ALT-100 Monoclonal Antibody (mAb) in Bone-Predominant Metastatic Androgen Pathway Modulation Resistant (APMR) Prostate Cancer -- The ALTAR-100 Trial

Inclusion Criteria:

• Male, age ≥ 18 years

• Prostate cancer, histologically confirmed or presumed on the basis of clinical, biochemical, and/or radiographic findings.

• Metastatic disease confined to bone and lymph nodes, with bone metastases predominant, documented on conventional imaging (CT/MRI and bone scan). Measurable soft tissue disease is not required.

• Androgen pathway modulation-resistant (APMR) disease per Prostate Cancer Working Group 4 (PCWG4) with progression on at least one prior androgen receptor pathway inhibitor documented as any of the following:

  1. Serum PSA progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week prior. The minimal start value is 2.0 ng/mL,
  2. Soft tissue progression defined as an increase ≥20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or more new lesions or unequivocal progression of existing non-target lesions,
  3. For PSMA-PET: Two new PSMA-avid lesions, or
  4. Progression of bone disease defined by the appearance of ≥2 new bone lesions on bone scan per PCWG4 criteria

• Ongoing androgen deprivation therapy (ADT) with a Gonadotropin-releasing hormone analogue, or prior bilateral orchiectomy, with serum testosterone <50 ng/dL

• ECOG performance status 0-2

• Life expectancy ≥6 months

• Adequate organ and marrow function defined as:

  1. ANC ≥1,500/µL
  2. Platelets ≥100,00/µL
  3. Hemoglobin ≥9.0 g/dL without transfusion within 14 days
  4. Total bilirubin ≤1.5 x ULN (≤ 3 x ULN for Gilbert's)
  5. AST and ALT ≤3 x ULN
  6. Creatinine clearance ≥30 mL/min

• Concurrent bone-modifying agent (including, but not limited to denosumab or bisphosphonates such as zoledronic acid or pamidronate), permitted but not required. If receiving one, it must have been at a stable dose and scheduled for ≥8 weeks before C1D1.

• Written informed consent obtained from the subject and the subject agrees to comply with all the study-related procedures.

• Subjects with partners of child-bearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 6 months following the last dose of study drug.

Exclusion Criteria:

• Visceral metastases, including liver, lung, adrenal, brain or peritoneal disease. Lymph node involvement is permitted
• Known pure small cell or neuroendocrine prostate carcinoma
• Radium-223 within 6 months of C1D1
• External beam radiotherapy to a bone lesion within 4 weeks of C1D1 or radiotherapy planned during the DLT window of 30 days after first dose of ALT-100.
• Impending skeletal-related event requiring immediate radiotherapy or surgical intervention or untreated spinal cord compression
• Chemotherapy, investigational therapy, or any systemic anticancer therapy other than ADT within 4 weeks or 5 half-lives of C1D1, whichever is shorter
• Prior exposure to any extracellular nicotinamide phosphoribosyltransferase (eNAMPT)-directed or toll-like receptor 4 (TLR4)-directed therapeutic agent.
• Known hypersensitivity to a monoclonal antibody, or prior grade ≥3 infusion-related reaction to a biologic
• Active infection requiring systemic therapy at C1D1
• Known HIV infection, or known active hepatitis B or hepatitis C, that is uncontrolled or requires a change in therapy. Testing is not required at screening
• Cardiovascular or thromboembolic disease that, in the investigator's judgment, is uncontrolled or would place the patient at undue risk on study
• Chronic systemic immunosuppressive therapy at doses that in the investigator's judgement would place the patient at undue infection risk
• Active osteonecrosis of the jaw, or invasive dental procedure planned during the DLT window of 30 days after first dose of ALT-100
• Another malignancy requiring active treatment, except non-melanoma skin cancer or adequately treated in situ disease
• Any condition that in the investigator's judgement would compromise safety or protocol compliance
• Administration of a vaccine containing live virus within 30 days prior to the first dose of trial treatment. Note: Most flu vaccines are killed viruses, with the exception of the intra-nasal vainer (Flu-Mist) which is an attenuated live virus and therefore prohibited for 30 days prior to first dose.
• Prisoners or subjects who are involuntarily incarcerated, or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.