E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced or metastatic colorectal cancer (CRC) which is resistant, refractory, or intolerant to at least 2 prior lines of therapy, that must include all of the following agents: fluoropyrimidine, irinotecan, platinum agent, an anti-epidermal growth factor receptor (EGFR) agent (if clinically indicated), an anti-vascular endothelial growth factor (VEGF) agent (if clinically indicated), an immune checkpoint inhibitor (if clinically indicated), and a BRAF inhibitor (if clinically indicated). |
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E.1.1.1 | Medical condition in easily understood language |
Advanced or metastatic colorectal cancer, which is resistant and refractory to at least 2 prior lines of therapy |
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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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal 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 |
To assess the tolerability and antitumor activity of U3-1402 in subjects with advanced or metastatic CRC who are resistant, refractory, or intolerant to at least 2 prior lines of therapy |
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E.2.2 | Secondary objectives of the trial |
To investigate the durability of U3-1402 antitumor activity in subjects with advanced or metastatic CRC To further investigate the antitumor activity of U3-1402 in subjects with advanced or metastatic CRC To evaluate the safety and tolerability of U3 1402 in subjects with advanced or metastatic CRC To evaluate HER3 protein expression in tumor tissue and its relationship with efficacy To assess the immunogenicity incidence against U3-1402 To characterize the 3 PK analytes of U3-1402 in subjects with advanced or metastatic CRC |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must satisfy all of the following criteria to be included in the study: 1. Subject has provided written informed consent prior to the start of any study-specific procedures. 2. Subjects ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is >18 years old). 3. Pathological/histological confirmation of advanced or metastatic colon or rectal adenocarcinoma. 4. Must be resistant, refractory, or intolerant to at least 2 prior lines of systemic therapy, that must include all of the following agents: a. Fluoropyrimidine b. Irinotecan c. Platinum agents (eg, oxaliplatin) d. An anti-EGFR agent, if clinically indicated (eg, RAS/BRAF wildtype) e. An anti-VEGF agent, unless contraindicated (eg, bevacizumab) f. An immune checkpoint inhibitor, if clinically indicated (eg, microsatellite instability-high [MSI-H] status) g. A BRAF inhibitor, if clinically indicated (eg, BRAF V600E positive) 5. Has at least 1 measurable lesion confirmed by blinded independent central review (BICR) as per (RECIST) Version (v) 1.1. 6. Willing to provide a required pre-treatment tumor biopsy and an additional archival tissue sample for the assessment of HER3 expression levels by IHC and exploratory biomarkers, defined as: a. Pre-treatment tumor biopsy. Subjects may be exempted from the requirement to provide a pre-treatment tumor biopsy if archival tumor tissue was collected within 3 months of screening during or after treatment with the last prior cancer treatment and is of sufficient quantity (2 cores or 20 slides with adequate tumor tissue content). b. An additional archival tissue sample collected greater than 3 months prior to screening must be available and of sufficient quantity, as defined above, at the time of screening. If an archival tissue sample (collected greater than 3 months prior to screening) is not available, a subject may be included provided the pre-treatment tumor biopsy is obtained and after discussion and agreement from Sponsor (Medical Monitor or designee). c. Consent to provide on-treatment tumor biopsy. When at least 10 on-treatment tumor biopsies per cohort have been collected, the Sponsor will provide written notification of a change to the requirement. 7. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. 8. Life expectancy ≥3 months. 9. Has adequate bone marrow reserve and organ function at baseline based on local laboratory data, defined as within 14 days prior to Cycle 1 Day 1 |
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E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria will be denied entry to the study: 1. Any history of interstitial lung disease (including pulmonary fibrosis or radiation pneumonitis), has current interstitial lung disease (ILD), or is suspected to have such disease by imaging during screening. 2. Clinically severe pulmonary compromise (based on Investigator’s assessment) resulting from intercurrent pulmonary illnesses including, but not limited to: a. any underlying pulmonary disorder (eg, pulmonary emboli, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion) b. any autoimmune, connective tissue or inflammatory disorder with pulmonary involvement (eg, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis) OR prior complete pneumonectomy. 3. Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior to Cycle 1 Day 1. Subjects who require use of bronchodilators, inhaled or topical steroids, or local steroid injections may be included in the study. 4. Evidence of leptomeningeal disease 5. 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. Subjects with clinically inactive or treated brain metastases who are asymptomatic (ie, without neurologic signs or symptoms and do not require treatment with corticosteroids or anticonvulsants) may be included in the study. Subjects must have a stable neurologic status for at least 2 weeks prior to Cycle 1 Day 1. 6. Inadequate washout period prior to Cycle 1 Day 1 of U3-1402: a. Whole brain radiation therapy <14 days or stereotactic brain radiation therapy <7 days; b. Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a previous cancer treatment regimen or clinical study <14 days or 5 half-lives, whichever is longer; c. Monoclonal antibodies other than immune checkpoint inhibitors, such as bevacizumab (anti-VEGF) and cetuximab (anti-EGFRs) <28 days; d. Immune checkpoint inhibitor therapy <21 days; e. Major surgery (excluding placement of vascular access) <4 weeks; f. Radiotherapy treatment to >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. 7. Prior treatment with an anti-HER3 antibody and/or antibody drug conjugate (ADC) that consists of an exatecan derivative that is any topoisomerase I inhibitor (eg, trastuzumab deruxtecan). 8. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 Grade ≤1 or baseline. 9. Had primary malignancies other than CRC within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated. 10. Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day 1, including: a. QT interval corrected for heart rate using Fridericia’s formula prolongation interval of >470 (ms) for females and >450 ms for males within 28 days; b. Left ventricular ejection fraction (LVEF) <50% by either echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan within 28 days; c. Resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg; d. Myocardial infarction within 6 months; e. New York Heart Association (NYHA) Classes 2 to 4 congestive heart failure (See Section 13.5) within 28 days; f. Uncontrolled angina pectoris within 6 months; g. Cardiac arrhythmia requiring antiarrhythmic treatment within 28 days. 11. 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. a. Subjects with past or resolved hepatitis B virus (HBV) infection are eligible if they met specific criteria (details listed in protocol) b. Subjects with a history of hep C infection will be eligible for enrolment 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 no less than 12 weeks, whichever is longer).
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E.5 End points |
E.5.1 | Primary end point(s) |
Objective Response Rate (ORR) is defined as the proportion of subjects with a best overall response (BOR) of confirmed complete response (CR) or partial response (PR). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Data are collected at baseline, then from the start of study treatment until disease progression or by BICR, death, lost to follow-up, or withdrawal of consent by the subject. |
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E.5.2 | Secondary end point(s) |
Duration of Response (DoR) is defined as the time from the first documented response (complete response [CR] or partial response [PR]) to the date of disease progression or death due to any cause. Objective Response Rate (ORR) is defined as the proportion of subjects with a best overall response (BOR) of confirmed CR or PR. Duration of Response (DoR) is defined as the duration from the first documented response to the date of disease progression or death due to any cause. Disease Control Rate (DCR) is defined as the proportion of subjects who achieved a confirmed BOR of CR, PR, or stable disease (SD). Time to Tumor Response (TTR) is defined as the time from the start of study treatment to the date of the first documentation of objective response (CR or PR) that is subsequently confirmed. Progression-Free Survival (PFS) is defined as the duration from the start of study treatment to the date of the first documentation of objective progressive disease (PD) or death due to any cause, whichever is earlier. Overall Survival (OS) is defined as the time from the start of study treatment to the date of death due to any cause. Incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse event of special interests (AESIs) (ILD and elevation of aminotransferases and TBL), ECOG PS, vital sign measurements, standard clinical laboratory parameters. AEs will be coded using the most recent version of MedDRA and will be graded using NCI-CTCAE v5.0. HER3 protein expression in tumor tissue (as determined by IHC) and correlation with efficacy Anti-drug Antibody (ADA) prevalence: The proportion of all subjects having a confirmed positive ADA sample at any point in time. ADA incidence: The proportion of subjects having treatment-emergent ADA. ADA titer will be determined for confirmed ADA-positive samples. Neutralizing antibodies: When neutralizing assay becomes available, confirmed ADA-positive samples may be analyzed for neutralizing activity. PK endpoints: Cmax, Tmax, Ctrough, AUClast, and AUCtau |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Data are collected at baseline, then from the start of study treatment until disease progression or by BICR, death, lost to follow-up, or withdrawal of consent by the subject. Death date is collected until the subject discontinues the study. HER3 data are collected at baseline (archival and pre-treatment tumor biopsy) and at Cycle 2. ADA prevalence, incidence, and titer for U3 1402 related data are collected from the start of study treatment until the end of treatment. Additional timepoints are specified in the protocol. |
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Japan |
United States |
Belgium |
France |
Italy |
Poland |
Spain |
United Kingdom |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |