Resumen

El propósito de este estudio es evaluar la eficacia y seguridad de lutecio (177Lu) vipivotide tetraxetan (AAA617) en participantes con cáncer de próstata oligometastásico (OMPC) que progresan después del tratamiento definitivo del tumor primario. Los datos generados por este estudio aportarán evidencia para el tratamiento con AAA617 en pacientes con cáncer de próstata en estadio temprano, con el fin de controlar la progresión del tumor recidivante hacia una enfermedad metastásica fatal, preservando la calidad de vida mediante el retraso del tratamiento con terapia de privación de andrógenos (TPA).

Descripción detallada

Todos los participantes serán evaluados para determinar su elegibilidad y se someterán a evaluaciones basales de la enfermedad, incluyendo una tomografía por emisión de positrones/tomografía computarizada (PET/TC) obligatoria con galio (68Ga) gozetotida (también conocido como \[68Ga\]Ga-PSMA-11) o piflufolastat (18F) (también conocido como \[18F\]DCFPyL), así como imágenes convencionales (IC, es decir, TC/RM y gammagrafía ósea). La PET/TC con piflufolastat (18F) se realizará en los países donde esté aprobada. La radioterapia estereotáctica corporal (SBRT, por sus siglas en inglés) se administrará a todas las lesiones metastásicas del cáncer de próstata (CP) después de la aleatorización y antes del inicio del tratamiento con AAA617 o de la observación. * La duración de los procedimientos de SBRT es de aproximadamente 3 semanas. * Para los participantes aleatorizados al brazo de investigación (AAA617), la duración del tratamiento será de hasta 4 ciclos de AAA617. Para los participantes aleatorizados al brazo de control (observación), la duración del tratamiento finalizará en la última fracción de la administración de SBRT. * La frecuencia de visitas será en la semana 1 y la semana 3 de cada uno de los 4 ciclos, y luego cada 16 semanas (para ambos brazos) hasta el primer evento de progresión de la enfermedad (RECIST 1.1). * La duración del estudio es de aproximadamente 6,5 años.

Elegibilidad

Edad mínima: 18 YearsEdad máxima: 100 YearsSexo: MALE

Criterios de inclusión

Histologically confirmed prostate cancer prior to randomization
Participants must have biochemically recurrent disease after definitive treatment to prostate by Radical Prostatectomy ((RP), (alone or with post-operative radiation to prostate bed/pelvic nodes)) or External beam Radiation Therapy (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 Radiation Therapy (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 definition of PSMA PET positivity, please refer to Section 8.1 and the 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/CT scan and one reader for CI: Reader will be blinded to PSMA PET scan results while reading CI scans. Reader 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 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 is 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

Criterios de exclusión

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:
ADT (including bilateral orchiectomy) and ARPIs used for metastatic prostate cancer treatment
Participants who received AR-directed therapy, whether ADT or an ARPI 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., Castration-Resistant Prostate Cancer (CRPC) participants)
Other hormonal therapy. e.g.,
•Use of estrogens, 5-α reductase inhibitors (finasteride, dutasteride), other steroidogenesis inhibitors (aminoglutethimide) 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 ≥3 months before randomization.
Radiopharmaceutical agents (e.g., Strontium-89, PSMA-targeted radioligand therapy)
Immunotherapy (e.g., sipuleucel-T)
Chemotherapy, except if administered in the adjuvant/neoadjuvant setting completed \> 12 months before randomization
Any other investigational or systemic agents for metastatic disease
Radiation therapy external beam 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), Poly Adenosine Diphosphate-Ribose Polymerase (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 Atrioventricular (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.
Other protocol defined Inclusion/Exclusion may apply.

Resumen

Descripción detallada

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

AAA617

Ubicaciones

Novartis Investigative Site

Novartis Investigative Site

Novartis Investigative Site

Patrocinadores

Contactos

Novartis Pharmaceuticals

Novartis Pharmaceuticals