A study investigating the use of EP0031 in patients with cancers having an abnormal RET gene.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ellipses Pharma Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 Mar 2023 → ongoing

Decision date (initial)

2023-08-07

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Ellipses Pharma Limited

External identifiers

EU CT number

2022-501636-42-00

ClinicalTrials.gov

NCT05443126

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Pharmacodynamic, Safety, Efficacy, Pharmacokinetic

Module A: To investigate the safety and tolerability of EP0031 given as monotherapy.
Modules B & C: To assess the efficacy of EP0031 given as monotherapy in patients with RET-altered tumours who have received one first generation SRI therapy and in patients with RET-altered tumours with no prior SRI therapy (by RECIST v1.1)
Module B: To assess the safety and tolerability in RET fusion positive NSCLC patients who have received a first-generation SRI therapy or who have received no prior SRI therapy.

Secondary objectives 1

1. Module A: To characterize the PK of EP0031 given as monotherapy, after a single dose and at steady state after multiple dosing. Modules B & C: To investigate the safety and tolerability of EP0031 given as monotherapy. To characterize the PK of EP0031 given as monotherapy. Module B: To investigate the efficacy. To characterise the PK.

Conditions and MedDRA coding

Advanced RET-altered malignancies

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 23

1. Inclusion criteria applicable to all patients: Male or female patients ≥ 18 years of age with a diagnosis of advanced solid tumour
2. Inclusion criteria for Modules B and C, Cohorts 1 and 2 (NSCLC): Measurable disease as defined by RECIST v1.1
3. 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)
4. Ability to swallow and retain oral medication
5. Documented RET‐altered cancers as determined by DNA‐ or  RNA‐based assay of tumour tissue and/or liquid biopsy
6. 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.
7. 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.
8. ECOG performance status of 0 or 1 and life expectancy > 3 months
9. Inclusion criteria for Modules B and C, Cohorts 3 and 4 (MTC): Measurable disease as defined by RECIST v1.1
10. 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)
11. Cohort 4: Patients with locally advanced or metastatic MTC with RET mutation with no prior SRI (one prior multi-kinase inhibitor is permitted)
12. Ability to understand and provide written informed consent before any study-specific procedures
13. Inclusion criteria for Module B, Cohorts 5 and 6 (other solid tumours): Solid tumour measurable by RECIST v1.1
14. Willing to participate in all required evaluations and procedures
15. Inclusion criteria for Module A: Measurable or non-measurable disease as per RECIST v1.1
16. 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
17. Inclusion criteria 14 as described in the Protocol.
18. Cohort 2a (monotherapy, first-line): Patients with locally advanced or metastatic NSCLC with RET fusion
19. Inclusion criteria 16 as described in the Protocol.
20. 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)
21. 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
22. 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
23. 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 25

1. 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
2. Breastfeeding or pregnancy
3. Receipt of any immunotherapy or antibody therapy within 21 days before the first dose of EP0031
4. 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
5. 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
6. 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
7. Active infection requiring systemic antibiotic, antifungal, or antiviral medication within 7 days prior to first dose of EP0031
8. 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)
9. 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
10. 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
11. 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
12. Active bleeding diatheses; patients on anticoagulation medication should be on a stable dose
13. Congestive heart failure Grade III–IV according to the New York Heart Association, myocardial infarction, or unstable angina within the previous 6 months
14. Uncontrolled hypertension (ie, sustained systolic BP > 150 mmHg or diastolic BP > 90 mmHg)
15. Corneal ulceration or untreated keratitis at the screening ophthalmic assessment
16. 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
17. Any major surgical procedure within 4 weeks of the first dose of study treatment or planned or anticipated during study treatment
18. Chronic glomerulonephritis or renal transplant
19. Known active hepatitis B or C infection
20. 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
21. 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
22. 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)
23. Serum calcium, magnesium, or potassium below institutional LLN (can be corrected prior to enrolment)
24. 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
25. Known hypersensitivity to other SRIs or to the excipients of EP0031

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Module A: Incidence of DLTs, AEs, SAEs, and changes in laboratory parameters, physical examination, vital signs, and ECG Modules B & C: Tumour response as per RECIST v1.1 (ORR, BOR, DOR, TTR, change in tumour size), PFS and OS. Module B: Incidence of DLTs, AEs, SAEs, and changes in laboratory parameters, physical examination, vital signs, and ECG

Secondary endpoints 2

1. Module A: Plasma PK parameters (AUC0-48, AUClast, AUCinf, Cmax and/or Cmin, tmax, t½, CL/F, V/F, and/or Vz/F) after single and multiple doses. Modules B & C: Incidence of AEs, SAEs, and changes in laboratory parameters, physical examination, vital signs, and ECG Plasma PK parameters (eg, AUC0-48, AUClast, AUCinf, Cmax and/or Cmin, tmax, t½, CL/F, V/F, and/or Vz/F).
2. Module B: Tumour response as per RECIST v1.1 (ORR, BOR, DOR, TTR, change in tumour size), PFS and OS. Plasma PK parameters (eg, AUC0-48, AUClast, AUCinf, Cmax and/or Cmin, tmax, t½, CL/F, V/F, and/or Vz/F) after single and multiple doses

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ellipses Pharma Limited

Sponsor organisation

Ellipses Pharma Limited

Address

10 Stratton Street

City

London

Postcode

W1J 8LG

Country

United Kingdom

Scientific contact point

Organisation

Ellipses Pharma Limited

Contact name

Sue Brook

Public contact point

Organisation

Ellipses Pharma Limited

Contact name

Sonia Serrano

Third parties 6

Locations

5 EU/EEA countries · 25 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 140 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

14 submissions — initial application plus substantial / non-substantial modifications