Metastatic Castration-Resistant Prostate Cancer
Conditions
Keywords
Phase 1, RADIODOSE, AAA617, metastatic castration-resistant prostate cancer, radiation dosimetry, mCRPC, Prostate-specific membrane antigen (PSMA), Dosimetry, [68Ga]Ga-PSMA-11, gallium (68Ga) gozetotide, [177Lu]Lu-PSMA-617, lutetium (177Lu) vipivotide tetraxetan, Radioligand Imaging (RLI), Radioligand Therapy (RLT)
Brief summary
The purpose of the study is to assess and evaluate dosimetry, safety, and tolerability following administration of up to 12 cycles of (177Lu) vipivotide tetraxetan (also referred to as \[177Lu\]Lu-PSMA-617 or 177Lu-PSMA-617 and hereafter identified as AAA617) in taxane-naïve adult participants with PSMA-positive mCRPC who progressed on a prior ARPI treatment with normal renal function or mild renal impairment (eGFR ≥ 60ml/min).
Detailed description
The study includes screening period, treatment period, and a post-treatment follow-up period. Screening Period: Approximately 106 participants will be enrolled to receive up to12 consecutive cycles of AAA617. Potential participants will be assessed for eligibility by verifying their baseline PSMA PET scan for mandatory confirmation of PSMA positivity prior to first cycle by local review. Treatment Period: Eligible participants will be treated with up to 12 cycles of 7.4 GBq AAA617 intravenously every 6 weeks, until radiographic progression, toxicity leading to treatment discontinuation, death, loss to follow-up, or withdrawal of consent, whichever occurs first. During treatment period, all participants who complete the initial 6 cycles of AAA617 treatment will undergo an additional PSMA-PET scan after Cycle 6 to re-assess PSMA expression level and to reassess eligibility of participants to receive additional AAA617 treatment cycles. Post-Treatment Follow-Up: All participants will undergo a PSMA-PET scan at end of treatment (EOT). The post-treatment follow-up period will consist of EOT; 42-days safety; EOT RLI; safety, survival and rPFS follow-up visits. The planned duration of treatment period is up to 74 weeks 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.
Interventions
DRUGAAA617
\[177Lu\]Lu-PSMA-617 will be administered as an intravenous infusion at a dose of 7.4 GBq (200mCi) (+/- 10%), every 6 weeks for up to 12 cycles.
Anatomical Therapeutic Chemical \[ATC\] code L02AE
DRUGGonadotropin-releasing hormone (GnRH) antagonists
Degarelix, Relugolix
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants will be assigned to a treatment arm based on their PSMA expressed target per PET images (based on central read).
Eligibility
Sex/Gender
MALE
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion 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 ≤ 1. * Participants must have histological confirmation of adenocarcinoma of the prostate. * Participants must be PSMA-positive per 68Ga-PSMA PET/CT scans at baseline * Participants must have a castrate level of serum/plasma testosterone (\< 50 ng/dL or \< 1.7 nmol/L) either by pharmaceutical or surgical methods. * Participants must have progressed only once on prior second generation ARPIs * Documented progressive mCRPC * Participants must have ≥ 1 metastatic lesion by conventional imaging that is present on screening/baseline CT, MRI, or bone scan * Renal: eGFR ≥ 60 mL/min/1.73m2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. * Participants must have recovered to ≤ Grade 2 from all clinically significant toxicities related to prior therapies except alopecia. Key
Exclusion criteria
* Previous treatment with any of the following within 6 months of study enrollment: Strontium 89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation * Any previous radioligand therapy. * Prior treatment with cytotoxic chemotherapy for metastatic castration-resistant or metastatic hormone-sensitive prostate cancer (mHSPC) (e.g., taxanes, platinum, estramustine, vincristine, methotrexate, etc.), immunotherapy or biological therapy \[including monoclonal antibodies\]. \[Note: Taxane exposure (maximum 6 cycles) in the adjuvant or neoadjuvant setting is allowed if 12 months have elapsed since completion of this adjuvant or neoadjuvant therapy. Prior treatment with sipuleucel-T is allowed\]. * Concurrent therapies: cytotoxic chemotherapy, immunotherapy, radioligand therapy, PARP inhibitor, biological, or investigational therapy * History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to ICF signature and/or clinically active significant cardiac disease * Concurrent serious acute or chronic nephropathy and/or moderate to severe renal impairment as determined by the principal investigator. * Diagnosed with other active malignancies that are expected to alter life expectancy or may interfere with disease assessment * Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 14 weeks after stopping study treatment. * Concurrent urinary outflow obstruction or unmanageable urinary incontinence * History of somatic or psychiatric disease/condition that may interfere with the aims and assessments of the study. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time activity curves (TACs) and absorbed radiation dose of AAA617 in organs | From Cycle 1 to Cycle 12; cycle = 42 days | Time activity curve (TAC) will be generated from the amount radioactivity in one given tissue. Time integrated activity coefficient and absorbed dose will be calculated |
| Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) | For up to 12 cycles in taxane-naive participants with progressive PSMA-positive mCRPC with nrmal kidney function or mild renal impairment; cycle = 42 days | The distribution of adverse events for Radioligand Therapy (RLT) will be done via the analysis of frequencies for Adverse Event (AEs) and Serious Adverse Event (SAEs) through the monitoring of relevant clinical and laboratory safety parameters. Adverse event monitoring should be continued for at least 42 days following the end of treatment (EOT) visit. Participants receiving the study treatment will continue to be followed for safety every 12 weeks during the long-term follow-up for selected adverse events |
| Percentage of participants with AAA617 dose reductions, interruptions and discontinuations | Up to 42 (+7) days after last AAA617 dose administration (Safety Follow-up) | The assessment of tolerability will be based on the frequency of participants with dose interruptions, reductions, and study treatment discontinuations. Dose reduction will be based on the worst toxicity demonstrated at the last dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK parameter Tmax of AAA617 from blood radioactivity data | Cycle 1, Cycle 4, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11 and Cycle 12; cycle = 42 days | Derived PK parameter Tmax, will be listed by patient and visit. The descriptive summary statistics will be provided by visit. Tmax is the time to reach the maximum concentration. |
| PK parameter AUC of AAA617 from blood radioactivity data | Cycle 1, Cycle 4, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11 and Cycle 12; cycle = 42 days | Derived PK parameter AUC will be listed by patient and visit. The descriptive summary statistics will be provided by visit. AUC: Area under the concentration-time curve. |
| PK parameter CL of AAA617 from blood radioactivity data | Cycle 1, Cycle 4, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11 and Cycle 12; cycle = 42 days | Derived PK parameter CL will be listed by patient and visit. The descriptive summary statistics will be provided by visit. Clearance (CL): Rate at which the body eliminates the drug. |
| PK parameter VZ of AAA617 from blood radioactivity data | Cycle 1, Cycle 4, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11 and Cycle 12; cycle = 42 days | Derived PK parameter Vz will be listed by patient and visit. The descriptive summary statistics will be provided by visit. Vz: volume of distribution during the terminal phase (Vz). |
| PK parameter terminal T1/2 of AAA617 from blood radioactivity data | Cycle 1, Cycle 4, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11, and Cycle 12; cycle = 42 days | Derived PK parameter terminal T1/2 will be listed by patient and visit. The descriptive summary statistics will be provided by visit. T1/2: Terminal half life. |
| Overall response rate (ORR) | From first patient first visit (FPFV) to end of study, until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 58 months | ORR is defined as the proportion of participants with BOR of confirmed CR or PR per investigator assessment and according to Prostate Cancer Working Group 3 (PCWG3) modified-RECIST v1.1. |
| Time activity curves (TACs) and absorbed radiation dose AAA617 in tumors | For up to 12 cycles; cycle = 42 days | Time activity curves (TACs) will be generated from the amount of radioactivity in one given tissue at a given moment. TACs will be fitted to mono- and bi-exponential curves. Time integrated activity coefficient and absorbed dose will be calculated. |
| Duration of response (DOR) | From first patient first visit (FPFV) to end of study, until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 58 months | DOR is defined as the duration of time between the date of the first documented BOR (CR or PR) per investigator assessment according to PCWG3 modified-RECIST v1.1 and the date of first documented progression or death due to any cause. |
| Radiographic Progressive free survival (rPFS) | From first patient first visit (FPFV) to end of study, until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 58 months | rPFS defined as the time from the date of first dose of study treatment to the date of the first documented radiographic disease progression as assessed by investigator and PCWG3 modified-RECIST v1.1 criteria or death due to any cause, whichever occurs first. |
| Prostate specific antigen (PSA) response | Baseline, (Cycle (C), Day (D)) C1D1, C2D1, C3D1, C4D1, C5D1, C6D1, C6D42, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, End Of Treatment (EOT), 6 weeks after EOT, every 12 weeks after EOT up to 12 months; each cycle = 42 days | PSA response is defined as percentage of participants who achieve any decrease from baseline that is confirmed by a second PSA measurement ≥4 weeks. Participants with any decrease in PSA will also be summarized by visit. |
| Overall survival (OS) | Cycle 1 to death event, approx. 5 years, (cycle = 42 days) | Overall survival is defined as the time from the first dose of study treatment to death due to any cause. |
| Duration of exposure to AAA617 and dose intensity | during treatment period (74 weeks) | Duration of exposure: Dose intensity is computed as the ratio of actual cumulative dose received and actual duration of exposure. |
| Disease Control rate (DCR) | From first patient first visit (FPFV) to end of study, until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 58 months | DCR is defined as the percentage of CR, PR, stable disease or non-CR/non-progressive disease (PD) per investigator assessment and according to PCWG3 modified-RECIST v1.1 assessment in soft tissue, lymph node, and visceral lesions. |
| Pharmacokinetic ( PK) concentration of AAA617 in blood over time | Cycle 1, Cycle 4, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11 and Cycle 12, cycle = 42 days | PK concentrations will be listed by patient and visit/sampling time point. The descriptive summary statistics will be provided by visit/sampling time point. |
| Pharmacokinetic (PK) parameter Cmax of AAA617 from blood radioactivity data | Cycle 1, Cycle 4, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11 and Cycle 12; cycle = 42 days | Derived PK parameter, Cmax will be listed by patient and visit. The descriptive summary statistics will be provided by visit. Cmax is the maximum drug concentration after dosing. |
Countries
Germany, Netherlands, Spain, Switzerland, United Kingdom, United States
Contacts
Primary ContactNovartis Pharmaceuticals
Backup ContactNovartis Pharmaceuticals
Outcome results
None listed