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Immediate Prostatectomy versus Cabozantinib Followed by Prostatectomy in Patients with Intermediate-High or High-Risk Prostate Cancer, The SPARC Study

Trial Status: Active

This phase II trial studies different biomarkers to gain a better understanding of how cabozantinib affects prostate cancer and the immune system in patients with intermediate-high or high-risk prostate cancer undergoing radical prostatectomy. Radical prostatectomy is a surgical procedure to remove the entire prostate and some of the tissue surrounding it. A biomarker is a biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease. A biomarker may be used to see how well the body responds to a treatment for a disease or condition. Biomarkers, obtained from blood and prostate tissue, include proteins (building blocks of the body, cells, and organs) involved in tumor growth and immune system activation, as well as genetic changes. Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. The purpose of this study is to determine the effect that cabozantinib has on these biomarkers and prostate cancer by comparing prostatectomy tissue and blood samples from patients who received cabozantinib to those who did not receive cabozantinib prior to prostatectomy. This study will also evaluate the safety and efficacy of cabozantinib in subjects with prostate cancer who are undergoing prostatectomy.

Inclusion Criteria

  • Karnofsky performance status (KPS) of >= 70
  • Histologic evidence of adenocarcinoma of the prostate who are deemed candidates for curative radical prostatectomy
  • Planned robotic or laparoscopic prostatectomy technique
  • Low risk for conversion to open prostatectomy, in the opinion of the treating surgeon
  • 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
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x local laboratory upper limit of normal (ULN) (within 14 days prior to first dose of study treatment)
  • Total serum bilirubin =< 1.5 x ULN, (for subjects with Gilbert’s disease =< 3 x ULN) (within 14 days prior to first dose of study treatment)
  • Absolute neutrophil count (ANC) >= 1500/L without granulocyte colony-stimulating factor support (within 14 days prior to first dose of study treatment)
  • White blood cell count >= 2500/mm^3 (within 14 days prior to first dose of study treatment)
  • Serum albumin >= 2.8 g/dl (within 14 days prior to first dose of study treatment)
  • Platelets >= 100,000/mm^3 (within 14 days prior to first dose of study treatment)
  • Hemoglobin >= 9.0 g/dL (within 14 days prior to first dose of study treatment)
  • Serum calcium =< 12.0 mg/dL (within 14 days prior to first dose of study treatment)
  • Serum creatinine =< 2.0 x ULN or calculated creatinine clearance >= 30mL/min. (within 14 days prior to first dose of study treatment)
  • Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=< 113.2 mg/mmol) (within 14 days prior to first dose of study treatment)
  • Written Authorization for Use and Release of Health and Research Study Information (Health Insurance Portability and Accountability Act [HIPAA] authorization per institutional requirements)
  • Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the trial
  • Willing/able to adhere to the prohibitions and restrictions specified in this protocol
  • 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

  • Prior treatment for prostate cancer
  • Major surgery or radiation therapy within 4 weeks of day 1 on study
  • Planned radiation therapy until at least 4 weeks after prostatectomy
  • National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 grade 3 hemorrhage within 4 weeks of day 1 on study
  • Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test >= 1.3 x the laboratory ULN within 7 days before day 1 on study
  • Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin and factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel). However, low-dose aspirin for cardio protection is allowed (per local applicable guidelines)
  • History of or known metastatic prostate cancer
  • QT interval by Fridericia (QTcF) interval > 500 msec on baseline electrocardiogram (EKG)
  • The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: * Cardiovascular disorders: ** 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 ** Stroke (including transient ischemic attack [TIA]), cerebrovascular accident (CVA), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism [PE]) within 6 months prior to screening * Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: ** Evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (e.g., 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 ** 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 * Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before first dose * Serious non-healing wound/ulcer/bone fracture * Other clinically significant disorders that would preclude safe study participation
  • Hypertension that cannot be controlled by medications (> 140/90 mm Hg despite optimal medical therapy)
  • Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication
  • Concurrent treatment on another clinical trial. Supportive care trials or non-treatment trials, e.g. quality of life (QOL), are allowed
  • 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
  • Inability to swallow tablets
  • 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

North Carolina

Durham
Duke University Medical Center
Status: ACTIVE
Contact: Michael R. Harrison
Phone: 919-668-4667

PRIMARY OBJECTIVE:

I. To compare pathologic apoptotic indices in prostatectomy specimens from patients who undergo immediate prostatectomy versus those treated with cabozantinib followed by prostatectomy.

SECONDARY OBJECTIVE:

I. To conduct immune phenotypic profiling on the peripheral blood and tumor microenvironment in prostatectomy specimens from patients who undergo immediate prostatectomy versus those treated with cabozantinib prior to prostatectomy.

EXPLORATORY OBJECTIVES:

I. To estimate the pathologic complete response rate (pCR) and =< pathologic T2 (=< pT2) rate in each arm.

II. To evaluate relapse-free survival in each arm.

III. To compare apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]), proliferation (Ki-67), and microvessel density (CD31) indices in prostatectomy specimens from patients who undergo immediate prostatectomy versus those treated with cabozantinib prior to prostatectomy.

IV. To measure expression levels of c-MET, VEGF, and HGF, as well as activation status of cMET in prostate tissue.

V. To describe changes in plasticity signaling markers associated with prostate tumors, including vimentin, AR, SNAIL, AXL, and N-cadherin, with cabozantinib exposure.

VI. To evaluate PTEN and p53 genomic and protein expression status in tumor tissue.

VII. To demonstrate that cabozantinib is safe and tolerable in patients undergoing radical prostatectomy.

VIII. To demonstrate that surgery is safe and feasible in patients undergoing treatment with cabozantinib.

IX. To collect plasma angiome samples (multiplex enzyme-linked immunosorbent assay [ELISA]) for analysis and correlation with primary and key secondary endpoints.

X. To describe gene expression patterns (in particular those associated with apoptosis, androgen receptor signaling, c-MET activation, and a cMET-specific endocytosis panel) correlated with cabozantinib administration using RNA sequencing analysis.

XI. To explore changes in serum and intratumoral androgen concentrations related to cabozantinib treatment.

XII. To collect cell-free DNA (cfDNA) for analysis and correlation with primary and key secondary endpoints.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive cabozantinib orally (PO) once daily (QD) on days 1-28 in the absence of disease progression or unacceptable toxicity. After a 2 week washout period, patients then undergo radical prostatectomy on day 43.

ARM B: Patients undergo radical prostatectomy on day 1.

After completion of study, patients in Arm A are followed up on days 57-85, and all patients are followed up for 3 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Duke University Medical Center

Principal Investigator
Michael R. Harrison

  • Primary ID Pro00101042
  • Secondary IDs NCI-2020-00761
  • Clinicaltrials.gov ID NCT03964337