[177Lu]Ludotadipep Treatment in Patients With Metastatic Castration-resistant Prostate Cancer.

Study Overview
=================
Brief Summary
-----------------
The study aims to evaluate the stability and efficacy after administration of [177Lu]Ludotadipep in patients with metastatic castration resistant prostate cancer (mCRPC), with dose-escalation applied to determine the appropriate dose.

Detailed Description
-----------------
[18F]PSMA PET/CT is conducted at the 2nd screening and only PSMA PET/CT positive patients can be enrolled (PSMA RADS 4 or more). Dose is administered by differentiated into 5 groups (6 subjects each) and sequentially elevated starting from a low dose to a high dose (50±5 mCi, 75±8 mCi, 100±10 mCi, 125±13 mCi, 150±15 mCi).

Official Title
-----------------
[177Lu]Ludotadipep Treatment in Patients With Metastatic Castration-resistant Prostate Cancer: Phase I Clinical Trial.

Conditions
-----------------
Metastatic Castration-resistant Prostate Cancer

Intervention / Treatment
-----------------
* Drug: [177Lu]Ludotadipep


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Among prostate cancer patients with blood testosterone ≤50ng/dL, mCRPC patients showing radiological progression after standard taxene-based anticancer treatment and 2nd generation hormone agent (abiraterone, enzalutamed, or both)) treatment or patients who are not eligible for such standard medical treatment at the discretion of an investigator or patients who refuse such standard treatment Patients who are positive on the [18F]PSMA PET/CT imaging Subjects who were fully informed by an investigator of the study objectives, details, and characteristics of the study drug prior to study enrollment, and had an informed consent form signed by the subject or caretaker or legally acceptable representative Male patients aged 20 years or older Subjects who are sexually active and have a female partner of childbearing potential should meet the followings Subjects should consent to practice contraception by continuously using a male condom from screening, throughout the study, and for at least 6 months after the last dose of the study drug Subjects should never donate sperms from screening, throughout the study, and for at least 6 months after the last dose of the study drug Subjects with a partner who is a woman of childbearing potential (including a pregnant or breastfeeding mother) should consent to maintain sexual abstinence or practice double contraception throughout the study * Double contraception: Corresponding to 2 or more of the followings - use of a condom, use of a non-hormonal intrauterine device, use of a diaphragm, use of a cervical cap, a sexual partner who has been vasectomized at least 3 months (as of the first screening visit) or a sexual partner medically diagnosed to be sterile ECOG _ Performance score ≤2 Life expectancy ≥6 months Exclusion Criteria: Subjects determined by an investigator to have a serious medical condition making study conduct difficult Subjects corresponding to the following conditions 1) Glomerular filtration rate ≤40 ml/min, 2) hemoglobin level ≤10.0 g/dL, 3) white cell count ≤4.0 × 109/L, 4) platelet count ≤100 × 109/L, 5) total bilirubin level ≥1.5 x upper normal limit, 6) serum albumin level ≤3.0 g/dL, 7) active ischemic heart disease or heart failure (New York Heart Association Classification III-IV), 8) uncontrolled diabetes/hypertension, 9) hyperkalemia >6.0 mmol/L Vulnerable subjects (the investigator involved in the study or his/her family, research staff or students of the investigator involved in the study) Patients with a persistent malignancy other than the prostate cancer Patients who participated in a therapeutic clinical trial within the past 30 days and administered an investigational product other than standard treatment Patients are excluded if treatment other than the treatment provided in this study is determined more appropriate as determined by the investigator based on the patient and disease characteristics

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose is administered by differentiated into 5 groups (6 subjects each) and sequentially elevated starting from a low dose to a high dose (50±5 mCi, 75±8 mCi, 100±10 mCi, 125±13 mCi, 150±15 mCi).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 50mCi<br>Using a drug product for which dose is determined (50±5 mCi dose), dilute with 0.9% NaCl 5 mL and slowly i.v. inject over 10 minutes, with 500 mL of 0.9% NaCl slowly administered for hydration over approximately 90 minutes from 30 minutes before treatment to 60 minutes after treatment. | Drug: [177Lu]Ludotadipep<br>* Dose is sequentially elevated starting from a low dose to a high dose (50±5 mCi, 75±8 mCi, 100±10 mCi, 125±13 mCi, 150±15 mCi). If DLT is observed in 2 or less of 6 subjects at each level, advance to the next step. If DLT is observed in 3 or more participants, no further subject will participate in the study at the relevant dose. Appropriateness of the dose elevation is evaluated 8-9 weeks after drug administration.<br>|
| Experimental: 75mCi<br>Using a drug product for which dose is determined (75±8 mCi dose), dilute with 0.9% NaCl 5 mL and slowly i.v. inject over 10 minutes, with 500 mL of 0.9% NaCl slowly administered for hydration over approximately 90 minutes from 30 minutes before treatment to 60 minutes after treatment. | Drug: [177Lu]Ludotadipep<br>* Dose is sequentially elevated starting from a low dose to a high dose (50±5 mCi, 75±8 mCi, 100±10 mCi, 125±13 mCi, 150±15 mCi). If DLT is observed in 2 or less of 6 subjects at each level, advance to the next step. If DLT is observed in 3 or more participants, no further subject will participate in the study at the relevant dose. Appropriateness of the dose elevation is evaluated 8-9 weeks after drug administration.<br>|
| Experimental: 100mCi<br>Using a drug product for which dose is determined (100±10 mCi dose), dilute with 0.9% NaCl 5 mL and slowly i.v. inject over 10 minutes, with 500 mL of 0.9% NaCl slowly administered for hydration over approximately 90 minutes from 30 minutes before treatment to 60 minutes after treatment. | Drug: [177Lu]Ludotadipep<br>* Dose is sequentially elevated starting from a low dose to a high dose (50±5 mCi, 75±8 mCi, 100±10 mCi, 125±13 mCi, 150±15 mCi). If DLT is observed in 2 or less of 6 subjects at each level, advance to the next step. If DLT is observed in 3 or more participants, no further subject will participate in the study at the relevant dose. Appropriateness of the dose elevation is evaluated 8-9 weeks after drug administration.<br>|
| Experimental: 125mCi<br>Using a drug product for which dose is determined (125±13 mCi dose), dilute with 0.9% NaCl 5 mL and slowly i.v. inject over 10 minutes, with 500 mL of 0.9% NaCl slowly administered for hydration over approximately 90 minutes from 30 minutes before treatment to 60 minutes after treatment. | Drug: [177Lu]Ludotadipep<br>* Dose is sequentially elevated starting from a low dose to a high dose (50±5 mCi, 75±8 mCi, 100±10 mCi, 125±13 mCi, 150±15 mCi). If DLT is observed in 2 or less of 6 subjects at each level, advance to the next step. If DLT is observed in 3 or more participants, no further subject will participate in the study at the relevant dose. Appropriateness of the dose elevation is evaluated 8-9 weeks after drug administration.<br>|
| Experimental: 150mCi<br>Using a drug product for which dose is determined (150±15 mCi dose), dilute with 0.9% NaCl 5 mL and slowly i.v. inject over 10 minutes, with 500 mL of 0.9% NaCl slowly administered for hydration over approximately 90 minutes from 30 minutes before treatment to 60 minutes after treatment. | Drug: [177Lu]Ludotadipep<br>* Dose is sequentially elevated starting from a low dose to a high dose (50±5 mCi, 75±8 mCi, 100±10 mCi, 125±13 mCi, 150±15 mCi). If DLT is observed in 2 or less of 6 subjects at each level, advance to the next step. If DLT is observed in 3 or more participants, no further subject will participate in the study at the relevant dose. Appropriateness of the dose elevation is evaluated 8-9 weeks after drug administration.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity | Dose-limiting toxicity is defined as CTCAE grade 4 thrombocytopenia (platelet count <25x109/L), grade 4 neutropenia (absolute neutrophil count (ANC) < 0.5 x 109), grade 3 febrile neutropenia (ANC <1000/mm3 and temperature >38.3℃ on at least 1 occasion or temperature ≥38℃ persisting for 1 hr), and other grade 3 or 4 non-hematological toxicity resulting from [177Lu]Ludotadipep, persisting for 5 days or more. | From date of randomization (IP administration (0h, visit3, Day 0   3)) until the date of grade 4 neutropenia, grade 3 febrile neutropenia, other grade 3 or 4 non-hematological toxicity resulting from [177Lu]Ludotadipep, persisting for 5 days or more. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA level assessment | Comparative assessment of the PSA level before and after administration of [177Lu]Ludotadipep | screening(Day -31   -20), , visit4 (Day10), visit5 (Day17), visit6(Day24), visit7(Day31), visit8(Day45), visit9(Day59), visit10 (Day87) | 
| Radiological assessment | Comparative assessment of the locations and the quantitative change of a lesion on [18F]PSMA PET/CT before and after administration of [177Lu]Ludotadipep, and assessment of the treatment response by comparing the intake of the target lesion from an imaging test at each time point. | 2nd screeing(Day -19   -1 ), visit7(Day31), visit9(Day59) | 
| Biodistribution | Assessment of the absorption (uptake) into the blood, lungs, liver, spleen, pancreas, kidneys, muscle, stomach, and tumor based on the level obtained from SPECT/CT imaging at 2 hours, 24 hours (1 day), 48 hours (2 days), 72 hours (3 days) and additionally perform planar scan at visit 4. | 2 hours, 24 hours (1 day), 48 hours (2 days), 72 hours (3 days) at visit3 (Day 0 3), visit 4(Day10) | 
| Whole-body absorbed dose | Calculation of the whole-body absorbed dose by evaluating the absorbed dose into the adrenals, brain, gallbladder, intestine, stomach, heart, kidney, liver, muscle, lungs, pancreas, red marrow, skin, spleen, testes, thymus, thyroid, and urinary bladder. | 2 hours, 24 hours (1 day), 48 hours (2 days), 72 hours (3 days) at visit3(Day 0 3) | 
| Safety assessment by baseline symptoms | Assessment of adverse events occured from screening (Day -31) and 2nd screening(Day -31   -20) before IP administration. | Screening(Day -31   -20), 2nd screening(Day -19   -1) | 
| Safety assessment by adverse events | Assessment of adverse events occured from IP administration (visit 3,Day 0 3) until visit10 (Day87) | visit 3(Day 0  3), visit4 (Day10), visit5 (Day17), visit6(Day24), visit7(Day31), visit8(Day45), visit9(Day59), visit10 (Day87) | 
| Number of participants with abnormal signs and symptom as assessed through physical examination | Number of participants with abnormal signs and symptom as assessed through physical examination from screening(Day -31   -20) to visit10 (Day87) | Screening(Day -31   -20), 2nd screening(Day -19   -1), visit 3(Day 0 3), visit4 (Day 10), visit5 (Day 17), visit6(Day24), visit7(Day31), visit8(Day45), visit9(Day59), visit10 (Day87) | 
| Systolic and diastolic blood pressure (mm Hg) | Assessment of masured value using systolic and diastolic blood pressure (mm Hg) from screening(Day -31   -20) to visit10 (Day87) | Screening(Day -31   -20), 2nd screening(Day -19   -1), visit 3(Day 0 3), visit4 (Day10), visit5 (Day17), visit6(Day24), visit7(Day31), visit8(Day45), visit9(Day59), visit10 (Day87) | 
| Body temperature (degrees Celsius) | Assessment of masured value using body temperature (degrees Celsius) from screening(Day -31   -20) to visit10 (Day87) | Screening(Day -31   -20), 2nd screening(Day -19   -1), visit 3(Day 0 3), visit4 (Day10), visit5 (Day17), visit6(Day24), visit7(Day31), visit8(Day45), visit9(Day59), visit10 (Day87) | 
| Pulse rate (beats per minute) | Assessment of masured value using pulse rate (beats per minute) from screening(Day -31   -20) to visit10 (Day87) | Screening(Day -31   -20), 2nd screening(Day -19   -1), visit 3(Day 0 3), visit4 (Day10), visit5 (Day17), visit6(Day24), visit7(Day31), visit8(Day45), visit9(Day59), visit10 (Day87) | 
| Number of participants with abnormal hematology values | Number of participants with abnormal hematology values ( WBC, WBC differential, Hemoglobin, Hematocrit, RBC, Platelet, free lutetium -at 3 minutes, 15 minutes, 30 minutes, 60 minutes, 180 minutes, 24 hours, 48 hours, and 72 hours after IP administration) from screening(Day -31   -20) to visit10 (Day87) except 2nd screening(Day -19   -1). | Screening(Day -31   -20), visit 3(Day 0 3), visit4 (Day10), visit5 (Day17), visit6(Day24), visit7(Day31), visit8(Day45), visit9(Day59), visit10 (Day87) | 
| Number of participants with abnormal chemistry values | Assessment of masured value using chemistry( free PSA, glucose, Total bilirubin, AST/ALT, Alkaline phosphatase, BUN/ Creatinine, Sodium, Potassium, Chloride, CA, Phosphorus, Total Protein, Albumin) from screening(Day -31   -20) to visit10 (Day87) except 2nd screening(Day -19   -1). | Screening(Day -31   -20), visit 3(Day 0 3), visit4 (Day10), visit5 (Day17), visit6(Day24), visit7(Day31), visit8(Day45), visit9(Day59), visit10 (Day87) | 
| Number of participants with abnormal urinalysis values | Assessment of masured value using urinalysis (Specific Gravity, Protein, pH, Glucose, Occult Blood, Ketone) from screening(Day -31   -20) to visit10 (Day87) except 2nd screening(Day -19   -1). | Screening(Day -31   -20), visit 3(Day 0 3), visit4 (Day10), visit5 (Day17), visit6(Day24), visit7(Day31), visit8(Day45), visit9(Day59), visit10 (Day87) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Prostate Cancer