Clinical trial NCT05114746: Study of 177Lu-PSMA-617 In Metastatic Castrate-Resistant Prostate Cancer in Japan
Official title: A Prospective, Open Label, Multicenter, Single Arm, Phase 2 Study of 177Lu-PSMA-617 in the Treatment of Participants With Progressive PSMA- Positive Metastatic Castration-resistant Prostate Cancer (mCRPC) in Japan
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Prostate Cancer
Keywords: 177Lu-PSMA-617
68Ga-PSMA-11
68Ge/68Ga Generator
metastatic castration-resistant prostate cancer
mCRPC
prostate-specific membrane antigen
PSMA
radioligand
taxane
enzalutamide
abiraterone
Overall Response Rate
ORR
Lead sponsor: Novartis
Sponsor class: INDUSTRY
Collaborators: name: Eckert & Ziegler Radiopharma GmbH
First posted: 2021-11-10
Enrollment: 110
Sex: MALE
Minimum age (years): 20
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the efficacy, tolerability, safety, pharmacokinetic (PK) and dosimetry of 177Lu-PSMA-617, in participants with progressive prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) in Japan. Furthermore, the safety, PK and dosimetry of 68Ga-PSMA-11 (PSMA imaging agent) are assessed in the same study.

Another purpose of this study is to provide humanistic perspective access to study treatment (68Ga-PSMA-11 and 177Lu-PSMA-617) for the eligible patients with PSMA-positive mCRPC until marketed products are available in Japan.

Furthermore, if data availability PK and dose rate of 177 Lu-PSMA-617 will be evaluated to refine discharge criteria in Japan.

After obtaining manufacturing and marketing approval in Japan, this clinical trial will continue as a post marketing trial.

Detailed description: This study is an open label, multicenter, single arm, phase II study to evaluate the efficacy, tolerability, safety, PK and dosimetry of 177Lu-PSMA-617 in participants with progressive PSMA-positive mCRPC in Japan. Furthermore, the safety, PK, and dosimetry of 68Ga-PSMA-11 (PSMA imaging agent) are also evaluated in this study.

This study consists of two populations:

1. Post-taxane population:

   The post-taxane population will include men with PSMA-positive mCRPC who received at least one ARDT (for example enzalutamide, abiraterone etc.) and were previously treated with at least one, but no more than two taxane regimens. Participants treated with only 1 prior taxane regimen are eligible if the participant's physician deems the participants unsuitable to receive a second taxane regimen.
2. Pre-taxane population; The pre-taxane population will include men with PSMA-positive mCRPC who were previously treated with one ARDT as last treatment and have not been exposed to a taxane-containing regimen in the CRPC or HSPC settings and for whom it is considered appropriate to delay taxane-based chemotherapy.

This is a 4-part study: Part 1 (a safety run-in part), Part 2 (post-taxane part), Part 3 (pre-taxane part) and Part 4 (expanded trial part).

1. Part 1 (safety run-in part) will confirm the tolerability and safety of recommended regimen, once every 6-weeks, 7.4 GBq of the 177Lu-PSMA-617. Minimum of 3 participants as 177Lu-PSMA-617 tolerability evaluable participants will be enrolled. Dosimetry and PK assessments of 177Lu-PSMA-617 are mandatory for participants enrolled in this part.
2. Part 2 (post-taxane part) will evaluate the efficacy, safety, PK and dosimetry of 177Lu-PSMA-617 plus BSC/BSoC, as well as safety, PK, and dosimetry of 68Ga-PSMA-11 in post-taxane participants with PSMA-positive mCRPC.
3. Part 3 (pre-taxane part) will evaluate the efficacy, safety, PK and dosimetry of 177Lu-PSMA-617, as well as safety, PK, and dosimetry of 68Ga-PSMA-11 in taxane naïve participants with PSMA-positive mCRPC
4. Part 4 (expanded trial part) will provide humanistic perspective access of study treatment (68Ga-PSMA-11 and 177Lu-PSMA-617) for the Japanese post-taxane participants with PSMA-positive mCRPC until marketed products are available in Japan. Additional safety and efficacy of 68Ga-PSMA-11 and of 177Lu-PSMA-617 will be evaluated.

Additionally, PK and dose rate will be evaluated (PK is optional and dose rate is mandatory in Part 4).

Approximately 80 eligible participants will be enrolled in Part 4 and approximately 10 evaluable participants PK data will be collected.

This study will consist of 3 periods: screening period, treatment period, and long term follow up.

Eligibility criteria: Key Inclusion Criteria:

* ECOG performance status:

  1. Post-taxane population only: 0 to 2.
  2. Pre-taxane population only: 0 to 1.
* Participants must have a previous histological, pathological, and/or cytological confirmation of prostate cancer.
* Part 1/2/3 only; Participants must have a positive 68Ga-PSMA-11 PET/CT scan, as determined by the sponsor's central reader, before the enrollment to 177Lu-PSMA-617 treatment period.
* Participants must have a positive 68Ga-PSMA-11 PET/CT scan, as determined by the local investigator, before the enrollment to 177Lu-PSMA-617 treatment period.
* Participants must have a castrate level of serum/plasma testosterone (\<50 ng/dL or \<1.7 nmol/L).
* Post-taxane population only: Participants must have received at least one ARDT (for example enzalutamide, abiraterone, apalutamide, or darolutamide, etc.) in either the hormone-sensitive/castrate-resistant or non-metastatic/metastatic prostate cancer setting.
* Pre-taxane population only: Participants must have progressed only once on prior second generation ARDT (abiraterone, enzalutamide, darolutamide, or apalutamide) and be a candidate for change in ARDT as assessed by the treating physician.

  1. first generation androgen receptor inhibitor therapy (e.g. bicalutamide) is allowed but not considered as prior ARDT therapy
  2. second generation ARDT must be the most recent therapy received.
* Post-taxane population only: Participants must have been previously treated with at least 1, but no more than 2 prior taxane regimens. A taxane regimen is defined as a minimum exposure of 2 cycles of a taxane. If a participant has received only 1 taxane regimen, the participant is eligible if :

  a. The participant's physician deems him unsuitable to receive a second taxane regimen (e.g., frailty assessed by geriatric or health status evaluation or intolerance, etc.).
* Participants must have progressive mCRPC. Documented progressive mCRPC will be based on at least 1 of the following criteria:

  1. Serum PSA progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week prior. 1.0 ng/mL is the minimal starting value if confirmed rise in PSA is the only indication of progression.
  2. 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.
  3. Progression of bone disease: two new lesions; only positivity on the bone scan defines metastatic disease to bone (PCWG3 criteria, Scher et al 2016).
* Part 1/2/3 only; Participants must have at least one measurable lesion per PCWG3-modified RECIST v1.1 on CT or MRI.

Key Exclusion Criteria:

* Previous treatment with any of the following within 6 months of the enrollment: Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation. Previous PSMA-targeted therapy is not allowed.
* Post-taxane population: Any systemic anti-cancer therapy (e.g. chemotherapy, immunotherapy or biological therapy \[including monoclonal antibodies\], ARDT is not included) within 28 days prior to day of the enrollment.
* Pre-taxane population: Prior treatment with PARP inhibitor, cytotoxic chemotherapy for castration resistant or castrate sensitive prostate cancer (e.g., taxanes, platinum, estramustine, vincristine, methotrexate, etc.), immunotherapy or biological therapy \[including monoclonal antibodies\]) \[Note: Taxane exposure (maximum 6 cycles) in the adjuvant or neoadjuvant setting is allowed if 12 months have elapsed since completion of this adjuvant or neoadjuvant therapy\]
* Known hypersensitivity to the components of 177Lu-PSMA-617, 68Ga-PSMA-11 or excipients or to drugs of similar classes.
* Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, PARP inhibitors, biological, AKT inhibitors or investigational therapy.
* Participants 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.
* Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression.

Primary outcomes:
measure: Part 1 (safety run-in part): Dose Limiting Toxicity (DLT) during 1 cycle (6 weeks)
timeFrame: Cycle 2 Day 1 (Day 42)
measure: Part 2 (Post-taxane part) and Part 3 (Pre-taxane part): Overall Response Rate (ORR) based on local assessment
timeFrame: From date of the first administration of 177Lu-PSMA-617 until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 2 years
Secondary outcomes:
measure: Part 2 and Part 3 (main part): Overall Survival (OS)
timeFrame: From date of the first administration of 177Lu-PSMA-617 until date of death from any cause, assessed up to 2 years
measure: Part 2 and Part 3 (main part): Radiographic Progression-Free-Survival (rPFS) based on local assessment
timeFrame: From date of the first administration of 177Lu-PSMA-617 until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 2 years
measure: Part 2 and Part 3 (main part): Overall Response Rate (ORR) based on central review
timeFrame: From date of the first administration of 177Lu-PSMA-617 until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 2 years
measure: Part 2 and Part 3 (main part): Disease Control Rate (DCR) as per central and local review
timeFrame: From date of the first administration of 177Lu-PSMA-617 until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 2 years
measure: Part 2 and Part 3 (main part): Duration of Response (DOR) based on local imaging
timeFrame: From the date of the first documented response (CR or PR) to the date of first documented progression or death due to any cause, assessed up to 2 years
measure: Part 2 and Part3 (main part): Time to first symptomatic skeletal event (SSE) of 177Lu-PSMA-617
timeFrame: From the date of the first administration of 177Lu-PSMA-617 until the date of SSE or date of death from any cause, whichever comes first, assessed up to 2 years
measure: Part 2 and Part 3 (main part): Progression Free Survival (PFS)
timeFrame: From the date of the first administration of 177Lu-PSMA-617 until the date of progression or date of death from any cause, whichever comes first, assessed up to 2 years
measure: Part 2 and Part 3 (main part): Percentage of Participants with Biochemical Response as measured by Prostate Specific Antigen (PSA)
timeFrame: From Baseline till 30 days safety follow-up, assessed up to 2 years
measure: Part 2 and Part 3 (main part): Change from Baseline in European Quality of Life (EuroQol) - 5 Domain 5 Level scale (EQ-5D- 5L)
timeFrame: From Baseline up till end of treatment visit, an average of 13 months
measure: Part 2 and Part 3 (main part): Change from Baseline in Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire
timeFrame: From Baseline up till end of treatment visit, an average of 13 months
measure: Part 2 and Part 3 (main part): Change from Baseline in Brief Pain Inventory - Short Form (BPISF) Questionnaire: Pain Severity Score
timeFrame: From Baseline up till end of treatment visit, an average of 13 months
measure: Part 2 and Part 3 (main part): Change from Baseline in Brief Pain Inventory - Short Form (BPISF) Questionnaire: Pain Interference Score
timeFrame: From Baseline up till end of treatment visit, an average of 13 months
measure: Part 2 and Part 3 (main part): Percentage of Participants with treatment emergent adverse events
timeFrame: From Baseline till 30 days safety follow-up, assessed up to 2 years
measure: Part 2 and Part 3 (main part): Absorbed dose and Effective whole-body dose 68Ga-PSMA-11
timeFrame: 68Ga-PSMA-11 PET imaging acquired at Day 1 (0, 20, 40 , 60, 90, 180 and 255 minutes post infusion)
measure: Part 2 and Part 3 (main part): Absorbed dose and Effective whole-body dose of 177Lu-PSMA-617
timeFrame: 177Lu-PSMA-617 SPECT/CT imaging acquired at Day 1, 2, 3 and 8 of Cycle 1
measure: Part 2 and Part 3 (main part): Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of 68Ga-PSMA-11
timeFrame: Cycle 1 Day 1 (0.083, 0.25, 0.5, 0.75, 1.42, 2.92 and 4.08 hours post infusion)
measure: Part 2 and Part 3 (main part): Time of maximum observed drug concentration occurrence (Tmax) of 68Ga-PSMA-11
timeFrame: Cycle 1 Day 1 (0.083, 0.25, 0.5, 0.75, 1.42, 2.92 and 4.08 hours post infusion)
measure: Part 2 and Part 3 (main part): Observed maximum plasma concentration (Cmax) of 68Ga-PSMA-11
timeFrame: Cycle 1 Day 1 (0.083, 0.25, 0.5, 0.75, 1.42, 2.92 and 4.08 hours post infusion)
measure: Part 2 and Part 3 (main study): Area Under the plasma concentration-time Curve from the time 0 to the last observed quantifiable concentration (AUC(0-t)) of 68Ga-PSMA-11
timeFrame: Cycle 1 Day 1 (0.083, 0.25, 0.5, 0.75, 1.42, 2.92 and 4.08 hours post infusion)
measure: Part 2 and Part 3 (main study): AUC(0-t) divided by the dose administered (AUC(0- t)/D) of 68Ga-PSMA-11
timeFrame: Cycle 1 Day 1 (0.083, 0.25, 0.5, 0.75, 1.42, 2.92 and 4.08 hours post infusion)
measure: Part 2 and Part 3 (main study): Terminal elimination half-life (T1/2) of 68Ga-PSMA-11
timeFrame: Cycle 1 Day 1 (0.083, 0.25, 0.5, 0.75, 1.42, 2.92 and 4.08 hours post infusion)
measure: Part 2 and Part 3 (main study): Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) of 68Ga-PSMA-11
timeFrame: Cycle 1 Day 1 (0.083, 0.25, 0.5, 0.75, 1.42, 2.92 and 4.08 hours post infusion)
measure: Part 2 and Part 3 (main study): Total systemic clearance for intravenous administration (CL) of 68Ga-PSMA-11
timeFrame: Cycle 1 Day 1 (0.083, 0.25, 0.5, 0.75, 1.42, 2.92 and 4.08 hours post infusion)
measure: Part 2 and Part 3 (main study): volume of distribution during the terminal phase following intravenous elimination (Vz) of 68Ga-PSMA-11
timeFrame: Cycle 1 Day 1 (0.083, 0.25, 0.5, 0.75, 1.42, 2.92 and 4.08 hours post infusion)
measure: Part 2 and Part 3 (main part): Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of 177Lu-PSMA-617
timeFrame: Cycle 1 Day 1 (0, 0.33, 1, 2 and 4 hours post infusion), Cycle 1 Day 2 (24 hours post infusion), Cycle 1 Day 3 (48 hours post infusion), Cycle 1 Day 4 (72 hours post infusion), Cycle 1 Day 6 (120 hours post infusion)
measure: Part 2 and Part 3 (main part): Time of maximum observed drug concentration occurrence (Tmax) of 177Lu-PSMA-617
timeFrame: Cycle 1 Day 1 (0, 0.33, 1, 2 and 4 hours post infusion), Cycle 1 Day 2 (24 hours post infusion), Cycle 1 Day 3 (48 hours post infusion), Cycle 1 Day 4 (72 hours post infusion), Cycle 1 Day 6 (120 hours post infusion)
measure: Part 2 and Part 3 (main part): Observed maximum plasma concentration (Cmax) of 177Lu-PSMA-617
timeFrame: Cycle 1 Day 1 (0, 0.33, 1, 2 and 4 hours post infusion), Cycle 1 Day 2 (24 hours post infusion), Cycle 1 Day 3 (48 hours post infusion), Cycle 1 Day 4 (72 hours post infusion), Cycle 1 Day 6 (120 hours post infusion)
measure: Part 2 and Part 3 (main study): Area Under the plasma concentration-time Curve from the time 0 to the last observed quantifiable concentration (AUC(0-t)) of 177Lu-PSMA-617
timeFrame: Cycle 1 Day 1 (0, 0.33, 1, 2 and 4 hours post infusion), Cycle 1 Day 2 (24 hours post infusion), Cycle 1 Day 3 (48 hours post infusion), Cycle 1 Day 4 (72 hours post infusion), Cycle 1 Day 6 (120 hours post infusion)
measure: Part 2 and Part 3 (main study): AUC(0-t) divided by the dose administered (AUC(0- t)/D) of 177Lu-PSMA-617
timeFrame: Cycle 1 Day 1 (0, 0.33, 1, 2 and 4 hours post infusion), Cycle 1 Day 2 (24 hours post infusion), Cycle 1 Day 3 (48 hours post infusion), Cycle 1 Day 4 (72 hours post infusion), Cycle 1 Day 6 (120 hours post infusion)
measure: Part 2 and Part 3 (main study): Terminal elimination half-life (T^1/2) of 177Lu-PSMA-617
timeFrame: Cycle 1 Day 1 (0, 0.33, 1, 2 and 4 hours post infusion), Cycle 1 Day 2 (24 hours post infusion), Cycle 1 Day 3 (48 hours post infusion), Cycle 1 Day 4 (72 hours post infusion), Cycle 1 Day 6 (120 hours post infusion)
measure: Part 2 and Part 3 (main study): Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) of 177Lu-PSMA-617
timeFrame: Cycle 1 Day 1 (0, 0.33, 1, 2 and 4 hours post infusion), Cycle 1 Day 2 (24 hours post infusion), Cycle 1 Day 3 (48 hours post infusion), Cycle 1 Day 4 (72 hours post infusion), Cycle 1 Day 6 (120 hours post infusion)
measure: Part 2 and Part 3 (main study): Total systemic clearance for intravenous administration (CL) of 177Lu-PSMA-617
timeFrame: Cycle 1 Day 1 (0, 0.33, 1, 2 and 4 hours post infusion), Cycle 1 Day 2 (24 hours post infusion), Cycle 1 Day 3 (48 hours post infusion), Cycle 1 Day 4 (72 hours post infusion), Cycle 1 Day 6 (120 hours post infusion)
measure: Part 2 and Part 3 (main study): volume of distribution during the terminal phase following intravenous elimination (Vz) of 177Lu-PSMA-617
timeFrame: Cycle 1 Day 1 (0, 0.33, 1, 2 and 4 hours post infusion), Cycle 1 Day 2 (24 hours post infusion), Cycle 1 Day 3 (48 hours post infusion), Cycle 1 Day 4 (72 hours post infusion), Cycle 1 Day 6 (120 hours post infusion)
measure: Part 4 (expanded trial part): Overall Response Rate (ORR) based on local assessment
timeFrame: From date of the first administration of 177Lu-PSMA-617 until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 2 years
measure: Part 4 (expanded trial part): Radiographic Progression-Free-Survival (rPFS) based on local assessment
timeFrame: From date of the first administration of 177Lu-PSMA-617 until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 2 years
measure: Part 4 (expanded trial part): Progression Free Survival (PFS)
timeFrame: From the date of the first administration of 177Lu-PSMA-617 until the date of progression or date of death from any cause, whichever comes first, assessed up to 2 years
measure: Part 4 (expanded trial part): Overall Survival (OS)
timeFrame: From date of the first administration of 177Lu-PSMA-617 until date of death from any cause, assessed up to 2 years
Other outcomes:
Locations:
city: Kashiwa
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Fukushima city
country: Japan
facility: Novartis Investigative Site
state: Fukushima
city: Sapporo city
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Kobe
country: Japan
facility: Novartis Investigative Site
state: Hyogo
city: Kanazawa
country: Japan
facility: Novartis Investigative Site
state: Ishikawa
city: Yokohama-city
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Chiba
country: Japan
facility: Novartis Investigative Site
city: Kyoto
country: Japan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: