Safety, Pharmacokinetics, and Preliminary Efficacy of VIR-5500 (AMX-500) in Prostate Cancer

Prior treatment

• Have a concomitant medical or inflammatory condition that may increase the risk of toxicity to VIR-5500 (AMX-500)
• Any prior treatment with a GnRH analogue or ARSI
• Any prior anticancer pharmacotherapy or surgery for metastatic prostate cancer
• Are progressing rapidly while taking a second-generation androgen-signaling inhibitor
• Currently receiving either strong or moderate inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study

Other illness

• Have acute or chronic infections
• Have had significant cardiovascular disease within the last 3 months

Other

• Have dominant histopathological features representative of sarcomatoid, spindle cell, or neuroendocrine small cell components
• Have known active CNS metastases and/or carcinomatous meningitis
• Have lesions in proximity of vital organs
  • Applicable to mHSPC cohorts only:
• Have a history or presence of clinically relevant CNS pathology within 12 months of enrollment
• Abnormal liver function test (LFT) values during screening

• Have metastatic disease, defined by ≥ 1 metastatic lesion that is present on baseline computed tomography (CT), magnetic resonance imaging (MRI), or bone scan imaging
• Have had prior bilateral orchiectomy and/or are receiving androgen deprivation therapy (ADT) and have a castrate level of serum testosterone (\< 50 ng/dL or \< 1.7 nmol/L)
• Have documented progressive mCRPC based on ≥ 1 of the following criteria (per PCWG3):
  • PSA level ≥ 1 ng/mL that has increased on ≥ 2 successive occasions ≥ 1 week apart
  • Nodal or visceral progression as defined by RECIST v1.1 with PCWG3 modifications
  • Appearance of ≥ 2 new lesions in bone scan
• Have been treated with ≥ 1 second-generation androgen-signaling inhibitor, including abiraterone, apalutamide, darolutamide, and/or enzalutamide
• Have been treated with ≥ 1 prior taxane regimens (example (e.g.), docetaxel, cabazitaxel) in either mHSPC or mCRPC setting
• Participants with known mutations in BRCA1/2 must have received a PARP inhibitor if an approved therapy is locally available, and participant is considered suitable for this therapy
• Are deemed unsuitable for standard of care (Only applicable for Part 1)
• Have metastatic disease, defined by ≥ 1 metastatic lesion that is present on baseline CT, MRI, or bone scan imaging
• Have documented progressive disease (PD) based on ≥ 1 of the following criteria (per PCWG3):
  • PSA level ≥ 1 ng/mL that has increased on ≥ 2 successive occasions ≥ 1 week apart
  • Nodal or visceral progression, as defined by RECIST v1.1 with PCWG3 modifications
  • Appearance of ≥ 2 new lesions in bone scan
• Have had prior bilateral orchiectomy and/or are receiving ADT and have a castrate level of serum testosterone (\< 50 ng/dL or \< 1.7 nmol/L)
• Have received PSMA-targeted radioligand-based therapy, such as 177Lu-PSMA-617 in any setting
• Have been treated with ≥ 1 second-generation androgen-signaling inhibitor, including abiraterone, apalutamide, darolutamide, and/or enzalutamide
• Have been treated with ≥ 1 prior taxane regimens (e.g., docetaxel, cabazitaxel) in either mHSPC or mCRPC setting
• Participants with known mutations in BRCA1/2 must have received a PARP inhibitor if an approved therapy is locally available, and participant is considered suitable for this therapy
• Prior treatment with ARSI (including but not limited to abiraterone, enzalutamide, darolutamide, or apalutamide). Participants without prior ARSI treatment in the mCRPC setting are also allowed
• No prior exposure to taxane-based chemotherapy or other cytotoxic agents, including antibody-drug conjugates (ADCs) administered specifically for the treatment of mCRPC
• Participants with known mutations in BRCA1/2 must have received a PARP inhibitor if an approved therapy is locally available, and participant is considered suitable for this therapy
• Have metastatic disease, defined by ≥ 1 metastatic lesion that is present on baseline CT, MRI, or bone scan imaging
• Have documented PD based on ≥ 1 of the following criteria (per PCWG3):
  • PSA level ≥ 1 ng/mL that has increased on ≥ 2 successive occasions ≥ 1 week apart
  • Nodal or visceral progression, as defined by RECIST v1.1 with PCWG3 modifications
  • Appearance of ≥ 2 new lesions in bone scan
• Have had prior bilateral orchiectomy and/or are receiving ADT and have a castrate level of serum testosterone (\< 50 ng/dL or \< 1.7 nmol/L)
• Histologically documented prostate adenocarcinoma which is de novo or recurrent and considered castration-sensitive
• Metastatic disease prior to first dose, with clear evidence of ≥ 1 bone lesion (defined as one lesion with positive uptake on bone scan) and/or ≥ 1 soft tissue lesion (measurable and/or non-measurable) that can be accurately assessed at baseline and is suitable for repeated assessment with CT and/or MRI. Participants with metastatic disease identified by PSMA-PET only, will not be eligible. Participants with disease limited to regional pelvic lymph nodes only are not eligible
• Participants should have high-risk OR high-volume disease per the following criteria:
  • High-risk is defined as presence of at least 2 of the following: Gleason score of greater than or equal to (≥) 8; presence of 3 or more lesions on bone scan; presence of measurable visceral (excluding lymph node disease) metastasis on CT or MRI
  • High-volume disease is defined as: Presence of visceral metastases OR 4 bone lesions, with ≥1 beyond the vertebral bodies and pelvis
• Participant is receiving ADT with a GnRH analogue or has undergone bilateral orchiectomy starting ≥ 14 days and \< 4 months prior to first dose with no radiographic evidence of disease progression or rising PSA levels prior to first day of dosing
• Have BRPC defined by meeting all of the following criteria:
  • Prostate cancer initially treated by radical prostatectomy or radiotherapy (including brachytherapy) or both, with curative intent
  • PSA doubling time ≤ 12 months at the time of study entry
  • Screening PSA ≥ 1 ng/mL in patients who have had radical prostatectomy (with or without radiotherapy) as primary treatment for prostate cancer and at least 2 ng/mL above the nadir in patients who had radiotherapy only as primary treatment for prostate cancer
  • Screening serum testosterone \> 150 ng/dL
• Participant is of Japanese descent and will be participating at a site in Japan
• Have metastatic disease, defined by ≥ 1 metastatic lesion that is present on baseline CT, MRI, or bone scan imaging
• Have had prior bilateral orchiectomy and/or are receiving an ADT and have a castrate level of serum testosterone (\< 50 ng/dL or \< 1.7 nmol/L)
• Have documented progressive mCRPC based on ≥ 1 of the following criteria (per PCWG3:
  • PSA level ≥ 1 ng/mL that has increased on ≥ 2 successive occasions ≥ 1 week apart
  • Nodal or visceral progression as defined by RECIST v1.1 with PCWG3 modifications
  • Appearance of ≥ 2 new lesions in bone scan
• Have been treated with ≥ 1 second-generation androgen-signaling inhibitor, including but not limited to abiraterone, apalutamide, darolutamide, and/or enzalutamide
• Have been treated with ≥ 1 prior taxane regimens (e.g., docetaxel, cabazitaxel) in either the mHSPC or mCRPC setting
• Prior treatment with PSMA-targeted radioligand therapy, immunotherapy, sipuleucel-T, PARP inhibitors, and radium-223 is allowed
• Participants with known mutations in BRCA1/2 must have received a PARP inhibitor if an approved therapy is locally available, and participant is considered suitable for this therapy
• Participant is of Chinese descent and will be participating at a site in China
• Have metastatic disease, defined by ≥ 1 metastatic lesion that is present on baseline CT, MRI, or bone scan imaging
• Have had prior bilateral orchiectomy and/or are receiving ADT and have a castrate level of serum testosterone (\< 50 ng/dL or \< 1.7 nmol/L)
• Have documented progressive mCRPC based on ≥ 1 of the following criteria (per PCWG3):
  • PSA level ≥ 1 ng/mL that has increased on ≥ 2 successive occasions ≥ 1 week apart
  • Nodal or visceral progression as defined by RECIST v1.1 with PCWG3 modifications
  • Appearance of ≥ 2 new lesions in bone scan
• Have been treated with ≥ 1 second-generation androgen-signaling inhibitor, including but not limited to abiraterone, apalutamide, darolutamide, and/or enzalutamide
• Have been treated with ≥ 1 prior taxane regimens (e.g., docetaxel, cabazitaxel) in either the mHSPC or mCRPC setting
• Prior treatment with PSMA-targeted radioligand therapy, immunotherapy, sipuleucel-T, PARP inhibitors, and radium-223 is allowed
• Participants with known mutations in BRCA1/2 must have received a PARP inhibitor if an approved therapy is locally available, and participant is considered suitable for this therapy