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

• ClinicalTrials.gov Identifier: NCT03837353
• Recruitment Status: Recruiting
• First Posted: February 12, 2019
• Last Update Posted: April 2, 2020
• Sponsor: NYU Langone Health
• Collaborator: Leap Therapeutics, Inc.
• Information provided by (Responsible Party): NYU Langone Health

Tracking Information

• First Submitted Date: January 22, 2019
• First Posted Date: February 12, 2019
• Last Update Posted Date: April 2, 2020
• Actual Study Start Date: April 1, 2019
• Estimated Primary Completion Date: March 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 8, 2019)

• Measure of Dose Limiting Toxicities [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Prostate Cancer

Intervention

• 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)

Study Arms

• 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).

  Interventions:

  • Drug: DKN-01 300 mg
  • Drug: DKN-01 600 mg
  • Drug: Docetaxel 75 mg/m2
  • Drug: DKN-01 150 mg
• 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)
  Interventions:

  • Drug: DKN-01 300 mg
  • Drug: DKN-01 600 mg
  • Drug: Docetaxel 75 mg/m2
  • Drug: DKN-01 150 mg
• 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)
  Interventions:

  • Drug: DKN-01 300 mg
  • Drug: DKN-01 600 mg
  • Drug: Docetaxel 75 mg/m2
  • Drug: DKN-01 150 mg
• 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.

  Interventions:

  • Drug: DKN-01 300 mg
  • Drug: DKN-01 600 mg
  • Drug: DKN-01 150 mg
• Experimental: Cohort 2B
  Cohort 2B: DKN-01 at MTD or highest dose tested: Days 1 and 15 (28-day cycles)
  Interventions:

  • Drug: DKN-01 300 mg
  • Drug: DKN-01 600 mg
  • Drug: DKN-01 150 mg

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 8, 2019): 97
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 2021
• Estimated Primary Completion Date: March 2021 (Final data collection date for primary outcome measure)

Eligibility 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.
• 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 guidelines.

• 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 (per PCWG3).

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

  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 (per PCWG3).
  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 cells/μl).
  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 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.

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.
• 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 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 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 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:

  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 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.

Sex/Gender

• Sexes Eligible for Study: Male
• Gender Based Eligibility: Yes

• Ages: 18 Years to 100 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Casey Konys; (212)-263-1208; casey.konys@nyumc.org

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03837353
• Other Study ID Numbers: 17-01747
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.
• Access Criteria: The investigator who proposed to use the data.

• Responsible Party: NYU Langone Health
• Study Sponsor: NYU Langone Health
• Collaborators: Leap Therapeutics, Inc.

Investigators

• Principal Investigator: David Wise, MD; New York Langone Medical Center

• PRS Account: NYU Langone Health
• Verification Date: April 2020