Prostate Cancer Clinical Trial
177Lu-PSMA-617 vs. Androgen Receptor-directed Therapy in the Treatment of Progressive Metastatic Castrate Resistant Prostate Cancer
The purpose of this study is to determine whether 177Lu-PSMA-617 improves the rPFS or death compared to a change in ARDT in mCRPC participants that were previously treated with an alternate ARDT and not exposed to a taxane-containing regimen in the CRPC or mHSPC settings.
Approximately 450 participants will be randomized (225 per treatment group).
This is a phase III, open label, multicenter randomized study where it is considered appropriate to delay taxane-based chemotherapy.
The study aims at evaluating the superiority of 177Lu-PSMA-617 over a change of ARDT treatment in prolonging rPFS. The primary endpoint of rPFS will be assessed via blinded independent centralized review of radiographic images provided by the treating physician and as outlined in PCWG3 Guidelines.
The study will also evaluate whether 177Lu-PSMA-617 improves the overall survival (OS) in participants with progressive PSMA-positive mCRPC compared to participants treated with a change in ARDT treatment. OS is defined as the time from randomization to death due to any cause.
Treatment duration: approximately 43 months.
Screening period At screening, the participants will be assessed for eligibility and will undergo a 68Ga-PSMA-11 positron emission tomography (PET)/computed tomography (CT) scan to evaluate PSMA positivity. Only participants with PSMA positive cancer and confirmed eligibility criteria will be randomized.
Randomization period The participants will be randomized 1:1 to receive 177Lu-PSMA-617 or a change of the ARDT treatment. The ARDT change will include approved Androgen Receptor (AR) axis targeted therapy (abiraterone or enzalutamide). Supportive care will be allowed in both arms at the discretion of the investigator and includes available care for the eligible participant according to best institutional practice for mCRPC treatment, including androgen deprivation therapy (ADT). Investigational agents, biological products, immunotherapy, cytotoxic chemotherapy, other systemic radioisotopes (e.g. radium-223), Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors or hemi-body radiotherapy treatment must not be administered during the study treatment period. ARDT must not be administered concomitantly with 177Lu-PSMA-617.
Treatment period • 177Lu-PSMA-617 treatment arm Participants randomized to the investigational arm will receive 7.4 GBq +/- 10% of 177Lu-PSMA-617 once every 6 weeks for 6 cycles. Best supportive care, including ADT, may be used.
After the last day of study treatment period of 177Lu-PSMA-617 (i.e. after completion of 6 cycles of treatment OR treatment discontinuation for any reason), the participants must have an End of Treatment (EOT) visit and enter the Post-treatment Follow-up.
• ARDT treatment arm For participants randomized to the ARDT treatment arm, the change of ARDT treatment for each participant will be selected by the treating physician prior to randomization and will be administered per the physician's orders. Best supportive care, including ADT, may be used. After the last day of study treatment (treatment discontinuation for any reason) or upon radiographic progression as assessed by blinded centralized review, the participants must have an End of Treatment (EOT) and enter the Post-treatment Follow-up.
End of Treatment
Randomized treatment may be discontinued if:
The participant chooses to discontinue treatment
Completion of the 6 cycles of 177Lu-PSMA-617
Serious non-compliance to the protocol
Unequivocal clinical progression
It is important that the scheduled imaging assessments continue until BICR-determined progression. PSA progression is strongly discouraged as a criterion for initiation of a new neoplastic therapy prior to BICR-determined progression. PCWG3 guidelines should be followed to guide discontinuation of treatment.
End of Treatment visit must be performed ≤ 7 days after the last day of study treatment period. EOT is to occur before the participant is to enter the post-treatment Follow-up period of the study and before the initiation of any subsequent anticancer treatment, outside of what is allowed in the study.
If a participant withdraws consent for the treatment period of the study, an EOT must be done and the participant will enter the Post-treatment Follow-up unless he specifically withdraws post-treatment Follow-up.
Crossover period Upon confirmation of rPFS by BICR, participants randomized to the ARDT arm will either be allowed to crossover to receive 177Lu-PSMA-617 within 28 days of central confirmation of radiographic progression or may continue to receive any other therapy per the discretion of the treating physician in the Post-treatment Follow-up.
In order for a participant randomized to the change in ARDT arm to cross over to receive 177Lu-PSMA-617, he must meet the following criteria:
Confirmed radiographical progression as assessed by BICR
No intervening antineoplastic therapy is administered after the randomized treatment
Any unresolved toxicity from prior therapy should be controlled and must be no greater than CTCAE grade 2 or baseline at the time of starting 177Lu-PSMA-617.
ECOG performance status 0-1 at the time of crossover
Adequate organ function at the time of crossover:
Agreement to continue with the study visit schedule
If the patient has not undergone specific assessments defined below within 7 days prior to commencing treatment of crossover, they must complete the following assessments in order to ensure the above criteria are met prior initiation of 177Lu-PSMA-617:
Hematology and biochemistry
Adverse events assessment
A participant, who is deemed to have disease progression per investigator assessment, but not by BICR, is not eligible to crossover at that time. Such participant should continue to receive randomized study treatment until progression determined by BICR.
If crossover to 177Lu-PSMA-617 is selected, then 177Lu-PSMA-617 will be administered with the same dose/schedule as for participants who were initially randomized to receive 177Lu-PSMA-617.
After the last day of study treatment period of 177Lu-PSMA-617 or upon second radiographic progression (rPFS2), the participants must have a second End of Treatment (EOT2) and enter the Post-treatment Follow-up. The participant can receive any other therapy per the discretion of the treating physician in the Post-treatment Follow-up.
Post-treatment Follow-up period
30 day Safety Follow-up All randomized and/or treated participants should have a safety follow-up conducted approximately 30 days after the EOT visit.
Long term follow-up Long term follow-up starts after the 30 Days Safety follow-up and lasts until the accrual of events for the planned OS-based analysis (key secondary endpoint).
In long term follow-up safety and efficacy information will be collected:
Safety: all medically significant adverse events (all SAEs) deemed to be related to 177Lu-PSMA-617. This will include potential late onset radiation toxicity.
Efficacy: In any participant entering long term follow-up discontinuing for reasons other than BICR-determined radiographic progression, tumor assessments must be performed every 8 weeks after first dose of study treatment for the first 24 weeks (week 9, 17, 25) and then every 12 weeks (week 37, 49, etc) until confirmation of radiographic progression by BICR
The long-term follow-up period will also include the collection of survival information and other assessments.
Other: Other data collected during long-term follow-up includes blood sampling for hematology, chemistry testing, coagulation, DNA and tumor samples for biomarkers. The visits will be carried out every 12 weeks (± 28 days) until death, lost to follow-up, withdrawal of consent or accrual of the number of events required for the planned analyses for OS for the study, whichever occurs first.
This follow-up will allow to collect information on medically significant long-term toxicities such as long-term radiotoxicity.
Duration of long term follow-up is expected to continue till end of study.
If the participant withdraws consent for the collection of blood samples, PROs, and imaging assessments during the long-term follow-up, information on survival, SAEs related to study treatment and post-treatment antineoplastic therapy will be collected.
Participants eligible for inclusion in this study must meet all of the following criteria:
Signed informed consent must be obtained prior to participation in the study
Participants must be adults ≥ 18 years of age
Participants must have an ECOG performance status of 0 to 1
Participants must have histological pathological, and/or cytological confirmation of adenocarcinoma of the prostate
Participants must be 68Ga-PSMA-11 PET/CT scan positive, and eligible as determined by the sponsor's central reader
Participants must have a castrate level of serum/plasma testosterone (< 50 ng/dL or < 1.7 nmol/L)
Participants must have progressed only once on prior second generation ARDT (abiraterone, enzalutamide, darolutamide, or apalutamide)
first generation androgen receptor inhibitor therapy (e.g. bicalutamide) is allowed but not considered as prior AEDT therapy
second generation ARDT must be the most recent therapy received
Participants 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 increases in PSA measured at least 1 week apart. The minimal start value is 2.0 ng/mL. 1.0 ng/ml is the minimal starting value if confirmed rise in PSA is the only indication of progression.
Soft-tissue progression defined [PCWG3-modified RECIST v1.1 (Eisenhauer et al 2009, Scher et al 2016)]
Progression of bone disease two new lesions only positivity on the bone scan defines metastatic disease to bone (PCWG3 criteria (Scher et al 2016))
Participants must have ≥ 1 metastatic lesion that is present on screening/baseline CT, MRI, or bone scan imaging obtained prior to randomization.
Participants must have recovered to ≤ Grade 2 from all clinically significant toxicities related to prior therapies (i.e. prior chemotherapy, radiation, etc.) except alopecia
Participants must have adequate organ function:
Bone marrow reserve:
ANC ≥ 1.5 x 109/L
Platelets ≥100 x 109/L
Hemoglobin ≥ 9 g/dL
Total bilirubin < 2 x the institutional upper limit of normal (ULN). For participants with known Gilbert's Syndrome ≤ 3 x ULN is permitted
ALT or AST ≤ 3.0 x ULN OR ≤ 5.0 x ULN for participants with liver metastases
eGFR ≥ 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation
Albumin ≥ 2.5 g/dL
Candidates for change in ARDT as assessed by the treating physician • Participants cannot have previously progressed nor had intolerable toxicity to both enzalutamide and abiraterone.
Participants meeting any of the following criteria are not eligible for inclusion in this study:
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
Prior treatment with PARP inhibitors, cytotoxic chemotherapy for castration resistant or castrate sensitive prostate cancer (e.g., taxanes, platinum, estramustine, vincristine, methotrexate, etc.), immunotherapy or biological therapy [including monoclonal antibodies]) [Note: Taxane exposure (maximum 6 cycles) in the adjuvant or neoadjuvant setting is allowed if 12 months have elapsed since completion of this adjuvant or neoadjuvant therapy]. Prior treatment with sipuleucel-T is allowed.
Any investigational agents within 28 days prior to day of randomization
Known hypersensitivity to any of the study treatments or its excipients or to drugs of similar classes
Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, PARP inhibitor, biological therapy, or investigational therapy
Transfusion or use of bone marrow stimulating agents for the sole purpose of making a participant eligible for study inclusion
Patients with a history of CNS metastases that are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic integrity. Participants with CNS metastases are eligible if received therapy (surgery, radiotherapy, gamma knife), asymptomatic and neurologically stable without corticosteroids. Participants with epidural disease, canal disease and prior cord involvement are eligible if those areas have been treated, are stable, and not neurologically impaired.
Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression
History or current diagnosis of the following ECG abnormalities indicating significant risk of safety for study participants:
Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block)
History of familial long QT syndrome or known family history of Torsades de Pointe
Cardiac or cardiac repolarization abnormality, including any of the following: History of myocardial infarction (MI), angina pectoris, or CABG within 6 months prior to starting study treatment
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
HIV-infected participants who are at a low risk of AIDS-related outcomes may participate in this trial.
Participants with an active documented COVID-19 infection (any grade of disease severity) at time of informed consent may be included only when completely recovered (in accordance with local guidance).
Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. Participants with a prior history of malignancy that has been adequately treated and who have been disease free for more than 3 years prior to randomization are eligible, as are participants with adequately treated non-melanoma skin cancer and superficial bladder cancer
Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 14 weeks after stopping study treatment. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time period specified above. If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF
Unmanageable concurrent bladder outflow obstruction or urinary incontinence. Note: Participants with bladder outflow obstruction or urinary incontinence, which is manageable and controlled with best available standard of care (incl. pads, drainage) are allowed.
History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study
Any condition that precludes raised arms position
Presence of any mutations or biomarkers that are known to as predictors of better response to treatments other than ARDT (e.g., AR-V7 or BRCA)
Not able to understand and to comply with study instructions and requirements
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There are 81 Locations for this study
Longmont Colorado, 80501, United States
Gainesville Florida, 32610, United States
New Orleans Louisiana, 70112, United States
Boston Massachusetts, 02114, United States
Boston Massachusetts, 02115, United States
Boston Massachusetts, 02215, United States
Troy Michigan, 48098, United States
Rochester Minnesota, 55905, United States
Saint Louis Missouri, 63110, United States
Omaha Nebraska, 68130, United States
Omaha Nebraska, 68154, United States
New York New York, 10016, United States
New York New York, 10017, United States
New York New York, 10029, United States
Durham North Carolina, 27710, United States
Columbus Ohio, 43221, United States
Myrtle Beach South Carolina, 29572, United States
Nashville Tennessee, 37203, United States
Dallas Texas, 75246, United States
Dallas Texas, 75390, United States
Houston Texas, 77030, United States
Salt Lake City Utah, 84106, United States
Norfolk Virginia, 23502, United States
Roanoke Virginia, 24014, United States
Seattle Washington, 98105, United States
Milwaukee Wisconsin, 53226, United States
Innsbruck Tyrol, 6020, Austria
Linz , A-401, Austria
Wien , 1090, Austria
Bruxelles , 1200, Belgium
Gent , 9000, Belgium
Liege , 4000, Belgium
Roeselare , 8800, Belgium
Vancouver British Columbia, V5Z 4, Canada
Montreal Quebec, H2W 1, Canada
Montreal Quebec, H3T 1, Canada
Olomouc CZE, 775 2, Czechia
Angers cedex 02 , 49055, France
Bordeaux , 33076, France
Clermont-Ferrand , 63011, France
Lyon Cedex , 69373, France
Paris , 75970, France
Villejuif Cedex , 94800, France
Essen , 45147, Germany
Koeln , 50937, Germany
Muenchen , 80377, Germany
Rostock , 18057, Germany
Nijmegen Netherland, 6525 , Netherlands
Maastricht , 6229 , Netherlands
Utrecht , 3584C, Netherlands
Gliwice Slaskie, 44-10, Poland
Bratislava Slovak Republic, 83310, Slovakia
Malaga Andalucia, 29010, Spain
Sevilla Andalucia, 41013, Spain
Barcelona Catalunya, 08035, Spain
Barcelona Catalunya, 08036, Spain
Hospitalet de LLobregat Catalunya, 08907, Spain
Valencia Comunidad Valenciana, 46009, Spain
Santiago de Compostela Galicia, 15706, Spain
El Palmar Murcia, 30120, Spain
Pamplona Navarra, 31008, Spain
Barcelona , 08041, Spain
Madrid , 28009, Spain
Madrid , 28040, Spain
Madrid , 28041, Spain
Madrid , 28222, Spain
Valencia , 46026, Spain
Goteborg , 413 4, Sweden
Lund , 221 8, Sweden
Stockholm , 17176, Sweden
Baden , 5404, Switzerland
Lausanne , 1011, Switzerland
Zuerich , 8091, Switzerland
Guildford Surrey, GU2 7, United Kingdom
Sutton Surrey, SM2 5, United Kingdom
Middlesbrough Yorkshire, TS4 3, United Kingdom
Cambridge , CB2 2, United Kingdom
Coventry , CV2 2, United Kingdom
London , EC1A , United Kingdom
London , NW1 2, United Kingdom
London , NW3 2, United Kingdom
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