capsule form via the oral route.
Background therapies include cisplatin, carboplatin, and pemetrexed, which are administered through intravenous infusion.
Efficacy
The assessment of efficacy in patients with advanced RET-altered malignancies is conducted through several parameters. In Modules B and C, efficacy is evaluated based on tumor response as defined by RECIST v1.1. Specific measures include objective response rate, best overall response, duration of response, time to response, and change in tumor size. Additionally, progression-free survival and overall survival are utilized as clinical endpoints.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Inclusion criteria applicable to all patients: Male or female patients ≥ 18 years of age with a diagnosis of advanced solid tumour
- Inclusion criteria for Modules B and C, Cohorts 1 and 2 (NSCLC): Measurable disease as defined by RECIST v1.1
- Cohort 1a (monotherapy): Patients with locally advanced or metastatic NSCLC with RET fusion who have received one prior first-generation SRI and one line of platinum-based doublet chemotherapy ± immunotherapy (in any order)
- Ability to swallow and retain oral medication
- Documented RET‐altered cancers as determined by DNA‐ or RNA‐based assay of tumour tissue and/or liquid biopsy
- Patients with RET‐altered cancers that may be eligible for the study, who have not received a prior SRI should be well informed and consented about alternative treatment options including approved RET‐targeted therapies.
- Patients with RET‐altered cancers that may be eligible for the study having progressed on a prior SRI should be well informed and consented about alternative approved therapies, as applicable.
- ECOG performance status of 0 or 1 and life expectancy > 3 months
- Inclusion criteria for Modules B and C, Cohorts 3 and 4 (MTC): Measurable disease as defined by RECIST v1.1
- Cohort 3: Patients with locally advanced or metastatic MTC with RET mutation who have received one prior first -generation SRI (one prior multi-kinase inhibitor is permitted)
- Cohort 4: Patients with locally advanced or metastatic MTC with RET mutation with no prior SRI (one prior multi-kinase inhibitor is permitted)
- Ability to understand and provide written informed consent before any study-specific procedures
- Inclusion criteria for Module B, Cohorts 5 and 6 (other solid tumours): Solid tumour measurable by RECIST v1.1
- Willing to participate in all required evaluations and procedures
- Inclusion criteria for Module A: Measurable or non-measurable disease as per RECIST v1.1
- Cohort 1b (monotherapy): Patients with locally advanced or metastatic NSCLC with RET fusion who have received one prior first-generation SRI in the first-line setting
- Inclusion criteria 14 as described in the Protocol.
- Cohort 2a (monotherapy, first-line): Patients with locally advanced or metastatic NSCLC with RET fusion
- Inclusion criteria 16 as described in the Protocol.
- Patients in the paired biopsy cohort must have progressed on prior SRI and have a tumour that is accessible (provided that the Investigator judges the biopsy is technically feasible with minimal risk to the patient and with patient consent)
- Cohort 5: Patients with other locally advanced or metastatic solid tumours with RET fusions (tumour agnostic) who have received one prior first-generation SRI. Up to three prior lines of standard therapies are permitted
- Cohort 6: Patients with other locally advanced or metastatic solid tumours with RET fusions (tumour agnostic) with no prior SRI and no satisfactory alternative treatment option. Up to three prior lines of standard therapies are permitted
- Inclusion criterion for paired biopsy cohort (relevant to Module B, Cohorts 1a, 1b, 3, and 5, only): Patients who have a tumour that is accessible, and this will not interfere with RECIST assessments
Exclusion Criteria
- Any known major driver gene alterations other than RET. If a patient has any other significant molecular alterations besides RET, the Investigator should discuss with the Medical Monitor whether the patient can be enrolled
- Breastfeeding or pregnancy
- Receipt of any immunotherapy or antibody therapy within 21 days before the first dose of EP0031
- Any other invasive malignancy that has been active or treated within the past 2 years, with the exception of cervical intraepithelial neoplasia and non-melanoma skin cancer
- Any unresolved toxicities from prior systemic therapy greater than CTCAE Grade 1 at the time of starting study drug, with the exception of alopecia and Grade 2 chemotherapy-induced neuropathy
- Spinal cord compression or brain metastases. Patients with stable brain metastases who have completed definitive therapy, and have a stable neurological status for at least 4 weeks after completion of definitive therapy can be enrolled. Patients with asymptomatic brain metastases may be eligible for inclusion if, in the opinion of the Investigator, immediate definitive treatment is not indicated
- Active infection requiring systemic antibiotic, antifungal, or antiviral medication within 7 days prior to first dose of EP0031
- Severe or uncontrolled medical condition (eg, severe Parkinson’s disease, active inflammatory bowel disease, severe chronic obstructive pulmonary disease, or ILD/pneumonitis – patients with a history of ILD/pneumonitis that has recovered to ≤ Grade 1 can be enrolled after discussion with the Medical Monitor)
- Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: a. ANC < 1.5 × 109/L b. Platelet count < 100 × 109/L c. Haemoglobin < 90 g/L
- Any clinically important abnormalities in rhythm, conduction, or morphology on resting ECG (eg, complete left bundle branch block, third-degree heart block, confirmed QTcF > 470 msec on screening ECG). Controlled AF is permitted
- Any factor that increases the risk of QTc prolongation or of arrhythmic events (eg, congenital long QT syndrome, immediate family history of long QT syndrome, or sudden cardiac death under 40 years of age, or requirement for concomitant medications that are known to prolong the QTc interval and cause Torsade de Pointes within < 5 half-lives before the first dose of EP0031
- Active bleeding diatheses; patients on anticoagulation medication should be on a stable dose
- Congestive heart failure Grade III–IV according to the New York Heart Association, myocardial infarction, or unstable angina within the previous 6 months
- Uncontrolled hypertension (ie, sustained systolic BP > 150 mmHg or diastolic BP > 90 mmHg)
- Corneal ulceration or untreated keratitis at the screening ophthalmic assessment
- For MTC patients: involvement of the trachea or oesophagus, or complete encasement of great vessels (eg, aorta or pulmonary artery) that could result in -life-threatening complications due to rapid tumour regression
- Any major surgical procedure within 4 weeks of the first dose of study treatment or planned or anticipated during study treatment
- Chronic glomerulonephritis or renal transplant
- Known active hepatitis B or C infection
- Receipt of any systemic anti-cancer therapy (with the exception of immunotherapy or antibody therapy) and radiotherapy within 2 weeks or < 5 half-lives, whichever is shorter, before the first dose of EP0031. Exceptions: GnRH or LHRH agonists, aromatase inhibitors, or SERMs that the patient has been on for the previous 28 days for the primary cancer are allowed, provided they are not on the list of prohibited concomitant medications
- Receipt of any strong inhibitor or inducer of CYP3A4 within 2 weeks or < 5 half-lives, whichever is shorter, before the first dose of EP0031
- Impaired hepatic or renal function as demonstrated by any of the following laboratory values: a. AST or ALT ≥ 3 × ULN b. Patients with liver metastases: AST or ALT ≥ 5 x ULN c. Total bilirubin ≥ 1.5 × ULN d. CrCl ≤ 50 mL/min (based on Cockcroft Gault)
- Serum calcium, magnesium, or potassium below institutional LLN (can be corrected prior to enrolment)
- Patients with active HIV infection. Patients living with HIV will be eligible if they have CD4+ T-cell count ≥ 350 cells/μL, no history of AIDS-defining opportunistic infections in the past 12 months, and can be managed on a regimen consistent with the permitted concomitant medications defined in this protocol
- Known hypersensitivity to other SRIs or to the excipients of EP0031
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 01 Dec 2022 | 30 |
 Germany | Recruiting | 01 Dec 2022 | 20 |
 Italy | Recruiting | 01 Dec 2022 | 20 |
 Poland | Recruiting | 01 Dec 2022 | 10 |
 Spain | Recruiting | 01 Dec 2022 | 40 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PEMETREXED | Other | — | INTRAVENOUS INFUSION | — | — | SUB09655MIG |
CISPLATIN | Other | — | INTRAVENOUS INFUSION | — | — | SUB07483MIG |
CARBOPLATIN | Other | — | INTRAVENIOUS INFUSION | — | — | SUB06614MIG |