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

• ClinicalTrials.gov Identifier: NCT03042312
• Recruitment Status: Terminated
• First Posted: February 3, 2017
• Results First Posted: March 24, 2021
• Last Update Posted: March 24, 2021
• Sponsor: Endocyte
• Information provided by (Responsible Party): Endocyte

Tracking Information

• First Submitted Date: January 18, 2017
• First Posted Date: February 3, 2017
• Results First Submitted Date: January 14, 2021
• Results First Posted Date: March 24, 2021
• Last Update Posted Date: March 24, 2021
• Actual Study Start Date: July 12, 2017
• Actual Primary Completion Date: January 15, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 1, 2021)

• Number of Participants With Treatment Emergent Adverse Events [ 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 ]
  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.
• Number of Participants Achieving PSA Response at Week 12 [ Time Frame: Week 12 ]
  PSA response was defined as the proportion of patients who had a >= 50% decrease in PSA from Baseline at Week 12.

Original Primary Outcome Measures (submitted: February 2, 2017)

Assessment of the clinical safety of 177Lu-PSMA-617 RLP as assessed by number of participants with abnormal laboratory values and/or adverse events [ Time Frame: 48 months ]

number of participants with abnormal laboratory values and/or adverse events that are related to treatment.

Current Secondary Outcome Measures (submitted: March 1, 2021)

• Percent Change in PSA From Baseline to Week 12 [ Time Frame: 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.
• Maximum Percent Change in PSA Response [ 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 ]
  Maximal baseline to follow-up PSA decline, at any time during or after therapy was evaluated in both treatment groups.
• PSA Progression and Death Events [ 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 ]
  PSA progression was defined as:

  1. 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),
  2. 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.
• RECIST 1.1 Overall Response by Follow-up Assessment Visit [ 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. ]
  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.
• RECIST 1.1 Disease Control Rate by Follow-up Assessment Visit [ 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. ]
  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.
• Prostate Cancer Working Group 3 (PCWG3) Bone Scan Clinical Impression 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 ]
  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.
• Change From Baseline in Expanded Prostate Cancer Index Composite Short Form (EPIC-26) [ Time Frame: 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.
• Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status [ 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 ]
  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.

Original Secondary Outcome Measures (submitted: February 2, 2017)

• Assessment of the clinical efficacy of 177Lu-PSMA-617 RLP [ Time Frame: 48 months ]
  Patients with baseline to follow-up decline in tumor marker level (PSA) ≥50% at 12 weeks will be considered as responders
• Determination of PSA progression-free survival (PFS) measured from start of therapy until death or PSA progression. [ Time Frame: 48 months ]
  For patients with PSA decline after start of treatment , PSA progression is defined as time from baseline to time the PSA increases to 25% and 2 ng/ml above nadir which is confirmed by a second value ≥3 weeks later For patients without PSA decline, PSA progression is defined, as time from baseline to time the PSA increases to 25% and 2 ng/ml above baseline which is confirmed by a second value ≥3 weeks later. Data will be given separately for the both treatment groups (6.0 vs. 7.4 GBq 177Lu-PSMA-617) and a statistical significant difference will be tested.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Lutetium-177 (Lu177) Prostate-Specific Antigen (PSMA)-Directed EndoRadiotherapy
• Official Title: PSMA-directed endoRadiothErapy of Castration-reSISTant Prostate Cancer (RESIST-PC). A Phase II Clinical Trial
• 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.

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 Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Castration Resistant Prostate Cancer

Intervention

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 Name: Lu177 RLT

Study Arms

• 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
  Intervention: Drug: 177Lu-PSMA-617
• 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
  Intervention: Drug: 177Lu-PSMA-617

• Publications *: Gafita A, Calais J, Grogan TR, Hadaschik B, Wang H, Weber M, Sandhu S, Kratochwil C, Esfandiari R, Tauber R, Zeldin A, Rathke H, Armstrong WR, Robertson A, Thin P, D'Alessandria C, Rettig MB, Delpassand ES, Haberkorn U, Elashoff D, Herrmann K, Czernin J, Hofman MS, Fendler WP, Eiber M. Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study. Lancet Oncol. 2021 Aug;22(8):1115-1125. doi: 10.1016/S1470-2045(21)00274-6. Epub 2021 Jul 8.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: January 14, 2021): 71
• Original Estimated Enrollment (submitted: February 2, 2017): 200
• Actual Study Completion Date: January 15, 2020
• Actual Primary Completion Date: January 15, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03042312
• Other Study ID Numbers: PSMA-617-02; 133661 ( Other Identifier: Original sponsor )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Endocyte
• Original Responsible Party: Excel Diagnostics and Nuclear Oncology Center
• Current Study Sponsor: Endocyte
• Original Study Sponsor: Excel Diagnostics and Nuclear Oncology Center
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Endocyte
• Verification Date: March 2021