Immediate Prostatectomy vs. Cabozantinib Followed by Prostatectomy in Men With High-Risk Prostate Cancer
Condition: Prostate Cancer; Prostate Cancer Adenocarcinoma; Non-Metastatic
MeSH terms: Prostatic Neoplasms
Intervention: Cabozantinib; Radical Prostatectomy
Intervention description: Cabozantinib 40 mg by mouth daily for 4 weeks.; Radical prostatectomy as part of routine medical care.
Phase: Phase 2
Study type: Interventional
Primary purpose: Other
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No

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.
    

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:

               -  Prostate cancer in at least 2 cores with a Gleason score ≥ 7 (4+3 or 3+4) in at
                  least 1 of those 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 14 days before Day 1 on study (Arm A subjects only) or within 14
             days of the completion of screening (Arm B subjects only).

          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.