Clinical trial NCT06379217: NEPC Study: An Exploratory Safety and Efficacy Study With PSMA, SSTR2 and GRPR Targeted Radioligand Therapy in Metastatic Neuroendocrine Prostate Cancer.
Official title: A Phase I, Open-label, Multi-center Exploratory Safety and Efficacy Study With PSMA, SSTR2 and GRPR Targeted Radioligand Therapy in Metastatic Neuroendocrine Prostate Cancer.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Metastatic Neuroendocrine Prostate Cancer
Keywords: [68Ga]Ga-PSMA-11
[177Lu]Lu-PSMA-617
[68Ga]Ga-DOTA-TATE
[177Lu]Lu-DOTA-TATE
[68Ga]Ga-NeoB
[177Lu]Lu-NeoB
Neuroendocrine prostate cancer (NEPC)
Metastatic Neuroendocrine Prostate Cancer (mNEPC)
Radioligand Imaging (RLI)
Radioligand Therapy (RLT)
Prostate-specific membrane antigen (PSMA)
Somatostatin Receptor 2 (SSTR2)
Gastrin Releasing Peptide Receptor (GRPR)
Phase 1
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2024-04-23
Enrollment: 36
Sex: MALE
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be assigned to a treatment arm based on their predominantly expressed target per PET images (based on central read):

* \[177Lu\]Lu-PSMA-617 will be assigned to those with predominant PSMA expression
* \[177Lu\]Lu-DOTA-TATE will be assigned to those with predominant SSTR2 expression
* \[177Lu\]Lu-NeoB will be assigned to those with predominant GRPR expression
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the change in the expression of treatment targets on the surface of tumor cells (Prostate Specific Membrane Antigen (PSMA), Somatostatin Receptor 2 (SSTR2), and Gastrin Releasing Peptide Receptor (GRPR) between the start and after the completion of radioligand therapy (RLT). Study will use radioligand imaging (RLI) to determine predominantly expressed target on the surface of tumor cells. Based on predominant expression of target, corresponding RLT targeting PSMA, SSTR2, or GRPR RLT will be given for up to 6 cycles every 6 weeks as intravenous (i.v.) injection in participants with metastatic neuroendocrine prostate cancer (mNEPC).

Detailed description: The screening period for each subject includes imaging with 3 radioligand imaging (RLI) compounds to assess expression level of PSMA, SSTR2 and GRPR. Participants will be assigned to the radioligand treatment (RLT) corresponding to their predominantly expressed target based on blinded independent central review (BICR). During the treatment period, participants will receive up to 6 cycles of the assigned RLT, corresponding to a total dose of 44.4 GBq (+/-10%) for \[177Lu\]Lu-PSMA-617 or \[177Lu\]Lu-DOTA-TATE , and 55.5 GBq (+/-10%) for \[177Lu\]Lu-NeoB. No crossover to a different type of RLT is allowed.

At end of treatment (EoT) with RLT, participants will be scanned again with the 3 RLIs. All EoT PET/CT scans should be performed using the same PET/CT camera, acquisition and reconstruction protocols as used for screening PET/CT for the participant.

The post-treatment follow-up period consists of a 42-days post EoT safety follow-up visit and long-term follow-up until radiographic disease progression, death, lost to follow-up or withdrawal of consent, whichever occurs first.

The planned duration of treatment is up to 36 weeks for all treatment arms in this study, with treatment given every 6 weeks. Participants may be discontinued from treatment earlier due to unacceptable toxicity or disease progression, and/or at the discretion of the Investigator or the participant.

Eligibility criteria: Key Inclusion criteria:

* Participants must have metastatic prostate cancer with neuroendocrine differentiation as determined by at least one of the following:

  1. Histologically small cell or neuroendocrine cancer from a primary prostate or metastatic biopsy confirmed by local laboratory.
  2. Expression of NEPC markers (e.g., chromogranin or synaptophysin) in tumor tissue by IHC confirmed by local laboratory
  3. Progression of visceral metastases in the absence of PSA progression
  4. Serum chromogranin A \> 5x normal limit, or neuron-specific enolase \> 2x normal limit with control for proton-pump inhibitors (PPI) drugs among concomitant treatment
  5. Prostate adenocarcinoma with molecular features of neuroendocrine differentiated cancer (e.g., 2 of the following 3: PTEN, TP53, or RB loss)
* PSMA and/or SSTR2 and/or GRPR PET-positive participants, with at least one measurable lesion per RECIST 1.1 with moderate target expression in at least one of the 3 PET scans
* Castrate level of serum/plasma testosterone (\< 50 ng/dl, or \< 1.7 nmol/L) for participants with adenocarcinoma component or stable testosterone level for participants with pure neuroendocrine carcinoma
* Recovered to ≤ Grade 2 from all clinically significant toxicities related to prior therapy
* Participant has adequate bone marrow and organ function (as assessed by central laboratory for eligibility)
* ECOG status =\< 2

Key Exclusion criteria:

* Previous treatment with any of the following within 6 months prior to Screening: Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation
* Previous PSMA, SSTR2, or GRPR targeted radioligand therapy
* Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy or investigational therapy
* History of CNS metastases that are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic integrity
* Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression
* History or current diagnosis of ECG abnormalities indicating significant risk of safety for study participants

Other protocol-defined inclusion/exclusion criteria may apply.

Primary outcomes:
measure: Number/extent of lesions with at least a moderate uptake of any of the Radioligand Imaging (RLI)
timeFrame: Baseline (baseline imaging is performed during the 42 day screening period)
measure: Percentage changes in quantitative PET parameters.
timeFrame: End of Treatment (from date of baseline imaging scans to end of treatment scans, 7 weeks after last radioligand therapy infusion, approximately 36 weeks)
Secondary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: From date of assignment to one of the treatment arms until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 31 months
measure: Disease Control Rate (DCR)
timeFrame: From date of assignment to one of the treatment arms until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 31 months
measure: Duration of response (DOR)
timeFrame: 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 approximately 31 months
measure: Radiographic Progression-free Survival (rPFS)
timeFrame: From date of assignment to one of the treatment arms until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 31 months
measure: Proportion of participants with a decline in PSA level
timeFrame: Baseline, Cycle 1 Day 1 (each cycle is 42 days), Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, End Of Treatment, 6 weeks after End of Treatment
measure: Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) for Radioligand Therapy (RLT)
timeFrame: Up to 42 days after last dose administration (Safety Follow-up) and every 12 weeks until end of long term follow up (Long-term FU) for selected AEs and SAEs
measure: Dose modifications for [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-NeoB
timeFrame: Up to 42 days after last dose administration (Safety Follow-up)
measure: Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) for Radioligand Imaging (RLI)
timeFrame: Continuously from informed consent for the first 6 weeks and selected AEs and SAEs thereafter
measure: Blood radioactivity concentration of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE, [177Lu]Lu-NeoB)
timeFrame: Cycle 1 Day 1 (each cycle is 42 days) pre-dose, post-dose/end of infusion (EOI) and then 0.5 hrs, 2 hrs, 4 hrs, 6 hrs 24 hrs, 48 hrs, 168 hrs post EOI. Cycle 3 Day 1 EOI, 1 hr, 48 hrs post EOI. Cycle 5 Day 1 EOI, and then 1 hr, 48 hrs post EOI.
measure: Blood mass concentration of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE, [177Lu]Lu-NeoB)
timeFrame: Cycle 1 Day 1 (each cycle is 42 days) pre-dose, post-dose/end of infusion (EOI) and then 0.5 hrs, 2 hr, 4 hr, 6 hrs, 24 hrs, 48 hrs 168 hrs post EOI. Cycle 3 Day 1 EOI, 1 hr, 48 hrs post EOI. Cycle 5 Day 1 EOI, and then 1 hr, 48 hrs post EOI.
measure: Observed maximum blood concentrations (Cmax) of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-NeoB
timeFrame: Cycle 1 Day 1 (each cycle is 42 days) pre-dose, post-dose/end of infusion (EOI) and then 0.5 hrs , 2 hrs, 4 hrs, 6 hrs, 24 hrs, 48 hrs, 168 hrs post EOI. Cycle 3 Day 1 EOI, 1 hr, 48 hrs post EOI. Cycle 5 Day 1 EOI, and then 1 hr, 48 hrs post EOI.
measure: Time of maximum blood concentration (Tmax) occurence of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-NeoB
timeFrame: Cycle 1 Day 1 (each cycle is 42 days) pre-dose, post-dose/end of infusion (EOI) and then 0.5 hours (h), 2 hrs, 4 hrs, 6 hrs, 24 hrs, 48 hrs, 168 hrs post EOI. Cycle 3 Day 1 EOI, 1 hr, 48 hrs post EOI. Cycle 5 Day 1 EOI, and then 1 hr, 48 hrs post EOI.
measure: Area under the blood concentration time curve (AUC) of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-NeoB
timeFrame: Cycle 1 Day 1 (each cycle is 42 days) pre-dose, post-dose/end of infusion (EOI) and then 0.5 hrs , 2 hrs, 4 hrs, 6 hrs, 24 hrs, 48 hrs, 168 hrs post EOI. Cycle 3 Day 1 EOI, 1 hr, 48 hrs post EOI. Cycle 5 Day 1 EOI, and then 1 hr, 48 hrs post EOI.
measure: Total systemic clerance (CL) of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-NeoB
timeFrame: Cycle 1 Day 1 (each cycle is 42 days) pre-dose, post-dose/end of infusion (EOI) and then 0.5 hrs, 2 hrs, 4 hrs, 6 hrs, 24 hrs, 48 hrs, 168 hrs post EOI. Cycle 3 Day 1 EOI, 1 hr, 48 hrs post EOI. Cycle 5 Day 1 EOI, and then 1 hr, 48 hrs post EOI.
measure: Volume of distribution during the terminal phase (Vz) of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-NeoB
timeFrame: Cycle 1 Day 1 (each cycle is 42 days) pre-dose, post-dose/end of infusion (EOI) and then 0.5 hrs, 2 hrs, 4 hrs, 6 hrs, 24 hrs, 48 hrs, 168 hrs post EOI. Cycle 3 Day 1 EOI, 1 hr, 48 hrs post EOI. Cycle 5 Day 1 EOI, and then 1 hr, 48 hrs post EOI.
measure: Terminal half-life (T^1/2) of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-NeoB
timeFrame: Cycle 1 Day 1 (each cycle is 42 days) pre-dose, post-dose/end of infusion (EOI) and then 0.5 hrs, 2 hrs, 4 hrs, 6 hrs, 24 hrs, 48 hrs, 168 hrs post EOI. Cycle 3 Day 1 EOI, 1 hr, 48 hrs post EOI. Cycle 5 Day 1 EOI, and then 1 hr, 48 hrs post EOI.
measure: Absorbed radiation doses of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-NeoB
timeFrame: Cycle 1 Day 1 (each cycle is 42 days), Cycle 1 Day 2, Cycle 1 Day 3, Cycle 1 Day 8, Cycle 3 Day 1, Cycle 3 Day 3, Cycle 5 Day 1, Cycle 5 Day 3 (Cycle 3 Day 2, Cycle 3 Day 8, Cycle 5 Day 2 and Cycle 5 Day 8 where required by local authorities)
measure: Time Activity Curves (TACs) of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-NeoB
timeFrame: Cycle 1 Day 1 (each cycle is 42 days), Cycle 1 Day 2, Cycle 1 Day 3, Cycle 1 Day 8, Cycle 3 Day 1, Cycle 3 Day 3, Cycle 5 Day 1, Cycle 5 Day 3 (Cycle 3 Day 2, Cycle 3 Day 8, Cycle 5 Day 2 and Cycle 5 Day 8 where required by local authorities)
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Omaha
country: United States
facility: Nebraska Cancer Specialists
state: Nebraska
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Ctr
state: New York
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Lille
country: France
facility: Novartis Investigative Site
city: Nantes
country: France
facility: Novartis Investigative Site
city: Meldola
country: Italy
facility: Novartis Investigative Site
state: FC
city: Reggio Emilia
country: Italy
facility: Novartis Investigative Site
state: RE
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Sutton
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: