A Phase II Study of AAA617 Alone and AAA617 in Combination With ARPI in Patients With PSMA PET Scan Positive CRPC

• Status: Not yet recruiting
• Trial end date: 2028-11-10
• Target enrollment: 0
• Participant gender: Male

Summary

The purpose of this study is to evaluate the efficacy and safety of AAA617 alone (Lutetium [177Lu] vipivotide tetraxetan) and in combination with an Androgen Receptor Pathway Inhibitors (ARPI) in participants with PSMA-positive, castration-resistant prostate cancer and no evidence of metastasis in conventional imaging (CI) (i.e., CT/MRI and bone scans). Approximately 120 participants will be randomized.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Novartis Pharmaceuticals
• Treatments: 177Lu-PSMA-617; Gallium 68 PSMA-11

Criteria

Inclusion Criteria:

articipants eligible for inclusion in this study must meet all of the following criteria:

1. Signed informed consent must be obtained prior to participation in the study

2. Participants must be adults ≥18 years of age at the time of informed consent

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening

4. Participants must have a life expectancy ≥12 months as determined by the Investigator

5. Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, signet cell, or small cell features prior to randomization

6. CRPC demonstrated during continuous androgen deprivation therapy (ADT)/post orchiectomy, defined as 3 consecutive rises of PSA, at least 1 week apart, resulting in two ≥ 50% increases over the nadir

7. Participants must have ongoing androgen deprivation therapy with a GnRH agonist/antagonist or prior bilateral orchiectomy at the time of randomization

8. Castrate level of serum testosterone (< 1.7 nmol/l [50 ng/dL]) on GnRH agonist or antagonist therapy or after bilateral orchiectomy prior to randomization

9. PSADT of ≤ 10 months (PSADT will be calculated using a linear regression model of the normal logarithm of PSA and time (Pound et al 1999)

10. The most recent local PSA and the screening PSA should be ≥ 2 μg/L (2 ng/mL). In the event of prior first-generation anti-androgen (e.g., bicalutamide, flutamide, nilutamide) use, the most recent local PSA and the central PSA assessed at screening must be obtained at least 4 weeks after the last dose of the androgen receptor inhibitor

11. Participants must have evidence of PSMA-positive disease as seen on a AAA517 or piflufolastat F 18 PET/CT scan at baseline as determined by BICR (refer to Section 8.5.2 for details) and must have a negative conventional imaging for M1 disease.

12. Participants must have adequate organ function including the following laboratory values at the screening visit:

Bone marrow reserve

• Absolute neutrophil count (ANC) ≥1.5 x 109/L

• Platelets ≥100 x 109/L

• Hemoglobin ≥9 g/dL Hepatic

• Total bilirubin ≤2 x the institutional upper limit of normal (ULN). For participants with known Gilbert's Syndrome ≤3 x ULN is permitted

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 x ULN.

• Albumin ≥2.5 g/dL Renal

• eGFR ≥ 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation

13. Human immunodeficiency virus -infected participants who are healthy and have a low risk of acquired immune deficiency syndrome -related outcomes can participate in this trial

Exclusion Criteria:

Participants meeting any of the following criteria are not eligible for inclusion in this study.

1. Prior or present evidence of metastatic disease as assessed locally by CT/MRI for soft tissue disease and whole-body radionuclide bone scan for bone disease where only radionuclide bone scan reading will be used for assessment of inclusion/exclusion. Exception: Participants with soft tissue pelvic disease may be eligible (e.g., lymph nodes below bifurcation of common iliac arteries (N1) is permissible if the short axis of the largest lymph node is <20 mm). Participants with M1 disease on PSMA PET scans are also allowed to participate.

2. Unmanageable concurrent bladder outflow obstruction or urinary incontinence. Note:

participants with bladder outflow obstruction or urinary incontinence, which is manageable with best available standard of care (incl. pads, drainage) are allowed

3. Participants who could benefit from local therapy (e.g., surgery or radiation) to the prostate or pelvis. Such participants could be enrolled after completing local therapy if their PSA levels continue to rise and meet trial entry criteria.

4. Prior therapy with

• Second generation anti-androgens (e.g., enzalutamide, apalutamide and darolutamide)

• CYP17 inhibitors (e.g., abiraterone acetate, orteronel, galeterone, ketoconazole). Short duration ketoconazole treatment (<28 days) is permitted.

• 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 > 2 years before randomization

• Any other investigational agents for CRPC

5. Use of estrogens, 5-α reductase inhibitors (finasteride, dutasteride), other steroidogenesis inhibitors (aminoglutethamide) or first-generation anti-androgens (bicalutamide, flutamide, nilutamide, cyproterone) within 28 days before randomization

6. Initiation of treatment with bisphosphonate or denosumab within 12 weeks before randomization. Note: Participants receiving bone loss prevention treatment on a stable dose (e.g. bisphosphonate or denosumab) for at least 28 days before randomization can continue the treatment during the study

7. Herbal and non-herbal products that may decrease PSA levels (i.e., saw palmetto, pomegranate juice) within 28 days before randomization

8. Systemic (oral/IV/IM) corticosteroids within 28 days before randomization. Note: Short term use (≤ 4 weeks) of corticosteroids during the study is allowed if clinically indicated

9. Radiation therapy (external beam radiation therapy [EBRT] and brachytherapy) within 28 days before randomization

10. Other concurrent cytotoxicity chemotherapy, immunotherapy, radioligand therapy, PARP inhibitor, biological therapy or investigational therapy at the time of randomization

11. Use of other investigational drugs within 28 days prior to day of randomization

12. Known hypersensitivity or contraindication to any of the study treatments or its excipients or to drugs of similar chemical classes, or to PSMA-targeted PET imaging agents

13. Transfusion during the screening period for the sole purpose of making a subject eligible for study inclusion

14. Diagnosed 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 free for more than 3 years are eligible, as are participants with adequately treated non-melanoma skin cancer, superficial bladder cancer

15. Concurrent serious (as determined by the Investigator) medical conditions, including, but not limited to, uncontrolled infection, known active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the Investigator would impair study participation or cooperation. Participants with an active documented COVID-19 infection (any grade of disease severity) at time of informed consent may be included only when completely recovered (in accordance with local guidance)

16. History of seizure or condition that may pre-dispose to seizure (e.g., prior cortical stroke or transient ischemic attack within 1 year prior to randomization, brain arteriovenous malformation, schwannoma, meningioma, or other benign Central Nervous System or meningeal disease which may require treatment with surgery or radiation therapy)

17. 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 atrio-ventricularblock without a pacemaker

• History of familial long QT syndrome or known family history of Torsades de Pointe

• Resting heart rate (physical exam or 12 lead ECG) <60 bpm

18. History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study

19. Any condition that precludes raised arms position

20. Sexually active males unwilling to use a condom during intercourse for the period specified in Section 8.4.6

21. Participants not able to understand and to comply with study instructions and requirements