| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with human epidermal growth factor receptor 3-overexpressing (HER3-high) and hormone-receptor positive (HR+) advanced breast cancer who have already received standard therapy for HR+ advanced breast cancer (ABC), including only one line of chemotherapy for ABC. |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with advanced breast cancer with hormonal expression and with a high intensity presence of the HER3 receptor on cancer cells and who have already received standard treatment |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10072737 |
| E.1.2 | Term | Advanced breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The main objective of ICARUS-BREAST01 is to evaluate the overall anti-tumor activity of U3-1402, as measured by objective response rate (ORR) based on investigator assessment, in patients with HER3-high (≥75% tumor cell membrane staining seen at 10x objective) and HR+ ABC who have progressed on previous standard therapies for HR+ ABC. |
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| E.2.2 | Secondary objectives of the trial |
1/ To evaluate the efficacy of U3-1402 in terms of:
a. ORR based on centralized review.
b. Duration of response (DOR).
c. Progression Free Survival (PFS) based on investigator and centralized review.
d. Clinical benefit rate (CBR)
e. Overall survival (OS)
2/ To evaluate the safety and tolerability of U3-1402, in terms of:
a. Frequency and severity of all adverse events (AEs), tTEAEs, SAEs, and adverse events of special interest (AESIs), defined by NCI-CTCAE v5.0
b. Treatment discontinuation, interruptions and dose reductions due to any AEs
c. Frequency and severity of laboratory abnormalities defined by NCI-CTCAE v5.0
d. ECG abnormalities (including QT/QTc interval data) and left ventricular ejection fraction (LVEF) decrease (measured by echocardiography (ECHO) or cardiac magnetic resonance imaging (MRI) if indicated) defined by NCI-CTCAE v5.0 Eastern Cooperative Oncology Group performance status [ECOG PS] changes
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Female or male patient aged ≥18 years.
2. Patient with histologically-confirmed HER3-high (≥75% of tumor cell membrane positivity at 10x objective) unresectable locally advanced or metastatic on most recent tumor tissue sample available. Tumors have also to be hormone receptor positive (estrogen receptor positive (ER+) and/or, progesterone receptor positive (PR+)) and HER2-neg (IHC2+/ in situ hybridization (ISH) negative or IHC1+ or IHC0+) at the time of the first breast cancer diagnosis. If the tumor was ER+ and/or PR+ at diagnosis and became ER- and/or PR- in the following biopsies, patient can still continue the study.
3. Patient with a documented radiologic unresectable or metastatic progression.
4. Patient may have received anthracyclines and taxanes as (neo) adjuvant treatment (which do not count as a line of treatment) and must have received one line of chemotherapy for ABC, but not more than one line. All patients must be resistant to endocrine therapy and CDK4/6 inhibitors. Previous treatment with PI3K inhibitors, mTOR inhibitors, AKT-inhibitors, poly ADP ribose polymerase (PARP)-inhibitors is allowed.
5. Patient must have metastatic site easily accessible to biopsy (with exception of bone metastasis) and must have accepted to perform pre-treatment, on-treatment and end-of-treatment biopsies.
6. Patient must have at least one radiologically measurable lesion according to response evaluation criteria in solid tumors (RECIST) V1.1 criteria.
7. Patient must have an ECOG PS 0 or 1 at the time of screening.
8. Patient must have a life expectancy ≥12 weeks.
9. Patient must have adequate bone marrow reserve and organ function, based on local laboratory data within 14 days prior to Cycle 1, Day 1 (...)
10. Female patients of reproductive/childbearing potential must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 7 months after the last dose of study drug. Methods considered as highly effective methods of contraception include:
• Intrauterine device (IUD)
• Intrauterine hormone-releasing system (IUS)
• Bilateral tubal occlusion
• Vasectomized partner
• Complete sexual abstinence defined as refraining from heterosexual intercourse during and upon completion of the study and for at least 7 months for females after the last dose of study drug. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not an acceptable method of contraception.
A female is considered of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy) with surgery at least 1 month before the first dose or confirmed by follicle stimulating hormone (FSH) test.
Female patients must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration.
11. If male, the patient must be surgically sterile, must withhold heterosexual intercourse, or must be or willing to use a highly effective birth control upon enrollment, during the treatment period, and for at least 4 months following the last dose of study drug.
Male patients must not freeze or donate sperm starting at screening and throughout the study period, and for at least 4 months after the final study drug administration.
12. Patient must understand, sign, and date the written informed consent from form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedure as per protocol.
13. Patient must be affiliated to a social security system or beneficiary of the same.
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| E.4 | Principal exclusion criteria |
1. Patient with a breast cancer amenable for resection or radiation therapy with curative intent.
2. Any history of ILD (including pulmonary fibrosis or radiation pneumonitis), has current ILD, or is suspected to have ILD as assessed by imaging during screening.
3. Patient with clinically severe pulmonary compromise (...) resulting from intercurrent pulmonary illnesses including, but not limited to: Any underlying pulmonary disorder (...), restrictive lung disease, pleural effusion); Any autoimmune, connective tissue or inflammatory disorder with pulmonary involvement (...); OR prior pneumonectomy.
4. Patient receiving chronic systemic corticosteroids dosed at >10 mg prednisone or equivalent or any form of immunosuppressive therapy prior to Cycle 1 Day 1. Patients who require use of bronchodilators, inhaled steroids, or local steroid injections may be included in the study.
5. Evidence of any leptomeningeal disease.
6. Has clinically significant corneal disease.
7. Any evidence of severe or uncontrolled systemic diseases (...).
8. Evidence of clinically active spinal cord compression or brain metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Patients with clinically inactive or treated brain metastases who are asymptomatic (...) may be included in the study. Patients must have a stable neurologic status for at least 2 weeks prior to Cycle 1 Day 1.
9. Inadequate washout period prior to Cycle 1 Day 1, defined as:
a. Whole brain radiation therapy <14 days or stereotactic brain radiation therapy <7 days.
b. Any cytotoxic chemotherapy, investigational agents, or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than EGFR TKI), <14 days or 5 half-lives, whichever is longer.
c. Immune checkpoint inhibitor therapy < 21 days.
d. Endocrine therapy < 21 days
e. Major surgery (excluding placement of vascular access) < 28 days.
f. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation < 28 days or palliative radiation therapy < 14 days.
g. Chloroquine or hydroxychloroquine ≤ 14 days.
h. Live virus vaccination <28 days.
10. Prior treatment with an anti-HER3 antibody and/or ADC containing an exatecan derivative that is a topoisomerase I inhibitor (eg, trastuzumab deruxtecan).
11. Patients with grade ≤2 unresolved toxicities from previous anticancer therapy (other than alopecia), as defined by the NCI-CTCAE version 5.0.
12. Has known hypersensitivity to either the drug substances or inactive ingredients in the drug product.
13. Has any primary malignancy other than locally advanced or metastatic breast cancer within 3 years prior to Cycle 1 Day 1, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated.
14. Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day 1, including: QT interval corrected by Fridericia's formula (QTcF) prolongation interval of >470 ms for females and >450 ms for males (in electrocardiograms (ECGs) performed at baseline in triplicate, approximately 1 minute apart); Left ventricular ejection fraction (LVEF) <50% by either echocardiogram (ECHO) or cardiac MRI if clinically indicated according to the investigator or consulting cardiologist.
15. Active Hepatitis B and/or Hepatitis C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1, Day 1.
Patients with past or resolved HBV infection are eligible if:
a. HBsAg negative and anti-HBc positive; OR
b. HBsAg positive and HBV DNA viral load is documented to be ≤ 2000 IU/mL in the absence of anti-viral therapy and during the previous 12 weeks prior to the viral load evaluation with normal transaminases (in the absence of liver metastasis); OR
c. HBsAg positive and HBV DNA viral load is documented to be ≤ 2000 IU/mL in the absence of anti-viral therapy and during the previous 12 weeks prior to the viral load evaluation with liver metastasis and abnormal transaminases AST/ALT <3 ULN.
d. Patients with a history of Hepatitis C infection will be eligible for enrollment only if the viral load according to local standards of detection, is documented to be below the level of detection in the absence of anti-viral therapy during the previous 12 weeks (ie, sustained viral response according to the local product label but not less than 12 weeks, whichever is longer).
16. Female patient who is pregnant or breastfeeding or intends to become pregnant during the study.
17. Patients with HIV or active COVID-19 infection.
18. Patient with any psychological, familial, sociological or geographical condition potentially hindering compliance with the study protocol procedures and follow-up schedule.
19. Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is anti-tumor activity of U3-1402, measured by the confirmed ORR. ORR is defined as the proportion of subjects who achieved a confirmed complete response (CR) or partial response (PR) assessed by investigators. Confirmation of response must be demonstrated with an assessment 4 weeks or later from the initial response. Treatment objective response will be radiologically assessed every 6 weeks using RECIST v1.1. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1. The secondary efficacy endpoints will be evaluated as follows:
a. DOR is defined as the time from the date of the first documentation of objective response (CR or PR) to the date of the first documentation of progression (PD) or death due to any cause. Duration of response will be measured for responding subjects (CR or PR) only.
b. PFS is defined as the time from date of first dose until the date of the first objective documentation of disease progression or death from any cause, whichever occurs first. For patients without documented radiological progression, follow-up will be censored at the date of last radiological assessment without progression, unless death occurs within 12 weeks following the date of last known progression-free, in which case the death will be counted as a PFS event.
c. CBR is defined as the presence of at least a PR or CR, or a stable disease (SD) >6 months.
d. OS is defined as the time from date of first dose until death. Patients alive at last follow-up will be censored at this date.
2. Safety and tolerability of U3-1402 will be evaluated continuously through: frequency and severity of any AEs, TEAEs, SAEs, AESIs graded by NCI-CTCAE v5.0; proportion of treatment discontinuations, interruptions, and dose reductions due to any AEs; frequency and severity of laboratory abnormalities defined by NCI-CTCAE v5.0; frequency and severity of QTcF prolongation; LVEF decrease or cardiac dysfunction graded according to NCI-CTCAE v5.0.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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