A Phase II, Open-Label Randomized Study of Immediate Prostatectomy vs. Cabozantinib Followed by Prostatectomy in Men With High-Risk Prostate Cancer (SPARC)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 3
- 试验地点
- 1
- 主要终点
- Apoptotic Index in Prostatectomy Specimens From Patients Who Undergo Immediate Prostatectomy (Arm B) Versus Those Treated With Cabozantinib Followed by Prostatectomy (Arm A)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Male, age ≥ 18 years old.
- •ECOG performance status of 0 or 1
- •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:
- •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.
- •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).
- •Written Authorization for Use and Release of Health and Research Study Information (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.
排除标准
- •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.
- •NCI CTCAE v4.0 grade 3 hemorrhage within 4 weeks of Day 1 on study.
- •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).
- •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).
- •History of or known metastatic prostate cancer.
- •QTcf interval > 500 msec on baseline EKG.
- •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 ≥
- •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.
- •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. 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.
研究组 & 干预措施
Cabozantinib Followed by Prostatectomy (Arm A)
Experimental group will received cabozantinib for 4 weeks, followed by a 2 week drug washout before a prostatectomy.
干预措施: Radical Prostatectomy (Procedure)
Cabozantinib Followed by Prostatectomy (Arm A)
Experimental group will received cabozantinib for 4 weeks, followed by a 2 week drug washout before a prostatectomy.
干预措施: Cabozantinib (Drug)
Immediate Prostatectomy (Arm B)
Control group will receive an immediate prostatectomy.
干预措施: Radical Prostatectomy (Procedure)
结局指标
主要结局
Apoptotic Index in Prostatectomy Specimens From Patients Who Undergo Immediate Prostatectomy (Arm B) Versus Those Treated With Cabozantinib Followed by Prostatectomy (Arm A)
时间窗: At prostatectomy (Arm A: Day 43, Arm B: Day 1)
Apoptotic index as measured by cleaved caspase-3 levels in tumor tissue
次要结局
- Immune Phenotyping of Myeloid-derived Suppressor Cells (MDSCs)(Arm A: Screening, Day 29, Day 43, Day 57-85; Arm B: Screening, Day 1)
- Immune Phenotyping of Neutrophils(Arm A: Screening, Day 29, Day 43, Day 57-85; Arm B: Screening, Day 1)
- Immunohistochemical (IHC) Analysis of CD8+(At prostatectomy (Arm A: Day 43, Arm B: Day 1))
- Immune Phenotyping of M1 Macrophages(Arm A: Screening, Day 29, Day 43, Day 57-85; Arm B: Screening, Day 1)
- Immune Phenotyping of M2 Macrophages(Arm A: Screening, Day 29, Day 43, Day 57-85; Arm B: Screening, Day 1)
- Immunohistochemical (IHC) Analysis of Programmed Death Ligand-1 (PD-L1)(At prostatectomy (Arm A: Day 43, Arm B: Day 1))
- Immunohistochemical (IHC) Analysis of Cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4)(At prostatectomy (Arm A: Day 43, Arm B: Day 1))
- Immunohistochemical (IHC) Analysis of Interleukin-1 Receptor Antagonist (IL-1RA)(At prostatectomy (Arm A: Day 43, Arm B: Day 1))
- Description of the Neutrophil Chemotactic Factor CXCL12(At prostatectomy (Arm A: Day 43, Arm B: Day 1))
- Description of the Neutrophil Chemotactic Factor HMGB1(At prostatectomy (Arm A: Day 43, Arm B: Day 1))
- Description of the MDSC-promoting Cytokine CCL5(At prostatectomy (Arm A: Day 43, Arm B: Day 1))
- Description of the MDSC-promoting Cytokine CCL12(At prostatectomy (Arm A: Day 43, Arm B: Day 1))
- Description of the MDSC-promoting Cytokine CD40(At prostatectomy (Arm A: Day 43, Arm B: Day 1))