A Parallel Arm Phase 1b/2a Study of DKN-01 as Monotherapy or in Combination With Docetaxel for the Treatment of Advanced Prostate Cancer With Elevated DKK1

• Age >18 years.

• Have a histologically or cytologically confirmed cancer of prostate origin (adenocarcinoma, poorly differentiated carcinoma, or neuroendocrine carcinoma are all allowed).

  • Patients with pure neuroendocrine carcinoma must have had at least one line of platinum-based chemotherapy unless the patient is intolerant of or is refusing chemotherapy.
  • Patients with pure neuroendocrine carcinoma do not need to have been previously treated with androgen receptor (AR) signaling inhibitors (abiraterone or enzalutamide or apalutamide or darolutamide) but must have castrate testosterone and have castration-resistant disease.
• Surgically or medically castrated, with testosterone levels of \< 50 ng/dL (\< 2.0 nM). If the patient is being treated with luteinizing hormone-releasing hormone (LHRH) agonists (patient who have not undergone orchiectomy), this therapy must have been initiated at least 4 weeks prior to C1D1 and must be continued throughout the study.
• Cohorts 1A, 1B: Patients must have progressed despite 1 or more androgen receptor (AR) signaling inhibitors (abiraterone or enzalutamide or apalutamide or darolutamide) and have not received prior taxane-based chemotherapy for prostate cancer. Prior treatment with an AR signaling inhibitor for castration-sensitive disease will be allowed if the time to progression was within 1 year after starting drug. Prior treatment with a taxane-based chemotherapy for castration-sensitive disease will be exclusionary. (Prior treatment with an AR signaling inhibitor is not required for pure prostate neuroendocrine carcinoma as in inclusion 2.)
• Cohorts 2A and 2B: Patients must have progressed despite 1 or more AR signaling inhibitor (abiraterone or enzalutamide or apalutamide or darolutamide) and either had disease progression, were intolerant of, or refused 1 or more taxane-based chemotherapies for mCRPC. (Prior treatment with an AR signaling inhibitor is not required for pure prostate neuroendocrine carcinoma as in inclusion 2.)

• Cohort 1B. Patients must have measurable disease per RECIST v1.1 guidelines AND must have either:

  • PSA progression is defined by Prostate Cancer Working Group 3 (PCWG3) criteria as a minimum of two consecutive rising levels, with an interval of ≥1 week between each determination with a minimum PSA of 1 ng/mL, if PSA is the sole evidence of progression, OR
  • Radionuclide bone progression as defined by at least two new metastatic lesions (per PCWG3), OR
  • Soft tissue progression on transaxial imaging: new or progressive soft tissue masses on computed tomography (CT) or magnetic resonance imaging (MRI) scans as defined by RECIST v1.1.

• Cohorts 1A, 2A, 2B. Patients must have baseline progression defined as one of the following:

  • PSA progression is defined by PCWG3 criteria as a minimum of two consecutive rising levels, with an interval of ≥1 week between each determination with a minimum PSA of 2 ng/mL.
  • Radionuclide bone progression as defined by at least two new metastatic lesions (per PCWG3).
  • Soft tissue progression on transaxial imaging: new or progressive soft tissue masses on computed tomography (CT) or magnetic resonance imaging (MRI) scans as defined by RECIST v1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
• Estimated life expectancy of at least 3 months, in the judgment of the Investigator.

• Required initial laboratory values within 14 days of C1D1:

  • Total bilirubin within normal limits for the institution. (For Cohorts 2A and 2B, total bilirubin \< 3 × ULN is acceptable with known liver metastases).
  • For Cohorts 1A, 1B transaminases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] ≤1.5 × the upper limit of normal (ULN). For Cohorts 2A and 2B, AST and ALT ≤ 5.0 × ULN is acceptable with known liver metastases.
  • Creatinine ≤2.0 or calculated creatinine clearance ≥50 mL/min using the Cockcroft and Gault Method (Cockroft and Gault 1976).
  • Absolute neutrophil count ≥1000 cells/µl.
  • Absolute lymphocyte count ≥500/µl.
  • Hemoglobin ≥8.5 g/dL.
  • Platelet count ≥100,000 cells/µl. (For Cohorts 2A and 2B, Platelet count ≥75,000 cells/µl).
  • International normalized ratio (INR) (prothrombin time [PT])/partial thromboplastin time (PTT) ≤1.5 × ULN unless receiving anticoagulant, in which case INR ≤3.0 and no active bleeding, (ie, no clinically significant bleeding within 14 days prior to first dose of study therapy.
• Sexually active male patients must agree to use adequate contraception (hormonal or barrier method of birth control) during the study and for 6 months after their last dose of study drug. Should a patient's partner become pregnant or suspect she is pregnant while participating in the study, the Investigator should be immediately informed.
• Reliable and willing to make themselves available for the duration of the study and are willing to follow study-specific procedures.
• Provided written informed consent prior to any study-specific procedures.
• Submission of a next-generation sequencing report from prostate cancer tissue or ctDNA from a CLIA certified lab if available. If no such report is available, a statement attesting to the lack of such a report is sufficient for eligibility.

Exclusion Criteria:

• Any anti-cancer therapy (with the exception of luteinizing hormone-releasing hormone [LHRH] analog or antagonist) within 2 weeks prior to initiation of study treatment.
• Any investigational anti-cancer therapy within 4 weeks of initiation of study treatment.
• New York Heart Association Class III or IV heart failure, or myocardial infarction within the past 6 months, or unstable arrhythmia within 3 months.
• Uncontrolled bacterial, viral, or fungal infections, within 7 days of study entry.
• History of malignancy other than prostate cancer within 2 years prior to screening, except for malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as non-melanoma skin carcinoma or ductal carcinoma in situ.
• Known to be human immunodeficiency virus (HIV) positive, have positive hepatitis B surface antigen (HBSAg), or positive hepatitis C antibody (HCAb) test. (Hepatitis C antibody-positive patients with an undetectable hepatitis C virus (HCV) RNA will be eligible.)
• History of solid organ transplant (ie, heart, lungs, liver, or kidney).
• History of autologous/allogenic bone marrow transplant.
• Serious nonmalignant disease that could compromise protocol objectives in the opinion of the Investigator and/or Sponsor.
• Major surgical procedures or significant traumatic injury within 4 weeks prior to study entry (minor surgical procedures within 1 week of study entry). Note: Diagnostic cystoscopy is not exclusionary at any time during screening. History of osteonecrosis of the hip. Other hip pathology such as degenerative disease or malignant involvement are not exclusionary. Screening of asymptomatic patients is not required.

• Active or untreated central nervous system (CNS) malignancy or metastasis. Screening for CNS metastases of asymptomatic patients without a history of CNS metastases is not required. Patients with treated CNS metastases are eligible provided they meet all of the following criteria:

  • Evaluable disease outside the CNS.
  • No history of intracranial or intraspinal hemorrhage.
  • No evidence of significant vasogenic edema.
  • No ongoing requirement for corticosteroids as therapy for CNS disease. (Anti-convulsants at a stable dose for > one month is allowed.)
  • No stereotactic radiation, whole brain radiation within 4 weeks of C1D1.
  • Patients with CNS metastases treated by neurosurgical resection or brain biopsy within 3 month prior to C1D1 will not be allowed.
  • Radiographic demonstration of interim stability (ie, no progression) between completion of CNS-directed therapy and the screening radiographic study.
  • Screening CNS radiographic study ≥4 weeks since completion of radiotherapy or surgical resection and ≥2 weeks since discontinuation of corticosteroids.
• Any other condition, disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications.
• Active substance abuse.
• Receipt of any live vaccine within 30 days before the first dose of study treatment or anticipation that such a live vaccine will be required during study participation.
• Previously treated with an anti-DKK1 therapy.