Neuroendocrine Tumors
Conditions
Brief summary
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.
Interventions
Satoreotide tetraxetan administered in 3 cycles at intervals of 8 weeks (+ up to 2 additional optional cycles)
OTHERAmino acid solution
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)
OTHERAntiemetic
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).
Sponsors
Ipsen
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written informed consent. 2. Patients of either gender, aged ≥ 18 years. 3. 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.). 4. 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. 5. Karnofsky performance score ≥ 60. 6. Life expectancy of at least 6 months. 7. 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 8. 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. 9. 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. 10. Measurable disease based on RECIST v1.1. 11. 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. 12. Calculated GFR ≥ 55 mL/min. 13. 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
1. Known hypersensitivity to 177Lu, to DOTA, to JR11 or to any of the excipients of 177Lu-OPS201. 2. Any previous peptide receptor radionuclide therapy (PRRT). 3. Diagnosis of thymic NET. 4. Presence of active infection at screening or history of serious infection within the previous 6 weeks. 5. Administration of any other investigational medicinal product within 60 days prior to entry. 6. Prior or planned administration of a therapeutic radiopharmaceutical within 8 half-lives of the radionuclide including any time during the current study. 7. Any extensive radiotherapy ≤ 3 months before enrolment. 8. Chemotherapy ≤ 3 months before enrolment. 9. Nephrectomy, renal transplant or concomitant nephrotoxic therapy putting the subject at high risk of renal toxicity during the study as assessed by the investigator. 10. 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). 11. 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. 12. 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 13. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLT) | From the start of the first study medication (Cycle 1 Day 1) up to EOCT, maximum of 16 weeks. | 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. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion in Cycle 1 | The AUC of 177Lu-IPN01072 radioactivity in discernible organs were computed for each administration of 177Lu-IPN01072. |
| AUC of 177Lu-IPN01072 in Blood in Cycle 1 | Pre-infusion (Baseline), 5 and 30 minutes, 1, 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion in Cycle 1 | The AUC of 177Lu-IPN01072 radioactivity in blood were computed for each administration of 177Lu-IPN01072. |
| Terminal Half-Life (T1/2) of Radioactivity Concentrations of the Radiopharmaceutical in Blood in Cycle 1 | Pre-infusion (Baseline), 5 and 30 minutes, 1, 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion in Cycle 1 | The terminal half-life was defined as the largest half-life of the decay curve of blood activity. |
| Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | 4, 24, 48, 72 to 96 and 144 to 168 hours post infusion 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. |
| Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion 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). |
| Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion 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. |
| Cumulative Amount of Lu-177 Radioactivity Excreted Into the Urine (0 to 48 Hours) [Ae (0-48h)] in Cycle 1 | 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. | Urine was collected during the first 48 hours post infusion to determine the renal excretion of 177Lu-IPN01072 at Cycle 1 only. |
| Time to Reach Maximum Plasma Concentration (Tmax) of IPN01072 in Cycle 1 | 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 | The PK sampling was performed from Day 1 to Day 3 post infusion done at Cycle 1 for Part B only. |
| Maximum Observed Plasma Concentration (Cmax) of IPN01072 in Cycle 1 | 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 | The PK sampling was performed from Day 1 to Day 3 post infusion done at Cycle 1 for Part B only. |
| AUC From Time Zero to Infinity (AUCinf) of IPN01072 in Cycle 1 | 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 | The PK sampling was performed from Day 1 to Day 3 post infusion done at Cycle 1 for Part B only. |
| Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion 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. |
| Apparent Total Plasma Clearance of IPN01072 (Total CL) in Cycle 1 | 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 | The PK sampling was performed from Day 1 to Day 3 post infusion done at Cycle 1 for Part B only. |
| Apparent Volume of Distribution During Terminal Phase (Vz) of IPN01072 in Cycle 1 | 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 | The PK sampling was performed from Day 1 to Day 3 post infusion done at Cycle 1 for Part B only. |
| Ae (0-48h) of IPN01072 in Cycle 1 | 0 to 4 hours, 4 to 24 hours, 24 to 48 hours in Cycle 1 of Part B | 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. |
| Fraction of IPN01072 Excreted Into the Urine (Fe) in Cycle 1 | 0 to 4 hours, 4 to 24 hours, 24 to 48 hours in Cycle 1 in Part B | 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. |
| Overall Response Rate (ORR) | 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. | 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. |
| Disease Control Rate (DCR) | 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. | 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. |
| Best Overall Response | 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. | 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. |
| Progression Free Survival (PFS) | 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. | 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. |
| Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Baseline (Day 1) and EOCT visit (30 months) | 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). |
| Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Baseline (Day 1) and EOCT visit (30 months) | 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). |
| T1/2 of IPN01072 in Cycle 1 | 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 | The PK sampling was performed from Day 1 to Day 3 post infusion done at Cycle 1 for Part B only. |
| Maximal Uptake (%) of 177Lu-IPN01072 in Blood in Cycle 1 | Pre-infusion (Baseline), 5 and 30 minutes, 1, 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion 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. |
Countries
Australia, Austria, Canada, Denmark, France, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
This Phase 1/2, open-label study was conducted in participants with somatostatin receptor positive neuroendocrine tumour (NETs) at 8 investigational sites in Australia, Austria, Canada, Denmark, France, Switzerland and United Kingdom between 06 March 2017 and 22 February 2022. The sponsor terminated the study early for strategic reasons and this decision was not due to any safety or tolerability concern of the study drug.
Pre-assignment details
The study was performed in 2 parts, Part A and Part B. Study consists of a screening period (up to 4 weeks), Treatment period (3 core treatment cycles in each Part A and Part B; 2 additional cycles in Part B only) and followed by long-term follow-up (LTFU) period (2 years). Each cycle was 8 weeks (+ up to 4 weeks if toxicity) apart. A total 40 participants were treated in this study. Due to initial findings, Cohorts 2, 4, 5, 7 and 8 in Part B were not performed in this study.
Participants by arm
| Arm | Count |
|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq Participants received 4.5 GBq 177Lu-IPN01072 (target dose of 300 mcg ±50 mcg) IV infusion on Day 1 of 3 treatment cycles. Each cycle was 8 weeks apart (+2 weeks or up to +4 weeks in case of AE which had not adequately recovered). | 15 |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq Participants received 6 GBq 177Lu-IPN01072 (target dose of 300 mcg) IV infusion on Day 1 of 3 treatment cycles. The radioactivity dose was reduced to 4.5 GBq in Cohort 1 adapted as recommended by DRB. As a result, Cohort 1 adapted was similar to Cohort 1 except the radioactivity dose was 4.5 GBq. Each cycle was 8 weeks apart (+2 weeks or up to +4 weeks in case of AEs which had not adequately recovered). | 6 |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq Participants received 4.5 GBq 177Lu-IPN01072 (target dose of 300 mcg in Cycle 1; 700 mcg in Cycle 2; 300 mcg in Cycle 3) IV infusion on Day 1 of 3 treatment cycles. Target dose was 300 mcg for additional cycles, if any. Each cycle was 8 weeks apart (+2 weeks or up to +4 weeks in case of AEs which had not adequately recovered). | 9 |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq Participants received of 4.5 GBq 177Lu-IPN01072 (target dose of 300 mcg in Cycle 1; 1300 mcg in Cycle 2; 300 mcg in Cycle 3) IV infusion on Day 1 of 3 treatment cycles. Target dose was 300 mcg for additional cycles, if any. Each cycle was 8 weeks apart (+2 weeks or up to +4 weeks in case of AEs which had not adequately recovered). | 10 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Consent Withdrawn | 0 | 1 | 2 | 0 |
| Overall Study | Death | 1 | 0 | 0 | 0 |
| Overall Study | Never entered LTFU period | 1 | 0 | 0 | 2 |
| Overall Study | Other | 0 | 0 | 1 | 2 |
| Overall Study | Progressive Disease | 4 | 4 | 3 | 3 |
Baseline characteristics
| Characteristic | Part A: 177Lu-IPN01072 4.5 GBq | Part B Cohort 1: 177Lu-IPN01072 6 GBq | Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Total |
|---|---|---|---|---|---|
| Age, Continuous | 62.7 years STANDARD_DEVIATION 12.9 | 65.3 years STANDARD_DEVIATION 8.9 | 55.0 years STANDARD_DEVIATION 16 | 56.7 years STANDARD_DEVIATION 13.7 | 59.9 years STANDARD_DEVIATION 13.5 |
| Age, Customized <65 | 7 Participants | 3 Participants | 6 Participants | 7 Participants | 23 Participants |
| Age, Customized >=65 | 8 Participants | 3 Participants | 3 Participants | 3 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 6 Participants | 9 Participants | 10 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 15 Participants | 6 Participants | 9 Participants | 9 Participants | 39 Participants |
| Sex: Female, Male Female | 8 Participants | 2 Participants | 3 Participants | 6 Participants | 19 Participants |
| Sex: Female, Male Male | 7 Participants | 4 Participants | 6 Participants | 4 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 15 | 0 / 6 | 0 / 9 | 1 / 10 | 3 / 40 |
| other Total, other adverse events | 15 / 15 | 6 / 6 | 9 / 9 | 10 / 10 | 39 / 40 |
| serious Total, serious adverse events | 2 / 15 | 1 / 6 | 2 / 9 | 3 / 10 | 8 / 40 |
Outcome results
Primary
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.
Time frame: From the start of the first study medication (Cycle 1 Day 1) up to EOCT, maximum of 16 weeks.
Population: The SAS included all participants who received 177Lu-IPN01072.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Number of Participants With Dose Limiting Toxicities (DLT) | 3 Participants |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Number of Participants With Dose Limiting Toxicities (DLT) | 0 Participants |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Number of Participants With Dose Limiting Toxicities (DLT) | 2 Participants |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Number of Participants With Dose Limiting Toxicities (DLT) | 1 Participants |
| All Participants | Number of Participants With Dose Limiting Toxicities (DLT) | 6 Participants |
Primary
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.
Time frame: 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
Population: The SAS included all participants who received 177Lu-IPN01072.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 15 Participants |
| Part A: 177Lu-IPN01072 4.5 GBq | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 2 Participants |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 6 Participants |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 1 Participants |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 9 Participants |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 2 Participants |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 3 Participants |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 10 Participants |
| All Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 40 Participants |
| All Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 8 Participants |
Secondary
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.
Time frame: 0 to 4 hours, 4 to 24 hours, 24 to 48 hours in Cycle 1 of Part B
Population: The IPN01072 PK set in urine (Part B only) included all participants in the ITT set who received at least 1 dose of study medication and have no major protocol deviations affecting the urine PK variables and who had all urine IPN01072 levels to estimate the main urine PK parameters. Results were combined for IPN01072 PK analysis performed at cycle 1, as pre-specified according to study protocol and the data analysis plan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Ae (0-48h) of IPN01072 in Cycle 1 | 141 mcg | Standard Deviation 65.9 |
Secondary
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.
Time frame: 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
Population: The IPN01072 PK set in plasma (Part B only) included all participants in the ITT set who received at least 1 dose of study medication and have no major protocol deviations affecting the plasma PK variables and who had a sufficient number of plasma levels to estimate the main PK parameters. Only data from the participants analyzed were reported. Results were combined for IPN01072 PK analysis performed at cycle 1, as pre-specified according to study protocol and the data analysis plan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Apparent Total Plasma Clearance of IPN01072 (Total CL) in Cycle 1 | 9.58 L/h | Standard Deviation 12.8 |
Secondary
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.
Time frame: 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
Population: The IPN01072 PK set in plasma (Part B only) included all participants in the ITT set who received at least 1 dose of study medication and have no major protocol deviations affecting the plasma PK variables and who had a sufficient number of plasma levels to estimate the main PK parameters. Only data from the participants analyzed were reported. Results were combined for IPN01072 PK analysis performed at cycle 1, as pre-specified according to study protocol and the data analysis plan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Apparent Volume of Distribution During Terminal Phase (Vz) of IPN01072 in Cycle 1 | 68.7 Liter | Standard Deviation 52 |
Secondary
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.
Time frame: 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion in Cycle 1
Population: The PP-DAS included all participants in the ITT-DAS for whom no major protocol violations occurred affecting dosimetry variables. Only data from the participants analyzed were reported.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | Spleen | 6701 MBq*hour |
| Part A: 177Lu-IPN01072 4.5 GBq | Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | Kidney (left + right) | 9596 MBq*hour |
| Part A: 177Lu-IPN01072 4.5 GBq | Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | Liver | 6745 MBq*hour |
| Part A: 177Lu-IPN01072 4.5 GBq | Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | Bone marrow (Image-based) | 174 MBq*hour |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | Spleen | 7949 MBq*hour |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | Bone marrow (Image-based) | 352 MBq*hour |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | Kidney (left + right) | 8966 MBq*hour |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | Liver | 17918 MBq*hour |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | Bone marrow (Image-based) | 138 MBq*hour |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | Spleen | 7727 MBq*hour |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | Kidney (left + right) | 6239 MBq*hour |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | Kidney (left + right) | 7578 MBq*hour |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | Spleen | 8179 MBq*hour |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | Bone marrow (Image-based) | 157 MBq*hour |
| All Participants | Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | Spleen | 7772 MBq*hour |
| All Participants | Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | Bone marrow (Image-based) | 175 MBq*hour |
| All Participants | Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | Kidney (left + right) | 8239 MBq*hour |
| All Participants | Area Under the Concentration Time Curve (AUC) of 177Lu-IPN01072 in Discernible Organs in Cycle 1 | Liver | 11133 MBq*hour |
Secondary
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.
Time frame: 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
Population: The IPN01072 PK set in plasma (Part B only) included all participants in the ITT set who received at least 1 dose of study medication and have no major protocol deviations affecting the plasma PK variables and who had a sufficient number of plasma levels to estimate the main PK parameters. Only data from the participants analyzed were reported. Results were combined for IPN01072 PK analysis performed at cycle 1, as pre-specified according to study protocol and the data analysis plan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | AUC From Time Zero to Infinity (AUCinf) of IPN01072 in Cycle 1 | 45.8 ng*hour (h)/mL | Standard Deviation 20.6 |
Secondary
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.
Time frame: Pre-infusion (Baseline), 5 and 30 minutes, 1, 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion in Cycle 1
Population: The radiopharmaceutical PK set included all participants in the ITT set who received at least 1 dose of study medication and had at least 1 measured radioactive concentration in blood. Only data from the participants analyzed were reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | AUC of 177Lu-IPN01072 in Blood in Cycle 1 | 623 MBq*hour/L |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | AUC of 177Lu-IPN01072 in Blood in Cycle 1 | 901 MBq*hour/L |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | AUC of 177Lu-IPN01072 in Blood in Cycle 1 | 690 MBq*hour/L |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | AUC of 177Lu-IPN01072 in Blood in Cycle 1 | 720 MBq*hour/L |
| All Participants | AUC of 177Lu-IPN01072 in Blood in Cycle 1 | 726 MBq*hour/L |
Secondary
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.
Time frame: 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.
Population: The ITT included all participants in the eligible participants set who received study medication.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Best Overall Response | PR | 6 Participants |
| Part A: 177Lu-IPN01072 4.5 GBq | Best Overall Response | SD | 8 Participants |
| Part A: 177Lu-IPN01072 4.5 GBq | Best Overall Response | PD | 1 Participants |
| Part A: 177Lu-IPN01072 4.5 GBq | Best Overall Response | Not Evaluable (NE) | 0 Participants |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Best Overall Response | PR | 1 Participants |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Best Overall Response | Not Evaluable (NE) | 0 Participants |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Best Overall Response | SD | 5 Participants |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Best Overall Response | PD | 0 Participants |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Best Overall Response | Not Evaluable (NE) | 0 Participants |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Best Overall Response | SD | 7 Participants |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Best Overall Response | PD | 0 Participants |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Best Overall Response | PR | 2 Participants |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Best Overall Response | PR | 4 Participants |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Best Overall Response | SD | 5 Participants |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Best Overall Response | Not Evaluable (NE) | 1 Participants |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Best Overall Response | PD | 0 Participants |
| All Participants | Best Overall Response | Not Evaluable (NE) | 1 Participants |
| All Participants | Best Overall Response | PD | 1 Participants |
| All Participants | Best Overall Response | SD | 25 Participants |
| All Participants | Best Overall Response | PR | 13 Participants |
Secondary
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).
Time frame: Baseline (Day 1) and EOCT visit (30 months)
Population: The ITT included all participants in the eligible participants set who received study medication. Only data from the participants analyzed were reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Social function | -19.67 score on a scale | Standard Deviation 15.83 |
| Part A: 177Lu-IPN01072 4.5 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Endocrine symptoms | -5.12 score on a scale | Standard Deviation 13.31 |
| Part A: 177Lu-IPN01072 4.5 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Disease related worries | -8.98 score on a scale | Standard Deviation 14.63 |
| Part A: 177Lu-IPN01072 4.5 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | G. I. symptoms | -3.58 score on a scale | Standard Deviation 13.49 |
| Part A: 177Lu-IPN01072 4.5 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Treatment related symptom | 5.62 score on a scale | Standard Deviation 21.47 |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Social function | -22.30 score on a scale | — |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Treatment related symptom | -6.70 score on a scale | — |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | G. I. symptoms | -6.70 score on a scale | — |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Disease related worries | -22.20 score on a scale | — |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Endocrine symptoms | 11.10 score on a scale | — |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Treatment related symptom | 9.01 score on a scale | Standard Deviation 15.11 |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Endocrine symptoms | -0.00 score on a scale | Standard Deviation 5.93 |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | G. I. symptoms | 2.50 score on a scale | Standard Deviation 7.04 |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Social function | -4.15 score on a scale | Standard Deviation 8.29 |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Disease related worries | 3.46 score on a scale | Standard Deviation 16.53 |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Disease related worries | -18.05 score on a scale | Standard Deviation 13.87 |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Endocrine symptoms | -5.55 score on a scale | Standard Deviation 11.1 |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Social function | -30.53 score on a scale | Standard Deviation 5.55 |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Treatment related symptom | -0.30 score on a scale | Standard Deviation 8.15 |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | G. I. symptoms | -13.30 score on a scale | Standard Deviation 17.22 |
| All Participants | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Treatment related symptom | 5.28 score on a scale | Standard Deviation 17.56 |
| All Participants | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Social function | -16.67 score on a scale | Standard Deviation 15.17 |
| All Participants | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Endocrine symptoms | -2.98 score on a scale | Standard Deviation 11.13 |
| All Participants | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | Disease related worries | -7.06 score on a scale | Standard Deviation 16.37 |
| All Participants | Change From Baseline in QLQ Gastro-intestinal. Neuroendocrine Tumour (GI.NET)21 at EOCT Visit | G. I. symptoms | -3.33 score on a scale | Standard Deviation 12.81 |
Secondary
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).
Time frame: Baseline (Day 1) and EOCT visit (30 months)
Population: The ITT included all participants in the eligible participants set who received study medication. Only data from the participants analyzed were reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Global Health Status | 1.27 score on a scale | Standard Deviation 23.54 |
| Part A: 177Lu-IPN01072 4.5 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Physical functioning | -2.05 score on a scale | Standard Deviation 11.03 |
| Part A: 177Lu-IPN01072 4.5 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Role functioning | 3.85 score on a scale | Standard Deviation 29.79 |
| Part A: 177Lu-IPN01072 4.5 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Emotional functioning | 11.52 score on a scale | Standard Deviation 30.15 |
| Part A: 177Lu-IPN01072 4.5 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Cognitive functioning | 6.41 score on a scale | Standard Deviation 19.89 |
| Part A: 177Lu-IPN01072 4.5 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Social functioning | 15.38 score on a scale | Standard Deviation 33.65 |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Cognitive functioning | 0.00 score on a scale | — |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Social functioning | 0.00 score on a scale | — |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Global Health Status | 16.70 score on a scale | — |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Role functioning | 0.00 score on a scale | — |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Emotional functioning | -25.00 score on a scale | — |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Physical functioning | 0.00 score on a scale | — |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Emotional functioning | -4.16 score on a scale | Standard Deviation 7.74 |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Cognitive functioning | -6.26 score on a scale | Standard Deviation 12.43 |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Global Health Status | -6.24 score on a scale | Standard Deviation 14.61 |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Role functioning | -0.01 score on a scale | Standard Deviation 19.9 |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Physical functioning | -0.82 score on a scale | Standard Deviation 6.61 |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Social functioning | -2.09 score on a scale | Standard Deviation 5.9 |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Emotional functioning | 10.43 score on a scale | Standard Deviation 12.51 |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Physical functioning | 10.00 score on a scale | Standard Deviation 20 |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Role functioning | 12.50 score on a scale | Standard Deviation 25 |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Social functioning | 12.50 score on a scale | Standard Deviation 25 |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Cognitive functioning | 12.50 score on a scale | Standard Deviation 15.95 |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Global Health Status | 29.15 score on a scale | Standard Deviation 28.43 |
| All Participants | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Cognitive functioning | 3.20 score on a scale | Standard Deviation 17.66 |
| All Participants | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Role functioning | 3.85 score on a scale | Standard Deviation 25.08 |
| All Participants | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Physical functioning | 0.26 score on a scale | Standard Deviation 11.7 |
| All Participants | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Social functioning | 8.97 score on a scale | Standard Deviation 26.35 |
| All Participants | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Emotional functioning | 5.12 score on a scale | Standard Deviation 23.7 |
| All Participants | Change From Baseline in Quality of Life (QoL) Questionnaire (QLQ)-C30 at EOCT Visit | Global Health Status | 3.84 score on a scale | Standard Deviation 23.83 |
Secondary
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.
Time frame: 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion in Cycles 1 and 3
Population: The PP-DAS included all participants in the ITT-DAS for whom no major protocol violations occurred affecting dosimetry variables. Only data from the participants analyzed were reported.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 1: Spleen | 2.88 Gray |
| Part A: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 1: Liver | 0.720 Gray |
| Part A: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 3: Kidney (left + right) | 12.3 Gray |
| Part A: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 3: Spleen | 6.93 Gray |
| Part A: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 3: Liver | 2.08 Gray |
| Part A: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 1: Kidney (left + right) | 4.31 Gray |
| Part A: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 3: Bone marrow (image-based) | 1.11 Gray |
| Part A: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 1: Bone marrow (image-based) | 0.319 Gray |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 1: Kidney (left + right) | 3.85 Gray |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 3: Spleen | 7.58 Gray |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 1: Liver | 0.810 Gray |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 1: Spleen | 4.35 Gray |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 1: Bone marrow (image-based) | 0.715 Gray |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 3: Bone marrow (image-based) | 1.48 Gray |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 3: Kidney (left + right) | 9.41 Gray |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 1: Spleen | 4.00 Gray |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 3: Kidney (left + right) | 8.91 Gray |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 3: Bone marrow (image-based) | 1.09 Gray |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 1: Bone marrow (image-based) | 0.375 Gray |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 3: Spleen | 9.21 Gray |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 1: Kidney (left + right) | 3.25 Gray |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 3: Bone marrow (image-based) | 0.840 Gray |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 1: Spleen | 3.55 Gray |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 3: Kidney (left + right) | 10.1 Gray |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 3: Spleen | 8.08 Gray |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 1: Bone marrow (image-based) | 0.285 Gray |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 1: Kidney (left + right) | 3.55 Gray |
| All Participants | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 3: Spleen | 8.32 Gray |
| All Participants | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 1: Bone marrow (image-based) | 0.400 Gray |
| All Participants | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 1: Kidney (left + right) | 3.73 Gray |
| All Participants | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 1: Liver | 0.765 Gray |
| All Participants | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 1: Spleen | 3.45 Gray |
| All Participants | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 3: Bone marrow (image-based) | 1.10 Gray |
| All Participants | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 3: Kidney (left + right) | 10.8 Gray |
| All Participants | Cumulative Absorbed Organ Doses of 177Lu-IPN01072 in Cycles 1 and 3 | Cycle 3: Liver | 2.08 Gray |
Secondary
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.
Time frame: 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.
Population: The Radiopharmaceutical PK Set (Part A and Part B) included all participants in the ITT set who received at least 1 dose of study medication and had at least 1 measured radioactive concentration in blood.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Cumulative Amount of Lu-177 Radioactivity Excreted Into the Urine (0 to 48 Hours) [Ae (0-48h)] in Cycle 1 | 2586 Mbq |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Cumulative Amount of Lu-177 Radioactivity Excreted Into the Urine (0 to 48 Hours) [Ae (0-48h)] in Cycle 1 | 3106 Mbq |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Cumulative Amount of Lu-177 Radioactivity Excreted Into the Urine (0 to 48 Hours) [Ae (0-48h)] in Cycle 1 | 2640 Mbq |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Cumulative Amount of Lu-177 Radioactivity Excreted Into the Urine (0 to 48 Hours) [Ae (0-48h)] in Cycle 1 | 2621 Mbq |
| All Participants | Cumulative Amount of Lu-177 Radioactivity Excreted Into the Urine (0 to 48 Hours) [Ae (0-48h)] in Cycle 1 | 2787 Mbq |
Secondary
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.
Time frame: 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.
Population: The ITT included all participants in the eligible participants set who received study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Disease Control Rate (DCR) | 93.3 percentage of participants |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Disease Control Rate (DCR) | 100.0 percentage of participants |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Disease Control Rate (DCR) | 100.0 percentage of participants |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Disease Control Rate (DCR) | 90.0 percentage of participants |
| All Participants | Disease Control Rate (DCR) | 95.0 percentage of participants |
Secondary
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.
Time frame: 0 to 4 hours, 4 to 24 hours, 24 to 48 hours in Cycle 1 in Part B
Population: The IPN01072 PK set in urine (Part B only) included all participants in the ITT set who received at least 1 dose of study medication and had no major protocol deviations affecting the urine PK variables and who had all urine IPN01072 levels available to estimate the main urine PK parameters. Results were combined for IPN01072 PK analysis performed at cycle 1, as pre-specified according to study protocol and the data analysis plan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Fraction of IPN01072 Excreted Into the Urine (Fe) in Cycle 1 | 52.9 percentage of drug excreted into urine | Standard Deviation 24.2 |
Secondary
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.
Time frame: 4, 24, 48, 72 to 96 and 144 to 168 hours post infusion in Cycle 1
Population: The PP-DAS included all participants in the ITT-DAS for whom no major protocol violations occurred affecting dosimetry variables. Only data from the participants analyzed were reported.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | Spleen | 8.07 Gray |
| Part A: 177Lu-IPN01072 4.5 GBq | Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | Kidney (left + right) | 8.55 Gray |
| Part A: 177Lu-IPN01072 4.5 GBq | Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | Liver | 1.26 Gray |
| Part A: 177Lu-IPN01072 4.5 GBq | Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | Bone marrow (image-based assay) | 0.97 Gray |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | Spleen | 6.00 Gray |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | Bone marrow (image-based assay) | 3.59 Gray |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | Kidney (left + right) | 4.87 Gray |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | Liver | 0.81 Gray |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | Bone marrow (image-based assay) | 0.50 Gray |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | Spleen | 5.90 Gray |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | Kidney (left + right) | 5.86 Gray |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | Kidney (left + right) | 5.07 Gray |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | Spleen | 4.09 Gray |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | Bone marrow (image-based assay) | 0.69 Gray |
| All Participants | Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | Spleen | 8.07 Gray |
| All Participants | Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | Bone marrow (image-based assay) | 3.59 Gray |
| All Participants | Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | Kidney (left + right) | 8.55 Gray |
| All Participants | Highest Absorbed Dose of 177LU-IPN01072 to Each Discernible Organ in Cycle 1 | Liver | 1.26 Gray |
Secondary
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.
Time frame: Pre-infusion (Baseline), 5 and 30 minutes, 1, 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion in Cycle 1
Population: The radiopharmaceutical pharmacokinetic (PK) set included all participants in the ITT set who received at least 1 dose of study medication and had at least 1 measured radioactive concentration in blood. Only data from the participants analyzed were reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Maximal Uptake (%) of 177Lu-IPN01072 in Blood in Cycle 1 | 3.66 percentage/liter (L) |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Maximal Uptake (%) of 177Lu-IPN01072 in Blood in Cycle 1 | 2.98 percentage/liter (L) |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Maximal Uptake (%) of 177Lu-IPN01072 in Blood in Cycle 1 | 2.77 percentage/liter (L) |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Maximal Uptake (%) of 177Lu-IPN01072 in Blood in Cycle 1 | 3.32 percentage/liter (L) |
| All Participants | Maximal Uptake (%) of 177Lu-IPN01072 in Blood in Cycle 1 | 3.03 percentage/liter (L) |
Secondary
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.
Time frame: 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
Population: The IPN01072 PK set in plasma (Part B only) included all participants in the ITT set who received at least 1 dose of study medication and have no major protocol deviations affecting the plasma PK variables and who had a sufficient number of plasma levels to estimate the main PK parameters. Only data from the participants analyzed were reported. Results were combined for IPN01072 PK analysis performed at cycle 1, as pre-specified according to study protocol and the data analysis plan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Maximum Observed Plasma Concentration (Cmax) of IPN01072 in Cycle 1 | 10.7 nanogram (ng)/milliliter (mL) | Standard Deviation 5.47 |
Secondary
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.
Time frame: 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion in Cycle 1
Population: The Per Protocol Dosimetry Analysis Set (PP-DAS) included all participants in the Intent-To-Treat Dosimetry Analysis Set (ITT-DAS) for whom no major protocol violations occurred affecting dosimetry variables. Only data from the participants analyzed were reported.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | Liver | 1.52 percentage of injected drug activity |
| Part A: 177Lu-IPN01072 4.5 GBq | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | All lesions | 0.651 percentage of injected drug activity |
| Part A: 177Lu-IPN01072 4.5 GBq | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | Spleen | 1.50 percentage of injected drug activity |
| Part A: 177Lu-IPN01072 4.5 GBq | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | Kidney (left + right) | 1.96 percentage of injected drug activity |
| Part A: 177Lu-IPN01072 4.5 GBq | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | Bone marrow (image-based) | 0.0469 percentage of injected drug activity |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | All lesions | 2.36 percentage of injected drug activity |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | Bone marrow (image-based) | 0.0420 percentage of injected drug activity |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | Liver | 4.31 percentage of injected drug activity |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | Spleen | 1.27 percentage of injected drug activity |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | Kidney (left + right) | 1.76 percentage of injected drug activity |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | Kidney (left + right) | 1.60 percentage of injected drug activity |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | All lesions | 1.18 percentage of injected drug activity |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | Bone marrow (image-based) | 0.0250 percentage of injected drug activity |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | Spleen | 1.78 percentage of injected drug activity |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | Kidney (left + right) | 1.67 percentage of injected drug activity |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | Bone marrow (image-based) | 0.0219 percentage of injected drug activity |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | Spleen | 1.79 percentage of injected drug activity |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | All lesions | 1.43 percentage of injected drug activity |
| All Participants | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | Kidney (left + right) | 1.76 percentage of injected drug activity |
| All Participants | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | Liver | 2.63 percentage of injected drug activity |
| All Participants | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | Bone marrow (image-based) | 0.0380 percentage of injected drug activity |
| All Participants | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | All lesions | 0.932 percentage of injected drug activity |
| All Participants | Maximum Uptake (%) of 177Lu-IPN01072 at Target Lesions and Discernible Organs in Cycle 1 | Spleen | 1.67 percentage of injected drug activity |
Secondary
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.
Time frame: 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.
Population: The ITT included all participants in the eligible participants set who received study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Overall Response Rate (ORR) | 40.0 percentage of participants |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Overall Response Rate (ORR) | 16.7 percentage of participants |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Overall Response Rate (ORR) | 22.2 percentage of participants |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Overall Response Rate (ORR) | 40.0 percentage of participants |
| All Participants | Overall Response Rate (ORR) | 32.5 percentage of participants |
Secondary
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.
Time frame: 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.
Population: The ITT included all participants in the eligible participants set who received study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Progression Free Survival (PFS) | 29.7 months |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Progression Free Survival (PFS) | 21.2 months |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Progression Free Survival (PFS) | 25.1 months |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Progression Free Survival (PFS) | 11.1 months |
| All Participants | Progression Free Survival (PFS) | 28.1 months |
Secondary
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).
Time frame: 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion in Cycle 1
Population: The PP-DAS included all participants in the ITT-DAS for whom no major protocol violations occurred affecting dosimetry variables. Only data from the participants analyzed were reported.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Bone marrow (image-based) | 0.0796 Gray/GBq |
| Part A: 177Lu-IPN01072 4.5 GBq | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Spleen | 0.769 Gray/GBq |
| Part A: 177Lu-IPN01072 4.5 GBq | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Kidney (left + right) | 1.05 Gray/GBq |
| Part A: 177Lu-IPN01072 4.5 GBq | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Liver | 0.186 Gray/GBq |
| Part A: 177Lu-IPN01072 4.5 GBq | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Lesions | 2.56 Gray/GBq |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Kidney (left + right) | 0.720 Gray/GBq |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Lesions | 3.90 Gray/GBq |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Bone marrow (image-based) | 0.135 Gray/GBq |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Liver | 0.170 Gray/GBq |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Spleen | 0.945 Gray/GBq |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Lesions | 6.82 Gray/GBq |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Kidney (left + right) | 0.880 Gray/GBq |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Bone marrow (image-based) | 0.0850 Gray/GBq |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Spleen | 0.985 Gray/GBq |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Spleen | 0.805 Gray/GBq |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Kidney (left + right) | 0.765 Gray/GBq |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Lesions | 13.5 Gray/GBq |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Bone marrow (image-based) | 0.0650 Gray/GBq |
| All Participants | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Kidney (left + right) | 0.879 Gray/GBq |
| All Participants | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Spleen | 0.840 Gray/GBq |
| All Participants | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Lesions | 5.00 Gray/GBq |
| All Participants | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Bone marrow (image-based) | 0.0900 Gray/GBq |
| All Participants | Specific Absorbed Dose Per Organ and Lesions of 177Lu-IPN01072 in Cycle 1 | Liver | 0.179 Gray/GBq |
Secondary
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.
Time frame: 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
Population: The IPN01072 PK set in plasma (Part B only) included all participants in the ITT set who received at least 1 dose of study medication and have no major protocol deviations affecting the plasma PK variables and who had a sufficient number of plasma levels to estimate the main PK parameters. Only data from the participants analyzed were reported. Results were combined for IPN01072 PK analysis performed at cycle 1, as pre-specified according to study protocol and the data analysis plan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | T1/2 of IPN01072 in Cycle 1 | 6.09 hours | Standard Deviation 1.59 |
Secondary
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.
Time frame: Pre-infusion (Baseline), 5 and 30 minutes, 1, 4, 24, 48, 72 to 96 hours, 144 to 168 hours post infusion in Cycle 1
Population: The radiopharmaceutical PK set included all participants in the ITT set who received at least 1 dose of study medication and had at least 1 measured radioactive concentration in blood. Only data from the participants analyzed were reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Terminal Half-Life (T1/2) of Radioactivity Concentrations of the Radiopharmaceutical in Blood in Cycle 1 | 68.3 hours |
| Part B Cohort 1: 177Lu-IPN01072 6 GBq | Terminal Half-Life (T1/2) of Radioactivity Concentrations of the Radiopharmaceutical in Blood in Cycle 1 | 109 hours |
| Part B Cohort 3: 177Lu-IPN01072 4.5 GBq | Terminal Half-Life (T1/2) of Radioactivity Concentrations of the Radiopharmaceutical in Blood in Cycle 1 | 123 hours |
| Part B Cohort 6: 177Lu-IPN01072 4.5 GBq | Terminal Half-Life (T1/2) of Radioactivity Concentrations of the Radiopharmaceutical in Blood in Cycle 1 | 145 hours |
| All Participants | Terminal Half-Life (T1/2) of Radioactivity Concentrations of the Radiopharmaceutical in Blood in Cycle 1 | 127 hours |
Secondary
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.
Time frame: 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
Population: The IPN01072 PK set in plasma (Part B only) included all participants in the ITT set who received at least 1 dose of study medication and have no major protocol deviations affecting the plasma PK variables and who had a sufficient number of plasma levels to estimate the main PK parameters. Only data from the participants analyzed were reported. Results were combined for IPN01072 PK analysis performed at cycle 1, as pre-specified according to study protocol and the data analysis plan.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: 177Lu-IPN01072 4.5 GBq | Time to Reach Maximum Plasma Concentration (Tmax) of IPN01072 in Cycle 1 | 0.083 hours |