A study to investigate the safety and efficacy of ONA-255 in participants with advanced cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ona Therapeutics S.L.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Dec 2025 → ongoing

Decision date (initial)

2025-11-19

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Ona Therapeutics S.L.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Pharmacodynamic, Efficacy

Phase 1a: Determine the minimum biological active dose (MBAD), and the maximum tolerated dose (MTD) of ONA 255 single agent.
Phase 1b: Determine the optimal dose and recommended Phase 2 dose (RP2D) of ONA 255 single agent in HR+/HER2- aBC
If applicable: Determine the optimal dose and RP2D of ONA 255 in metastatic GC/GEJ cancer
Phase 2a: Assess the preliminary Overall Response Rate of ONA-255 single agent at the RP2D level

Secondary objectives 4

1. 1. All phases: Assess safety and tolerability of ONA-255 as single agent.
2. 2. All phases: Assess immunogenicity
3. 3. Phase 1a and 1b: Characterization the PK profile of ONA-255, total antibody (tAB), and MMAE
4. 4. Phase 2a: Further PK assessments of the PK profile of ONA-255, total antibody (tAB), and MMAE based on sparse sampling

Conditions and MedDRA coding

Advanced cancer; breast cancer; metastatic gastric / gastroesophageal junction cancer

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

Spanish Agency Of Medicines And Medical Devices

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 1. Female/male with advanced breast cancer or metastatic gastric /gastroesophageal junction cancer ≥ 18 years of age on date of informed consent signature
2. 2. Histopathologically confirmed advanced HR+/HER2- breast cancer, based on either a new biopsy obtained from a metastatic lesion during screening or an archival formalin fixed paraffin-embedded (FFPE) metastatic tissue sample collected within 12 months prior to the date of screening. HR+ is defined as estrogen receptor (ER) and/or progesterone receptor (PR) expression in more than 1% of tumour cells. HER2- is defined as an immunohistochemistry (IHC) score of 0–1+ or 2+ with a negative FISH, CISH, or SISH test. OR Histopathological confirmed metastatic gastric / gastroesophageal adenocarcinoma. Either new biopsy from metastatic lesion during screening or archival biopsy sample from a metastatic lesion (paraffin embedded) which was collected within 12 months from the date of screening needs to be available
3. 3. Phase 1a: Participants with advanced HR+/HER2- breast cancer or metastatic gastric/gastroesophageal junction cancer who have no effective or tolerable standard therapy options, or for whom standard-of-care therapy is unavailable or inappropriate.
4. 3. Phase 1b: aBC cohorts: Participants with advanced HR+/HER2- breast cancer who has progressive or primary resistant disease following at least 1 line of standard endocrine therapy—including a CDK4/6 inhibitor—and at least 1 line of chemotherapy or antibody-drug conjugate. This includes chemotherapy administered within 1 year prior to study enrollment in the early disease setting. OR If applicable (cohort is opened for enrolment) – metastatic GC/GEJ cancer cohort(s): Participants with metastatic gastric or gastroesophageal junction cancer who have progressed or shown primary resistance after at least 2 lines of standard therapy. For HER2-positive patients, treatment must have included trastuzumab-based therapy.
5. 3. Phase 2a: aBC cohort: Participants with advanced HR+/HER2- breast cancer who has progressive or primary resistant disease following at least 1 line of standard endocrine therapy—including a CDK4/6 inhibitor—and at least 1 line of chemotherapy or antibody-drug conjugate, but not more than 3 lines of chemotherapy or antibody-drug conjugate. This includes chemotherapy administered within 1 year prior to study enrollment in the early disease setting. OR If applicable (cohort is opened for enrolment) – metastatic GC/GEJ cancer cohort: • Participants with metastatic gastric or gastroesophageal junction cancer who have progressed or shown primary resistance after at least 2 lines of standard therapy. For HER2-positive participants, treatment must have included trastuzumab-based therapy. • Participants with HER2-negative metastatic gastric or gastroesophageal junction cancer who have progressed or shown primary resistance after at least 1 line of standard therapy and have contraindications to antiangiogenic treatment.
6. 4. ECOG performance status of 0 or 1
7. 5. Adequate laboratory values for bone marrow (without transfusion support less than 1 week ago) and organ function: •Absolute neutrophil count ≥ 1.5 x 109/L •Platelets ≥ 75 × 109/L •Haemoglobin ≥ 9 g/dL without RBC transfusion within 7 days of screening •Potassium, sodium, and calcium (corrected for serum albumin), within normal limits •Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥60 ml/min for study participants with serum creatinine ≥ 1.5 × ULN (calculated by the Cockcroft-Gault Method) •In absence of liver metastasis, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN. If the study participant has liver metastases, ALT and AST should be ≤ 5 × ULN. •Total serum bilirubin ≤ 1.5 x ULN; (total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in study participants with Gilbert‘s Syndrome).
8. 6. At least 1 measurable lesion per RECIST 1.1
9. 7. If female of childbearing potential, agrees to use highly effective form of contraception during the study and for 6 months and 20 days after the last treatment with ONA-255 or is of postmenopausal status. • Highly effective methods of contraception as defined by: i. Bilateral tubal ligation ii. Hormonal contraception iii. Intrauterine device iv. Vasectomised sexual partner (provided that partner is the sole sexual partner of the WOCBP study participant and that the vasectomised partner has received medical assessment of the surgical success) v. Sexual abstinence, ie, refraining from heterosexual intercourse (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the study participant) •Postmenopausal status as defined by: vi. Prior bilateral oophorectomy vii. Age ≥ 60 years viii. Age < 60 years and amenorrhoea for ≥ 12 months (in the absence of chemotherapy, tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the postmenopausal range per local normal range
10. 8. For male study participants: if fertile and sexually active, and the partner is of childbearing potential (see definition in inclusion #7), agrees to use methods of highly effective contraception (see definition in inclusion criterion #7) during the study and for 3 months and 20 days after the last treatment with ONA-255
11. 9. Has a life-expectancy of ≥ 6 months
12. 10. Has given written informed consent before start of any study-specific activity
13. 11. Is willing and able to comply with the requirements of the protocol

Exclusion criteria 22

1. 1. Brain metastases that are untreated, symptomatic, or require medication to control symptoms, or if treated, are not stable for at least 2 weeks
2. 2. Visceral crisis with signs and symptoms of impeding or manifested severe organ dysfunction
3. 3. Major surgery, chemotherapy, radiotherapy, investigational agent, or other anticancer therapy (within 3 weeks before enrolment for myelotoxic therapies and 14 days for non myelotoxic therapies)
4. 4. Prior radiation therapy to ≥ 25% of the bone marrow
5. 5. Prior therapy with an antibody-drug conjugate within 5 half-lives or 4 weeks (whatever is shorter) of enrolment
6. 6. Have received a strong CYP3A inducer within 21 days of the first study drug administration or a strong CYP3A inhibitor within 14 days of the first dose of study drug.
7. 7. QTc interval is > 470 msec (average of screening triplicate ECG) or a family or personal history of long QT syndrome
8. 8. Known abnormalities in coagulation, that in the judgment of the investigator, increase the safety risk
9. 9. Unresolved toxicity from previous anti-cancer treatment of ≥ Grade 2 (NCT CTCAE grading version 5.0). Study participants with alopecia of Grade 2 are not excluded. Persistent ≥ Grade 1 neuropathy (NCT CTCAE grading version 5.0)
10. 10. Known human immunodeficiency virus (HIV) infection or active hepatitis (HBV or HCV)
11. 11. Severe acute or chronic medical condition (eg, not well controlled diabetes, keratitis, pneumonitis), substance abuse, or psychiatric condition, that in the judgment of the investigator, would put the study participant at a high risk of unwarranted side effects or prevent the participant from being compliant with study procedures or may confound the study interpretation
12. 12. Patients with large amount of pleural effusion or ascites requiring more than weekly drainage
13. 13. Known auto-immune hepatitis
14. 14. Infection requiring intravenous antibiotic treatment within 1 week prior to enrolment
15. 15. Requiring immunosuppressive therapy or systemic daily chronic corticosteroids above methylprednisolone equivalent of ≥ 10 mg/day
16. 16. Laboratory abnormality that may increase the risk associated with investigational product administration or may interfere with the interpretation of study results
17. 17. Concurrent other malignancy or malignancy within 3 years of enrolment, with the exception of adequately treated, basal or squamous cell carcinoma, non melanomatous skin cancer or curatively resected cervical cancer with no evidence of disease within the last 1 year
18. 18. Known or suspected allergies or hypersensitivities to any of the excipients of the study drug ONA-255 (refer to the IB)
19. 19. Has previously received a FGFR4 inhibitor or an MMAE ADC in a clinical study
20. 20. Currently pregnant, breastfeeding, or lactating
21. 21. Psychological, social, familial, or geographic factors that would prevent the study participant to attend study visits
22. 22. Study participants under guardianship or family empowerment measures.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Phase 1a: Number and proportion of participants who experience at least 1 dose limiting toxicity (DLT) as confirmed by SMC based on incidence, nature, and severity of TEAEs, and SAEs graded according to NCI CTCAE v5.0 as well as on changes from baseline in physical examination, vital signs, and clinical laboratory tests during the first 21-day cycle. MBAD (first evaluable response to treatment with ONA-255 – either ctDNA decline or RECIST tumour response – whatever is occurring at a lower dose)
2. Phase 1a (cont.): MBAD (first evaluable response to treatment with ONA-255 – either ctDNA decline or RECIST tumour response – whatever is occurring at a lower dose)
3. Phase 1b: Safety and tolerability of ONA-255 monotherapy as assessed by Treatment Related Adverse Events (TRAE), drug interruptions, dose reductions and treatment discontinuations under consideration of preliminary antitumor data
4. Phase 2a: Investigator-assessed ORR defined as the proportion of study participants with a best overall response of complete (CR) or partial (PR) response as per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Eisenhauer at al., 2009)

Secondary endpoints 8

1. Safety: Incidence of SAEs - Incidence of TEAEs and TRAEs - Rate of treatment modification (dose interruption, dose reductions) and treatment discontinuations - Changes in clinical laboratory measures with laboratory abnormal graded according to NCT-CTCAE version 5.0 - Clinically significant changes in physical examination - Changes in vital signs (blood pressure, respiratory rate and temperature)
2. Safety (cont.): Changes in ECOG performance status - Changes in 12-lead ECGs to evaluate the heart rate, atrial ventricular conduction, QTcF, and arrhythmias
3. Efficacy: - Investigator assessed ORR (CR + PR) for entire study using RECIST 1.1 response criteria - Clinical Benefit rate (CBR) (CR + PR + SD ≥ 6 months) for entire study / RP2D - Time to Response for entire study / RP2D - Duration of Response (DoR) (CR + PR) for entire study / RP2D
4. Efficacy (cont.): - PFS for entire study / RP2D - PFS2 (time from enrolment/randomisation to this study to objective disease progression under subsequent treatment, or death from any cause, whichever is first)
5. Immunogenicity: - ADA prevalence and incidence Titre and neutralizing antibodies will be determined when -- ADA is positive
6. Pharmacokinetic Cycle 1 and/or Cycle 3: Cmax, Ctrough, tmax, AUC(0-last), AUC(0-504), AUC(0 inf) (Cycle 1 only), CL (for MMAE: CL/F), Vss (for MMAE: Vz/F), t1/2
7. Exploratory Endpoints: - Tumour tissue: FGFR4 expression (IHC, mRNA as part of RNADX assessment) - Tumour tissue: molecular subtype by PAM50 assay and other genomic signatures (RNA) - Tumour tissue: ESR1/PIK3CA/TP53/RB1 mutation status (DNA sequencing) - Tumour tissue and plasma (DNA): DNADX subtypes and signatures, including, eg, ER signaling, RB-LOH; for plasma also tumour fraction (ctDNA)
8. Exploratory Endpoints (cont.): - Tumour tissue: HER2 status (IHC) - Tumour tissue: implantation of fresh patient-derived tumour tissue in an animal model to study the mechanism of response and resistance to ONA-25

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ona Therapeutics S.L.

Sponsor organisation

Ona Therapeutics S.L.

Address

Calle Baldiri Reixac Num. 10, Poligono Industrial Parc Cientific De Barcelona Poligono Industrial Parc Cientific De Barcelona

City

Barcelona

Postcode

08028

Country

Spain

Scientific contact point

Organisation

Ona Therapeutics S.L.

Contact name

Mercè de Frias

Public contact point

Organisation

Ona Therapeutics S.L.

Contact name

Mercè de Frias

Third parties 8

Locations

1 EU/EEA country · 6 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 11 files

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

Application history

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