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, 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
- Toxicity
- Completion of the 6 cycles of 177Lu-PSMA-617
- Serious non-compliance to the protocol
- BICR-determined progression
- 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 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 1 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:
- ECOG-PS
- Vital signs
- 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 8, 16,
24) and then every 12 weeks (week 36, 48, 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 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.
Inclusion Criteria:
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study
2. Participants must be adults ≥ 18 years of age
3. Participants must have an ECOG performance status of 0 to 1
4. Participants must have histological pathological, and/or cytological confirmation of
adenocarcinoma of the prostate
5. Participants must be 68Ga-PSMA-11 PET/CT scan positive, and eligible as determined by
the sponsor's central reader
6. Participants must have a castrate level of serum/plasma testosterone (< 50 ng/dL or <
1.7 nmol/L)
7. Participants must have received one prior approved ARDT (for example, abiraterone,
enzalutamide, darolutamide, or apalutamide, etc.) and have documented progression on
therapy
8. 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 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 [PCWG3-modified RECIST v1.1 (Eisenhauer et al
2009, Scher et al 2016)]
- Progression of bone disease: evaluable disease or one or more new bone lesions(s)
by bone scan (PCWG3 criteria (Scher et al 2016))
9. Participants must have ≥ 1 metastatic lesion that is present on screening/baseline CT,
MRI, or bone scan imaging obtained ≤ 28 days prior to beginning study therapy
10. Participants must have recovered to ≤ Grade 2 from all clinically significant
toxicities related to prior therapies (i.e. prior chemotherapy, radiation, etc.)
except alopecia
11. Participants must have adequate organ function:
- Bone marrow reserve:
- ANC ≥ 1.5 x 109/L
- Platelets ≥100 x 109/L
- Hemoglobin ≥ 9 g/dL
- Hepatic:
- 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
- Renal:
- eGFR ≥ 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD)
equation
12. Albumin ≥ 2.5 g/dL
13. Candidates for change in ARDT as assessed by the treating physician
Exclusion Criteria:
Participants meeting any of the following criteria are not eligible for inclusion in this
study:
1. 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
2. Previous PSMA-targeted radioligand therapy
3. Prior treatment with 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]
4. Any investigational agents within 28 days prior to day of randomization
5. Known hypersensitivity to any of the study treatments or its excipients or to drugs of
similar classes
6. Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or
investigational therapy
7. Transfusion or use of bone marrow stimulating agents for the sole purpose of making a
participant eligible for study inclusion
8. 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.
9. Symptomatic cord compression, or clinical or radiologic findings indicative of
impending cord compression
10. 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
11. 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) and had no symptoms for at least 28
days before the first dose of study medication.
12. 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
are eligible, as are participants with adequately treated non-melanoma skin cancer,
superficial bladder cancer
13. Sexually active males unwilling to use a condom during intercourse while taking study
treatment and for 6 months 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
14. Concurrent bladder outflow obstruction or unmanageable urinary incontinence
15. History of somatic or psychiatric disease/condition that may interfere with the
objectives and assessments of the study
16. Any condition that precludes raised arms position
17. Presence of any mutations or biomarkers that are known as predictors of better
response to treatments other than ARDT (e.g., AR-V7 or BRCA) as assessed by the
investigator
18. Not able to understand and to comply with study instructions and requirements
