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

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ClinicalTrials.gov Identifier: NCT03964337
Recruitment Status : Not yet recruiting
First Posted : May 27, 2019
Last Update Posted : October 18, 2019
Sponsor:
Collaborator:
Exelixis
Information provided by (Responsible Party):
Duke University

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Prostate Cancer Prostate Cancer Adenocarcinoma Non-Metastatic Drug: Cabozantinib Procedure: Radical Prostatectomy Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 33 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
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)
Estimated Study Start Date : December 2019
Estimated Primary Completion Date : January 2021
Estimated Study Completion Date : January 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: Cabozantinib Followed by Prostatectomy (Arm A)
Experimental group will received cabozantinib for 4 weeks, followed by a 2 week drug washout before a prostatectomy.
Drug: Cabozantinib
Cabozantinib 40 mg by mouth daily for 4 weeks.
Other Name: Cabometyx

Procedure: Radical Prostatectomy
Radical prostatectomy as part of routine medical care.

Active Comparator: Immediate Prostatectomy (Arm B)
Control group will receive an immediate prostatectomy.
Procedure: Radical Prostatectomy
Radical prostatectomy as part of routine medical care.




Primary Outcome Measures :
  1. 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) ]
    Apoptotic index as measured by cleaved caspase-3 levels in tumor tissue


Secondary Outcome Measures :
  1. 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 ]
    Percentage of MDSCs in peripheral blood and tumor tissue

  2. Immune phenotyping of neutrophils [ Time Frame: Arm A: Screening, Day 29, Day 43, Day 57-85; Arm B: Screening, Day 1 ]
    Percentage of neutrophils in peripheral blood and tumor tissue

  3. Immune phenotyping of M1 macrophages [ Time Frame: Arm A: Screening, Day 29, Day 43, Day 57-85; Arm B: Screening, Day 1 ]
    Percentage of M1 macrophages in peripheral blood and tumor tissue

  4. Immune phenotyping of M2 macrophages [ Time Frame: Arm A: Screening, Day 29, Day 43, Day 57-85; Arm B: Screening, Day 1 ]
    Percentage of M2 macrophages in peripheral blood and tumor tissue

  5. Immunohistochemical (IHC) analysis of CD8+ [ Time Frame: At prostatectomy (Arm A: Day 43, Arm B: Day 1) ]
    Percentage of CD8+ positive cells in tumor tissue

  6. Immunohistochemical (IHC) analysis of programmed death ligand-1 (PD-L1) [ Time Frame: At prostatectomy (Arm A: Day 43, Arm B: Day 1) ]
    Percentage of PD-L1 positive cells in tumor tissue

  7. Immunohistochemical (IHC) analysis of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) [ Time Frame: At prostatectomy (Arm A: Day 43, Arm B: Day 1) ]
    Percentage of CTLA-4 positive cells in tumor tissue

  8. Immunohistochemical (IHC) analysis of interleukin-1 receptor antagonist (IL-1RA) [ Time Frame: At prostatectomy (Arm A: Day 43, Arm B: Day 1) ]
    Percentage of IL-1RA positive cells in tumor tissue

  9. Description of the neutrophil chemotactic factor CXCL12 [ Time Frame: At prostatectomy (Arm A: Day 43, Arm B: Day 1) ]
    Percentage of neutrophil chemotactic factor CXCL12 positive cells in tumor tissue

  10. Description of the neutrophil chemotactic factor HMGB1 [ Time Frame: At prostatectomy (Arm A: Day 43, Arm B: Day 1) ]
    Percentage of neutrophil chemotactic factor HMGB1 positive cells in tumor tissue

  11. Description of the MDSC-promoting cytokine CCL5 [ Time Frame: At prostatectomy (Arm A: Day 43, Arm B: Day 1) ]
    Percentage of MDSC-promoting cytokine CCL5 positive cells in tumor tissue

  12. Description of the MDSC-promoting cytokine CCL12 [ Time Frame: At prostatectomy (Arm A: Day 43, Arm B: Day 1) ]
    Percentage of MDSC-promoting cytokine CCL12 positive cells in tumor tissue

  13. Description of the MDSC-promoting cytokine CD40 [ Time Frame: At prostatectomy (Arm A: Day 43, Arm B: Day 1) ]
    Percentage of MDSC-promoting cytokine CD40 cells in tumor tissue



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03964337


Contacts
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Contact: Julia Rasmussen, MS, RN, BSN 919-681-1030 julia.rasmussen@duke.edu

Locations
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United States, North Carolina
Duke University Medical Center Not yet recruiting
Durham, North Carolina, United States, 27710
Contact: Julia Rasmussen, MS, RN, BSN    919-681-1030    julia.rasmussen@duke.edu   
Sponsors and Collaborators
Duke University
Exelixis
Investigators
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Principal Investigator: Michael Harrison, MD Duke Cancer Institute

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Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT03964337     History of Changes
Other Study ID Numbers: Pro00101042
First Posted: May 27, 2019    Key Record Dates
Last Update Posted: October 18, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Prostatic Neoplasms
Adenocarcinoma
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type