Clinical Trials /

Immediate Prostatectomy vs. Cabozantinib Followed by Prostatectomy in Men With High-Risk Prostate Cancer

NCT03964337

Description:

This is a prospective, randomized, open-label, phase II trial of cabozantinib in subjects with untreated, high risk prostate cancer undergoing radical prostatectomy. This multicenter study will enroll 30 subjects. Duke is the lead site for this trial. There will be a second site selected TBD. Patients will be assigned (first 9 subjects only) or randomized 2:1 to either: (1) cabozantinib 40 mg by mouth daily for 4 weeks, followed by a 2 week drug washout period before prostatectomy (n = 20), or (2) immediate prostatectomy within 12 weeks of registration (n = 10). The first 9 subjects (6 subjects assigned to cabozantinib treatment, 3 subjects assigned to immediate prostatectomy) will constitute the Safety Lead-In Cohort, which will be only accrued at Duke. After six subjects have received cabozantinib and completed the 57-85 day safety visit without triggering a stopping rule, subjects may be accrued at the ex-Duke site. The primary goal is to compare pathologic apoptotic indices (cleaved caspase-3) in prostatectomy specimens from patients who undergo immediate prostatectomy (controls) versus those who receive with cabozantinib followed by prostatectomy. The secondary objective is to conduct immune phenotypic profiling on the peripheral blood and tumor microenvironment in prostatectomy specimens from both groups. A statistical analysis will be used to compare the apoptotic indices between the two groups.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Immediate Prostatectomy vs. Cabozantinib Followed by Prostatectomy in Men With High-Risk Prostate Cancer
  • Official Title: A Phase II, Open-Label Randomized Study of Immediate Prostatectomy vs. Cabozantinib Followed by Prostatectomy in Men With High-Risk Prostate Cancer (SPARC)

Clinical Trial IDs

  • ORG STUDY ID: Pro00101042
  • NCT ID: NCT03964337

Conditions

  • Prostate Cancer
  • Prostate Cancer Adenocarcinoma
  • Non-Metastatic

Interventions

DrugSynonymsArms
CabozantinibCabometyxCabozantinib Followed by Prostatectomy (Arm A)

Purpose

This is a prospective, randomized, open-label, phase II trial of cabozantinib in subjects with untreated, high risk prostate cancer undergoing radical prostatectomy. This multicenter study will enroll 30 subjects. Duke is the lead site for this trial. There will be a second site selected TBD. Patients will be assigned (first 9 subjects only) or randomized 2:1 to either: (1) cabozantinib 40 mg by mouth daily for 4 weeks, followed by a 2 week drug washout period before prostatectomy (n = 20), or (2) immediate prostatectomy within 12 weeks of registration (n = 10). The first 9 subjects (6 subjects assigned to cabozantinib treatment, 3 subjects assigned to immediate prostatectomy) will constitute the Safety Lead-In Cohort, which will be only accrued at Duke. After six subjects have received cabozantinib and completed the 57-85 day safety visit without triggering a stopping rule, subjects may be accrued at the ex-Duke site. The primary goal is to compare pathologic apoptotic indices (cleaved caspase-3) in prostatectomy specimens from patients who undergo immediate prostatectomy (controls) versus those who receive with cabozantinib followed by prostatectomy. The secondary objective is to conduct immune phenotypic profiling on the peripheral blood and tumor microenvironment in prostatectomy specimens from both groups. A statistical analysis will be used to compare the apoptotic indices between the two groups.

Trial Arms

NameTypeDescriptionInterventions
Cabozantinib Followed by Prostatectomy (Arm A)ExperimentalExperimental group will received cabozantinib for 4 weeks, followed by a 2 week drug washout before a prostatectomy.
  • Cabozantinib
Immediate Prostatectomy (Arm B)Active ComparatorControl group will receive an immediate prostatectomy.

    Eligibility Criteria

            Inclusion Criteria:
    
              1. Male, age ≥ 18 years old.
    
              2. ECOG performance status of 0 or 1
    
              3. Histologic evidence of adenocarcinoma of the prostate who are deemed candidates for
                 curative radical prostatectomy.
    
              4. Planned robotic or laparoscopic prostatectomy technique.
    
              5. Low risk for conversion to open prostatectomy, in the opinion of the treating surgeon.
    
              6. Intermediate-high or high risk, clinically localized disease by the following
                 criteria:
    
                   -  Gleason score ≥4+3 and greater than or equal to 2 cores.
    
                   -  No definite evidence of metastasis, in the opinion of the investigator.
    
              7. Adequate organ function as defined by the following criteria within 14 days prior to
                 first dose of study treatment:
    
                   -  Aspartate transaminase (AST) and alanine transaminase (ALT) ≤3 x local laboratory
                      upper limit of normal (ULN)
    
                   -  Total serum bilirubin ≤1.5 x ULN, (for subjects with Gilbert's disease ≤ 3 x ULN)
    
                   -  Absolute neutrophil count (ANC) ≥1500/L without granulocyte colony-stimulating
                      factor support.
    
                   -  White blood cell count ≥ 2500/mm3
    
                   -  Serum albumin ≥ 2.8 g/dl
    
                   -  Platelets ≥100,000/mm3
    
                   -  Hemoglobin ≥9.0 g/dL
    
                   -  Serum calcium ≤12.0 mg/dL
    
                   -  Serum creatinine ≤ 2.0 x ULN or calculated creatinine clearance ≥ 30mL/min.
    
                   -  Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol).
    
              8. Written Authorization for Use and Release of Health and Research Study Information
                 (HIPAA authorization per institutional requirements)
    
              9. Evidence of a personally signed and dated informed consent document indicating that
                 the subject has been informed of all pertinent aspects of the trial.
    
             10. Willing/able to adhere to the prohibitions and restrictions specified in this
                 protocol.
    
             11. Agrees to use a condom (even men with vasectomies) and another effective method of
                 birth control if subject is having sex with a woman who is pregnant or a woman of
                 childbearing potential while on study drug and for 4 months following the last dose of
                 study drug.
    
            Exclusion Criteria:
    
              1. Prior treatment for prostate cancer.
    
              2. Major surgery or radiation therapy within 4 weeks of Day 1 on study.
    
              3. Planned radiation therapy until at least 4 weeks after prostatectomy.
    
              4. NCI CTCAE v4.0 grade 3 hemorrhage within 4 weeks of Day 1 on study.
    
              5. Prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥ 1.3 x the
                 laboratory ULN within 7 days before Day 1 on study.
    
              6. Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin
                 and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel). However, low-dose
                 aspirin for cardio protection is allowed (per local applicable guidelines).
    
              7. History of or known metastatic prostate cancer.
    
              8. QTcf interval > 500 msec on baseline EKG.
    
              9. The subject has uncontrolled, significant intercurrent or recent illness including,
                 but not limited to, the following conditions:
    
                 a. Cardiovascular disorders:
    
                 i. Symptomatic congestive heart failure (CHF) New York Heart Association Class 3 or 4,
                 unstable angina pectoris, ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2.
                 coronary/peripheral artery bypass graft (CABG), within 6 months prior to screening.
    
                 ii. Stroke (including transient ischemic attack [TIA]), cerebrovascular accident
                 (CVA), myocardial infarction (MI), or other ischemic event, or thromboembolic event
                 (eg, deep venous thrombosis, pulmonary embolism (PE)) within 6 months prior to
                 screening.
    
                 b. Gastrointestinal (GI) disorders including those associated with a high risk of
                 perforation or fistula formation:
    
                 i. Evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory
                 bowel disease (eg, Crohn's disease), diverticulitis, cholecystitis, symptomatic
                 cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic
                 duct or common bile duct, or gastric outlet obstruction.
    
                 ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess
                 within 6 months before first dose.
    
                 Note: Complete healing of an intra-abdominal abscess must be confirmed before first
                 dose.
    
                 c. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5
                 ml) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage)
                 within 12 weeks before first dose.
    
                 d. Serious non-healing wound/ulcer/bone fracture. e. Other clinically significant
                 disorders that would preclude safe study participation.
    
             10. Hypertension that cannot be controlled by medications (>140/90 mm Hg despite optimal
                 medical therapy).
    
             11. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in
                 the normal range with medication.
    
             12. Concurrent treatment on another clinical trial. Supportive care trials or
                 non-treatment trials, e.g. QOL, are allowed.
    
             13. Other severe acute or chronic medical or psychiatric condition or laboratory
                 abnormality that may increase the risk associated with study participation or study
                 drug administration, or may interfere with the interpretation of study results, and in
                 the judgment of the investigator would make the subject inappropriate for entry into
                 this study.
    
             14. Inability to swallow tablets.
    
             15. Diagnosis of another malignancy within 2 years before first dose of study treatment,
                 except for superficial skin cancers, or localized, low grade tumors deemed cured and
                 not treated with systemic therapy.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:Male
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Apoptotic index in prostatectomy specimens from patients who undergo immediate prostatectomy (Arm B) versus those treated with cabozantinib followed by prostatectomy (Arm A)
    Time Frame:At prostatectomy (Arm A: Day 43, Arm B: Day 1)
    Safety Issue:
    Description:Apoptotic index as measured by cleaved caspase-3 levels in tumor tissue

    Secondary Outcome Measures

    Measure:Immune phenotyping of Myeloid-derived suppressor cells (MDSCs)
    Time Frame:Arm A: Screening, Day 29, Day 43, Day 57-85; Arm B: Screening, Day 1
    Safety Issue:
    Description:Percentage of MDSCs in peripheral blood and tumor tissue
    Measure:Immune phenotyping of neutrophils
    Time Frame:Arm A: Screening, Day 29, Day 43, Day 57-85; Arm B: Screening, Day 1
    Safety Issue:
    Description:Percentage of neutrophils in peripheral blood and tumor tissue
    Measure:Immune phenotyping of M1 macrophages
    Time Frame:Arm A: Screening, Day 29, Day 43, Day 57-85; Arm B: Screening, Day 1
    Safety Issue:
    Description:Percentage of M1 macrophages in peripheral blood and tumor tissue
    Measure:Immune phenotyping of M2 macrophages
    Time Frame:Arm A: Screening, Day 29, Day 43, Day 57-85; Arm B: Screening, Day 1
    Safety Issue:
    Description:Percentage of M2 macrophages in peripheral blood and tumor tissue
    Measure:Immunohistochemical (IHC) analysis of CD8+
    Time Frame:At prostatectomy (Arm A: Day 43, Arm B: Day 1)
    Safety Issue:
    Description:Percentage of CD8+ positive cells in tumor tissue
    Measure:Immunohistochemical (IHC) analysis of programmed death ligand-1 (PD-L1)
    Time Frame:At prostatectomy (Arm A: Day 43, Arm B: Day 1)
    Safety Issue:
    Description:Percentage of PD-L1 positive cells in tumor tissue
    Measure:Immunohistochemical (IHC) analysis of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)
    Time Frame:At prostatectomy (Arm A: Day 43, Arm B: Day 1)
    Safety Issue:
    Description:Percentage of CTLA-4 positive cells in tumor tissue
    Measure:Immunohistochemical (IHC) analysis of interleukin-1 receptor antagonist (IL-1RA)
    Time Frame:At prostatectomy (Arm A: Day 43, Arm B: Day 1)
    Safety Issue:
    Description:Percentage of IL-1RA positive cells in tumor tissue
    Measure:Description of the neutrophil chemotactic factor CXCL12
    Time Frame:At prostatectomy (Arm A: Day 43, Arm B: Day 1)
    Safety Issue:
    Description:Percentage of neutrophil chemotactic factor CXCL12 positive cells in tumor tissue
    Measure:Description of the neutrophil chemotactic factor HMGB1
    Time Frame:At prostatectomy (Arm A: Day 43, Arm B: Day 1)
    Safety Issue:
    Description:Percentage of neutrophil chemotactic factor HMGB1 positive cells in tumor tissue
    Measure:Description of the MDSC-promoting cytokine CCL5
    Time Frame:At prostatectomy (Arm A: Day 43, Arm B: Day 1)
    Safety Issue:
    Description:Percentage of MDSC-promoting cytokine CCL5 positive cells in tumor tissue
    Measure:Description of the MDSC-promoting cytokine CCL12
    Time Frame:At prostatectomy (Arm A: Day 43, Arm B: Day 1)
    Safety Issue:
    Description:Percentage of MDSC-promoting cytokine CCL12 positive cells in tumor tissue
    Measure:Description of the MDSC-promoting cytokine CD40
    Time Frame:At prostatectomy (Arm A: Day 43, Arm B: Day 1)
    Safety Issue:
    Description:Percentage of MDSC-promoting cytokine CD40 cells in tumor tissue

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Duke University

    Last Updated