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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).

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)

177Lu-3BP-227 (also called 177Lu-IPN01087)

Ipsen Medical Director

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.

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

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).

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.

The pharmacokinetic (PK) sampling was performed from Day 1 to Day 5 post infusion for each treatment cycle.

The PK sampling was performed from Day 1 to Day 5 post infusion for each treatment cycle.

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.

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).

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).

The cumulative absorbed dose to the discernible organs (i.e., organs showing uptake) was evaluated by image-based analysis.

The PK sampling was performed from Day 1 to Day 3 post infusion of 177Lu-3BP-227 in Cycle 1.

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.

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.

The PFS was defined as the time from date of first study medication administration until progression, according to RECIST 1.1.

The OS was defined from first study medication administration until death, according to RECIST 1.1.

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.

Changes in tumor markers in serum relevant and specific to the underlying tumor disease was determined.

Ipsen

Safety population contained all participants who received at least 1 dose of study medication.

Participants received 177Lu-3BP-227 2.5 GBq fractionated into 2 IV administrations separated by 4 to 5 weeks during the core trial period.

Cohort 1: 177Lu-3BP-227 2.5 GBq

Participants received 177Lu-3BP-227 4.0 GBq fractionated into 2 IV administrations separated by 4 to 5 weeks during the core trial period.

Cohort 2: 177Lu-3BP-227 4.0 GBq

Participants received 177Lu-3BP-227 5.5 GBq fractionated into 2 IV administrations separated by 4 to 5 weeks during the core trial period.

Cohort 3: 177Lu-3BP-227 5.5 GBq

Participants received 177Lu-3BP-227 6.5 GBq fractionated into 2 IV administrations separated by 4 to 5 weeks during the core trial period.

Cohort 4: 177Lu-3BP-227 6.5 GBq

Participants received 177Lu-3BP-227 7.5 GBq fractionated into 2 IV administrations separated by 4 to 5 weeks during the core trial period.

Cohort 5: 177Lu-3BP-227 7.5 GBq

Total

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

Included population contained all screened participants who were included in the study and received the therapeutic dose.

The sponsor terminated the study early and phase 1 dose expansion and phase 2 were not started. The decision to terminate the study was not due to any safety or tolerability concern, or any event associated with the use of 177Lu-3BP-227.

Medical Director

Phase 1: Number of Participants With Dose-Limiting Toxicities (DLT)

All cycles: Body

All cycles: Bone marrow

All cycles: Left kidney

All cycles: Right kidney

All cycles: Healthy liver

All cycles: Spleen

Participants received 177Lu-3BP-227 dose range of 2.5 to 7.5 GBq fractionated into 2 IV administrations separated by 4 to 5 weeks during the core trial period.

All Participants

Dosimetry population included all participants with organ dosimetry data and with no major protocol deviations with an impact on dosimetry analysis. Since the study drug administered to different groups had same composition/specific activity, no difference in drug distribution was expected between groups. Because uptake results were expressed as percentage of administered 177Lu-3BP-227 activity, no difference in uptake was expected between groups and results were reported combining all groups.

Phase 1: Maximum Uptake (%) of 177Lu-3BP-227 at Target Lesions and Discernible Organs

Due to the early termination of the study, the PK analysis data was not collected.

Phase 1: Maximal Concentration (Cmax) of 177Lu-3BP-227

Phase 1: Time Post Injection to Achieve Cmax of 177Lu-3BP-227

Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of 177Lu-3BP-227

Phase 1: Half-life (t1/2) of 177Lu-3BP-227

Cycle 1

Cycle 2

Dosimetry population included all participants with organ dosimetry data and with no major protocol deviations with an impact on dosimetry analysis. Since the study drug administered to the different groups had the same composition/specific activity, no difference in drug distribution was expected between groups and results were reported combining all groups.

Phase 1: Number of Participants With Highest Absorbed Dose of 177Lu-3BP-227 to Each Discernible Organ

Dosimetry population included all participants with organ dosimetry data and with no major protocol deviations with an impact on dosimetry analysis. Since study drug administered to different groups had same composition/specific activity and since the specific absorbed dose is expressed relatively to the administered activity (Gray/Gbq), no difference in specific absorbed dose was expected between groups and results were reported combining all groups.

Phase 1: Specific Absorbed Dose to the Target Lesions of 177Lu-3BP-227

Phase 1: Specific Absorbed Dose Per Organ of 177Lu-3BP-227

Cycle 2: Bone marrow

Cycle 2: Healthy liver

Cycle 2: Left kidney

Cycle 2: Right kidney

Dosimetry population included all participants with organ dosimetry data and with no major protocol deviations with an impact on dosimetry analysis. Cumulative absorbed doses on Cycles 1 and 2 are only presented for participants who have performed the 2 cycles.

Phase 1: Cumulative Absorbed Organ Doses of 177Lu-3BP-227

Phase 1: Cmax of 3BP-227

Phase 1: AUC of 3BP-227

Phase 1: t1/2 of 3BP-227

Phase 1: Clearance of 3BP-227

Phase 1: Volume of Distribution of 3BP-227

Phase 1: Cumulative Amount of Unchanged 3BP-227 Excreted Into the Urine

Phase 1: Renal Clearance of 3BP-227 From Plasma

Primary Pharmacodynamic population (for tumor response) included all participants who received at least 2 therapeutic doses of 177Lu-3BP-227 and reached the end of Cycle 2 or EOCT visit with available post-baseline tumor assessment based on RECIST 1.1 and with no major protocol deviations with an impact on the analysis.

Phase 1: Number of Participants With Objective Response Rate (ORR)

Phase 1: Number of Participants With Disease Control Rate (DCR)

Due to the early termination of the study, survival analysis on PFS was not collected.

Phase 1: Progression-Free Survival (PFS)

Due to the early termination of the study, survival analysis on OS was not collected.

Phase 1: Overall Survival (OS)

Due to the early termination of the study, metabolic tumor response was not collected.

Phase 1: Metabolic Tumor Response Using Positron Emission Tomography (PET) Response Criteria In Solid Tumors (PERCIST) Version 1.0 or Practical PERCIST

Cycle 1 Day 1

Cycle 2 Day 1

EOCT

Early Withdrawal

Pharmacodynamic population included all participants who received at least 1 therapeutic dose and with available post-baseline pharmacodynamics/efficacy data.

Phase 1: Tumor Marker Levels in Serum - Cancer Antigen 19-9

Phase 1: Tumor Marker Levels in Serum - Carcinoembryonic Antigen

Participants received 177Lu-3BP-227 2.5 Gigabecquerel (GBq) fractionated into 2 intravenous (IV) administrations separated by 4 to 5 weeks during the core trial period.

Spots Global Cancer Trial Database for metastatic tumours