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
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cohort 1A Cohort 1A Dose Level 1: DKN-01 300 mg intravenously (IV) on Days 1 and 15, docetaxel 75 mg/m2 on Day 1 every 3 weeks (21- day cycles). Dose Level 2: DKN-01 600 mg IV on Days 1 and 15, docetaxel 75 mg/m 2 on Day 1 every 3 weeks (21-day cycles). Dose Level -1: DKN-01 150 mg IV on Days 1 and 15, docetaxel 75 mg/m 2 on Day 1 every 3 weeks (21-day cycles). |
Drug: DKN-01 300 mg
DKN-01 300 mg intravenously (IV)
Drug: DKN-01 600 mg
DKN-01 600 mg IV
Drug: Docetaxel 75 mg/m2
Docetaxel 75 mg/m2, Day 1 of every 3 Weeks
Drug: DKN-01 150 mg
DKN-01 150 mg intravenously (IV)
|
| Experimental: Cohort 1B Cohort 1B: DKN-01 at MTD or highest dose tested: Days 1 and 15, docetaxel 75 mg/m2 Day 1 of every 3 weeks (21-day cycles) |
Drug: DKN-01 300 mg
DKN-01 300 mg intravenously (IV)
Drug: DKN-01 600 mg
DKN-01 600 mg IV
Drug: Docetaxel 75 mg/m2
Docetaxel 75 mg/m2, Day 1 of every 3 Weeks
Drug: DKN-01 150 mg
DKN-01 150 mg intravenously (IV)
|
| Experimental: Cohort 1C Cohort 1C: DKN-01 at MTD or highest dose tested: Days 1 and 15, docetaxel 75 mg/m2 Day 1 of every 3 weeks (21-day cycles) |
Drug: DKN-01 300 mg
DKN-01 300 mg intravenously (IV)
Drug: DKN-01 600 mg
DKN-01 600 mg IV
Drug: Docetaxel 75 mg/m2
Docetaxel 75 mg/m2, Day 1 of every 3 Weeks
Drug: DKN-01 150 mg
DKN-01 150 mg intravenously (IV)
|
| Experimental: Cohort 2A Dose Level 1: DKN-01 300 mg IV on Days 1 and 15 of a 28-day cycle. Dose Level 2: DKN-01 600 mg IV on Days 1 and 15 of a 28-day cycle. Dose Level -1: DKN-01 150 mg IV on Days 1 and 15 of a 28-day cycle. |
Drug: DKN-01 300 mg
DKN-01 300 mg intravenously (IV)
Drug: DKN-01 600 mg
DKN-01 600 mg IV
Drug: DKN-01 150 mg
DKN-01 150 mg intravenously (IV)
|
| Experimental: Cohort 2B Cohort 2B: DKN-01 at MTD or highest dose tested: Days 1 and 15 (28-day cycles) |
Drug: DKN-01 300 mg
DKN-01 300 mg intravenously (IV)
Drug: DKN-01 600 mg
DKN-01 600 mg IV
Drug: DKN-01 150 mg
DKN-01 150 mg intravenously (IV)
|
Outcome Measures
Primary Outcome Measures
- Measure of Dose Limiting Toxicities [baseline to End of Cycle 1 (each cycle is 28 days)]
Starting from Cohort 1 Day 1 to Cohort 2 Day 1
- Measure of Dose Limiting Tolerability [Baseline to End of Cycle 1 (each cycle is 28 days)]
Starting from Cohort 1 Day 1 to Cohort 2 Day 1
- Measure of clinical response to treatment [Baseline to study completion (approximately 36 Months)]
Repeat tumor imaging confirming PD (iCPD) by iRECIST per Investigator
- Number of subjects with adverse drug reactions and toxicities [Baseline until 30 days after last dose of study drug as assessments at a minimum of 2 weeks]
Evaluated by NCI CTCAE v 4.0 of DKN-01 monotherapy or in combination with docetaxel
Eligibility Criteria
Criteria
Inclusion Criteria:
-
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.
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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.
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Patients must be DKK1-high as determined by either:
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Elevated DKK1 RNA expression in ≥1% of cells as defined by central laboratory testing of a fresh biopsy or archival specimen OR
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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 guidelines.
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Cohort 1C. Patients must have progression of disease defined as one of the following:
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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.
-
Radionuclide bone progression as defined by at least two new metastatic lesions (per PCWG3).
- 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 mRECIST v1.1.
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Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
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Estimated life expectancy of at least 3 months, in the judgment of the Investigator.
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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.
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Required initial laboratory values within 14 days of C1D1:
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Total bilirubin within normal limits for the institution. (For Cohorts 2A and 2B, total bilirubin < 3 × ULN is acceptable with known liver metastases).
-
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).
-
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.
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Absolute lymphocyte count ≥500/μl.
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Hemoglobin ≥9.0 g/dL.
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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) ≤1.2 × 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.
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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.
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Reliable and willing to make themselves available for the duration of the study and are willing to follow study-specific procedures.
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Provided written informed consent prior to any study-specific procedures.
Exclusion Criteria:
-
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 treatment.
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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.
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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.)
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History of solid organ transplant (ie, heart, lungs, liver, or kidney).
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History of autologous/allogenic bone marrow transplant.
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Serious nonmalignant disease that could compromise protocol objectives in the opinion of the Investigator and/or Sponsor.
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Major surgical procedures or significant traumatic injury within 4 weeks prior to study entry (minor procedures within 1 week of study entry).
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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.
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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
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CNS metastases are eligible provided they meet all of the following criteria:
-
Evaluable disease outside the CNS.
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No history of intracranial or intraspinal hemorrhage.
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No evidence of significant vasogenic edema.
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No ongoing requirement for corticosteroids as therapy for CNS disease. (Anti-convulsants at a stable dose for > one month is allowed.)
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No stereotactic radiation, whole brain radiation within 4 weeks of C1D1.
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Patients with CNS metastases treated by neurosurgical resection or brain biopsy within 3 month prior to C1D1 will not be allowed.
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Radiographic demonstration of interim stability (ie, no progression) between completion of CNS-directed therapy and the screening radiographic study.
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Screening CNS radiographic study ≥4 weeks since completion of radiotherapy or surgical resection and ≥2 weeks since discontinuation of corticosteroids.
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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.
-
Previously treated with an anti-DKK1 therapy.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of California, San Francisco | San Francisco | California | United States | 94143 |
| 2 | Johns Hopkins University | Baltimore | Maryland | United States | 21218 |
| 3 | Washington University | Saint Louis | Missouri | United States | 63130 |
| 4 | Veterans Affairs New York Harbor Healthcare System | New York | New York | United States | 10010 |
| 5 | NYU Langone Health | New York | New York | United States | 10016 |
Sponsors and Collaborators
- NYU Langone Health
- Leap Therapeutics, Inc.
Investigators
- Principal Investigator: David Wise, MD, PhD, New York Langone Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 17-01747