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

Study Overview
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Brief Summary
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This study was conducted to advance new treatment for patients with metastatic or locally advanced cancers expressing Neurotensin receptor 1 (NTSR1). This study was the first time the investigational drug called 177Lu-3BP-227 was administered to patients under controlled conditions of a clinical study. The purpose of this study was to evaluate how safe the 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 also 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.

Official Title
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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

Conditions
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Pancreatic Ductal Adenocarcinoma, Colorectal Cancer, Gastric Cancer, Squamous Cell Carcinoma of the Head and Neck, Bone Cancer, Advanced Cancer, Recurrent Disease, Metastatic Tumours

Intervention / Treatment
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* Drug: 177Lu-3BP-227 (also called 177Lu-IPN01087)


Participation Criteria
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Eligibility Criteria
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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 adenocarcinoma (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 kidneys. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 177Lu-3BP-227<br>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). | Drug: 177Lu-3BP-227 (also called 177Lu-IPN01087)<br>* 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)<br>* Other names: 177Lu-IPN01087;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of Participants With Dose-Limiting Toxicities (DLT) | DLTs were defined for a list of predefined study medication-related adverse events (AEs) as specified in the protocol, according to the National Cancer Institute - Common Terminology Criteria for Adverse Events scale version 5.0 that occurred during the defined DLT assessment period (during Cycle 1 or 2). | From the start of the first study medication (Cycle 1 Day 1) up to EOCT, maximum of 16 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Maximum Uptake (%) of 177Lu-3BP-227 at Target Lesions and Discernible Organs | 177Lu-3BP-227 uptake in organs and lesions was evaluated centrally, using nuclear medicine images, as part of the dosimetry workflow. Uptake activity for organs of interest (i.e., body, bone marrow, left kidney, right kidney, healthy liver, and spleen) was determined. The uptake activity was expressed relatively to the injected 177Lu-3BP-227 activity calculated as the ratio of the uptake activity divided by the administered activity at the time of injection. | Measurements were performed at 0 to 1 hours, 2 to 4 hours, 16 to 24 hours, 40 to 48 hours, 72 to 96 hours post infusion in each treatment cycle. | 
| Phase 1: Maximal Concentration (Cmax) of 177Lu-3BP-227 | The pharmacokinetic (PK) sampling was performed from Day 1 to Day 5 post infusion for each treatment cycle. | Pre-infusion and at the end of infusion, and 5 minutes, 30 minutes, 90 minutes, 4 hours, 24 hours, 48 hours and 72 to 96 hours post infusion in each treatment cycle. | 
| Phase 1: Time Post Injection to Achieve Cmax of 177Lu-3BP-227 | The PK sampling was performed from Day 1 to Day 5 post infusion for each treatment cycle. | Pre-infusion and at the end of infusion, and 5 minutes, 30 minutes, 90 minutes, 4 hours, 24 hours, 48 hours and 72 to 96 hours post infusion in each treatment cycle. | 
| Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of 177Lu-3BP-227 | The PK sampling was performed from Day 1 to Day 5 post infusion for each treatment cycle. | Pre-infusion and at the end of infusion, and 5 minutes, 30 minutes, 90 minutes, 4 hours, 24 hours, 48 hours and 72 to 96 hours post infusion in each treatment cycle. | 
| Phase 1: Half-life (t1/2) of 177Lu-3BP-227 | The PK sampling was performed from Day 1 to Day 5 post infusion for each treatment cycle. | Pre-infusion and at the end of infusion, and 5 minutes, 30 minutes, 90 minutes, 4 hours, 24 hours, 48 hours and 72 to 96 hours post infusion in each treatment cycle. | 
| Phase 1: Number of Participants With Highest Absorbed Dose of 177Lu-3BP-227 to Each Discernible Organ | The absorbed dose to the target lesions and discernible organs (i.e., organs showing uptake) was evaluated by image-based analysis. The organs considered for 177Lu-3BP-227 image-based dosimetry assessment included: healthy liver, total liver, bone marrow, left kidney, right kidney, intestine (large and small), spleen, pancreas, stomach wall, right ovary, left ovary, uterus, right testis, left testis, thymus, right thyroid gland, left thyroid gland, prostate gland and total body. The organ that had the highest absorbed dose of treatment for each participant in each treatment cycle was determined. | From the start of the first study medication (Day 1) up to EOCT, maximum of 16 weeks. | 
| Phase 1: Specific Absorbed Dose to the Target Lesions of 177Lu-3BP-227 | The specific absorbed dose to the target lesions was evaluated by image-based analysis. Results for all studied diseases (pancreatic ductal adenocarcinoma and colorectal carcinoma) at all anatomical locations (cervical, intrapelvic, liver, lung, lymph node, and pancreas) for all cycles (Cycle 1 and 2) are reported. The specific absorbed dose (Gray/GBq) was calculated as the absorbed dose to the target lesions (in Gray) divided by the activity of 177Lu-3BP-227 administered (in GBq). | From the start of the first study medication (Day 1) up to EOCT, maximum of 16 weeks. | 
| Phase 1: Specific Absorbed Dose Per Organ of 177Lu-3BP-227 | The specific absorbed dose per organ was evaluated by image-based analysis. The specific absorbed dose (Gray/GBq) was calculated as the absorbed dose to an organ (in Gray) divided by the activity of 177Lu-3BP-227 administered (in GBq). | From the start of the first study medication (Day 1) up to EOCT, maximum of 16 weeks. | 
| Phase 1: Cumulative Absorbed Organ Doses of 177Lu-3BP-227 | The cumulative absorbed dose to the discernible organs (i.e., organs showing uptake) was evaluated by image-based analysis. | From the start of the first study medication (Day 1) up to EOCT, maximum of 16 weeks. | 
| Phase 1: Cmax of 3BP-227 | The PK sampling was performed from Day 1 to Day 3 post infusion of 177Lu-3BP-227 in Cycle 1. | Pre-infusion and at the end of infusion, and 5 minutes, 30 minutes, 90 minutes, 4 hours, 6 hours, 8 hours, 24 hours and 48 hours post infusion of 177Lu-3BP-227 in Cycle 1. | 
| Phase 1: AUC of 3BP-227 | The PK sampling was performed from Day 1 to Day 3 post infusion of 177Lu-3BP-227 in Cycle 1. | Pre-infusion and at the end of infusion, and 5 minutes, 30 minutes, 90 minutes, 4 hours, 6 hours, 8 hours, 24 hours and 48 hours post infusion of 177Lu-3BP-227 in Cycle 1. | 
| Phase 1: t1/2 of 3BP-227 | The PK sampling was performed from Day 1 to Day 3 post infusion of 177Lu-3BP-227 in Cycle 1. | Pre-infusion and at the end of infusion, and 5 minutes, 30 minutes, 90 minutes, 4 hours, 6 hours, 8 hours, 24 hours and 48 hours post infusion of 177Lu-3BP-227 in Cycle 1. | 
| Phase 1: Clearance of 3BP-227 | The PK sampling was performed from Day 1 to Day 3 post infusion of 177Lu-3BP-227 in Cycle 1. | Pre-infusion and at the end of infusion, and 5 minutes, 30 minutes, 90 minutes, 4 hours, 6 hours, 8 hours, 24 hours and 48 hours post infusion of 177Lu-3BP-227 in Cycle 1. | 
| Phase 1: Volume of Distribution of 3BP-227 | The PK sampling was performed from Day 1 to Day 3 post infusion of 177Lu-3BP-227 in Cycle 1. | Pre-infusion and at the end of infusion, and 5 minutes, 30 minutes, 90 minutes, 4 hours, 6 hours, 8 hours, 24 hours and 48 hours post infusion of 177Lu-3BP-227 in Cycle 1. | 
| Phase 1: Cumulative Amount of Unchanged 3BP-227 Excreted Into the Urine | The PK sampling was performed from Day 1 to Day 3 post infusion of 177Lu-3BP-227 in Cycle 1. | Pre-infusion and at the end of infusion, and 5 minutes, 30 minutes, 90 minutes, 4 hours, 6 hours, 8 hours, 24 hours and 48 hours post infusion of 177Lu-3BP-227 in Cycle 1. | 
| Phase 1: Renal Clearance of 3BP-227 From Plasma | The PK sampling was performed from Day 1 to Day 3 post infusion of 177Lu-3BP-227 in Cycle 1. | Pre-infusion and at the end of infusion, and 5 minutes, 30 minutes, 90 minutes, 4 hours, 6 hours, 8 hours, 24 hours and 48 hours post infusion of 177Lu-3BP-227 in Cycle 1. | 
| Phase 1: Number of Participants With Objective Response Rate (ORR) | The ORR was defined as number of participants with a best overall response (BOR) characterized as either a complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) relative to the total number of evaluable participants. | From the start of the first study medication (Day 1) up to EOCT, maximum of 16 weeks. | 
| Phase 1: Number of Participants With Disease Control Rate (DCR) | The DCR was defined as number of participants with a BOR characterized as CR, PR or stable disease according to RECIST 1.1 relative to the total number of evaluable participants. | From the start of the first study medication (Day 1) up to EOCT, maximum of 16 weeks. | 
| Phase 1: Progression-Free Survival (PFS) | The PFS was defined as the time from date of first study medication administration until progression, according to RECIST 1.1. | From the start of the first study medication (Day 1) up to EOCT, maximum of 16 weeks. | 
| Phase 1: Overall Survival (OS) | The OS was defined from first study medication administration until death, according to RECIST 1.1. | From the start of the first study medication (Day 1) up to EOCT, maximum of 16 weeks. | 
| Phase 1: Metabolic Tumor Response Using Positron Emission Tomography (PET) Response Criteria In Solid Tumors (PERCIST) Version 1.0 or Practical PERCIST | Tumor response assessments were planned to perform by the site investigator (local) for the phase 1 and dose escalation part and by independent reader (central) for the phase 2. All fluorine-18 fluorodeoxyglucose-PET images were used for the metabolic tumor response assessments as described in PERCIST version 1.0 by the Investigator and/or independent readers. | From the start of the first study medication (Day 1) up to EOCT, maximum of 16 weeks. | 
| Phase 1: Tumor Marker Levels in Serum - Cancer Antigen 19-9 | Changes in tumor markers in serum relevant and specific to the underlying tumor disease was determined. | Cycle 1 Day 1, Cycle 2 Day 1, EOCT (maximum of 16 weeks) and early withdrawal | 
| Phase 1: Tumor Marker Levels in Serum - Carcinoembryonic Antigen | Changes in tumor markers in serum relevant and specific to the underlying tumor disease was determined. | Cycle 1 Day 1, Cycle 2 Day 1, EOCT (maximum of 16 weeks) and early withdrawal |