The primary objective of this study is to compare overall survival (OS) in patients with progressive PSMA-positive mCRPC who receive 177Lu-PSMA-617 in addition to best supportive/best standard of care versus patients treated with best supportive/…
ID
Source
Brief title
Condition
- Reproductive neoplasms male malignant and unspecified
- Prostatic disorders (excl infections and inflammations)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
One of the primary endpoints is OS and is defined as the time from
randomization to the date of death from any cause. The 2nd now added primary
endpoint is rPFS (radiographic Progression Free Survival).
Secondary outcome
The key secondary endpoints include the following:
1.
2. RECIST response to include:
a. Objective response rate (ORR) (CR + PR) as measured by RECIST v1.1 response
in soft tissue, lymph node and visceral lesions. Duration of Response (DOR)
will also be measured in patients with a CR or PR from date of first response
to the date of RECIST progression or death.
b. Disease Control Rate (DCR) (CR + PR + stable disease [SD]) as measured by
RECIST v1.1 response in soft tissue, lymph node and visceral lesions.
3. The time to a first SSE defined as date of randomization to the date of
first new symptomatic pathological bone fracture, spinal cord compression,
tumor-related orthopedic surgical intervention, or requirement for radiation
therapy to relieve bone pain or death from any cause, whichever occurs first.
Additional Secondary endpoints
1. To evaluate the safety and tolerability of 177Lu-PSMA-617
2. Aspects of HRQoL will be reported using the EuroQol 5-dimensions 5-level
[EQ-5D-5L] questionnaire, Functional Assessment of Cancer Therapy - Prostate
[FACT-P] questionnaire and Brief Pain Inventory - Short Form [BPI-SF]
3. Health economics
4. Progression-free survival is defined as the date of randomization to the
date of first evidence of radiographic progression, clinical progression, PSA
progression, or death from any cause, whichever occurs first.
a. Radiographic progression is defined as the date of radiographic disease
progression as outlined in the Prostate Cancer Working Group 3 (PCWG3)
Guidelines.
b. Unequivocal clinical progression. Unequivocal evidence of clinical
progression is defined as:
* - Marked escalation in cancer related pain that is assessed by the
investigator to indicate the need for other systemic chemotherapy
*- Immediate need for initiation of new anticancer treatment, surgical or
radiological intervention for complications due to tumor progression even in
the absence of radiological progression
*- Marked deterioration in ECOG performance status to >= Grade 3 and/or in the
opinion of the investigator ECOG deterioration indicates clinical progression
*- In the opinion of the investigator, it is in the best interest of the
patient to discontinue treatment due to clinical progression
c. PSA progression is defined as the date that a >= 25% increase in PSA and an
absolute increase of 2 ng/mL or more from the nadir is documented and confirmed
by a second consecutive value obtained 3 or more weeks later. Rises in PSA
within the first 12 weeks will be ignored in the absence of other evidence of
disease progression (PCWG3 Guidance). Where no decline from baseline is
documented, PSA progression is 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.
5. Biochemical response endpoints:
a. Proportion of subjects who are PSA responders, defined as a patient who has
achieved a >=50% decrease from baseline that is confirmed by a second PSA
measurement >=4 weeks.
b. Alkaline phosphatase [ALP] and lactate dehydrogenase [LDH] levels will also
be collected.
Background summary
The novel therapeutic drug 177Lu-PSMA-617 was developed by the German Cancer
Research Center, Deutsches Krebsforschungszentrum (DKFZ) in collaboration with
University Hospital Heidelberg for the treatment of patients with metastatic
prostate cancer (Kratochwil et al 2015, Hillier et al 2009). Based on
preclinical data that demonstrated high PSMA binding affinity and compound
internalization, prolonged tumor uptake, rapid kidney clearance, and high
tumor-to-background ratio, 177Lu-PSMA-617 proceeded into clinical development
at investigative sites in Germany.
Over 20 compassionate use publications and prospective Phase 2 clinical trial
data describe the use of 177Lu-PSMA-617 in patients who have been exposed to
approved agents. In the post-taxane, post-androgen axis inhibitor setting
177Lu-PSMA-617 has demonstrated a well-established, predictable, well tolerated
safety profile. Clinical series have confirmed 8% incidence of Grade 1 to 2
xerostomia, less than 10% asymptomatic hematological of Grade 3 to 4 toxicity
and no significant renal toxicity. Efficacy has been demonstrated on multiple
clinically significant endpoints, including PSA response, soft tissue lesion
response measured by RECIST, PFS, OS, pain and quality of life. No standard
dose and schedule have been developed.
The preliminary clinical evidence indicates 177Lu-PSMA-617 may demonstrate
clinical benefit in patients with mCRPC in a setting where patients had been
exposed to chemotherapy and NAADs and there is no recommended standard of care.
This Phase 3 study will assess the efficacy of 177Lu-PSMA-617 in patients with
progressive PSMA-positive mCRPC by measuring overall survival in a randomized,
prospective, open-label trial.
Study objective
The primary objective of this study is to compare overall survival (OS) in
patients with progressive PSMA-positive mCRPC who receive 177Lu-PSMA-617 in
addition to best supportive/best standard of care versus patients treated with
best supportive/best standard of care alone. A 2nd endpoint, radiographic
progression free survival - rPFS - has been added as alternative primary
endpoint.
Key secondary objectives are an arm-to-arm comparison of the following:
• Response Evaluation Criteria in Solid Tumors (RECIST) response
• Time to a first symptomatic skeletal event (SSE)
Additional Secondary Objectives:
• Safety and tolerability of 177Lu-PSMA-617
• Health-related quality of life (HRQoL; EQ-5D-5L, FACT-P and Brief Pain
Inventory - Short Form (BPI-SF))
• Health economics
• Progression-free survival (PFS) (radiographic, clinical, or prostate-specific
antigen [PSA] progression-free survival)
• Biochemical response as measured by PSA. Alkaline phosphatase [ALP] levels
and lactate dehydrogenase [LDH] levels will also be measured.
Study design
Patients with PSMA positive scans will be randomized in a 2:1 ratio to receive
either 177Lu-PSMA-617 plus best supportive/best standard of care or to receive
best supportive/best standard of care only. Best supportive/best standard of
care will be determined by the treating physician/investigator but will exclude
investigational agents, cytotoxic chemotherapy, other systemic radioisotopes,
and hemi-body radiotherapy. Novel androgen axis drugs [NAADs] (such as
abiraterone or enzalutamide) are allowed.
The study is open-label and patients will be monitored throughout the 6 to
10-month treatment period for survival, disease progression, and adverse events.
A long-term follow-up period will include the collection of survival and
treatment updates, adverse events assessment, as well as blood for hematology
and chemistry testing. During follow-up, patients will be contacted every 3
months (±1 month) via phone, email, or letter for 24 months or until the the
overall censoring rate for survival reduces to a level identified in the SAP.
An End of Treatment visit should occur once a patient is to enter the long term
follow up. This visit should occur approximately 30 days from the last dose of
177Lu-PSMA-617 or best supportive/best standard of care, but before the
initiation of subsequent anti-cancer treatment, outside of what is allowed on
study.
Intervention
Patients randomized to receive the investigational product will receive 7.4 GBq
(±10%) 177Lu-PSMA-617 intravenously every 6 weeks (±1 week) for a maximum of 6
cycles. After 4 cycles, patients will be assessed for (1) evidence of response,
(2) residual disease, and (3) tolerance to 177Lu-PSMA-617. If the patient meets
the criteria above, and agrees to continue with additional treatment of
177Lu-PSMA-617 radioligand therapy, the investigator may administer 2
additional cycles. A maximum of 6 cycles of radioligand therapy is allowed.
After the last cycle of 177Lu-PSMA-617, patients can continue best
supportive/best standard of care alone.
If the patient does not meet all of the criteria or does not agree to
additional 177Lu-PSMA-617 treatment, then no additional doses of 177Lu-PSMA-617
will be administered after Cycle 4. These patients can continue on best
supportive/best standard of care alone after Cycle 4.
Radiographic imaging will be done every 8 weeks (±4 days) during the first 24
weeks of treatment and every 12 weeks (± 4 days) thereafter, regardless of
treatment delays, through the End of Treatment visit.
The previous 2 PSA values will be noted before randomization. Serum
testosterone and PSA levels will be measured within 3 days prior to Day 1 of
each cycle. Hematology and chemistry will be done weekly during Cycle 1 (within
3 days prior to each time point) and within 3 days prior to Days 1, 15, and 29
in Cycles 2 to 6 (i.e. every two weeks). After Cycle 6, hematology and
chemistry will be done every 8 weeks (±1 week) until the patient starts long
term follow up.
Patients will complete the BPI-SF, EQ-5D-5L and FACT-P questionnaires about
their pain level and HRQoL during screening and prior to treatment on Day 1 of
each cycle and through the End of Treatment visit. Patients will be monitored
throughout the study for SSEs.
Study burden and risks
Patients will be randomized to 1 of 2 treatment arms. Randomization will be
stratified to avoid bias in treatment selection. Treatment will be open-label.
Patients may experience side effects related to the 177LU-PSMA-617 and
radiation. For full list of side effects please refer to Appendix E of the ICF.
In addition to side effects patients may experience discomforts and risks
associated with the study procedures and visits.
Novartis Pharmaceuticals Corporation, One Health Plaza 8910
East Hanover NJ 07936-1080
US
Novartis Pharmaceuticals Corporation, One Health Plaza 8910
East Hanover NJ 07936-1080
US
Listed location countries
Age
Inclusion criteria
1. Patients must have the ability to understand and sign an approved ICF.
2. Patients must have the ability to understand and comply with all protocol
requirements.
3. Patients must be >=18 years of age.
4. Patients must have an ECOG performance status of 0 to 2.
5. Patients must have a life expectancy >6 months.
6. Patients must have histological, pathological, and/or cytological
confirmation of prostate cancer.
7. Patients must be 68Ga-PSMA-11 PET/CT scan positive, and eligible , as
determined by the sponsor's central reader.
8. Patients must have a castrate level of serum/plasma testosterone (<50 ng/dL
or <1.7 nmol/L).
9. Patients must have received at least one NAAD (such as enzalutamide and/or
abiraterone).
10. 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.)
11. Patients must have progressive mCRPC. Documented progressive mCRPC will be
based on at least 1 of the following criteria:
a. 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.
b. 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.
c. Progression of bone disease: evaluable disease or new bone lesions(s) by
bone scan (2+2 PCWG3 criteria, Scher et al 2016).
12. 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.
13. Patients must have recovered to <= Grade 2 from all clinically significant
toxicities related to prior therapies (i.e. prior chemotherapy, radiation,
immunotherapy, etc.).
14. Patients must have adequate organ function:
a. Bone marrow reserve:
• White blood cell (WBC) count >=2.5 × 109/L (2.5 × 109/L is equivalent to 2.5 ×
103/µL and 2.5 × K/µL and 2.5 × 103/cumm and 2500/µL) OR absolute neutrophil
count (ANC) >=1.5 × 109/L (1.5 × 109/L is equivalent to 1.5 × 103/µL and 1.5 ×
K/µL and 1.5 × 103/cumm and 1500/µL)
• Platelets >=100 × 109/L (100 × 109/L is equivalent to 100 × 103/µL and 100 ×
K/µL and 100 × 103/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 × ULN is permitted
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <=3.0 × ULN
OR <=5.0 × ULN for patients with liver metastases
c. Renal:
• Serum plasma creatinine <=1.5 x ULN or creatinine clearance >=50 mL/min
15. Albumin >3.0 g/dL (3.0 g/dL is equivalent to 30 g/L)
16.
17. 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:
18. 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.
19. The best standard of care/ best supportive care options planned for this
patient: a. Are allowed by the protocol b. Have been agreed to by the treating
investigator and patient c. Allow for the management of the patient without
177Lu-PSMA-617.
Exclusion criteria
1. Previous treatment with any of the following within 6 months of
randomization: Strontium-89, Samarium-153, Rhenium-186, Rhenium188, Radium-223
hemi-body irradiation. Any of the listed radio ligand therapies and hemi-body
irradiation require a 6 month wash out period. PSMA-targeted radioligand
therapy is not allowed.
2. Any systemic anti-cancer therapy (e.g. chemotherapy, immunotherapy or
biological therapy [including monoclonal antibodies]) within 28 days prior to
day of randomization.
3. Any investigational agents within 28 days prior to day of randomization.
4. Known hypersensitivity to the components of the study therapy or its analogs.
5. Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy,
or investigational therapy.
6. Transfusion for the sole purpose of making a subject eligible for study
inclusion.
7. Patients with a history of 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).
8. A superscan as seen in the baseline bone scan.
9. Symptomatic cord compression, or clinical or radiologic findings indicative
of impending cord compression.
10. 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, active hepatitis B or C, or other significant co-morbid
conditions that in the opinion of the investigator would impair study
participation or cooperation. This applies to known active Hep B or C -
screening is not required.
11. Diagnosed with other malignancies that are expected to alter life
expectancy or may interfere with disease assessment. Patients with adequately
treated non-melanoma skin cancer, superficial bladder cancer and patients with
prior history of malignancy who have been disease free for more than 3 years
are eligible.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-000459-41-NL |
| ClinicalTrials.gov | NCT03511664 |
| CCMO | NL66744.091.18 |