metastatic or locally advanced cancers expressing Neurotensin Receptor 1 (NTSR1).
Conditions
Interventions
For both screening and treatment formulations, the specific activity of the IMP
is 25 µg 3BP-227 per 1 GBq of 177Lu.
The screening IMP formulation consists of 1 GBq in a total volume of 10 mL.
The t
e.g. one group receives a 10 mg
tablet of product X twice daily and the other group receives a placebo tablet
twice daily.
Sponsors
Ipsen Pharma SAS
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Phase I Eligible subjects meet all the following inclusion criteria: (1) Signed informed consent form prior to all study procedures. (2) Aged 18 years or older. (3) Histologically or cytologically confirmed unresectable or locally advanced or metastatic disease and has received prior lines of standard-of-care chemotherapy/treatment and has no further suitable treatment option and a documented decision by a multidisciplinary oncology board including a specialist of the concerned pathology. (4) Subjects have: (a) PDAC or, (b) CRC or, (c) GC or, (d) GIST or (e) SCCHN or (f) ES. (5) Tumour 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 performance status of 0 or 1 (unless disability is related to surgery in ES and agreed by the sponsor). (10) Adequate organ function as evidenced by: (a) Leukocytes *3000/*L (b) Absolute neutrophil count *1500/*L (c) Platelets *75,000/*L (d) Hb >9 g/dL or >10 g/dL (if history of cardiac disease) (e) Total serum bilirubin *2 times upper normal institutional limits (ULN) (f) Aspartate aminotransferase/alanine aminotransferase (ALT) *2.5×ULN (or *5×ULN, if subject has liver metastases) (g) eGFR *55 mL/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 followup 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.
Exclusion criteria
Exclusion criteria: Phase I/II Eligible subjects must not have any of the following conditions: (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 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 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 non measurable 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 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 kidney. (10) Criterion 10 is removed by protocol amendment. (11) Any unresolved NCI-CTCAE Grade 2 or higher toxicity (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. Eligibility criteria for phase II will be reviewed as soon as phase I results are available.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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 and ends 6 weeks after the second administration. 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. | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 using 18F-FDG-PET 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) Change | — |
Countries
Netherlands
Outcome results
None listed