RESIST-PC: Lutetium-177 (Lu177) Prostate-Specific Antigen (PSMA)-Directed EndoRadiotherapy

• Sponsor: Endocyte (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03042312
• Collaborator: (none)
• Enrollment: 71
• Locations: 2
• Arms: 2
• Actual Duration (Months): 30.1
• Patients Per Site: 35.5
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

This was an open-label, multicenter, prospective trial to assess safety and efficacy of 177Lu-PSMA-617 in patients with metastatic castration resistant prostate cancer.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Castration Resistant Prostate Cancer	Drug: 177Lu-PSMA-617	Phase 2

Detailed Description

Upon inclusion patients were randomized in a 1:1 ratio into two treatment doses. Radioligand therapy (RLT) were performed by repeated intravenous (i.v.) injection of 6.0 gigabecquerel (GBq) (+/- 10%) or 7.4 GBq (+/- 10%) 177Lu-PSMA-617 every 8+/- 1 weeks until reaching four cycles or threshold maximum dose to the kidneys of 23 Gray (Gy). All doses after labeling were presented in buffered solution for i.v. injection.

In the initial plan for the study design a total of 200 patients with histologically proven prostate cancer and metastatic castration-resistant prostate cancer (mCRPC) were to be enrolled, however due to early stopping of enrollment only 71 patients were enrolled at time of data base lock. Each patient underwent a screening visit within 14 days prior to receiving study drug. Treatment was continued until either of the following conditions applied:

• Prostate-specific antigen (PSA)/radiographic progression at >= 12 weeks

• Completion of four RLT cycles

• 23 Gy kidney dose would be exceeded by the next cycle as estimated by dosimetry

• Patient withdrawal (e.g. appearance of intolerable adverse events).

Study Design

• Study Type: Interventional
• Actual Enrollment: 71 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: PSMA-directed endoRadiothErapy of Castration-reSISTant Prostate Cancer (RESIST-PC). A Phase II Clinical Trial
• Actual Study Start Date: Jul 12, 2017
• Actual Primary Completion Date: Jan 15, 2020
• Actual Study Completion Date: Jan 15, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 177Lu-PSMA-617 (6.0 GBq) Repeated i.v. application of 6.0 GBq (gigabequerel)(+/- 10%, arm 1) every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry	Drug: 177Lu-PSMA-617; Lutetium (177Lu) -DOTA (1,4,7,10-tetra-azacyclododecane-N,N',N'',N'''-tetraacetic acid )-PSMA has three components: PSMA is the targeting vector , DOTA (1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid) is a radiometal chelator and a linking group, and 177Lu is the beta emitter that upon internalization delivers radiation to the nucleus of tumor cells to cause DNA damage. The targeting vector utilizes glu-urea-lys sequence which is an inhibitor capable of binding to the domain of PSMA. These components have been previously used in human subjects and in medical research.; Other Names: Lu177 RLT
Experimental: 177Lu-PSMA-617 (7.4 GBq) Repeated i.v. application of 7.4 GBq (gigabequerel)(+/- 10%, arm 2) of drug every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry	Drug: 177Lu-PSMA-617; Lutetium (177Lu) -DOTA (1,4,7,10-tetra-azacyclododecane-N,N',N'',N'''-tetraacetic acid )-PSMA has three components: PSMA is the targeting vector , DOTA (1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid) is a radiometal chelator and a linking group, and 177Lu is the beta emitter that upon internalization delivers radiation to the nucleus of tumor cells to cause DNA damage. The targeting vector utilizes glu-urea-lys sequence which is an inhibitor capable of binding to the domain of PSMA. These components have been previously used in human subjects and in medical research.; Other Names: Lu177 RLT

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment Emergent Adverse Events [From first dosing (Day 0) up to last follow-up visit or until the event has resolved to baseline grade or better or the event was assessed stable by the investigator or the patient was lost to follow-up or withdrew consent, up to 24 months]

   Treatment-emergent adverse events (TEAEs) were collected from first dosing up to last follow-up visit or until the event has resolved to baseline grade or better or the event was assessed stable by the investigator or the patient was lost to follow-up or withdrew consent. The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.

2. Number of Participants Achieving PSA Response at Week 12 [Week 12]

   PSA response was defined as the proportion of patients who had a >= 50% decrease in PSA from Baseline at Week 12.

Secondary Outcome Measures

1. Percent Change in PSA From Baseline to Week 12 [Week 12]

   Percent change in PSA from Baseline to Week 12 was reported for participants who had a baseline and a week 12 valid assessments.

2. Maximum Percent Change in PSA Response [Every 6 weeks during the treatment and every 3 (+/- 1) months after last treatment until reaching endpoint or 24 months after the first treatment]

   Maximal baseline to follow-up PSA decline, at any time during or after therapy was evaluated in both treatment groups.

3. PSA Progression and Death Events [Date of randomization to the date of first documented PSA progression or death, whichever occurs first, reported between day of first patient randomized up to 24 months after the first treatment]

   PSA progression was defined as: For patients with PSA decline: PSA progression was defined as the date that a >= 25% increase in PSA and an absolute increase of 2 ng/mL or more from the nadir was documented and confirmed by a second consecutive value obtained 3 or more weeks later. Rises in PSA within the first 12 weeks were ignored (PCWG3 Guidance), For patients without PSA decline: PSA progression was defined as a >= 25% increase from the baseline value along with an increase in absolute value of 2 ng/mL or more after 12 weeks of treatment.

4. RECIST 1.1 Overall Response by Follow-up Assessment Visit [Before 3rd radioligand therapy (RLT) cycle, and then every 3 (+/- 1) months after last treatment dose until disease progression or 24 months after the first treatment dose.]

   For each follow-up imaging assessment by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for target, non-target, and new lesions assessed by CT or MRI: the number of participants with an overall response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD). The timing of follow-up imaging assessments varied depending on how many RLT cycles a participant received. Therefore, regardless of when the imaging assessments occurred, each participant's first follow-up imaging was combined as Follow-up 1, each participant's second follow-up imaging was combined as Follow-up 2, each participant's third follow-up imaging was combined as Follow-up 3, and each participant's fourth follow-up imaging was combined as Follow-up 4.

5. RECIST 1.1 Disease Control Rate by Follow-up Assessment Visit [Before 3rd radioligand therapy (RLT) cycle, and then every 3 (+/- 1) months after last treatment dose until disease progression or 24 months after the first treatment dose.]

   The proportion of participants with an overall response of Complete Response (CR), Partial Response (PR) and Stable Disease (SD) was reported using investigator assessments per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for target, non-target, and new lesions assessed by CT or MRI. The timing of follow-up imaging assessments varied depending on how many RLT cycles a participant received. Therefore, regardless of when the imaging assessments occurred, each participant's first follow-up imaging was combined as Follow-up 1, each participant's second follow-up imaging was combined as Follow-up 2, each participant's third follow-up imaging was combined as Follow-up 3, and each participant's fourth follow-up imaging was combined as Follow-up 4.

6. Prostate Cancer Working Group 3 (PCWG3) Bone Scan Clinical Impression by Visit [Screening, Week 8, Week 10, Week 16, Week 18, Week 22, Week 24, Follow-up Week 4, Follow-up Week 6, Follow-up Week 8]

   Investigator's assessed bone metastases using the Prostate Cancer Working Group 3 (PCWG3) criteria; new lesions had to be confirmed on a second scan (2+2 rule). The investigator documented their clinical impression of each PCWG3 assessment as Improved, Stable or Progression. The number of participants with a clinical impression of Improved, Stable or Progression according to PCWG3 using investigators assessments was reported by visit.

7. Change From Baseline in Expanded Prostate Cancer Index Composite Short Form (EPIC-26) [Baseline, Month 3, Month 6, Follow-up Month 3]

   The Expanded Prostate Cancer Index-Composite (EPIC) is a well-established patient-reported outcome (PRO) questionnaire developed to monitor health-related quality of life outcomes among prostate cancer. The 26-item version of EPIC, also known as EPIC Short Form or EPIC-26, contains 26 items and 5 domains: Urinary Incontinence (Items 1-4), Urinary Irritative/Obstructive (Items 5-8), Bowel (Items 10-15), Sexual (Items 16-21), and Hormonal (Items 22-26). Response options for each EPIC item form a Likert scale, and multi-item scale scores are transformed linearly to a 0 to 100 scale for each domain, with higher scores representing better health-related quality of life.

8. Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status [Baseline, Treatment Visit 1, Treatment Visit 2, Treatment Visit 3, Treatment Visit 4, Follow-up Month 3, Follow-up Month 12, Follow-up Month 15]

   The Eastern Cooperative Oncology Group Performance Status (ECOG PS) score classifies participants according to their functional impairment, with scores ranging from 0 (fully active) to 5 (dead). ECOG PS: 0 = fully active, able to carry on all pre-disease performance without restriction; 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work; 2 = ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours; 3 = capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4 = completely disabled, cannot carry on any self-care, totally confined to bed or chair; 5 = dead.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Prostate cancer proven by histopathology

2. Unresectable metastases

3. Progressive disease, both docetaxel naive and docetaxel treated.

4. Castration resistant disease with confirmed testosterone level ≤50 ng/ml under prior androgen deprivation therapy (ADT)

5. Positive 68Ga-PSMA-11 PET/CT (positron emission computed tomography ) or diagnostic 177Lu-PSMA-617 scintigraphy

6. ECOG 0-2

7. Sufficient bone marrow capacity as defined by WBC (white blood cell ) ≥2.500/μl, PLT (platelet) count ≥100.000/μl, Hb≥9.9 g/dl and ANC≥1500 mm3 for the first cycle and WBC≥2.000/ μl,PLT count ≥75.000/μl, Hb≥8.9 g/dl and ANC≥1000 mm3 for the subsequent cycles

8. Signing of the Informed Consent Form

9. Patients enrolling in this trail should have received either Enzalutamide or Abiraterone

Exclusion Criteria:

1. Less than 6 weeks since last myelosuppressive therapy (including Docetaxel, Cabazitaxel, 223Ra, 153Sm) or other radionuclide therapy.

2. Glomerular Filtration Rate (GFR) <40 ml/min

3. Serum creatinine > 1.5 ULN

4. AST and ALT>5xULN

5. Urinary tract obstruction or marked hydronephrosis

6. Diffuse bone marrow involvement confirmed by super-scans

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	David Geffen School of Medicine at UCLA	Los Angeles	California	United States	90095
2	Excel Diagnostics and Nuclear Oncology Center	Houston	Texas	United States	77042

Sponsors and Collaborators

• Endocyte

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Jun 1, 2018
• Statistical Analysis Plan - May 15, 2020

More Information

Publications

None provided.

• Responsible Party: Endocyte
• ClinicalTrials.gov Identifier: NCT03042312
• Other Study ID Numbers: PSMA-617-02; 133661
• First Posted: Feb 3, 2017
• Last Update Posted: Mar 24, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Prostatic Neoplasms; 177Lu-PSMA-617

Study Results

Participant Flow

Recruitment Details	This study was conducted at 2 centers in the USA

Arm/Group Title	177Lu-PSMA-617 (6.0 GBq)	177Lu-PSMA-617 (7.4 GBq)
Arm/Group Description	Repeated i.v. application of 6.0 GBq (gigabequerel)(+/- 10%, arm 1) every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry	Repeated i.v. application of 7.4 GBq (gigabequerel)(+/- 10%, arm 2) of drug every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry
Period Title: Overall Study
STARTED	28	43
Safety Population	23	41
COMPLETED	18	31
NOT COMPLETED	10	12

Baseline Characteristics

Arm/Group Title	177Lu-PSMA-617 (6.0 GBq)	177Lu-PSMA-617 (7.4 GBq)	Total
Arm/Group Description	Repeated i.v. application of 6.0 GBq (gigabequerel)(+/- 10%, arm 1) every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry	Repeated i.v. application of 7.4 GBq (gigabequerel)(+/- 10%, arm 2) of drug every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry	Total of all reporting groups
Overall Participants	28	43	71
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	72.1 (8.39)	69.1 (8.62)	70.3 (8.60)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	28 100%	43 100%	71 100%
Race/Ethnicity, Customized (Number) [Number]
Asian	1 3.6%	1 2.3%	2 2.8%
Black or African American	0 0%	1 2.3%	1 1.4%
White	26 92.9%	41 95.3%	67 94.4%
Other	1 3.6%	0 0%	1 1.4%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events
Description	Treatment-emergent adverse events (TEAEs) were collected from first dosing up to last follow-up visit or until the event has resolved to baseline grade or better or the event was assessed stable by the investigator or the patient was lost to follow-up or withdrew consent. The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.
Time Frame	From first dosing (Day 0) up to last follow-up visit or until the event has resolved to baseline grade or better or the event was assessed stable by the investigator or the patient was lost to follow-up or withdrew consent, up to 24 months

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	177Lu-PSMA-617 (6.0 GBq)	177Lu-PSMA-617 (7.4 GBq)
Arm/Group Description	Repeated i.v. application of 6.0 GBq (gigabequerel)(+/- 10%, arm 1) every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry	Repeated i.v. application of 7.4 GBq (gigabequerel)(+/- 10%, arm 2) of drug every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry
Measure Participants	23	41
Treatment-Emergent Adverse Events (TEAEs)	22 78.6%	39 90.7%
Serious TEAEs	4 14.3%	8 18.6%
Drug-related TEAEs	20 71.4%	37 86%
Serious drug-related TEAEs	1 3.6%	4 9.3%
TEAEs leading to reduction of Lu-PSMA-617	0 0%	2 4.7%
TEAEs leading to discontinuation of Lu-PSMA-617	0 0%	1 2.3%
TEAEs leading to death	2 7.1%	1 2.3%

2. Primary Outcome

Title	Number of Participants Achieving PSA Response at Week 12
Description	PSA response was defined as the proportion of patients who had a >= 50% decrease in PSA from Baseline at Week 12.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with a value at both baseline and post baseline were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 (6.0 GBq)	177Lu-PSMA-617 (7.4 GBq)
Arm/Group Description	Repeated i.v. application of 6.0 GBq (gigabequerel)(+/- 10%, arm 1) every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry	Repeated i.v. application of 7.4 GBq (gigabequerel)(+/- 10%, arm 2) of drug every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry
Measure Participants	14	25
PSA Response (< 50% decline)	5 17.9%	8 18.6%
PSA Response (>= 50% decline)	6 21.4%	6 14%
PSA Response (Increase from Baseline)	3 10.7%	11 25.6%

3. Secondary Outcome

Title	Percent Change in PSA From Baseline to Week 12
Description	Percent change in PSA from Baseline to Week 12 was reported for participants who had a baseline and a week 12 valid assessments.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with a value at both baseline and post baseline were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 (6.0 GBq)	177Lu-PSMA-617 (7.4 GBq)
Arm/Group Description	Repeated i.v. application of 6.0 GBq (gigabequerel)(+/- 10%, arm 1) every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry	Repeated i.v. application of 7.4 GBq (gigabequerel)(+/- 10%, arm 2) of drug every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry
Measure Participants	14	25
Mean (Standard Deviation) [Percent change in PSA]	-22.54 (75.513)	92.15 (301.932)

4. Secondary Outcome

Title	Maximum Percent Change in PSA Response
Description	Maximal baseline to follow-up PSA decline, at any time during or after therapy was evaluated in both treatment groups.
Time Frame	Every 6 weeks during the treatment and every 3 (+/- 1) months after last treatment until reaching endpoint or 24 months after the first treatment

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with a value at both baseline and post baseline were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 (6.0 GBq)	177Lu-PSMA-617 (7.4 GBq)
Arm/Group Description	Repeated i.v. application of 6.0 GBq (gigabequerel)(+/- 10%, arm 1) every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry	Repeated i.v. application of 7.4 GBq (gigabequerel)(+/- 10%, arm 2) of drug every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry
Measure Participants	23	40
Mean (Standard Deviation) [PSA percent change]	-3.63 (95.394)	8.75 (132.954)

5. Secondary Outcome

Title	PSA Progression and Death Events
Description	PSA progression was defined as: For patients with PSA decline: PSA progression was defined as the date that a >= 25% increase in PSA and an absolute increase of 2 ng/mL or more from the nadir was documented and confirmed by a second consecutive value obtained 3 or more weeks later. Rises in PSA within the first 12 weeks were ignored (PCWG3 Guidance), For patients without PSA decline: PSA progression was defined as a >= 25% increase from the baseline value along with an increase in absolute value of 2 ng/mL or more after 12 weeks of treatment.
Time Frame	Date of randomization to the date of first documented PSA progression or death, whichever occurs first, reported between day of first patient randomized up to 24 months after the first treatment

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with a value at both baseline and post baseline were included in the analysis

Arm/Group Title	177Lu-PSMA-617 (6.0 GBq)	177Lu-PSMA-617 (7.4 GBq)
Arm/Group Description	Repeated i.v. application of 6.0 GBq (gigabequerel)(+/- 10%, arm 1) every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry	Repeated i.v. application of 7.4 GBq (gigabequerel)(+/- 10%, arm 2) of drug every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry
Measure Participants	28	43
Deaths without PSA progression	2 7.1%	2 4.7%
Participants with PSA progression, but who did not die	11 39.3%	17 39.5%

6. Secondary Outcome

Title	RECIST 1.1 Overall Response by Follow-up Assessment Visit
Description	For each follow-up imaging assessment by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for target, non-target, and new lesions assessed by CT or MRI: the number of participants with an overall response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD). The timing of follow-up imaging assessments varied depending on how many RLT cycles a participant received. Therefore, regardless of when the imaging assessments occurred, each participant's first follow-up imaging was combined as Follow-up 1, each participant's second follow-up imaging was combined as Follow-up 2, each participant's third follow-up imaging was combined as Follow-up 3, and each participant's fourth follow-up imaging was combined as Follow-up 4.
Time Frame	Before 3rd radioligand therapy (RLT) cycle, and then every 3 (+/- 1) months after last treatment dose until disease progression or 24 months after the first treatment dose.

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with a value at both baseline and post baseline were included in the analysis

Arm/Group Title	177Lu-PSMA-617 (6.0 GBq)	177Lu-PSMA-617 (7.4 GBq)
Arm/Group Description	Repeated i.v. application of 6.0 GBq (gigabequerel)(+/- 10%, arm 1) every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry	Repeated i.v. application of 7.4 GBq (gigabequerel)(+/- 10%, arm 2) of drug every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry
Measure Participants	28	43
Complete Response	1 3.6%	1 2.3%
Partial Response	3 10.7%	4 9.3%
Stable Disease	1 3.6%	7 16.3%
Progressive Disease	6 21.4%	9 20.9%
Complete Response	3 10.7%	1 2.3%
Partial Response	0 0%	3 7%
Stable Disease	0 0%	0 0%
Progressive Disease	1 3.6%	1 2.3%
Complete Response	1 3.6%	0 0%
Partial Response	0 0%	0 0%
Stable Disease	0 0%	1 2.3%
Progressive Disease	0 0%	0 0%
Complete Response	0 0%	0 0%
Partial Response	1 3.6%	0 0%
Stable Disease	0 0%	0 0%
Progressive Disease	0 0%	0 0%

7. Secondary Outcome

Title	RECIST 1.1 Disease Control Rate by Follow-up Assessment Visit
Description	The proportion of participants with an overall response of Complete Response (CR), Partial Response (PR) and Stable Disease (SD) was reported using investigator assessments per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for target, non-target, and new lesions assessed by CT or MRI. The timing of follow-up imaging assessments varied depending on how many RLT cycles a participant received. Therefore, regardless of when the imaging assessments occurred, each participant's first follow-up imaging was combined as Follow-up 1, each participant's second follow-up imaging was combined as Follow-up 2, each participant's third follow-up imaging was combined as Follow-up 3, and each participant's fourth follow-up imaging was combined as Follow-up 4.
Time Frame	Before 3rd radioligand therapy (RLT) cycle, and then every 3 (+/- 1) months after last treatment dose until disease progression or 24 months after the first treatment dose.

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with a value at both baseline and post baseline were included in the analysis

Arm/Group Title	177Lu-PSMA-617 (6.0 GBq)	177Lu-PSMA-617 (7.4 GBq)
Arm/Group Description	Repeated i.v. application of 6.0 GBq (gigabequerel)(+/- 10%, arm 1) every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry	Repeated i.v. application of 7.4 GBq (gigabequerel)(+/- 10%, arm 2) of drug every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry
Measure Participants	28	43
Follow-up 1	17.9 63.9%	27.9 64.9%
Follow-up 2	10.7 38.2%	9.3 21.6%
Follow-up 3	3.6 12.9%	2.3 5.3%
Follow-up 4	3.6 12.9%

8. Secondary Outcome

Title	Prostate Cancer Working Group 3 (PCWG3) Bone Scan Clinical Impression by Visit
Description	Investigator's assessed bone metastases using the Prostate Cancer Working Group 3 (PCWG3) criteria; new lesions had to be confirmed on a second scan (2+2 rule). The investigator documented their clinical impression of each PCWG3 assessment as Improved, Stable or Progression. The number of participants with a clinical impression of Improved, Stable or Progression according to PCWG3 using investigators assessments was reported by visit.
Time Frame	Screening, Week 8, Week 10, Week 16, Week 18, Week 22, Week 24, Follow-up Week 4, Follow-up Week 6, Follow-up Week 8

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with a value at both baseline and post baseline were included in the analysis

Arm/Group Title	177Lu-PSMA-617 (6.0 GBq)	177Lu-PSMA-617 (7.4 GBq)
Arm/Group Description	Repeated i.v. application of 6.0 GBq (gigabequerel)(+/- 10%, arm 1) every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry	Repeated i.v. application of 7.4 GBq (gigabequerel)(+/- 10%, arm 2) of drug every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry
Measure Participants	28	43
Improved	0 0%	0 0%
Stable	1 3.6%	0 0%
Progression	0 0%	0 0%
Improved	1 3.6%	3 7%
Stable	1 3.6%	2 4.7%
Progression	0 0%	1 2.3%
Improved	0 0%	3 7%
Stable	2 7.1%	1 2.3%
Progression	0 0%	0 0%
Improved	0 0%	2 4.7%
Stable	2 7.1%	0 0%
Progression	0 0%	0 0%
Improved	0 0%	0 0%
Stable	0 0%	3 7%
Progression	1 3.6%	0 0%
Improved	0 0%	0 0%
Stable	0 0%	1 2.3%
Progression	0 0%	0 0%
Improved	0 0%	0 0%
Stable	0 0%	1 2.3%
Progression	0 0%	0 0%
Improved	0 0%	0 0%
Stable	0 0%	0 0%
Progression	0 0%	1 2.3%
Improved	0 0%	0 0%
Stable	0 0%	0 0%
Progression	0 0%	1 2.3%
Improved	0 0%	0 0%
Stable	1 3.6%	0 0%
Progression	1 3.6%	0 0%

9. Secondary Outcome

Title	Change From Baseline in Expanded Prostate Cancer Index Composite Short Form (EPIC-26)
Description	The Expanded Prostate Cancer Index-Composite (EPIC) is a well-established patient-reported outcome (PRO) questionnaire developed to monitor health-related quality of life outcomes among prostate cancer. The 26-item version of EPIC, also known as EPIC Short Form or EPIC-26, contains 26 items and 5 domains: Urinary Incontinence (Items 1-4), Urinary Irritative/Obstructive (Items 5-8), Bowel (Items 10-15), Sexual (Items 16-21), and Hormonal (Items 22-26). Response options for each EPIC item form a Likert scale, and multi-item scale scores are transformed linearly to a 0 to 100 scale for each domain, with higher scores representing better health-related quality of life.
Time Frame	Baseline, Month 3, Month 6, Follow-up Month 3

Outcome Measure Data

Analysis Population Description

ITT Population. For each domain, only participants with a value at both baseline and post baseline were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 (6.0 GBq)	177Lu-PSMA-617 (7.4 GBq)
Arm/Group Description	Repeated i.v. application of 6.0 GBq (gigabequerel)(+/- 10%, arm 1) every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry	Repeated i.v. application of 7.4 GBq (gigabequerel)(+/- 10%, arm 2) of drug every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry
Measure Participants	28	43
Urinary Incontinence (Baseline)	78.3 (26.87)	77.4 (24.64)
Urinary Incontinence (Change from BL@Month 3)	4.9 (12.57)	9.7 (20.88)
Urinary Incontinence (Change from BL@Month 6)	11.1 (19.20)	-6.3 (14.66)
Urinary Incontinence (Change from BL@Follow-up Month 3)	-2.1 (9.55)
Urinary Irritative/Obstructive (Baseline)	83.2 (20.73)	84.8 (19.13)
Urinary Irritative/Obstructive (Change from BL@Month 3)	17.9 (25.37)	-1.4 (4.17)
Urinary Irritative/Obstructive (Change from BL@Month 6)	2.1 (9.55)	6.3 (8.84)
Urinary Irritative/Obstructive (Change from BL@Follow-up Month 3)	8.3 (9.55)
Bowel (Baseline)	90.8 (14.60)	88.4 (14.77)
Bowel (Change from BL@Month 3)	-1.0 (8.55)	4.0 (18.57)
Bowel (Change from BL@Month 6)	-4.2 (8.33)	4.9 (16.75)
Bowel (Change from BL@Follow-up Month 3)	-8.3 (18.16)
Sexual (Baseline)	8.8 (9.74)	11.7 (19.66)
Sexual (Change from BL@Month 3)	-4.4 (11.68)	7.8 (15.76)
Sexual (Change from BL@Month 6)	-4.7 (5.02)	7.3 (5.82)
Sexual (Change from BL@Follow-up Month 3)	4.6 (4.85)
Hormonal (Baseline)	77.0 (18.19)	73.6 (16.13)
Hormonal (Change from BL@Month 3)	4.4 (16.35)	10.4 (24.62)
Hormonal (Change from BL@Month 6)	1.7 (28.87)	10.0 (10.00)
Hormonal (Change from BL@Follow-up Month 3)	8.3 (7.64)

10. Secondary Outcome

Title	Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status
Description	The Eastern Cooperative Oncology Group Performance Status (ECOG PS) score classifies participants according to their functional impairment, with scores ranging from 0 (fully active) to 5 (dead). ECOG PS: 0 = fully active, able to carry on all pre-disease performance without restriction; 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work; 2 = ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours; 3 = capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4 = completely disabled, cannot carry on any self-care, totally confined to bed or chair; 5 = dead.
Time Frame	Baseline, Treatment Visit 1, Treatment Visit 2, Treatment Visit 3, Treatment Visit 4, Follow-up Month 3, Follow-up Month 12, Follow-up Month 15

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with a value at both baseline and post baseline were included in the analysis.

Arm/Group Title	177Lu-PSMA-617 (6.0 GBq)	177Lu-PSMA-617 (7.4 GBq)
Arm/Group Description	Repeated i.v. application of 6.0 GBq (gigabequerel)(+/- 10%, arm 1) every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry	Repeated i.v. application of 7.4 GBq (gigabequerel)(+/- 10%, arm 2) of drug every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry
Measure Participants	28	43
Baseline	0.9 (0.81)	0.9 (0.61)
Change from BL@Treatment Visit 1	-0.2 (0.60)	0.0 (0.54)
Change from BL@Treatment Visit 2	-0.3 (0.60)	-0.1 (0.63)
Change from BL@Treatment Visit 3	-0.2 (0.73)	-0.2 (0.50)
Change from BL@Treatment Visit 4	-0.1 (0.93)	-0.3 (0.48)
Change from BL@Follow-up Month 3	0.0 (NA)
Change from BL@Follow-up Month 12	-1.0 (NA)
Change from BL@Follow-up Month 15	0.0 (NA)

Adverse Events

Time Frame	Adverse events (AEs) were collected from informed consent signature through to 24 months after first 177Lu-PSMA-617 treatment therapy.
Adverse Event Reporting Description	Any sign or symptom that occurs after written informed consent provided. For TEAE from first dosing (Day 0) up to last follow-up visit or until the event has resolved to baseline grade or better or the event was assessed stable by the investigator or the patient was lost to follow-up or withdrew consent.
Arm/Group Title	177Lu-PSMA-617 (6.0 GBq)		177Lu-PSMA-617 (7.4 GBq)
Arm/Group Description	Repeated i.v. application of 6.0 GBq (gigabequerel)(+/- 10%, arm 1) every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry		Repeated i.v. application of 7.4 GBq (gigabequerel)(+/- 10%, arm 2) of drug every 8+/- 1 weeks; RLT until reaching four cycles or threshold maximum dose to the kidneys of 23 Gy as determined by dosimetry
All Cause Mortality
	177Lu-PSMA-617 (6.0 GBq)		177Lu-PSMA-617 (7.4 GBq)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/23 (13%)		3/41 (7.3%)
Serious Adverse Events
	177Lu-PSMA-617 (6.0 GBq)		177Lu-PSMA-617 (7.4 GBq)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/23 (17.4%)		8/41 (19.5%)
Blood and lymphatic system disorders
Anaemia	0/23 (0%)		1/41 (2.4%)
Thrombocytopenia	0/23 (0%)		1/41 (2.4%)
Gastrointestinal disorders
Abdominal pain	0/23 (0%)		1/41 (2.4%)
Gastrointestinal haemorrhage	0/23 (0%)		1/41 (2.4%)
General disorders
Death	0/23 (0%)		1/41 (2.4%)
Infections and infestations
Pneumonia	0/23 (0%)		1/41 (2.4%)
Injury, poisoning and procedural complications
Subdural haematoma	1/23 (4.3%)		0/41 (0%)
Musculoskeletal and connective tissue disorders
Osteoporosis	1/23 (4.3%)		0/41 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	0/23 (0%)		1/41 (2.4%)
Metastases to central nervous system	2/23 (8.7%)		0/41 (0%)
Metastases to meninges	0/23 (0%)		1/41 (2.4%)
Renal and urinary disorders
Acute kidney injury	0/23 (0%)		1/41 (2.4%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	0/23 (0%)		1/41 (2.4%)
Other (Not Including Serious) Adverse Events
	177Lu-PSMA-617 (6.0 GBq)		177Lu-PSMA-617 (7.4 GBq)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/23 (95.7%)		38/41 (92.7%)
Blood and lymphatic system disorders
Anaemia	4/23 (17.4%)		3/41 (7.3%)
Leukopenia	0/23 (0%)		1/41 (2.4%)
Lymphadenopathy	1/23 (4.3%)		0/41 (0%)
Lymphopenia	0/23 (0%)		1/41 (2.4%)
Ear and labyrinth disorders
Deafness	0/23 (0%)		1/41 (2.4%)
Endocrine disorders
Hypothyroidism	0/23 (0%)		1/41 (2.4%)
Eye disorders
Dry eye	1/23 (4.3%)		3/41 (7.3%)
Lacrimation increased	0/23 (0%)		1/41 (2.4%)
Gastrointestinal disorders
Abdominal pain	1/23 (4.3%)		1/41 (2.4%)
Constipation	6/23 (26.1%)		9/41 (22%)
Diarrhoea	3/23 (13%)		13/41 (31.7%)
Dry mouth	11/23 (47.8%)		26/41 (63.4%)
Frequent bowel movements	0/23 (0%)		1/41 (2.4%)
Hyperaesthesia teeth	1/23 (4.3%)		0/41 (0%)
Lip dry	0/23 (0%)		1/41 (2.4%)
Nausea	12/23 (52.2%)		18/41 (43.9%)
Saliva altered	1/23 (4.3%)		0/41 (0%)
Vomiting	4/23 (17.4%)		8/41 (19.5%)
General disorders
Asthenia	0/23 (0%)		1/41 (2.4%)
Chest pain	1/23 (4.3%)		1/41 (2.4%)
Fatigue	13/23 (56.5%)		21/41 (51.2%)
Feeling hot	0/23 (0%)		1/41 (2.4%)
Oedema peripheral	0/23 (0%)		1/41 (2.4%)
Pain	3/23 (13%)		5/41 (12.2%)
Pyrexia	0/23 (0%)		2/41 (4.9%)
Infections and infestations
Bronchitis	0/23 (0%)		1/41 (2.4%)
Herpes zoster	1/23 (4.3%)		0/41 (0%)
Urinary tract infection	0/23 (0%)		1/41 (2.4%)
Investigations
Blood lactate dehydrogenase increased	1/23 (4.3%)		0/41 (0%)
Glomerular filtration rate decreased	1/23 (4.3%)		0/41 (0%)
Weight decreased	0/23 (0%)		1/41 (2.4%)
Metabolism and nutrition disorders
Decreased appetite	1/23 (4.3%)		5/41 (12.2%)
Dehydration	0/23 (0%)		1/41 (2.4%)
Hyponatraemia	1/23 (4.3%)		1/41 (2.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/23 (13%)		2/41 (4.9%)
Back pain	2/23 (8.7%)		1/41 (2.4%)
Bone pain	1/23 (4.3%)		2/41 (4.9%)
Musculoskeletal chest pain	0/23 (0%)		2/41 (4.9%)
Musculoskeletal stiffness	0/23 (0%)		1/41 (2.4%)
Neck pain	0/23 (0%)		1/41 (2.4%)
Pain in extremity	1/23 (4.3%)		2/41 (4.9%)
Nervous system disorders
Dizziness	0/23 (0%)		2/41 (4.9%)
Headache	2/23 (8.7%)		2/41 (4.9%)
Parosmia	1/23 (4.3%)		0/41 (0%)
Taste disorder	4/23 (17.4%)		7/41 (17.1%)
Psychiatric disorders
Depression	0/23 (0%)		1/41 (2.4%)
Renal and urinary disorders
Bladder pain	0/23 (0%)		1/41 (2.4%)
Dysuria	1/23 (4.3%)		1/41 (2.4%)
Pollakiuria	0/23 (0%)		1/41 (2.4%)
Reproductive system and breast disorders
Prostatic pain	0/23 (0%)		1/41 (2.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/23 (0%)		3/41 (7.3%)
Epistaxis	1/23 (4.3%)		0/41 (0%)
Rhinorrhoea	0/23 (0%)		1/41 (2.4%)
Wheezing	0/23 (0%)		1/41 (2.4%)
Skin and subcutaneous tissue disorders
Dry skin	1/23 (4.3%)		0/41 (0%)
Pain of skin	0/23 (0%)		1/41 (2.4%)
Vascular disorders
Haematoma	0/23 (0%)		2/41 (4.9%)

Limitations/Caveats

The study began on 05-Jul-17 as an Investigator Initiated Trial and sponsorship was transferred to Endocyte on 01-Jun-18. Recruitment was stopped before the target sample size was achieved based on strategic considerations.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.