Overview
Sponsor-declared trial summary
Phase
Phase I and Phase II (Integrated) - Other
Status
Ongoing, recruitment ended
Participants planned
275
Countries
5
Sites
25
Solid Tumors, Colorectal Cancer and Breast Cancer
Phase 1a: ELVN-002 + Trastuzumab: Evaluate the safety and tolerability of ELVN-002 in combination with trastuzumab in participants with advanced stage HER2 positive solid tumors. Determine the recommended dose(s) (RD) of ELVN-002 in combination with trastuzumab in participants with advanced stage HER2 positive solid tu…
Key facts
- Sponsor
- Enliven Therapeutics Inc.
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Neoplasms [C04]
- Trial duration
- 23 Sep 2024 → ongoing
- Decision date (initial)
- 2024-08-20
- Transition trial
- No
- Low-intervention
- No
- Rare-disease indication
- No
- Vulnerable population
- Yes
- Funding sources
- Enliven Therapeutics, Inc
External identifiers
- EU CT number
- 2023-509716-29-00
- ClinicalTrials.gov
- NCT06328738
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Dose response, Pharmacokinetic, Efficacy, Pharmacodynamic, Therapy
Phase 1a: ELVN-002 + Trastuzumab: Evaluate the safety and tolerability of ELVN-002 in combination with trastuzumab in participants with advanced stage HER2 positive solid tumors.
Determine the recommended dose(s) (RD) of ELVN-002 in combination with trastuzumab in participants with advanced stage HER2 positive solid tumors
Phase 1a: ELVN-002 + Trastuzumab + Chemotherapy: Evaluate the safety and tolerability of treatment of ELVN-002 + trastuzumab + CAPEOX or mFOLFOX6 chemotherapy (capecitabine with oxaliplatin or 5-fluorouracil/leucovorin with oxaliplatin) in participants with advanced stage HER2 positive colorectal cancer.
Evaluate the safety and tolerability of treatment of ELVN-002 + trastuzumab + chemotherapy (eribulin, capecitabine or paclitaxel), in participants with advanced stage HER2 positive breast cancer
Determine the RD(s) of ELVN-002 when given in combination with trastuzumab and chemotherapy in participants with advanced stage HER2 positive colorectal cancer or breast cancer, or in combination with trastuzumab and paclitaxel in HER2 positive solid tumors
Phase 1b: Evaluate the safety and tolerability of treatment with ELVN-002 and trastuzumab in HER2 positive colorectal and breast cancer, and in participants with advanced stage HER2 positive solid tumors.
Evaluate the safety and tolerability of treatment with ELVN-002 + trastuzumab + chemotherapy (CAPEOX or mFOLFOX6) in participants with advanced stage HER2 positive colorectal cancer (CRC)
Secondary objectives 7
- Phase 1a: Assess the pharmacokinetic (PK) profile of ELVN-002 when administered with trastuzumab +/- chemotherapy.
- Phase 1a: Assess preliminary anti-tumor activity of ELVN-002 + trastuzumab in participants with advanced stage solid tumors.
- Phase 1a: Assess preliminary anti-tumor activity of ELVN-002 + trastuzumab + chemotherapy in participants with advanced stage HER2 positive CRC or breast cancer
- Phase 1b: Evaluate the clinical benefit of treatment with ELVN-002 + trastuzumab in participants with advanced stage HER2 positive solid tumors
- Phase 1b: Evaluate the clinical benefit of treatment with ELVN-002 + trastuzumab + chemotherapy in participants with advanced stage HER2 positive CRC.
- Phase 1b: Evaluate the anti-tumor activity against brain metastases of ELVN-002 + trastuzumab +/- chemotherapy in participants with brain metastases at baseline.
- Phase 1b: Assess the PK of ELVN-002 in HER2 positive colorectal cancer.
Conditions and MedDRA coding
Solid Tumors, Colorectal Cancer and Breast Cancer
| Version | Level | Code | Term | System organ class |
|---|---|---|---|---|
| 23.0 | PT | 10065430 | HER2 positive breast cancer | 100000004864 |
| 21.0 | LLT | 10049280 | Solid tumour | 10029104 |
| 21.0 | PT | 10052360 | Colorectal adenocarcinoma | 100000004864 |
Study design 4 periods
| # | Title | Allocation | Blinding | Roles blinded | Arms |
|---|---|---|---|---|---|
| 1 | PART 1: Phase 1a: ELVN-002 in Combination with Trastuzumab Dose Escalation For the first dose cohort in Part 1, participants enrolled will receive ELVN-002 orally at 45 mg BID on Days 1-7 followed by 90 mg BID on Days 8 and subsequent days, which is a dose level that is ≤ the maximum tolerated dose (MTD) of ELVN-002 that has been deemed safe and tolerable by the Safety Review Committee in the ongoing monotherapy ELVN-002 study, ELVN-002-001. ELVN-002 will be administered orally starting on C1D1. ELVN-002 dosing will continue daily dosing throughout the DLT evaluation window. The first dose of trastuzumab will be administered IV at 8 mg/kg on C1, D2. Participants who successfully complete the DLT evaluation window will continue to receive ELVN-002 at the assigned daily dose level and trastuzumab in 21-day cycles. Starting with Cycle 2, the trastuzumab dose will be 6 mg/kg, administered IV Day 1 of 21-day cycles. Dosing for both ELVN-002 and trastuzumab will continue until disease progression or one of the protocol-specified stopping criteria has been met.
|
Not Applicable | None | Dose level/ Cohort 1: ELVN-002 45mg BID oward + Trastuzumab: (C1D2: 8 mg/kg (IV); Cycles 2+: 6 mg/kg (IV) Q21D) Dose level/ Cohort 2: ELVN-002 45mg BID (day 1-7) & 67.5mg BID (day 8 onward) + Trastuzumab: (C1D2: 8 mg/kg (IV); Cycles 2+: 6 mg/kg (IV) Q21D) Dose level/ Cohort 3: ELVN-002 45mg BID (day 1-7) & 90mg BID (day 8 onward) + Trastuzumab: (C1D2: 8 mg/kg (IV); Cycles 2+: 6 mg/kg (IV) Q21D) Dose level/ Cohort 4: ELVN-002 45mg BID (day 1-7), 90mg (day 8-14) & 135mg BID (day 15 onward) + Trastuzumab: (C1D2: 8 mg/kg (IV); Cycles 2+: 6 mg/kg (IV) Q21D) Dose level/ Cohort 5: ELVN-002 45mg BID (day 1-7), 90mg (day 8-14), 135mg BID (day 15-21) & 180mg (day 22 onward) + Trastuzumab: (C1D2: 8 mg/kg (IV); Cycles 2+: 6 mg/kg (IV) Q21D) |
|
| 2 | PART 2: ELVN-002 in Combination with Trastuzumab and Chemotherapy Dose Escalation For the first cohort in Part 2, participants will receive ELVN-002 at a dose at least 1 dose level lower than the highest dose tested in Part 1 that was found to be safe and tolerable combined
with trastuzumab.
ELVN-002 will be administered daily in combination with a fixed dose of trastuzumab and chemotherapy (CAPEOX, mFOLFOX6, eribulin, capecitabine, or paclitaxel). The first dose of ELVN-002 will be administered on C1D1, the first dose of chemotherapy will be administered on C1D2. The first dose of trastuzumab will be administered on C1D2 unless an alternative dosing schedule has been identified in Part 1. For subsequent dose cycles, trastuzumab and chemotherapy may be administered on the same day (the trastuzumab dose and schedule may be adjusted to allow the chemotherapy and trastuzumab to be administered on the same day consistent with local standard of care). In the setting of a response or stable disease, chemotherapy may be discontinued after 6 cycles or per institutional standard of care and the participant may continue to receive ELVN-002 and trastuzumab until progression or other stopping criteria are met For CAPEOX and mFOLFOX6, oxaliplatin may be discontinued due to neurotoxicity or per institutional standard of care and the participant may continue to receive capecitabine or 5-FU/LCV in addition to the ELVN-002 and trastuzumab
|
2 | None | Part 2A: ELVN-002 + Trastuzumab + CAPEOX Combination: ELVN-002 45mg BID onward + Trastuzumab: (8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Oxaliplatin 130 mg/ m2 (IV) D1 Q21days Capecitabine 1000 mg/m2 orally BID D1-D14 Q21D Part 2A: ELVN-002 + Trastuzumab + CAPEOX Combination: ELVN-002 45mg BID (day 1-7) & 67.5mg BID (day 8 onward) + Trastuzumab: (8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Oxaliplatin 130 mg/ m2 (IV) D1 Q21days Capecitabine 1000 mg/m2 orally BID D1-D14 Q21D Part 2A: ELVN-002 + Trastuzumab + CAPEOX Combination: ELVN-002 45mg BID (day 1-7) & 90 mg BID (day 8 onward) + Trastuzumab: (8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Oxaliplatin 130 mg/ m2 (IV) D1 Q21days Capecitabine 1000 mg/m2 orally BID D1-D14 Q21D Part 2A: ELVN-002 + Trastuzumab + CAPEOX Combination: ELVN-002 45mg BID (day 1-7), 90mg BID (day 8-14) &135mg BID (day 15 onward) + Trastuzumab: (8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Oxaliplatin 130 mg/ m2 (IV) D1 Q21days Capecitabine 1000 mg/m2 orally BID D1-D14 Q21D Part 2A: ELVN-002 + Trastuzumab + CAPEOX Combination: ELVN-002 45mg BID (day 1-7), 90mg BID (day 8-14), 135mg BID (day 15- 21) & 180mg BID (day 22 onward) + Trastuzumab: (8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Oxaliplatin 130 mg/ m2 (IV) D1 Q21days Capecitabine 1000 mg/m2 orally BID D1-D14 Q21D Part 2B: ELVN-002 + Trastuzumab + mFOLFOX Combination: ELVN-002 45mg BID onward + Trastuzumab: (6 mg/kg IV one dose 14 days later 4 mg/kg IV once every 14 days)+ Oxaliplatin 85 mg/m2 (IV) D1, D15 Q28D + Leucovorin 400 mg/m2 (IV) D1, D15 every 28 days+ 5-Fluorouracil 400 mg/m2 (IV) bolus followed by 2400 mg/m2 (IV) over 46-48 hours D1, D15 every 28 days Part 2B: ELVN-002 + Trastuzumab + mFOLFOX Combination: ELVN-002 45mg BID (day 1-7) & 67.5mg BID (day 8 onward) + Trastuzumab: (6 mg/kg IV one dose 14 days later 4 mg/kg IV once every 14 days)+ Oxaliplatin 85 mg/m2 (IV) D1, D15 Q28D + Leucovorin 400 mg/m2 (IV) D1, D15 every 28 days+ 5-Fluorouracil 400 mg/m2 (IV) bolus followed by 2400 mg/m2 (IV) over 46-48 hours D1, D15 every 28 days Part 2B: ELVN-002 + Trastuzumab + mFOLFOX Combination: ELVN-002 45mg BID (day 1-7) & 90 mg BID (day 8 onward) + Trastuzumab: (6 mg/kg IV one dose 14 days later 4 mg/kg IV once every 14 days)+ Oxaliplatin 85 mg/m2 (IV) D1, D15 Q28D + Leucovorin 400 mg/m2 (IV) D1, D15 every 28 days+ 5-Fluorouracil 400 mg/m2 (IV) bolus followed by 2400 mg/m2 (IV) over 46-48 hours D1, D15 every 28 days Part 2B: ELVN-002 + Trastuzumab + mFOLFOX Combination: ELVN-002 45mg BID (day 1-7), 90mg BID (day 8-14) &135mg BID (day 15 onward) + Trastuzumab: (6 mg/kg IV one dose 14 days later 4 mg/kg IV once every 14 days)+ Oxaliplatin 85 mg/m2 (IV) D1, D15 Q28D + Leucovorin 400 mg/m2 (IV) D1, D15 every 28 days+ 5-Fluorouracil 400 mg/m2 (IV) bolus followed by 2400 mg/m2 (IV) over 46-48 hours D1, D15 every 28 days Part 2B: ELVN-002 + Trastuzumab + mFOLFOX Combination: ELVN-002 45mg BID (day 1-7), 90mg BID (day 8-14), 135mg BID (day 15- 21) & 180mg BID (day 22 onward) + Trastuzumab: (6 mg/kg IV one dose 14 days later 4 mg/kg IV once every 14 days)+ Oxaliplatin 85 mg/m2 (IV) D1, D15 Q28D + Leucovorin 400 mg/m2 (IV) D1, D15 every 28 days+ 5-Fluorouracil 400 mg/m2 (IV) bolus followed by 2400 mg/m2 (IV) over 46-48 hours D1, D15 every 28 days Part 2C: ELVN-002 + Trastuzumab + Capecitabine Combination: ELVN-002 45mg BID onward + Trastuzumab: (All Cohorts 8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Capecitabine (1250 mg/m2 orally BID Days 1-14 every 21 days) Part 2C: ELVN-002 + Trastuzumab + Capecitabine Combination: ELVN-002 45mg BID (day 1-7) & 67.5mg BID (day 8 onward) + Trastuzumab: (8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Capecitabine (1250 mg/m2 orally BID Days 1-14 every 21 days) Part 2C: ELVN-002 + Trastuzumab + Capecitabine Combination: ELVN-002 45mg BID (day 1-7) & 90 mg BID (day 8 onward) + Trastuzumab: (8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Capecitabine (1250 mg/m2 orally BID Days 1-14 every 21 days) Part 2C: ELVN-002 + Trastuzumab + Capecitabine Combination: ELVN-002 45mg BID (day 1-7), 90mg BID (day 8-14) &135mg BID (day 15 onward) + Trastuzumab: (8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Capecitabine (1250 mg/m2 orally BID Days 1-14 every 21 days) Part 2C: ELVN-002 + Trastuzumab + Capecitabine Combination: ELVN-002 45mg BID (day 1-7), 90mg BID (day 8-14), 135mg BID (day 15- 21) & 180mg BID (day 22 onward) + Trastuzumab: (8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Capecitabine (1250 mg/m2 orally BID Days 1-14 every 21 days) Part 2D: ELVN-002 + Trastuzumab + Paclitaxel Combination: ELVN-002 45mg BID onward + Trastuzumab: ( 8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Paclitaxel (80 mg/m2 (IV) Day 1, 8, 15 Q21D) Part 2D: ELVN-002 + Trastuzumab + Paclitaxel Combination: ELVN-002 45mg BID (day 1-7) & 67.5mg BID (day 8 onward) + Trastuzumab: (8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Paclitaxel (80 mg/m2 (IV) Day 1, 8, 15 Q21D) Part 2D: ELVN-002 + Trastuzumab + Paclitaxel Combination: ELVN-002 45mg BID (day 1-7) & 90mg BID (day 8 onward) + Trastuzumab: (8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Paclitaxel (80 mg/m2 (IV) Day 1, 8, 15 Q21D) Part 2D: ELVN-002 + Trastuzumab + Paclitaxel Combination: ELVN-002 45mg BID (day 1-7), 90mg BID (day 8-14), 135mg BID (day 15 onward) + Trastuzumab: (8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Paclitaxel (80 mg/m2 (IV) Day 1, 8, 15 Q21D) Part 2D: ELVN-002 + Trastuzumab + Paclitaxel Combination: ELVN-002 45mg BID (day 1-7), 90mg BID (day 8-14), 135mg BID (day 15- 21) & 180mg BID (day 22 onward) + Trastuzumab: (8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Paclitaxel (80 mg/m2 (IV) Day 1, 8, 15 Q21D) Part 2E: ELVN-002 + Trastuzumab + Eribulin Combination: ELVN-002 45mg BID onward + Trastuzumab: (8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Eribulin (1.4 mg/m2 (IV) Day 1 and 8 every 21 days) Part 2E: ELVN-002 + Trastuzumab + Eribulin Combination: ELVN-002 45mg BID (day 1-7) & 67.5mg BID (day 8 onward) + Trastuzumab: (8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Eribulin (1.4 mg/m2 (IV) Day 1 and 8 every 21 days) Part 2E: ELVN-002 + Trastuzumab + Eribulin Combination: ELVN-002 45mg BID (day 1-7) & 90mg BID (day 8 onward) + Trastuzumab: (8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Eribulin (1.4 mg/m2 (IV) Day 1 and 8 every 21 days) Part 2E: ELVN-002 + Trastuzumab + Eribulin Combination: ELVN-002 45mg BID (day 1-7), 90mg BID (day 8-14), 135mg BID (day 15 onward) + Trastuzumab: (8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Eribulin (1.4 mg/m2 (IV) Day 1 and 8 every 21 days) Part 2E: ELVN-002 + Trastuzumab + Eribulin Combination: ELVN-002 45mg BID (day 1-7), 90mg BID (day 8-14), 135mg BID (day 15- 21) & 180mg BID (day 22 onward) + Trastuzumab: (8 mg/kg IV one dose 21 days later 6 mg/kg IV once every 21 days)+ Eribulin (1.4 mg/m2 (IV) Day 1 and 8 every 21 days) |
|
| 3 | PART 3: Phase 1b: ELVN-002 in Combination with Trastuzumab Dose Expansion The Phase 1b Dose Expansion cohorts with ELVN-002 in combination with trastuzumab will initiate once the RD(s) have been identified in Part 1. Part 3 may initiate enrollment prior to or in parallel with Part 2. Up to 5 tumor types may be expanded, with each cohort enrolling a maximum of 20 participants. If multiple RDs have been identified, more than one dose levels may be opened in parallel for expansion in specific tumor type. Futility will be conducted in each cohort independently after 10 to 12 participants have undergone at least 2 post-baseline tumor assessments or discontinued ELVN-002 permanently.
|
2 | None | Part 3A: ELVN-002 + Trastuzumab in HER2 positive colorectal cancer: Subject with HER2 positive colorectal cancer Part 3B: ELVN-002 + Trastuzumab in HER2 positive breast cancer: Subject with HER2 positive breast cancer Part 3C-E: ELVN-002 + Trastuzumab in HER2 positive solid tumors: Subject with HER2 positive solid tumors |
|
| 4 | Part 4: ELVN-002 Dose expansion + Trastuzumab +CAPEOX or mFOLFOX6 in HER2 positive CRC The Phase 1b Dose Expansion cohorts with ELVN-002 in combination with trastuzumab and CAPEOX or mFOLFOX6 in HER2 positive CRC will initiate once the RD(s) have been identified in Part 2. The decision whether to expand one or both chemotherapy combinations will be based on emerging data from Part 2. If multiple RDs have been identified, more than one dose level may be opened in parallel for expansion. Futility will be conducted after 10 participants have undergone at least 2 post-baseline tumor assessments or discontinued ELVN-002 permanently.
|
2 | None | Part 4: ELVN-002 + Trastuzumab +CAPEOX or mFOLFOX6 Dose expansion in HER2 positive: ELVN-002 Dose expansion + Trastuzumab +CAPEOX or mFOLFOX6 in HER2 positive CRC |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 8
- 1. Participants ≥ 18 years of age at the time of signing the informed consent.
- 2. Pathologically or histologically documented solid tumor.
- 3. Locally advanced or relapsed/refractory disease or unresectable metastatic disease.
- 4. HER2 positive disease (see protocol for futher information)
- 5. Prior Treatment based on Study Part and Histological Tumor Type (see protocol for futher information)
- 6. For Part 3 and Part 4 only (Phase 1b arms): at least 1 measurable lesion based on RECIST v1.1 within 6 weeks prior to first dose of ELVN-002.
- 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- 8. Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) (multigated acquisition [MUGA] allowed if ECHO cannot be performed) within 28 days of the first dose of ELVN-002
Exclusion criteria 24
- 1. Severe cardiac arrhythmias, requiring treatment, symptomatic congestive heart failure (≥ New York Heart Association Functional Classification [NYHAC] II), troponin levels consistent with myocardial infarction within 28 days prior to first dose of ELVN-002, or unstable angina.
- 2. History of another active malignancy within 2 years prior to the first dose except for previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively.
- 3. Serious medical or psychiatric illness likely to interfere with participation in this clinical trial.
- 4. Major surgery within 3 weeks of the first dose of ELVN-002.
- 5. Active or chronic liver disease, including active hepatitis B or C infection.
- 6. Active infection requiring systemic therapy within 14 days before the first dose of ELVN-002.
- 7. History of interstitial lung disease or pulmonary fibrosis.
- 8. Participants for any chemotherapy cohort: ongoing Grade 2 or higher neuropathy of any cause
- 9. Inability to swallow pills or any significant gastrointestinal disease which would preclude adequate oral absorption of medications.
- 10. Treatment with other anticancer therapy according to protocol.
- 11. Any brain lesion requiring immediate local therapy.
- 12. Ongoing use of corticosteroids for central nervous system (CNS) symptoms at a dose of > 2 mg daily of dexamethasone (or equivalent) unless have Sponsor approval.
- 13. Leptomeningeal disease.
- 14. Uncontrolled seizures.
- 15. Ongoing adverse effects from prior treatment > CTCAE Grade 1 except for Grade 2 alopecia
- 16. Corrected QT interval (QTc) of >470 milliseconds (ms) females or >450 ms for males based on average of screening triplicate 12-lead ECG by Fridericia (QTcF)
- 17. Known hypersensitivity to any component of ELVN-002 including inactive ingredients.
- 18. Primary immunodeficiency or known HIV infection. Except patients with undetectable viral load (undetectable viral load must be documented while receiving, for at least 30 days, an anti-retroviral therapy that is not prohibited per Appendix 12).
- 19. Known hypersensitivity to trastuzumab.
- 20. For the combination with eribulin: known hypersensitivity to eribulin or dehydrated alcohol.
- 21. For the combination cohorts with capecitabine: known hypersensitivity to capecitabine or anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate, talc, titanium dioxide, and synthetic yellow and red iron oxides; known DPD deficiency.
- 22. For the combination cohorts with 5-FU: known hypersensitivity to 5-FU or known DPD deficiency.
- 23. For the combination with paclitaxel: known hypersensitivity to Polyoxyl 35 castor oil, NF, dehydrated alcohol, or Citric Acid.
- 24. For the combination cohorts with oxaliplatin: known hypersensitivity oxaliplatin, any of the excipients or other platinum compounds.
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 5
- Phase 1a: ELVN-002 + Trastuzumab: • Incidence of dose limiting toxicities (DLTs)
- Phase 1a: ELVN-002 + Trastuzumab: • Incidence of adverse events (AEs), laboratory abnormalities, and electrocardiogram (ECG) abnormalities
- Phase 1a: ELVN-002 + Trastuzumab + Chemotherapy: • Incidence of dose limiting toxicities (DLTs)
- Phase 1a: ELVN-002 + Trastuzumab + Chemotherapy: • Incidence of dose limiting toxicities (DLTs)
- Phase 1a: ELVN-002 + Trastuzumab + Chemotherapy: • Incidence of adverse events (Aes), laboratory abnormalities, and electrocardiogram (ECG) abnormalities
Secondary endpoints 5
- Phase 1a: ELVN-002 plasma concentrations and PK parameters, including: area under the curve (AUC), maximum concentration (Cmax), timeat which Cmax is observed (Tmax), minimum concentration (Cmin), terminal half-life (T1/2), and other parameters such as dose proportionality and accumulation ratio
- Phase 1a: Confirmed ORR as assessed by investigators per RECIST v1.1
- Phase 1b: Confirmed ORR and DOR as assessed by ICR per RECIST v1.1
- Phase 1b: Brain metastases response
- Phase 1b: ELVN-002 plasma concentrations
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 16
5-FU medac 50 mg/ml, Injektionslösung
PRD536079 · Product
- Active substance
- Fluorouracil
- Pharmaceutical form
- SOLUTION FOR INJECTION
- Route of administration
- INTRAVENOUS
- Authorisation status
- Authorised
- ATC code
- L01BC02 — FLUOROURACIL
- Marketing authorisation
- 41196.00.00
- MA holder
- MEDAC GESELLSCHAFT FÜR KLINISCHE SPEZIALPRÄPARATE MBH (WEDEL)
- MA country
- Germany
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- Yes
- Modification description
- It has been labelled for Clinical Trials according to EU Legislation
HALAVEN 0.44 mg/ml solution for injection
PRD3616237 · Product
- Active substance
- Eribulin
- Pharmaceutical form
- SOLUTION FOR INJECTION
- Route of administration
- INTRAVENOUS ADMINISTRATION
- Authorisation status
- Authorised
- ATC code
- L01XX41 — -
- Marketing authorisation
- EU/1/11/678/002
- MA holder
- EISAI GMBH
- MA country
- Iceland
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- Yes
- Modification description
- It has been labelled for Clinical Trials according to EU Legislation
Benda-5 FU 50 mg/ml Injektionslösung
PRD2947832 · Product
- Active substance
- Fluorouracil
- Pharmaceutical form
- SOLUTION FOR INJECTION
- Route of administration
- INTRAVENOUS
- Authorisation status
- Authorised
- ATC code
- L01BC02 — FLUOROURACIL
- Marketing authorisation
- 55983.00.00
- MA holder
- BENDALIS GMBH
- MA country
- Germany
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- Yes
- Modification description
- It has been labelled for Clinical Trials according to EU Legislation
Herceptin 150 mg powder for concentrate for solution for infusion
PRD2159200 · Product
- Active substance
- Trastuzumab
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- SUBCUTANEOUS USE
- Authorisation status
- Authorised
- ATC code
- L01XC03 — TRASTUZUMAB
- Marketing authorisation
- EU/1/00/145/001
- MA holder
- ROCHE REGISTRATION GMBH
- MA country
- Norway
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- Yes
- Modification description
- It has been labelled for Clinical Trials according to EU Legislation
PRD10185639 · Product
- Active substance
- ELVN-002-1
- Pharmaceutical form
- CAPSULE
- Route of administration
- ORAL
- Authorisation status
- Not Authorised
- MA holder
- ENLIVEN THERAPEUTICS
- Paediatric formulation
- No
- Orphan designation
- No
PRD11163527 · Product
- Active substance
- ELVN-002-1
- Pharmaceutical form
- CAPSULE
- Route of administration
- ORAL
- Authorisation status
- Not Authorised
- MA holder
- ENLIVEN THERAPEUTICS
- Paediatric formulation
- No
- Orphan designation
- No
PRD11776456 · Product
- Active substance
- ELVN-002-1
- Pharmaceutical form
- TABLET
- Route of administration
- ORAL
- Authorisation status
- Not Authorised
- MA holder
- ENLIVEN THERAPEUTICS
- Paediatric formulation
- No
- Orphan designation
- No
PRD10185640 · Product
- Active substance
- ELVN-002-1
- Pharmaceutical form
- CAPSULE
- Route of administration
- ORAL
- Authorisation status
- Not Authorised
- MA holder
- ENLIVEN THERAPEUTICS
- Paediatric formulation
- No
- Orphan designation
- No
PRD11776455 · Product
- Active substance
- ELVN-002-1
- Pharmaceutical form
- TABLET
- Route of administration
- ORAL
- Authorisation status
- Not Authorised
- MA holder
- ENLIVEN THERAPEUTICS
- Paediatric formulation
- No
- Orphan designation
- No
PRD11776457 · Product
- Active substance
- ELVN-002-1
- Pharmaceutical form
- TABLET
- Route of administration
- ORAL
- Authorisation status
- Not Authorised
- MA holder
- ENLIVEN THERAPEUTICS
- Paediatric formulation
- No
- Orphan designation
- No
PRD11424321 · Product
- Active substance
- ELVN-002-1
- Pharmaceutical form
- CAPSULE
- Route of administration
- ORAL
- Authorisation status
- Not Authorised
- MA holder
- ENLIVEN THERAPEUTICS
- Paediatric formulation
- No
- Orphan designation
- No
Capecitabin "Zentiva", filmovertrukne tabletter
PRD9851619 · Product
- Active substance
- Capecitabine
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL USE
- Authorisation status
- Authorised
- ATC code
- L01BC06 — CAPECITABINE
- Marketing authorisation
- 60472
- MA holder
- ZENTIVA, K.S.
- MA country
- Denmark
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- Yes
- Modification description
- It has been labelled for Clinical Trials according to EU Legislation
Capecitabine Accord 150 mg film-coated tablets
PRD1614129 · Product
- Active substance
- Capecitabine
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL USE
- Authorisation status
- Authorised
- ATC code
- L01BC06 — CAPECITABINE
- Marketing authorisation
- EU/1/12/762/020
- MA holder
- ACCORD HEALTHCARE S.L.U.
- MA country
- EU
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- Yes
- Modification description
- It has been labelled for Clinical Trials according to EU Legislation
Oxaliplatin AqVida 5 mg/ml Konzentrat zur Herstellung einer Infusionslösung
PRD1874310 · Product
- Active substance
- Oxaliplatin
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS INFUSION
- Authorisation status
- Authorised
- ATC code
- L01XA03 — OXALIPLATIN
- Marketing authorisation
- 88845.00.00
- MA holder
- AQVIDA GMBH
- MA country
- Germany
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- Yes
- Modification description
- It has been labelled for Clinical Trials according to EU Legislation
Paclitaxel AqVida 6 mg/ml Konzentrat zur Herstellung einer Infusionslösung
PRD5797516 · Product
- Active substance
- Paclitaxel
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENIOUS INFUSION
- Authorisation status
- Authorised
- ATC code
- L01CD01 — PACLITAXEL
- Marketing authorisation
- 88689.00.00
- MA holder
- AQVIDA GMBH
- MA country
- Germany
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- Yes
- Modification description
- It has been labelled for Clinical Trials according to EU Legislation
BENDAFOLIN 10 mg/ml Injektionslösung
PRD2832960 · Product
- Active substance
- Folinic Acid
- Substance synonyms
- LEUCOVORIN
- Pharmaceutical form
- SOLUTION FOR INJECTION
- Route of administration
- INTRAMUSCULAR OR INTRAVENOUS
- Authorisation status
- Authorised
- ATC code
- V03AF03 — CALCIUM FOLINATE
- Marketing authorisation
- 44048.05.00
- MA holder
- BENDALIS GMBH
- MA country
- Germany
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- Yes
- Modification description
- It has been labelled for Clinical Trials according to EU Legislation
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Enliven Therapeutics Inc.
- Sponsor organisation
- Enliven Therapeutics Inc.
- Address
- 6200 Lookout Road
- City
- Boulder
- Postcode
- 80301-3319
- Country
- United States
Scientific contact point
- Organisation
- Enliven Therapeutics Inc.
- Contact name
- Chief Medical Officer
Public contact point
- Organisation
- Enliven Therapeutics Inc.
- Contact name
- Chief Medical Officer
Third parties 10
| Organisation | City, country | Duties |
|---|---|---|
| Guardant Health Inc. ORG-100042461
|
Redwood City, United States | Other |
| Fisher Clinical Services Inc. ORG-100014726
|
Mount Prospect, United States | Other |
| Signant Health LLC ORG-100040732
|
Blue Bell, United States | Interactive response technologies (IRT) |
| Scout Clinical ORG-100042228
|
Dallas, United States | Other |
| Perceptive Informatics Inc. ORG-100013171
|
Billerica, United States | Other |
| Fisher Clinical Services GmbH ORG-100017323
|
Weil Am Rhein, Germany | Other |
| PPD Global Limited ORG-100007533
|
Cambridge, United Kingdom | On site monitoring, Code 11, Code 12, Code 13, Other, Code 2, Code 5, Code 8, Code 9 |
| Syneos Health Inc. ORG-100008382
|
Princeton, United States | Other |
| Pharmaceutical Product Development LLC ORG-100016999
|
Highland Heights, United States | Other |
| Syneos Health Clinique Inc. ORG-100028348
|
Quebec, Canada | Other |
Locations
5 EU/EEA countries · 25 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Belgium | Ended | 18 | 3 |
| France | Ongoing, recruitment ended | 36 | 4 |
| Italy | Ongoing, recruitment ended | 36 | 6 |
| Netherlands | Ended | 12 | 2 |
| Spain | Ongoing, recruitment ended | 54 | 10 |
| Rest of world
United States, Korea, Republic of
|
— | 119 | — |
Investigational sites
GasthuisZusters Antwerpen
Medical Oncology, Oosterveldlaan 24, 2610, Antwerp
Cliniques Universitaires Saint-Luc
Medical Oncology, Hippokrateslaan 10, Batiment 54, Sint-Lambrechts-Woluwe
Centre hospitalier universitaire de Liege
Centre Multidisciplinaire D'Oncologie Médicale, Avenue De L'hopital 1, 4000, Liege
Centre Hospitalier Universitaire De Poitiers
Medical Oncology Pôle régional de cancérologie, 2 Rue De La Miletrie, 86000, Poitiers
Institut de Cancérologie de l'Ouest
Medical Oncology, Boulevard Jacques Monod, 44805, Saint-Herblain cedex
Institut De Cancerologie Strasbourg Europe
Medical Oncology, 17 Rue Albert Calmette, 67200, Strasbourg
Institut Regional Du Cancer De Montpellier
Medical Oncology, 208 Avenue Des Apothicaires, 34298, Montpellier Cedex 5
Fondazione IRCCS San Gerardo Dei Tintori
Centro Ricerca Fase 1, Via Giovanni Battista Pergolesi 33, 20900, Monza
Istituto Europeo Di Oncologia S.r.l.
Divisione di Sviluppo di Nuovi Farmaci per Terapie Innovative, Via Giuseppe Ripamonti 435, 20141, Milan
Azienda USL IRCCS Di Reggio Emilia
Unità Clinica di Fase 1 - Oncologia Medica Provinciale, Viale Risorgimento 80, 42123, Reggio Emilia
Azienda Ospedaliero Universitaria Pisana
Centro di Farmacologia Clinica per La Sperimentazione dei Farmaci, Via Roma 67, 56126, Pisa
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
UOC Fase 1, Largo Francesco Vito 1, 00168, Rome
Azienda Ospedaliero Universitaria Renato Dulbecco
UOC Oncologia Medica Traslazionale- Centro Sperimentazioni di Fase I, Viale Europa, 88100, Catanzaro
Academisch Ziekenhuis Maastricht
Medical Oncology, P Debyelaan 25, 6229 HX, Maastricht
Stichting Radboud universitair medisch centrum
Medical Oncology, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen
Hospital Universitario Y Politecnico La Fe
Medical Oncology, Avenida Fernando Abril Martorell 106, 46026, Valencia
Hospital Hm Nou Delfos
Medical Oncology Department, Avinguda De Vallcarca 151, 08023, Barcelona
Hospital Quironsalud Barcelona
Oncology Medical Service, Placa D'alfonso Comin 5-7, 08023, Barcelona
Clinica Universidad De Navarra
Medical Oncology Service, Avenue Pio XII 36, 31008, Pamplona
Clinica Universidad De Navarra
Medical Oncology Service, Calle Marquesado De Santa Marta 1, 28027, Madrid
Hospital Beata Maria Ana
Medical Oncology Department, Calle Del Doctor Esquerdo No. 83, 28007, Madrid
Hospital Universitari Vall D Hebron
Medical Oncology Department . Early Drug Development Unit (UITM), Passeig De La Vall D'Hebron 119-129, 08035, Barcelona
Fundacion Instituto Valenciano De Oncologia
Medical Oncology, Calle Professor Beltran Baguena 8, 46009, Valencia
Hospital Universitario Fundacion Jimenez Diaz
Medical Oncology Service, Avenida De Los Reyes Catolicos 2, 28040, Madrid
Hospital Universitari Dexeus Grupo Quironsalud
Medical Oncology Service, Calle De Sabino Arana 5-19, 08028, Barcelona
Country notifications
Trial-start, recruitment-start, end and early-termination notifications submitted per Member State
| Country | Trial start | Trial end | Recruitment start | Recruitment end | Early termination |
|---|---|---|---|---|---|
| Belgium | 2024-10-14 | 2025-12-23 | 2025-02-04 | 2025-07-09 | |
| France | 2024-09-23 | 2024-11-21 | 2025-07-09 | ||
| Italy | 2024-09-26 | 2024-10-30 | 2025-07-09 | ||
| Netherlands | 2024-10-10 | 2025-07-09 | 2025-01-31 | 2025-07-09 | |
| Spain | 2024-09-26 | 2025-01-22 | 2025-07-09 |
Oversight and notifications
Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77
Unexpected events 1 · Art. 53 CTR
Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.
Unexpected event UE-110448
- Event date
- 2025-12-01
- Date aware
- 2025-12-01
- Submission date
- 2025-12-10
- Member states affected
- Belgium, France, Italy, Spain, Netherlands
- Event description
- The ELVN-002-003 study is closing. As part of this transition, the sponsor is requesting that all patients complete their final study visits no later than 30 June 2026.
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 55 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | D1_Enliven_ELVN-002-003_Protocol_2023-509716-29-00_Public | 3.2 |
| Recruitment arrangements (for publication) | K1_ELVN-002-003_Recruitment Arrangements_ES_Public | N/A |
| Recruitment arrangements (for publication) | K1_ELVN-002-003_Recruitment Arrangements_NL_English_Public | n/a |
| Recruitment arrangements (for publication) | K1_ELVN-002-003_Recruitment-Arrangements_FR_French_Public | 1.0 |
| Recruitment arrangements (for publication) | K1_ELVN-002-003_Recruitment-Arrangements_IT_Public | 2.0 |
| Recruitment arrangements (for publication) | K1_ELVN-002-003_Recruitment-Arrangements-and-Informed-Consent-Proc_BE_Eng_Public | 1 |
| Recruitment arrangements (for publication) | K2_ ELVN-002-003_GP-Letter_IT_Italian_Public | 1.0 |
| Subject information and informed consent form (for publication) | L1_ ELVN-002-003_Main-ICF_IT_Italian_Public | 5.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Main ICF_ Part 1_NL_Dutch_Public | 5.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Main ICF_ Part 2_NL_Dutch_Public | 5.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Main ICF_ Part 4_NL_Dutch_Public | 5.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Main ICF_BE_Dutch_Clean_Public | 5.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Main ICF_BE_English_Clean_Public | 5.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Main ICF_BE_French_Clean_Public | 5.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Main ICF_ES_Spanish_Public | 5.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Main ICF_Part 3_NL_Dutch_Public | 5.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Main ICF_Sponsor-Statement_BE_English_Public | 2.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Main-Group1-ICF_FR_French_clean_Public | 5.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Main-Group2-ICF_FR_French_clean_Public | 5.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Main-Group3-ICF_FR_French_clean_Public | 5.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Main-Group4-ICF_FR_French_clean_Public | 5.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_PP ICF_ES_Spanish_Public | 1.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Pregnancy-ICF_FR_French_clean_Public | 1.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Pregnancy-Safety-Follow-Up-ICF_BE_Dutch_Public | 1.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Pregnancy-Safety-Follow-Up-ICF_BE_English_Public | 1.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Pregnancy-Safety-Follow-Up-ICF_BE_French_Public | 1.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Pregnant-Partner-ICF_IT_Italian_Public | 1.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_Privacy-Addendum_IT_Italian_Public | 2.0 |
| Subject information and informed consent form (for publication) | L1_ELVN-002-003_SIS and ICF Pregnancy_NL_Dutch_Public | 1.0 |
| Subject information and informed consent form (for publication) | L2_ELVN-002-003_Patient-Card_FR_French_Public | 1.0.0 |
| Summary of Product Characteristics (SmPC) (for publication) | E2_Enliven_ELVN-002-003_ELVN-002_SmPC_IMP_NtF_Public | n/a |
| Summary of Product Characteristics (SmPC) (for publication) | E2_Enliven_ELVN-002-003_ELVN-002_SmPC_IMP_NtF_Public | n/a |
| Summary of Product Characteristics (SmPC) (for publication) | E2_Enliven_ELVN-002-003_ELVN-002_SmPC_IMP_NtF_Public | n/a |
| Summary of Product Characteristics (SmPC) (for publication) | E2_Enliven_ELVN-002-003_ELVN-002_SmPC_IMP_NtF_Public | n/a |
| Summary of Product Characteristics (SmPC) (for publication) | E2_Enliven_ELVN-002-003_ELVN-002_SmPC_IMP_NtF_Public | n/a |
| Summary of Product Characteristics (SmPC) (for publication) | E2_Enliven_ELVN-002-003_ELVN-002_SmPC_IMP_NtF_Public | n/a |
| Summary of Product Characteristics (SmPC) (for publication) | E2_Enliven_ELVN-002-003_ELVN-002_SmPC_IMP_NtF_Public | n/a |
| Summary of Product Characteristics (SmPC) (for publication) | E2_Enliven_ELVN-002-003_ELVN-002_SmPC_IMP_NtF_Public | n/a |
| Summary of Product Characteristics (SmPC) (for publication) | E2_Enliven_ELVN-002-003_SmPC_Medac-5 FU_NTF | N/A |
| Synopsis of the protocol (for publication) | D1_Enliven_ELVN-002-003_Layperson Synopsis_2023-509716-29-00_NLD_Public | 3.0 |
| Synopsis of the protocol (for publication) | D1_Enliven_ELVN-002-003_Protocol Synopsis_2023-509716-29-00_BE_DEU_Public | 3.2 |
| Synopsis of the protocol (for publication) | D1_Enliven_ELVN-002-003_Protocol synopsis_2023-509716-29-00_BE_DUT_Public | 3.2 |
| Synopsis of the protocol (for publication) | D1_Enliven_ELVN-002-003_Protocol Synopsis_2023-509716-29-00_BE_FRA_Public | 3.2 |
| Synopsis of the protocol (for publication) | D1_Enliven_ELVN-002-003_Protocol Synopsis_2023-509716-29-00_ENG_Public | 3.2 |
| Synopsis of the protocol (for publication) | D1_Enliven_ELVN-002-003_Protocol Synopsis_2023-509716-29-00_ES_SPA_Public | 3.2 |
| Synopsis of the protocol (for publication) | D1_Enliven_ELVN-002-003_Protocol Synopsis_2023-509716-29-00_FR_FRE_Public | 3.2 |
| Synopsis of the protocol (for publication) | D1_Enliven_ELVN-002-003_Protocol synopsis_2023-509716-29-00_IT_ITA_Public | 3.2 |
| Synopsis of the protocol (for publication) | D1_Enliven_ELVN-002-003_Protocol Synopsis_2023-509716-29-00_NL_Dutch_Public | 3.2 |
| Synopsis of the protocol (for publication) | D2_Enliven_ELVN-002-003_Layperson synopsis_2023-509716-29-00_BE_DEU_Public | 3.0 |
| Synopsis of the protocol (for publication) | D2_Enliven_ELVN-002-003_Layperson synopsis_2023-509716-29-00_BE_FRA_Public | 3.0 |
| Synopsis of the protocol (for publication) | D2_Enliven_ELVN-002-003_Layperson synopsis_2023-509716-29-00_BE_NLD_Public | 3.0 |
| Synopsis of the protocol (for publication) | D2_Enliven_ELVN-002-003_Layperson synopsis_2023-509716-29-00_ENG_Public | 3.0 |
| Synopsis of the protocol (for publication) | D2_Enliven_ELVN-002-003_Layperson synopsis_2023-509716-29-00_FRA_Public | 3.0 |
| Synopsis of the protocol (for publication) | D2_Enliven_ELVN-002-003_Layperson synopsis_2023-509716-29-00_ITA_Public | 3.0 |
| Synopsis of the protocol (for publication) | D2_Enliven_ELVN-002-003_Layperson synopsis_2023-509716-29-00_SPA_Public | 3.0 |
Application history
6 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2024-04-24 | Spain | Acceptable with conditions 2024-08-14
|
2024-08-14 |
| 2 | SUBSTANTIAL MODIFICATION | SM-1 | 2024-08-30 | Spain | Acceptable with conditions | 2024-09-20 |
| 3 | SUBSTANTIAL MODIFICATION | SM-2 | 2024-09-09 | Acceptable with conditions | 2024-09-26 | |
| 4 | SUBSTANTIAL MODIFICATION | SM-3 | 2024-12-13 | Spain | Acceptable 2025-04-04
|
2025-04-04 |
| 5 | SUBSTANTIAL MODIFICATION | SM-4 | 2025-05-20 | Spain | Acceptable 2025-08-11
|
2025-08-11 |
| 6 | NON SUBSTANTIAL MODIFICATION | NSM-1 | 2025-11-24 | Acceptable 2025-08-11
|
2025-11-24 |