| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Patients with unresecable, metastatic or locally advanced cancers expressing Neurotensin Receptor 1 (NTSR1).
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with unresecable, metastatic or locally advanced cancers expressing Neurotensin Receptor 1. |
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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 | 10033604 |
| E.1.2 | Term | Pancreatic cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061451 |
| E.1.2 | Term | Colorectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10017758 |
| E.1.2 | Term | Gastric cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060121 |
| E.1.2 | Term | Squamous cell carcinoma of head and neck |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 | 10033605 |
| E.1.2 | Term | Pancreatic cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052358 |
| E.1.2 | Term | Colorectal cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063916 |
| E.1.2 | Term | Metastatic gastric cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10051066 |
| E.1.2 | Term | Gastrointestinal stromal tumour |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10015560 |
| E.1.2 | Term | Ewing's sarcoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10015562 |
| E.1.2 | Term | Ewing's sarcoma metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase I
To establish the safety and tolerability of fractionated intravenous (i.v.) administrations of 177Lu-3BP-227 in subjects with unresectable, locally advanced or metastatic cancers expressing NTSR1.
Phase II
To estimate ORR of fractionated i.v. administrations of 177Lu-3BP-227 in subjects with unresectable, locally advanced or metastatic cancers expressing NTSR1.
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| E.2.2 | Secondary objectives of the trial |
Phase I
a) To determine the whole-body distribution of 177Lu-3BP-227 and pharmacokinetics (PK) of both 177Lu-3BP-227 and 3BP-227.
b) To determine the radiation dosimetry of 177Lu-3BP-227 (organ exposure to radiation).
c) To describe the preliminary antitumour activity of 177Lu-3BP-227.
Phase II
a) To further evaluate the safety profile of 177Lu-3BP-227 at the radioactivity recommended by the phase I results.
b) To further assess the response to treatment with 177Lu-3BP-227 using RECIST version 1.1 and/or positron emission tomography (PET) Response Criteria in Solid Tumours (PERCIST) version 1.0 criteria.
c) To further characterise the whole-body distribution and dosimetry of 177Lu-3BP-227 and PK of both 177Lu-3BP-227 and 3BP-227.
d) To describe the influence of 177Lu-3BP-227 on the health-related quality of life of treated subjects.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
(1) Signed informed consent form prior to all study procedures.
(2) Aged 18 years or older.
(3) Histologically or cytologically confirmed unresectable, locally advanced or metastatic disease and has received prior lines of standard-of-care chemotherapy/treatment and has no further suitable treatment options and a documented decision by a multidisciplinary oncology board including a specialist of the concerned pathology.
(4) Subjects have:
(a) PDAC, or
(b) CRC (colorectal adenocarcinoma), or
(c) GC (gastric adenocarcinoma), or
(d) Gastrointestinal Stromal Tumours (GIST), or
(e) SCCHN, or
(f) ES.
(5) Tumours showing:
(a) uptake of 177Lu-3BP-227 (screening formulation) in known primary or metastatic sites as judged by the investigator to be greater than
background; or
(b) uptake of 111In-3BP-227 in known primary or metastatic sites (for subjects who participated in Study D-FR-01087-002) as judged by the investigator to be greater than background.
(6) Measurable disease (based on RECIST version 1.1).
(7) Criterion 7 is removed by protocol amendment.
(8) Documentation of progressive disease in the 6 months prior to study start (treatment).
(9) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (unless if disability is related to surgery in ES and agreed with the
sponsor).
(10) Adequate organ function as evidenced by:
(a) Leukocytes ≥ 3000/μL
(b) Absolute neutrophil count ≥1500/μL
(c) Platelets ≥75,000/μL
(d) Hb >9g/dL or >10 g/dL (if history of cardiac disease)
(e) Total serum bilirubin ≤2×upper normal institutional limits (ULN)
(f) Aspartate aminotransferase/alanine aminotransferase ≤2.5×ULN (≤5×ULN if subject has liver metastases)
(g) Estimated glomerular filtration rate ≥55mL/min.
(11) Estimated life expectancy of >3 months.
(12) Female subjects must not be pregnant or lactating at study entry and during the course of the study and must not become pregnant for at least 6 months following the last study treatment. Women of childbearing potential must agree to use a highly effective method of contraception (see note below).
(13) Male subjects must not father children during the study and for at least 6 months after the last study treatment and in addition must agree
to use a condom for this period to protect his partner from contamination with the IMP. For males with partners who are of child bearing potential, effective contraception is a combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods), but these are not considered to be highly effective. A man is considered to be infertile if he has had bilateral orchidectomy or successful vasectomy. Effective contraception includes a female partner of childbearing potential if she is using highly efficacious contraception (see note below), but the male subject must agree to use a condom to protect his partner as described above.
(14) Must be willing and able to comply with study restrictions and to remain at the clinic for the required time during the study period and willing to return to the clinic for the follow-up evaluation, as specified in the protocol.
Phase II
The inclusion criteria for phase II will be revised based on the scenario adopted and indication(s) selected for investigation in phase II. This will be documented as part of a protocol amendment. |
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| E.4 | Principal exclusion criteria |
Phase I/II
(1) Prior treatment received
(a) Any antitumour treatment since last documented disease progression
(b) Any chemotherapy within 3 weeks or nitrosourea within 6 weeks prior to first treatment investigational medicinal product (IMP) administration
(c) Any curative radiotherapy within 4 weeks or palliative radiotherapy within 7 days prior to first treatment IMP administration
(d) Any, monoclonal antibodies within 4 weeks or tyrosine kinases inhibitors within 2 weeks prior to the first treatment IMP administration
(e) Any other IMP within 2 weeks prior to first treatment IMP administration, if the previous compound is a mechanism based molecularly targeted agent whose half-life (t1/2) is not well characterised.
(2) Brain metastases.
(3) Nephrectomy, renal transplant or concomitant nephrotoxic therapy putting the subject at high risk of renal toxicity during the study.
(4) Only nonmeasurable metastatic bone lesions.
(5) Existing or planned colostomy during study participation.
(6) Any history of inflammatory bowel disease.
(7)Any uncontrolled significant medical, psychiatric or surgical condition or laboratory finding, that would pose a risk to subject safety or interfere with study participation or interpretation of individual subject results.
(8) Clinically significant abnormalities on electrocardiogram (ECG) at screening including corrected QT interval (Fridericia's formula) >450 msec for males or 470 msec for females at screening.
(9) Previously received external beam irradiation to a field that includes more than 30% of the bone marrow or kidneys.
(10) Criterion 10 is removed by protocol amendment.
(11) Any unresolved NCI-CTCAE Grade 2 or higher (except alopecia) from previous antitumour treatment and/or medical/surgical procedures/interventions.
(12) Known allergy to IMP or its excipients administered in this study, including imaging contrast media.
(13) Positive pregnancy test (female subjects).
(14) Likely to be uncompliant or uncooperative during the study, in the judgment of the investigator.
(15) Unable to understand the nature, scope and possible consequences of the study, in the judgment of the investigator.
(16) Sponsor employees or investigator site personnel directly affiliated with this study, and their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I
For the dose escalation, the primary endpoint is MTCA or the maximum administered cumulative activity (MACA), if the MTCA is not identified during the dose escalation part. The primary variables used for the MTCA determination will be the incidence of DLTs (as defined above) and the organ exposure to radiation during two cycles of treatment. The DLT period for the determination of the primary endpoint starts at the first administration of 177Lu-3BP-227 to EOCT/ED.
Safety evaluation will encompass DLTs, frequency and nature of adverse events (AEs), abnormal findings from physical examination, vital signs, 12-lead ECG and 24-hour 3 lead ECG Holter, ECOG performance status treatment related deterioration and clinical laboratory tests abnormalities (including haematology, blood biochemistry, hormone analysis, urinalysis and pregnancy test).
In case the phase I dose expansion cohorts are implemented, the primary endpoint will be safety and tolerability measured by the type, severity, expectedness and frequency of AEs.
Phase II
The primary endpoint is ORR measured by CT or MRI using RECIST version 1.1. Tumour response assessments are performed every 8 weeks or at the time of occurrence of first clinical signs of disease progression as determined by the investigator. |
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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) |
Phase I
Pharmacokinetics, biodistribution and dosimetry
For biodistribution and dosimetry of 177Lu-3BP-227, the secondary endpoints are:
a) Maximal uptake (%); maximal concentration achieved (Cmax); time post injection to achieve maximal concentration (Tmax); area under the curve (AUC) at the target lesions, discernible organs and blood; terminal t1/2 of activity concentrations in blood.
b) Highest absorbed dose, specific absorbed dose to the target lesions (Gy/GBq), specific absorbed dose per organ (Gy/GBq) and cumulative absorbed organ doses (Gy).
For PK of 3BP-227, the secondary endpoints are:
c) Pharmacokinetic parameters including, but not limited to, Cmax, AUC, t1/2, clearance (CL), volume of distribution (Vd), cumulative amount of unchanged drug excreted into the urine (Ae), renal clearance of the drug from plasma (CLR), as measured in plasma and urine at defined timepoints.
Pharmacodynamic/efficacy
a) Objective response rate and disease control rate (DCR), as determined by RECIST version 1.1 in subjects who received IMP.
b) Progression-free survival (PFS) and overall survival (OS) rates as determined from start of study treatment until occurrence of event and/or end of observation period.
c) Evaluation of metabolic tumour response as determined by PERCIST (version 1.0) or practical PERCIST.
d) Changes in serum tumour markers relevant and specific to the underlying tumour disease from Day of the first treatment administration to EOCT, which is planned 6 weeks after the second 177Lu 3BP 227 dose administration.
Phase II
Efficacy
a) Disease control rate, time to progression, time to response, duration of response as per RECIST version 1.1.
b) Qualitative and quantitative changes in tumour-to-background uptake using PERCIST version 1.0.
c) Progression-free survival (PFS) and OS as determined from start of study treatment until occurrence of event and/or 6 and 12 months after start of study treatment.
d) Changes in serum tumour markers relevant and specific to the underlying tumour disease from baseline to EOCT.
Subject Reported Outcomes
a) Changes in health-related quality of life scores from baseline to EOCT measured by validated questionnaires.
Safety
a) Safety and tolerability measured by the type, severity, expectedness and frequency of AEs.
Pharmacokinetics, biodistribution and dosimetry
a) For PK, biodistribution and dosimetry, the endpoints will be similar as for phase I.
Exploratory endpoints
Phase I/II
a) Tumour uptake of 177Lu-3BP-227 and the correlation with NTSR1 expression on tumour biopsies.
b) If applicable, tumour microenvironment and other markers of interest (such as NTSR1 expression, Ki67, gene expression and DNA damage) in
tumour biopsies taken at baseline, at EOCT visit or at disease progression, whichever occurs earlier.
c) Genomic profiling in circulating cfDNA and in germline DNA.
d) Gene mutation status in correlation with clinical outcome.
e) Specific renal safety biomarkers specific for proximal tubulus toxicity.
Biobanking (optional):
Serum and whole blood ribonucleic acid samples will be stored for further biomarker analysis after the end of the study. Analysis of additional biomarkers from the biobank samples will be performed outside the scope of the main study and reported separately. |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| dosimetry, antitumour activity |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 6 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 |
| Belgium |
| France |
| Netherlands |
| Switzerland |
| United States |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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