Phase III Study of Lutetium (177Lu) Vipivotide Tetraxetan in PSMA-Positive Oligometastatic Prostate Cancer in Adult Males
- Trial ID
- 2022-502956-29-00
- Protocol
- CAAA617D12302
- Sponsor
- Novartis Pharma AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **metastasis-free survival (MFS)** as assessed by a Blinded Independent Review Committee (BIRC) using conventional imaging in adult participants with oligometastatic prostate cancer (OMPC) identified by prostate-specific membrane antigen (PSMA) Positron Emission Tomography (PET). Participants will receive lutetium (177Lu) vipivotide tetraxetan (AAA617) compared to observation. This objective is clinically relevant as it aims to determine the efficacy of AAA617 in delaying disease progression, which is crucial for improving patient outcomes in OMPC.
Secondary objectives include: - Evaluating the time to hormonal therapy (TTHT) for castration in participants receiving AAA617 versus observation. - Assessing investigator-assessed MFS by conventional imaging. - Evaluating the effect of AAA617 on time to prostate-specific antigen (PSA) progression. - Assessing the time to radiographic progression-free survival (rPFS) by BIRC and investigator. - Evaluating the time to next therapy (local or systemic). - Assessing the effect on 24-month PSA progression-free survival (PFS) (≥ 0.5 ng/mL). - Evaluating the impact on time to symptomatic progression. - Assessing the effect on Patient Reported Outcomes, including Functional Assessment of Cancer Therapy Prostate (FACT-P), Brief Pain Inventory - Short Form (BPI-SF), Functional Assessment of Cancer Therapy-Radionuclide Therapy (FACT-RNT), and European Quality of Life (EuroQoL) 5 Domain 5 Level scale (EQ-5D-5L). - Evaluating the time to symptomatic skeletal event (SSE). - Assessing the safety and tolerability of AAA617 using Common Terminology Criteria for Adverse Events (CTCAE). - Evaluating the effect on overall survival (OS).
Participants
The clinical trial involves a total of **243 participants** diagnosed with **oligometastatic prostate cancer (OMPC)**. The study population is exclusively male, with participants falling within the adult age range categories of 18-64 and 65-84 years. Participants were selected based on specific inclusion criteria, including a histologically confirmed diagnosis of prostate cancer and biochemical recurrence after definitive treatment. The trial does not include a vulnerable population. Participants are required to have a non-castration testosterone level greater than 100 ng/dL at screening. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial focuses on evaluating metastasis-free survival using PSMA Positron Emission Tomography (PET) imaging, with participants receiving AAA617 or undergoing observation. The selection process ensures that all metastatic lesions detected at screening are amenable to stereotactic body radiation therapy (SBRT), and participants must have a negative conventional imaging for M1 disease at screening.
Plans and Procedures
The clinical trial is designed as an international, prospective, open-label, multi-center, randomized Phase III study. The primary objective is to evaluate the **metastasis-free survival** (MFS) in adult male patients with oligometastatic prostate cancer (OMPC) who are positive for prostate-specific membrane antigen (PSMA). The trial compares the administration of **lutetium (177Lu) vipivotide tetraxetan** against observation to delay castration or disease recurrence. The study is expected to commence recruitment on June 24, 2024, and conclude by June 3, 2030.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as histologically confirmed prostate cancer and the presence of PSMA-positive metastatic lesions. The trial will include follow-up visits to monitor the participants' response to treatment and assess any adverse events. The end-of-study visit will evaluate the overall outcomes and gather final data on the primary and secondary endpoints, including time to hormonal therapy, time to PSA progression, and overall survival.
The expected duration of participant involvement is up to 24 months, depending on individual response and progression. Conditions that may lead to early termination from the study include the development of unequivocal M1 lesions on conventional imaging, inability to comply with study procedures, or withdrawal of consent. The trial will ensure rigorous monitoring and assessment by a Blinded Independent Review Committee (BIRC) to maintain the integrity and reliability of the data collected.
Treatment
The clinical trial involves the administration of **PIFLUFOLASTAT (18F)**, a radiopharmaceutical solution for injection. This experimental medication is administered intravenously with a maximum daily dose of 370 MBq (megabecquerels) and a total dose not exceeding 370 MBq. The treatment period is limited to a single day. **PIFLUFOLASTAT (18F)** is a chemically derived active substance, and its administration is monitored to ensure compliance with the dosing schedule.
Another experimental treatment in the study is the **Locametz 25 micrograms kit for radiopharmaceutical preparation**, containing the active substance **GOZETOTIDE**. This solution for injection is also administered intravenously. The maximum daily dose is 259 MBq, with a total dose not exceeding 259 MBq, and the treatment period is restricted to one day. The active substance is chemically synthesized, and participant compliance is closely monitored throughout the trial.
The study also includes the administration of **Pluvicto 1 000 MBq/mL solution for injection/infusion**, which contains the active substance **LUTETIUM (177LU) VIPIVOTIDE TETRAXETAN**. This solution is administered intravenously, with a maximum daily dose of 7.4 GBq (gigabecquerels) and a total dose not exceeding 29.6 GBq. The treatment period extends up to 24 weeks. The active substance is a protein-derived compound, and adherence to the dosing schedule is ensured through rigorous monitoring.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial. The study focuses on evaluating the efficacy and safety of the experimental medications in delaying castration or disease recurrence in patients with oligometastatic prostate cancer.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of **metastasis-free survival (MFS)**, as determined by a Blinded Independent Review Committee (BIRC). MFS is defined as the time from randomization to the first evidence of radiographically detectable bone or soft tissue distant metastasis by conventional imaging, such as CT/MRI and bone scans, or death from any cause, whichever occurs first. This assessment will utilize the RECIST 1.1 criteria.
Secondary endpoints include several parameters: time to hormonal therapy (TTHT), investigator-assessed MFS, time to PSA progression, radiographic progression-free survival (rPFS), time to next therapy, 24-month PSA progression-free survival (PFS), time to symptomatic progression, health-related quality of life (HRQoL) as assessed by FACT-P, BPI-SF, FACT-RNT, and EQ-5D-5L, time to symptomatic skeletal events (TTSSE), and overall survival (OS). Safety and tolerability will also be evaluated by monitoring the incidence and severity of adverse events (AEs) and serious adverse events (SAEs), as well as changes in laboratory values, vital signs, and ECGs.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically confirmed prostate cancer prior to randomization
- Participants must have biochemically recurrent disease after definitive treatment to prostate by RP, (alone or with post-operative radiation to prostate bed/pelvic nodes) or EBRT, (prostate alone or prostate with seminal vesicle and/or pelvic nodes) and/or brachytherapy prior to randomization. Biochemical recurrence (BCR) is defined as: nadir PSA + 2 ng/mL post XRT (if participant received-radiation therapy to intact prostate) and PSA > 0.2 ng/mL and rising post RP (with or without post-operation RT)
- Participants must have OMPC with 1-5 PSMA-positive metastatic lesions on screening PSMA PET/CT scan (with either gallium (68Ga) gozetotide or piflufolastat (18F)) as visually assessed by BIRC . For the definition of PSMA PET positivity of a lesion, please refer to Section 8.1 and Imaging Manual. Metastatic lesions may include regional/pelvic lymph nodes (N1), distant lymph nodes (M1a), bone (M1b), lung and others visceral (M1c) except liver and brain classified using American Joint Committee on Cancer (AJCC) 8. When counting the number of oligometastatic lesions, each lesion is counted as distinct metastasis irrespective of its anatomical location (e.g., one pelvic and one extra-pelvic lymph node will be counted as two metastatic lesions)
- At least 1 PSMA-positive lesion must be a distant metastasis (M1) per AJCC8 classification at screening. For AJCC M staging, PSMA PET/CT information should be used
- Participants must have a negative CI for M1 disease at screening. Note: • For a participant not to be eligible, CI positive M1 lesions should be unequivocal in CI scans, i.e., potentially not attributable to findings thought to represent something other than tumor (e.g., degenerative, or post-traumatic changes or Paget’s disease in bone lesions). For CI assessments, bone lesions must be assessed by bone scan only and soft tissue lesions must be assessed by CT/MRI scans only at screening . • Prior knowledge of PSMA PET positivity should not influence the radiologist (reader) in determination of CI positivity. Two different readers will be involved, one reader for PSMA PET scan and one reader for CI: Reader will be blinded to PSMA PET scan results while reading CI scans. Readers should not modify their assessment of CI scans (e.g. changing a lesion previously identified as equivocal in CI to unequivocal) after reading the PSMA PET/CT scan. Similarly, biopsy positivity should not influence the reader in the assessment of CI positivity. More details on the reading paradigm will be provided in the imaging charter. • MRI for radiation treatment planning may show M1 disease but this will not exclude the participant from the study if the lesion is deemed negative per baseline CT or bone scans. • Participants with pelvic disease (N1) seen in CI are allowed if the local spread is below common iliac bifurcation (per AJCC 8 definition of local disease). • Distant lymph node disease (M1a) that is visible per CI and less than 10mm in the short axis are not exclusionary irrespective of PSMA PET positivity. • If a previously surgically removed lesion was unequivocal for M1 by bone scan or CT, the participant is not eligible
- All metastatic lesions detected at screening must be amenable to SBRT
- Non-castration testosterone level >100 ng/dL at screening
Exclusion Criteria
- Participants with de novo OMPC at screening
- Unmanageable concurrent bladder outflow obstruction or urinary incontinence at screening. Note: participants with bladder outflow obstruction or urinary incontinence, which is manageable and controlled with best available standard of care (incl. pads, drainage) are allowed
- Prior therapy with: a. ADT (including bilateral orchiectomy) and ARPIs used for metastatic prostate cancer treatment • Participants who received AR-directed therapy, whether ADT or an AARPI or both, as neoadjuvant or adjuvant therapy as a component of their primary therapy, are eligible provided that they discontinued therapy ≥ 12 months prior to randomization for ADT (i.e., 12 months after the last day of the last injection) or ≥3 months if ARPI was given as monotherapy. ARPI's as a term includes both contemporary androgen synthesis inhibitors (e.g., abiraterone, galeterone, and orteneronel), and receptor inhibitors (enzalutamide, apalutamide and darolutamide). • Patients who biochemically relapsed after primary therapy may also have had treatment with AR directed therapy and participants who had SBRT with ADT are also eligible provided that the ARPI +/- ADT or ADT alone was terminated ≥12 months prior to randomization for ADT (i.e., 12 months after the last day of the last injection) or ≥3 months if ARPI was given as monotherapy. • Participants who received first generation anti-androgens (bicalutamide, flutamide, nilutamide, cyproterone) for biochemical recurrence or adjuvant/neoadjuvant therapy are eligible provided that they discontinued therapy ≥3 months prior to randomization. • Participants who have discontinued ADT due to disease progression are not eligible (i.e., CRPC participants) b. Other hormonal therapy. e.g., • Use of estrogens, 5-α reductase inhibitors (finasteride, dutasteride), other steroidogenesis inhibitors (aminoglutethamide) if used in the context of prostate cancer treatment. Same medications are allowed if used for other indications: e.g., Benign Prostatic Hyperplasia (BPH), if stopped at least ≥3 months before randomization. c. Radiopharmaceutical agents (e.g., Strontium-89, PSMA-targeted radioligand therapy) d. Immunotherapy (e.g., sipuleucel-T) e. Chemotherapy, except if administered in the adjuvant/neoadjuvant setting completed > 12 months before randomization f. Any other investigational or systemic agents for metastatic disease
- Radiation therapy, EBRT, and brachytherapy within 28 days before randomization
- Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, hormonal therapy (see ADT initiation guidance in Section 6.8.2), PARP inhibitor, biological therapy, or investigational therapy
- Diagnosed at screening with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, participants with a prior history of malignancy that has been adequately treated and who have been disease/treatment free for more than 3 years are eligible, as are participants with adequately treated non-melanoma skin cancer and superficial bladder cancer
- History or current diagnosis of ECG abnormalities indicating significant risk of safety for participants participating in the study such as: • Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, and clinically significant second- or third-degree AV block without a pacemaker • History of familial long QT syndrome or known family history of Torsades de Pointe •
- Participants in immediate need of ADT as assessed by the investigator.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 24 Jun 2024 | 19 |
 Belgium | Recruiting | 24 Jun 2024 | 15 |
 Czechia | Recruiting | 24 Jun 2024 | 11 |
 France | Recruiting | 24 Jun 2024 | 50 |
 Germany | Recruiting | 24 Jun 2024 | 12 |
 Greece | Recruiting | 24 Jun 2024 | 4 |
 Hungary | Recruiting | 24 Jun 2024 | 5 |
 Italy | Recruiting | 24 Jun 2024 | 30 |
 The Netherlands | Recruiting | 24 Jun 2024 | — |
 Slovakia | Recruiting | 24 Jun 2024 | 14 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Locametz 25 micrograms kit for radiopharmaceutical preparation | Test | KIT FOR RADIOPHARMACEUTICAL PREPARATION | INTRAVENOUS USE | 259 | 1 | PRD10117083 |
PIFLUFOLASTAT18F | Test | — | INTRAVENOUS USE | 370 | 1 | SUB189818 |
PIFLUFOLASTAT18F | Test | — | INTRAVENOUS USE | 370 | 1 | SUB189818 |
Pluvicto 1 000 MBq/mL solution for injection/infusion | Test | SOLUTION FOR INJECTION/INFUSION | INTRAVENOUS USE | 7.4 | 24 | PRD10117050 |