Study to Evaluate the Safety and Preliminary Efficacy of 177Lu-OPS201 in NETs

Study Overview
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Brief Summary
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The purpose of this clinical phase I/II study was to investigate the safety and tolerability of satoreotide tetraxetan (177Lu-IPN01072, formerly known as 177Lu-OPS201) used for the treatment of patients with neuroendocrine tumors (NETs). The secondary objectives of this study were the assessment of biodistribution, dosimetry and preliminary efficacy of satoreotide tetraxetan.

Official Title
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An International, Multicenter, Open-label Study to Evaluate Safety, Tolerability, Biodistribution, Dosimetry and Preliminary Efficacy of 177Lu-OPS201 for the Therapy of Somatostatin Receptor-positive Neuroendocrine Tumors (NETs)

Conditions
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Neuroendocrine Tumors

Intervention / Treatment
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* Drug: Satoreotide tetraxetan
* Other: Amino acid solution
* Other: Antiemetic


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent. Patients of either gender, aged ≥ 18 years. Women of childbearing potential (not surgically sterile or less than 2 years postmenopausal) must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 6 months after the last dose. Acceptable methods of contraception include abstinence, or double contraception: steroidal contraceptive (oral, transdermal, implanted, and injected) in conjunction with a barrier method (intrauterine device, condom etc.). Male patients must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 6 months after the last activity administration. Karnofsky performance score ≥ 60. Life expectancy of at least 6 months. Histologically confirmed diagnosis of - unresectable GEP NET (Grade I and Grade II according to WHO classification (2010, Annex 01), functioning and non-functioning). unresectable typical lung carcinoid or atypical lung carcinoid are acceptable (with the exception of Large Cell Bronchial Neuroendocrine Neoplasms and Small Cell Lung Cancers) (Caplin 2015). malignant, unresectable pheochromocytoma or paraganglioma Documentation of progressive disease based on RECIST v1.1 under prior anti-tumor therapy within 6 months of entry in the study (although the progression might have occurred more than 6 months before study entry). Patients should not have received further anti-tumor therapy once disease progression is documented. The images of this evaluation should be available for TGR evaluation. In countries where sunitinib or everolimus are marketed, patients with GEP NET and lung NET will be progressive under this prior anti-tumor treatment for the respective indication. Patients not suitable for everolimus/sunitinib therapy according to a tumor board decision (or comparable local practice) may also be enrolled into the study. Patients having everolimus/sunitinib therapy should have a wash-out phase of ≥ 4 weeks before the first treatment. Measurable disease based on RECIST v1.1. Confirmed presence of somatostatin receptors on technically evaluable tumor lesions documented by a positive Somatostatin Receptor Scan performed within 6 months prior to enrolment in the study. Calculated GFR ≥ 55 mL/min. Blood test results as follows: Leukocytes: ≥ 4*10^9/L Erythrocytes: ≥ 3.5*12^9/L Platelets: ≥ 100*10^9/L Albumin: > 30 g/L ALT, AST, AP: ≤ 5 times ULN (upper limit of normal) Bilirubin: ≤ 2 times ULN (2x 1.1 mg/dL) Exclusion Criteria: Known hypersensitivity to 177Lu, to DOTA, to JR11 or to any of the excipients of 177Lu-OPS201. Any previous peptide receptor radionuclide therapy (PRRT). Diagnosis of thymic NET. Presence of active infection at screening or history of serious infection within the previous 6 weeks. Administration of any other investigational medicinal product within 60 days prior to entry. Prior or planned administration of a therapeutic radiopharmaceutical within 8 half-lives of the radionuclide including any time during the current study. Any extensive radiotherapy ≤ 3 months before enrolment. Chemotherapy ≤ 3 months before enrolment. Nephrectomy, renal transplant or concomitant nephrotoxic therapy putting the subject at high risk of renal toxicity during the study as assessed by the investigator. Pregnant or breast-feeding women: A pregnancy test will be performed at the start of the study for all female patients of childbearing potential (i.e. not surgically sterile or up to 2 years postmenopausal). Any uncontrolled significant medical, psychiatric or surgical condition (active infection, unstable angina pectoris, cardiac arrhythmia, poorly controlled hypertension, poorly controlled diabetes mellitus [HbA1c ≥9%], uncontrolled congestive heart disease, etc.) or laboratory findings that, in the opinion of the investigator, might jeopardize the patient's safety or that would limit compliance with the objectives and assessments of the study. Note: the patient should be able to tolerate high volume load. Current history of any malignancy other than NET within 5 years of enrolment except for fully -resected non-melanoma skin cancer or cervical cancer in situ. Current history of malignancy; patients with a secondary tumor in remission of > 5 years can be included Any mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study, and/or evidence of an uncooperative attitude.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 177Lu-IPN01072<br>177Lu-IPN01072 administered in 3 cycles at intervals of 8 weeks (+ up to 2 additional optional cycles) | Drug: Satoreotide tetraxetan<br>* Satoreotide tetraxetan administered in 3 cycles at intervals of 8 weeks (+ up to 2 additional optional cycles)<br>* Other names: 177Lu-IPN01072;Other: Amino acid solution<br>* Given as an auxiliary product the day of the IMP infusion for safety reasons to protect the renal function. Centres can use their established amino acid infusion or Ipsen amino acid solution (auxiliary medical product OPS301)<br>* Other names: Arginine and lysine;Other: Antiemetic<br>* To counteract the known side effects of the amino acid infusion, such as nausea, dexamethasone (antiemetic) and as-required ondansetron will be administered 15 to 30 minutes before the start of the amino acid infusion (unless there are contraindications for these drugs).<br>* Other names: Ondansetron;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | AE is defined as any untoward medical occurrence in a subject or clinical trial subject administered a medicinal product, which did not necessarily have a causal relationship with this treatment. A serious AE (SAE) was classified as any untoward medical occurrence that at any dose results in death; AE was life threatening; required inpatient hospitalization or prolonged existing hospitalization; resulted in persistent or significant disability/ incapacity; was a congenital anomaly/birth defect; was an important medical event that may not result in death. TEAEs are defined as AEs that developed or worsened after start of treatment. | From the start of the first study medication (Cycle 1 Day 1) up to 6 months after the last dose of study medication, maximum of 33 months | 
| Number of Participants With Dose Limiting Toxicities (DLT) | DLTs were defined as study medication-related AEs with a severity of Grade 3 or higher are considered DLT, with the exception of hair loss, lymphopenia, nonfebrile neutropenia lasting <4 weeks and thrombocytopenia lasting <4 weeks. | 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 |
| --- | --- | --- |
| Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | 177Lu-IPN01072 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, kidney [left + right], healthy liver, and spleen) was determined. The maximal uptake in lesions was calculated for each lesion as: maximal activity divided injected activity*100. | 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion in Cycle 1 | 
| Maximal Uptake (%) of 177Lu-IPN01072 in Blood in Cycle 1 | 177Lu-IPN01072 uptake in blood was evaluated on site/locally using a gamma counter calibrated for 177Lu-IPN01072 according to the dosimetry operational manual. | Pre-infusion (Baseline), 5 and 30 minutes, 1, 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion in Cycle 1 | 
| Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | The AUC of 177Lu-IPN01072 radioactivity in discernible organs were computed for each administration of 177Lu-IPN01072. | 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion in Cycle 1 | 
| AUC of 177Lu-IPN01072 in Blood in Cycle 1 | The AUC of 177Lu-IPN01072 radioactivity in blood were computed for each administration of 177Lu-IPN01072. | Pre-infusion (Baseline), 5 and 30 minutes, 1, 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion in Cycle 1 | 
| Terminal Half-Life (T1/2) of Radioactivity Concentrations of the Radiopharmaceutical in Blood in Cycle 1 | The terminal half-life was defined as the largest half-life of the decay curve of blood activity. | Pre-infusion (Baseline), 5 and 30 minutes, 1, 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion in Cycle 1 | 
| Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | The absorbed dose to the discernible organs (i.e., organs showing uptake) was evaluated centrally, using nuclear medicine images, as part of the dosimetry workflow. The organs considered for 177LU-IPN01072 image-based dosimetry assessment included: liver, bone marrow, kidney (left + right), and spleen. Highest absorbed dose of 177Lu-IPN01072 was calculated as described in the Dosimetry calculation procedure manual. Maximum value observed for each discernible organs across participants has been reported. | 4, 24, 48, 72 to 96 and 144 to 168 hours post infusion in Cycle 1 | 
| Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | The specific absorbed dose was evaluated centrally, using nuclear medicine images, as part of the dosimetry workflow. Data are presented for all lesions, regardless of their anatomical localization. The organs considered for 177Lu-IPN01072 image-based dosimetry assessment included: liver, bone marrow, kidney (left + right), and spleen. The specific absorbed dose to the lesions was the absorbed dose by the lesion (unit: Gray) divided by the injected radioactivity (unit: GBq) for each lesion selected for dosimetry evaluation. The specific absorbed dose for a given organ was the absorbed dose by this organ (unit: Gray) divided by the injected radioactivity (unit: GBq). | 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion in Cycle 1 | 
| Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | The cumulative absorbed dose to the discernible organs (i.e., organs showing uptake) was evaluated centrally, using nuclear medicine images, as part of the dosimetry workflow. | 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion in Cycles 1 and 3 | 
| Cumulative Amount of Lu-177 Radioactivity Excreted Into the Urine (0 to 48 Hours) [Ae (0-48h)] in Cycle 1 | Urine was collected during the first 48 hours post infusion to determine the renal excretion of 177Lu-IPN01072 at Cycle 1 only. | 0 to 6 hours, 6 to 24 hours, 24 to 48 hours post-infusion in Cycle 1 of Part A; 0 to 4 hours, 4 to 24 hours, 24 to 48 hours in Cycle 1 of Part B. | 
| Time to Reach Maximum Plasma Concentration (Tmax) of IPN01072 in Cycle 1 | The PK sampling was performed from Day 1 to Day 3 post infusion done at Cycle 1 for Part B only. | Pre-infusion (Baseline) and 5 minutes, 30 minutes, 60 minutes, 4 hours, 6 hours, 8 hours, 24 hours, 48 hours after the end of the infusion in Cycle 1 | 
| Maximum Observed Plasma Concentration (Cmax) of IPN01072 in Cycle 1 | The PK sampling was performed from Day 1 to Day 3 post infusion done at Cycle 1 for Part B only. | Pre-infusion (Baseline) and 5 minutes, 30 minutes, 60 minutes, 4 hours, 6 hours, 8 hours, 24 hours, 48 hours after the end of the infusion in Cycle 1 | 
| AUC From Time Zero to Infinity (AUCinf) of IPN01072 in Cycle 1 | The PK sampling was performed from Day 1 to Day 3 post infusion done at Cycle 1 for Part B only. | Pre-infusion (Baseline) and 5 minutes, 30 minutes, 60 minutes, 4 hours, 6 hours, 8 hours, 24 hours, 48 hours after the end of the infusion in Cycle 1 | 
| T1/2 of IPN01072 in Cycle 1 | The PK sampling was performed from Day 1 to Day 3 post infusion done at Cycle 1 for Part B only. | Pre-infusion (Baseline) and 5 minutes, 30 minutes, 60 minutes, 4 hours, 6 hours, 8 hours, 24 hours, 48 hours after the end of the infusion in Cycle 1 | 
| Apparent Total Plasma Clearance of IPN01072 (Total CL) in Cycle 1 | The PK sampling was performed from Day 1 to Day 3 post infusion done at Cycle 1 for Part B only. | Pre-infusion (Baseline) and 5 minutes, 30 minutes, 60 minutes, 4 hours, 6 hours, 8 hours, 24 hours, 48 hours after the end of the infusion in Cycle 1 | 
| Apparent Volume of Distribution During Terminal Phase (Vz) of IPN01072 in Cycle 1 | The PK sampling was performed from Day 1 to Day 3 post infusion done at Cycle 1 for Part B only. | Pre-infusion (Baseline) and 5 minutes, 30 minutes, 60 minutes, 4 hours, 6 hours, 8 hours, 24 hours, 48 hours after the end of the infusion in Cycle 1 | 
| Ae (0-48h) of IPN01072 in Cycle 1 | Urine was collected during the first 48 hours post infusion to determine the renal excretion of 177Lu-IPN01072 at Cycle 1 for Part B only. | 0 to 4 hours, 4 to 24 hours, 24 to 48 hours in Cycle 1 of Part B | 
| Fraction of IPN01072 Excreted Into the Urine (Fe) in Cycle 1 | Urine was collected during the first 48 hours post infusion to determine the renal excretion of 177Lu-IPN01072 at Cycle 1 for Part B only. | 0 to 4 hours, 4 to 24 hours, 24 to 48 hours in Cycle 1 in Part B | 
| Overall Response Rate (ORR) | The ORR was defined as the percentage of participants who achieved a complete response (CR) or a partial response (PR) as best overall response (BOR) according centralized to response evaluation criteria in solid tumours (RECIST) version 1.1 from investigator assessment. Participants with no tumour assessment after the start of study treatment were not evaluated. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter (mm). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From the start of the first study medication (Cycle 1 Day 1) up to 2 years after the EOCT/death or lost to follow-up, maximum of 59 months. | 
| Disease Control Rate (DCR) | The DCR was defined as the percentage of participants who achieved a CR, a PR or a stable disease (SD) as BOR according to Investigator assessment RECIST version 1.1 criteria. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. | From the start of the first study medication (Cycle 1 Day 1) up to 2 years after the EOCT/death or lost to follow-up, maximum of 59 months. | 
| Best Overall Response | The BOR according to RECIST v1.1 was defined as the best response recorded from the initiation of treatment until the EOCT/end of additional cycles (EOAC)/early withdrawal (EW) Visit (during the core study part), prior to the Investigator assessment of PD. Progression was defined as at least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that was the smallest on study). In addition to the relative increase of 20%, the sum also demonstrated an absolute increase of at least 5 mm. | From the start of the first study medication (Cycle 1 Day 1) up to 2 years after the EOCT/death or lost to follow-up, maximum of 59 months. | 
| Progression Free Survival (PFS) | The PFS was defined as the time from start of study treatment until occurrence of tumour progression or death, according to Investigator assessment RECIST version 1.1. Estimation of the median was based on the Kaplan-Meier method. | From the start of the first study medication (Cycle 1 Day 1) up to 2 years after the EOCT/death or lost to follow-up, maximum of 59 months. | 
| Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | The European Organisation for Research and Treatment of Cancer (EORTC) score questionnaire (QLQ-C30) was used for QoL evaluation. Each scale in the questionnaire were scored (0 to 100) according to the EORTC recommendations in the EORTC QLQ-C30 scoring manual. The scale included a global health status, where high score for the global health status represents a high QoL. The functional scales consisted of physical functioning, role functioning, emotional functioning, cognitive functioning, social functioning, where a higher value reflects a better level of function. Nine symptoms scales included nausea and vomiting, pain, fatigue, dyspnoea, insomnia, appetite loss, constipation, diarrhoea and financial difficulties, where a higher value reflects worse symptoms. Baseline was defined as the last non-missing measurement collected prior to the first dose of study drug (Day 1). | Baseline (Day 1) and EOCT visit (30 months) | 
| Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | The GI.NET21 module was intended for use among participants with gastrointestinal related (GI.- related) neuroendocrine tumours, who vary in disease stage and treatments. The module comprises 21 questions, consisting of 5 scales (endocrine symptoms, G.I. symptoms, treatment related symptom, social function, disease related worries) and 4 single items that assessed muscle /bone pain symptom, sexual function, information/communication function, and body image. Each question was quoted from 1 (not at all) to 4 (very much). Each scale in the questionnaire was scored from 0 to 100. A higher value was equivalent to worse or more problems. Baseline was defined as the last non-missing measurement collected prior to the first dose of study drug (Day 1). | Baseline (Day 1) and EOCT visit (30 months) |