This is a non-randomized multi-center Phase 1b/2a dose escalation and dose expansion study
involving 85-97 patients testing DKN-01 as monotherapy or in combination with docetaxel in
metastatic castration-resistant prostate cancer. Patients need to be biomarker positive
(Dickkopf-1 [DKK1]) either in plasma or biopsy. Other biopsies for correlative studies are
encouraged but not mandatory. Pharmacokinetic (PK) testing of one pre-treatment blood sample
and one post-treatment blood sample will be mandatory on Day 1 of every cycle.
- Have a histologically or cytologically confirmed prostate adenocarcinoma or poorly
differentiated carcinoma of the prostate
- 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, and 1C. Patients must have received 1 or more androgen receptor (AR)
signaling inhibitors (abiraterone or enzalutamide) 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.
- Cohorts 2A and 2B. Patients must have received 1 or more AR signaling inhibitor
(abiraterone or enzalutamide) and either had disease progression, were intolerant of,
or refused 1 or more taxane-based chemotherapies for mCRPC.
- Patients must be DKK1-high as determined by either:
1. Elevated DKK1 RNA expression in ≥1% of cells as defined by central laboratory
testing of a fresh biopsy or archival specimen OR
2. DKK1 protein level in peripheral blood plasma that is above the reference limit
of a cohort of healthy male controls as established by central laboratory testing
- Cohort 1B. Patients must have progression of measurable disease per mRECIST v1.1
- Cohort 1C. Patients must have progression of disease defined as one of the following:
1. 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 2 ng/mL.
2. Radionuclide bone progression as defined by at least two new metastatic lesions
- Cohorts 1A, 2A, 2B. Patients must have baseline progression defined as one of the
1. 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.
2. Radionuclide bone progression as defined by at least two new metastatic lesions
3. 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 mRECIST 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.
- Disease-free of active second/secondary or prior malignancies for ≥2 years with the
exception of currently treated basal cell, squamous cell carcinoma of the skin, or
carcinoma in-situ of the cervix or breast.
- Required initial laboratory values within 14 days of C1D1:
1. Total bilirubin within normal limits for the institution. (For Cohorts 2A and 2B,
total bilirubin < 3 × ULN is acceptable with known liver metastases).
2. Transaminases [aspartate aminotransferase (AST) and alanine aminotransferase
(ALT)] ≤1.5 × the upper limit of normal (ULN) OR alkaline phosphatase ≤2.5 × ULN
(For Cohorts 2A and 2B, AST and ALT and alkaline phosphatase ≤ 5.0 × ULN is
acceptable with known liver metastases).
3. Creatinine ≤2.0 or calculated creatinine clearance ≥50 mL/min using the Cockcroft
and Gault Method (Cockroft and Gault 1976).
4. Absolute neutrophil count ≥1000 cells/μl.
5. Absolute lymphocyte count ≥500/μl.
6. Hemoglobin ≥9.0 g/dL.
7. Platelet count ≥100,000 cells/μl. (For Cohorts 2A and 2B, Platelet count ≥75,000
8. International normalized ratio (INR) (prothrombin time [PT])/ partial
thromboplastin time (PTT) ≤1.2 × 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
- 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.
- Any anti-cancer therapy (with the exception of luteinizing hormonereleasing 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
- Histological small cell or pure neuroendocrine carcinoma that has not yet been treated
with at least one line of platinum-based chemotherapy (Prostate adenocarcinoma with
immunohistochemical neuroendocrine differentiation but without histological small cell
that is naïve to platinumbased chemotherapy will be allowed.)
- 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.
- 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
- 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 procedures within 1 week of study entry).
- History of osteonecrosis of the hip. Other hip pathology such as degenerative disease
or malignant involvement are not exclusionary. Screening of asymptomatic patients is
- 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:
1. Evaluable disease outside the CNS.
2. No history of intracranial or intraspinal hemorrhage.
3. No evidence of significant vasogenic edema.
4. No ongoing requirement for corticosteroids as therapy for CNS disease.
(Anti-convulsants at a stable dose for > one month is allowed.)
5. No stereotactic radiation, whole brain radiation within 4 weeks of C1D1.
6. Patients with CNS metastases treated by neurosurgical resection or brain biopsy
within 3 month prior to C1D1 will not be allowed.
7. Radiographic demonstration of interim stability (ie, no progression) between
completion of CNS-directed therapy and the screening radiographic study.
8. 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
- 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.
- Previously treated with an anti-DKK1 therapy.