VISION: An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-positive Metastatic Castration-resistant Prostate Cancer (mCRPC)
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Enrollment
- 861
- Locations
- 88
- Primary Endpoint
- Radiographic Progression-free Survival (rPFS)
Study Overview
Brief Summary
The primary objective of this study was to compare the two alternate primary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) in patients with progressive prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who received 177Lu-PSMA-617 in addition to best supportive/best standard of care (BSC/BSoC) versus patients treated with best supportive/best standard of care alone.
Detailed Description
The study for each participant consisted of a Screening period, a Treatment period and a Follow-up period.
Sub-study A dosimetry, PK and ECG sub-study was conducted in a non-randomized cohort (AAA617+BSC/BSoC) of 30 patients at sites in Germany to provide a more complete assessment of the safety aspects of AAA617. Aside from additional assessments to collect data for dosimetry, PK, urinary metabolites and ECG, patients in the sub-study were screened for eligibility, treated and followed up similarly to the AAA617+BSC/BSoC (investigational arm) patients in the main study.
Screening and randomization:
During the screening period of up to 28 days before starting randomized treatment, each participant was assessed for PSMA positivity by gallium (68Ga) gozetotide imaging PET/scan per the pre-defined read rules, by the Sponsor's central reader. Only patients with PSMA-positive metastatic PC and meeting all other inclusion/exclusion criteria were randomized in a 2:1 ratio to receive either 177Lu-PSMA-617 plus BSC/BSoC or BSC/BSoC only. Randomized patients were stratified on the following factors: LDH level (=< or > 260 UI/L), presence of liver metastases (Yes or No), eastern cooperative oncology group (ECOG) score (0-1 or 2) and inclusion of NAAD in the BSC/BSoC (at time of randomization (Yes or No)). Protocol- specified BSC/BSoC for each patient was initiated by the investigating physician prior to patient randomization and maintained throughout the study. On-study changes to BSC/BSoC were allowed and at the discretion of the investigating physician.
Randomized treatment:
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Male
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Patients must have the ability to understand and sign an approved informed consent form (ICF).
- •Patients must have the ability to understand and comply with all protocol requirements.
- •Patients must be >= 18 years of age.
- •Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
- •Patients must have a life expectancy >6 months.
- •Patients must have histological, pathological, and/or cytological confirmation of prostate cancer.
- •Patients must be 68Ga-PSMA-11 Positron Emission Tomography (PET)/Computed Tomography (CT) scan positive, and eligible as determined by the sponsor's central reader.
- •Patients must have a castrate level of serum/plasma testosterone (<50 ng/dL or <1.7 nmol/L).
- •Patients must have received at least one NAAD (such as enzalutamide and/or abiraterone).
- •Patients must have been previously treated with at least 1, but no more than 2 previous taxane regimens. A taxane regimen is defined as a minimum exposure of 2 cycles of a taxane. If a patient has received only 1 taxane regimen, the patient is eligible if: a. The patient's physician deems him unsuitable to receive a second taxane regimen (e.g. frailty assessed by geriatric or health status evaluation, intolerance, etc.).
- •Patients must have progressive mCRPC. Documented progressive mCRPC will be based on at least 1 of the following criteria:
- •Serum/plasma PSA progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week prior. The minimal start value is 2.0 ng/mL.
- •Soft-tissue progression defined as an increase >= 20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or more new lesions.
- •Progression of bone disease: evaluable disease or new bone lesions(s) by bone scan (2+2 PCWG3 criteria, Scher et al 2016).
- •Patients must have >= 1 metastatic lesion that is present on baseline CT, MRI, or bone scan imaging obtained =< 28 days prior to beginning study therapy.
- •Patients must have recovered to =< Grade 2 from all clinically significant toxicities related to prior therapies (i.e. prior chemotherapy, radiation, immunotherapy, etc.).
- •Patients must have adequate organ function:
- •a. Bone marrow reserve:
- •White blood cell (WBC) count >= 2.5 x 10^9/L (2.5 x 10^9/L is equivalent to 2.5 x 10^3/μL and 2.5 x K/μL and 2.5 x 10^3/cumm and 2500/μL) OR absolute neutrophil count (ANC) >= 1.5 x 10^9/L (1.5 x 10^9/L is equivalent to 1.5 x 10^3/μL and 1.5 x K/μL and 1.5 x 10^3/cumm and 1500/μL)
- •Platelets >= 100 x 10^9/L (100 x 10^9/L is equivalent to 100 x 10^3/μL and 100 x K/μL and 100 x 10^3/cumm and 100,000/μL)
- •Hemoglobin >= 9 g/dL (9 g/dL is equivalent to 90 g/L and 5.59 mmol/L) b. Hepatic:
- •Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN). For patients with known Gilbert's Syndrome =< 3 x ULN is permitted
- •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 3.0 x ULN OR =< 5.0 x ULN for patients with liver metastases c. Renal:
- •Serum/plasma creatinine =< 1.5 x ULN or creatinine clearance >= 50 mL/min
- •Albumin >3.0 g/dL (3.0 g/dL is equivalent to 30 g/L) [Inclusion #16 has been removed]
- •HIV-infected patients who are healthy and have a low risk of AIDS-related outcomes are included in this trial.
- •For patients who have partners of childbearing potential: Partner and/or patient must use a method of birth control with adequate barrier protection, deemed acceptable by the principle investigator during the study and for 6 months after last study drug administration.
- •The best standard of care/ best supportive care options planned for this patient:
- •Are allowed by the protocol
- •Have been agreed to by the treating investigator and patient
- •Allow for the management of the patient without 177Lu-PSMA-617
Exclusion Criteria
- •Previous treatment with any of the following within 6 months of randomization: Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation. Previous PSMA-targeted radioligand therapy is not allowed.
- •Any systemic anti-cancer therapy (e.g. chemotherapy, immunotherapy or biological therapy [including monoclonal antibodies]) within 28 days prior to day of randomization.
- •Any investigational agents within 28 days prior to day of randomization.
- •Known hypersensitivity to the components of the study therapy or its analogs.
- •Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy.
- •Transfusion for the sole purpose of making a subject eligible for study inclusion.
- •Patients with a history of Central Nervous System (CNS) metastases must have received therapy (surgery, radiotherapy, gamma knife) and be neurologically stable, asymptomatic, and not receiving corticosteroids for the purposes of maintaining neurologic integrity. Patients with epidural disease, canal disease and prior cord involvement are eligible if those areas have been treated, are stable, and not neurologically impaired. For patients with parenchymal CNS metastasis (or a history of CNS metastasis), baseline and subsequent radiological imaging must include evaluation of the brain (MRI preferred or CT with contrast).
- •A superscan as seen in the baseline bone scan.
- •Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression.
- •Concurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to, New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, uncontrolled infection, known active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation.
- •Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, patients with a prior history of malignancy that has been adequately treated and who have been disease free for more than 3 years are eligible, as are patients with adequately treated non-melanoma skin cancer, superficial bladder cancer.
Arms & Interventions
177Lu-PSMA-617 plus best supportive/best standard of care (BS/BSOC)
Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used
Intervention: 177Lu-PSMA-617 (Drug)
177Lu-PSMA-617 plus best supportive/best standard of care (BS/BSOC)
Patients randomized to receive the investigational product received 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) might be used
Intervention: Best supportive/best standard of care (Other)
Best supportive/best standard of care (BS/BSOC) alone
Patients randomized to this arm received best supportive/best standard of care (BS/BSOC) as determined by the investigator
Intervention: Best supportive/best standard of care (Other)
Outcomes
Primary Outcomes
Radiographic Progression-free Survival (rPFS)
Time Frame: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021)
Radiographic progression-free survival (rPFS) was defined as the time (in months) from the date of randomization to the date of radiographic disease progression based on the central review assessment per the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria or death due to any cause. Patients who were alive without radiographic progression at the analysis data cut-off were censored for rPFS at the time of their last evaluable radiographic assessment. Date of censoring for rPFS: 1) The censoring date was the date when the last evaluable radiographic assessment (CT/MRI/bone scan) determined a lack of progression; 2) If there were no evaluable assessments, censoring occurred at the date of randomization; 3) Patients who had 2 or more consecutive missed tumor assessments immediately prior to PD or death were censored at the date of the last evaluable tumor assessment prior to those missing tumor assessments.
Overall Survival (OS)
Time Frame: From date of randomization until date of death from any cause, assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021) and up to 66 months (Final Analysis cut-off date = 14-Dec-2023)
Overall Survival (OS) was defined as the time (in months) from the date of randomization to the date of death due to any cause. If the patient was not known to have died, then OS was censored. The censoring date was date of the last study visit, or contact, until the cut-off date. The cut-off date was not used for last contact date, unless the patient was seen or contacted on that date. Final OS was analyzed at the time of Primary analysis (Primary Analysis cut-off date = 27-Jan-2021) and an updated descriptive analysis of OS was re-run at the time of final analysis (Final Analysis cut-off date 14-Dec-2023).
Secondary Outcomes
- Number of Participants With Randomized/Study Treatment-emergent Adverse Events (TEAE)(From randomization till 30 days safety follow-up, assessed up to 66 months (Final Analysis cut-off date = 14-Dec-2023))
- Overall Response Rate (ORR)(From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Disease Control Rate (DCR)(From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Duration of Response (DOR)(From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Time to First Symptomatic Skeletal Event (SSE)(From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Progression-free Survival (PFS)(From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Best Percentage Change From Baseline in Prostate-specific Antigen (PSA) Level(From date of randomization till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Percentage of Participants Achieving Prostate-specific Antigen (PSA) Response(From date of randomization till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Prostate-specific Antigen 80 (PSA80) Response(From date of randomization till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Duration of PSA Response(From date of first documented PSA response till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Best Percentage Change From Baseline in Alkaline Phosphatase (ALP) Level(From date of randomization till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Best Percentage Change From Baseline in Lactate Dehydrogenase (LDH) Level(From date of randomization till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Time to Worsening in BPI-SF Pain Intensity Scale(From date of randomization until date of End of Treatment (EoT), assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Time to Improvement After Worsening in BPI-SF Pain Intensity Scale(From date of randomization until date of End of Treatment (EoT), assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Time to Worsening in BPI-SF Pain Interference Scale(From date of randomization until date of End of Treatment (EoT), assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Time to Improvement After Worsening in BPI-SF Pain Interference Scale(From date of randomization until date of End of Treatment (EoT), assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Time to Worsening in BPI-SF Worst Pain Intensity Scale (Time to Disease Related Pain)(From date of randomization until date of End of Treatment (EoT), assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Change From Baseline in BPI-SF (Brief-Pain Inventory - Short Form) Pain Intensity Scale(Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks))
- Change From Baseline in BPI-SF (Brief-Pain Inventory - Short Form) Pain Interference Scale(Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks))
- Time to Worsening in FACT-P Total Score(From date of randomization until date of End of Treatment (EoT), assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Duration of Time in Hospital Following 177Lu-PSMA-617 Administration(From date of randomization till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Change From Baseline in FACT-P (Functional Assessment of Cancer Therapy - Prostate) Total Score(Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks))
- Time to Worsening in EQ-5D-5L Utility Score(From date of randomization until date of End of Treatment (EoT), assessed up to 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Change From Baseline in the European Quality of Life (EuroQol) - 5 Domain 5 Level Scale (EQ-5D-5L) Utility Score(Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks))
- Change From Baseline in the European Quality of Life (EuroQol) - 5 Domain 5 Level Scale (EQ-5D-5L) EQ-VAS(Baseline (BL), Cycle 2 to Cycle 13 (Week 1 Day 1), End of Treatment (EoT) (cycle duration for Cycle 1-6 = 6 weeks and for Cycle 7 and beyond = 12 weeks))
- Number of Participants Hospitalized as In-patient(From date of randomization till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Concomitant Drug Use for Health Economics Analysis(From date of randomization till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021))
- Therapeutic Interventions for Health Economics Analysis(From date of randomization till 30 days safety fup, assessed up to approximately 32 months (Primary Analysis cut-off date = 27-Jan-2021))