ONA-255 for Advanced breast cancer | Metastatic gastric cancer | Gastroesophageal junction adenocarcinoma

Inclusion criteria

• {"criterion_text":"- 1. Female/male with advanced breast cancer or metastatic gastric /gastroesophageal junction cancer ≥ 18 years of age on date of informed consent signature\n- 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\n- 9. Has a life-expectancy of ≥ 6 months\n- 10. Has given written informed consent before start of any study-specific activity\n- 11. Is willing and able to comply with the requirements of the protocol\n- 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\n- 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.\n- 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.\n- 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.\n- 4. ECOG performance status of 0 or 1\n- 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).\n- 6. At least 1 measurable lesion per RECIST 1.1\n- 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"}

Exclusion criteria

• {"criterion_text":"- 1. Brain metastases that are untreated, symptomatic, or require medication to control symptoms, or if treated, are not stable for at least 2 weeks\n- 10. Known human immunodeficiency virus (HIV) infection or active hepatitis (HBV or HCV)\n- 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\n- 12. Patients with large amount of pleural effusion or ascites requiring more than weekly drainage\n- 13. Known auto-immune hepatitis\n- 14. Infection requiring intravenous antibiotic treatment within 1 week prior to enrolment\n- 15. Requiring immunosuppressive therapy or systemic daily chronic corticosteroids above methylprednisolone equivalent of ≥ 10 mg/day\n- 16. Laboratory abnormality that may increase the risk associated with investigational product administration or may interfere with the interpretation of study results\n- 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\n- 18. Known or suspected allergies or hypersensitivities to any of the excipients of the study drug ONA-255 (refer to the IB)\n- 19. Has previously received a FGFR4 inhibitor or an MMAE ADC in a clinical study\n- 2. Visceral crisis with signs and symptoms of impeding or manifested severe organ dysfunction\n- 20. Currently pregnant, breastfeeding, or lactating\n- 21. Psychological, social, familial, or geographic factors that would prevent the study participant to attend study visits\n- 22. Study participants under guardianship or family empowerment measures.\n- 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)\n- 4. Prior radiation therapy to ≥ 25% of the bone marrow\n- 5. Prior therapy with an antibody-drug conjugate within 5 half-lives or 4 weeks (whatever is shorter) of enrolment\n- 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.\n- 7. QTc interval is > 470 msec (average of screening triplicate ECG) or a family or personal history of long QT syndrome\n- 8. Known abnormalities in coagulation, that in the judgment of the investigator, increase the safety risk\n- 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)"}

Primary endpoints

• {"endpoint_text":"- 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)","definition_or_measurement_approach":"DLTs confirmed by SMC based on incidence, nature and severity of TEAEs and SAEs graded per NCI CTCAE v5.0; assessed with changes from baseline in physical exam, vital signs and clinical labs during first 21-day cycle. MBAD defined as first evaluable response either ctDNA decline or RECIST tumour response."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"MBAD defined as first evaluable response either ctDNA decline or RECIST tumour response."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Assessment by incidence and nature of TRAEs, drug interruptions, dose reductions, treatment discontinuations, considered alongside preliminary antitumor data."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"ORR measured as proportion with best overall response CR or PR per RECIST v1.1 as assessed by investigator."}

Secondary endpoints

• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Incidence counts and CTCAE v5.0 grading for laboratory abnormalities; tracking of SAEs/TEAEs/TRAE and treatment modifications and clinically significant changes in exams and vital signs."}
• {"endpoint_text":"- Safety (cont.): Changes in ECOG performance status - Changes in 12-lead ECGs to evaluate the heart rate, atrial ventricular conduction, QTcF, and arrhythmias","definition_or_measurement_approach":"Changes recorded in ECOG status; serial 12-lead ECGs assessing HR, conduction, QTcF and arrhythmias."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"ORR and CBR by RECIST v1.1; Time to Response and DoR as per RECIST-based assessments at investigator sites."}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"PFS and PFS2 measured as time-to-event endpoints from enrolment/randomisation to progression or death with standard survival analysis."}
• {"endpoint_text":"- Immunogenicity: - ADA prevalence and incidence Titre and neutralizing antibodies will be determined when -- ADA is positive","definition_or_measurement_approach":"Anti-drug antibody (ADA) prevalence and incidence measured; titres and neutralizing antibodies assessed when ADA positive."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"PK parameters (Cmax, Ctrough, tmax, AUCs, clearance, volume, half-life) measured from plasma samples at specified PK timepoints in Cycle 1 and/or Cycle 3."}

Other endpoints

• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Tumour tissue and plasma molecular analyses including IHC, mRNA, PAM50, targeted DNA sequencing and ctDNA profiling per assay-specific methods (RNADX/DNADX)."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"HER2 assessed by IHC; optional implantation of fresh patient-derived tumour tissue in animal models to study response/resistance mechanisms."}

Spain

Earliest CTIS Part Ii Submission Date

14-10-2025

Latest Decision Or Authorization Date

19-11-2025

Processing Time Days

36

Number Of Sites

6

Number Of Participants

117

Primary sponsor

Full Name

Ona Therapeutics S.L.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Spain

Contract research organisations

Name

Iqvia Biotech Limited

Responsibilities

codes: [1,12,3,5,6,8]

Name

Medidata Solutions Inc.

Responsibilities

codes: [7]

Third parties

• {"country":"United Kingdom","full_name":"Iqvia Biotech Limited","duties_or_roles":"codes: [1,12,3,5,6,8]","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"codes: [7]","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Spain","full_name":"Alcura Health Espana S.A.","duties_or_roles":"IMP Distribution","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Docs24 Limited","duties_or_roles":"Printing and binding","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Discovery Life Sciences Biomarker Services GmbH","duties_or_roles":"Inmunohistochemistry","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"Imaging storage","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"Reveal Genomics S.L.","duties_or_roles":"Biomarkers (RNADx, DNADx and ctDNA)","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Charles River Laboratories Evreux","duties_or_roles":"Storage of materials, Bio Analysis","organisation_type":"Pharmaceutical company"}