Clinical Trials /

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

NCT03837353

Description:

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.

Related Conditions:
  • Prostate Adenocarcinoma
  • Prostate Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: s17-01747
  • NCT ID: NCT03837353

Conditions

  • Prostate Cancer

Interventions

DrugSynonymsArms
DKN-01 300 mgCohort 1A
DKN-01 600 mgCohort 1A
Docetaxel 75 mg/m2Cohort 1A
DKN-01 150 mgCohort 1A

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Cohort 1AExperimentalCohort 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).
  • DKN-01 300 mg
  • DKN-01 600 mg
  • Docetaxel 75 mg/m2
  • DKN-01 150 mg
Cohort 1BExperimentalCohort 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)
  • DKN-01 300 mg
  • DKN-01 600 mg
  • Docetaxel 75 mg/m2
  • DKN-01 150 mg
Cohort 1CExperimentalCohort 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)
  • DKN-01 300 mg
  • DKN-01 600 mg
  • Docetaxel 75 mg/m2
  • DKN-01 150 mg
Cohort 2AExperimentalDose 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.
  • DKN-01 300 mg
  • DKN-01 600 mg
  • DKN-01 150 mg
Cohort 2BExperimentalCohort 2B: DKN-01 at MTD or highest dose tested: Days 1 and 15 (28-day cycles)
  • DKN-01 300 mg
  • DKN-01 600 mg
  • DKN-01 150 mg

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.
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Measure of Dose Limiting Toxicities
Time Frame:baseline to End of Cycle 1 (each cycle is 28 days)
Safety Issue:
Description:Starting from Cohort 1 Day 1 to Cohort 2 Day 1

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:New York University School of Medicine

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