Study to Evaluate the Safety and Activity (Including Distribution) of 177Lu-3BP-227 in Subjects With Solid Tumours Expressing Neurotensin Receptor Type 1.

An International Multicentre, Open-Label First in Human Phase I/II Study to Evaluate the Safety, Tolerability, Biodistribution and Antitumour Activity of 177Lu-3BP-227 for the Treatment of Subjects With Solid Tumours Expressing Neurotensin Receptor 1

Sponsors

Lead Sponsor: Ipsen

Source Ipsen
Brief Summary

This study was being conducted to advance new treatment for patients with metastatic or locally advanced cancers expressing Neurotensin receptor 1 (NTSR1). This study was a first administration of a radioactive drug called 177Lu-3BP-227 to patients under controlled conditions of a clinical study. The purpose of this study is to evaluate how safe this investigational drug is as well to verify how well it is tolerated by patients after several intravenous administrations. In addition, the effect of the study drug on tumoral lesions and how it distributes throughout the body and at which rate it is removed from the body was evaluated. Since 177Lu-3BP-227 is a radio-labelled drug, it will also be measured how the emitted radiation is distributed throughout the body (dosimetry). The study consisted of a phase I dose escalation part. The study originally planned to include a phase II study however due to early termination (not due to safety concerns) the study did not progress to phase II and was stopped during phase I. For the phase I dose escalation part, it was anticipated that approximately 30 subjects will be included, in up to six escalation steps. No expansion cohorts were implemented.

Overall Status Terminated
Start Date 2018-05-03
Completion Date 2021-04-28
Primary Completion Date 2020-04-03
Phase Phase 1
Study Type Interventional
Primary Outcome
Measure Time Frame
Incidence of dose limiting toxicities (DLTs) and organ exposure to radiation - phase I From Day 1 (first administration) up to 6 weeks after the second administration
Secondary Outcome
Measure Time Frame
Maximal uptake (%) of 177Lu-3BP-227 at target lesions and discernible organs - phase I During the core study period from Day 1 up to 14 weeks (From Day 1 to Day 5 post infusion for each cycle of treatment)
Highest absorbed dose to the target lesions (Gy/GBq) of 177Lu-3BP-227 - phase I During the core study period from Day 1 up to 14 weeks (From Day 1 to Day 5 post infusion for each cycle of treatment)
Specific absorbed per organ (Gy/GBq) of 177Lu-3BP-227 - phase I During the core study period from Day 1 up to 14 weeks (From Day 1 to Day 5 post infusion for each cycle of treatment)
Cumulative absorbed organ doses (Gy) of 177Lu-3BP-227 - phase I During the core study period from Day 1 up to 14 weeks (From Day 1 to Day 5 post infusion for each cycle of treatment)
Observed maximal (peak) concentration (Cmax) of 3BP-227 - phase I Day 1: before infusion (baseline), at the end of infusion (0), 5, 30 minutes, 1 and 4, 6, 10 and 18 hours after the end of infusion; Day 2: 24 hours after the end of infusion; Day 3: 48 hours after the end of infusion
Area under the (plasma concentration versus time) curve (AUC) of 3BP-227 - phase I Day 1: before infusion (baseline), at the end of infusion (0), 5, 30 minutes, 1 and 4, 6, 10 and 18 hours after the end of infusion; Day 2: 24 hours after the end of infusion; Day 3: 48 hours after the end of infusion
Half-life (t1/2) of 3BP-227 - phase I Day 1: before infusion (baseline), at the end of infusion (0), 5, 30 minutes, 1 and 4, 6, 10 and 18 hours after the end of infusion; Day 2: 24 hours after the end of infusion; Day 3: 48 hours after the end of infusion
Clearance (CL) of 3BP-227 - phase I Day 1: before infusion (baseline), at the end of infusion (0), 5, 30 minutes, 1 and 4, 6, 10 and 18 hours after the end of infusion; Day 2: 24 hours after the end of infusion; Day 3: 48 hours after the end of infusion
Volume of distribution (Vd) of 3BP-227 - phase I Day 1: before infusion (baseline), at the end of infusion (0), 5, 30 minutes, 1 and 4, 6, 10 and 18 hours after the end of infusion; Day 2: 24 hours after the end of infusion; Day 3: 48 hours after the end of infusion
Cumulative amount of unchanged drug excreted into the urine (Ae) - phase I Day 1: before infusion (baseline), at the end of infusion (0), 5, 30 minutes, 1 and 4, 6, 10 and 18 hours after the end of infusion; Day 2: 24 hours after the end of infusion; Day 3: 48 hours after the end of infusion
Renal clearance of 177Lu-3BP-227 from plasma (CLR), as measured in plasma and urine - phase I Day 1: before infusion (baseline), at the end of infusion (0), 5, 30 minutes, 1 and 4, 6, 10 and 18 hours after the end of infusion; Day 2: 24 hours after the end of infusion; Day 3: 48 hours after the end of infusion
Objective response rate of 177Lu-3BP-227 - phase I From Day 1 up to 16 weeks (starts at the first administration and ends 6 weeks after the second administration)
Disease control rate of 177Lu-3BP-227 - phase I From Day 1 up to the end of the long-term follow up period of 60 months (whole study period)
Progression-free survival (PFS) - phase I From Day 1 up to the end of the long-term follow up period of 60 months (whole study period)
Overall survival (OS) - phase I From Day 1 up to the end of the long-term follow up period of 60 months (whole study period)
Evaluation of metabolic tumour response using Positron emission tomography (PET) Response Criteria In Solid Tumours (version 1.0) or practical PERCIST - phase I From Day 1 up to 16 weeks (starts at the first administration and ends 6 weeks after the second administration)
Changes in serum tumour markers relevant and specific to the underlying tumour disease - phase I From Day 1 up to 16 weeks (starts at the first administration and ends 6 weeks after the second administration)
Enrollment 14
Condition
Intervention

Intervention Type: Drug

Intervention Name: 177Lu-3BP-227 (also called 177Lu-IPN01087)

Description: The cumulative activity of the treatment investigational medicinal product (IMP) formulation will be administered in two intravenous (i.v.) infusions separated by at least 4 weeks (28 days). Up to 6 administrations can be given (2 cycles plus 4 optional additional)

Arm Group Label: 177Lu-3BP-227

Other Name: 177Lu-IPN01087

Eligibility

Criteria:

Inclusion Criteria : - Signed informed consent form prior to all study procedures - Aged 18 years or older. - 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 documented decision by a multidisciplinary oncology board including a specialist of the concerned pathology. - Subjects have (a) pancreatic ductal adenocarcinoma (PDAC), or (b) colorectal cancer (CRC), or (c) gastric adenocarcinoma (GC), or (d) gastrointestinal stromal tumours (GIST), or (e) squamous-cell carcinoma of head and neck (SCCHN), or (f) Ewing Sarcoma (ES) - Tumour showing: (a) by 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. - Measurable disease (based on RECIST version1.1). - Documentation of progressive disease in the 6 months prior to study start (treatment). - Eastern Cooperative Oncology Group performance status of 0 or 1 (unless if disability is related to surgery in ES and Agreed with the Sponsor). - Adequate organ function as evidenced by: (a) Leukocytes ≥3000/μL (b) Absolute neutrophil count ≥1500/µL (c) Platelets ≥75,000/µL (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) Estimated glomerular filtration rate (eGFR) ≥55 mL/min. - Estimated life expectancy >3 months. - 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 - For 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, but the male subject must agree to use a condom to protect his partner as described above. - 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. Exclusion Criteria : - Prior treatment received (a) Any antitumor 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-characterized. - Brain metastases. - Nephrectomy, renal transplant or concomitant nephrotoxic therapy putting the subject at high risk of renal toxicity during the study. - Only non-measurable metastatic bone lesions - Existing or planned colostomy during study participation. - Any history of inflammatory bowel disease. - 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. - 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. - Previously received external beam irradiation to a field that includes more than 30% of the bone marrow or kidney. - Any unresolved NCI-CTCAE Grade 2 or higher toxicity (except alopecia) from previous antitumor treatment and/or medical/surgical procedures/interventions. - Known allergy to IMP or its excipients administered in this study, including imaging contrast media. - Positive pregnancy test (female subjects). - Likely to be uncompliant or uncooperative during the study, in the judgment of the investigator. - Unable to understand the nature, scope, and possible consequences of the study, in the judgment of the investigator. - 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.

Gender:

All

Minimum Age:

18 Years

Maximum Age:

N/A

Healthy Volunteers:

No

Overall Official
Last Name Role Affiliation
Ipsen Medical Director Study Director Ipsen
Overall Contact

Last Name: Ipsen Recruitment Enquiries

Phone: see email

Email: [email protected]

Location
Facility:
The University of Texas MD Anderson Cancer Center | Houston, Texas, 77030, United States
Institut Jules Bordet | Brussels, 1000, Belgium
Centre Léon Bérard | Lyon, France
CHU Timone | Marseille, 13385, France
CHU Hôtel Dieu | Nantes, France
University Medical Center Groningen | Groningen, 9713, Netherlands
CHU Vaudois | Lausanne, Switzerland
Universitäts Spital Zürich | Zürich, 8091, Switzerland
Location Countries

Belgium

France

Netherlands

Switzerland

United States

Verification Date

2021-06-01

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Label: 177Lu-3BP-227

Type: Experimental

Description: Screening: 177Lu-IPN01087 - 25 µg 3BP-227 (IPN01087) per 1 GBq of 177Lu. 1 GBq in a total volume of 10 mL. Treatment phase: 177Lu-IPN01087 - 2.5 to 7.5 GBq escalation dose of 177Lu-3BP-227 (IPN01087) in a total volume of 20 mL for each cycle of administration (2 cycles plus 4 optional additional).

Study Design Info

Allocation: N/A

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

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