NCT07187869招募中1 期
Modulation of the Bone Immune Microenvironment Following Cabozantinib Treatment of Bone Metastatic Clear Cell Renal Cell Carcinoma: Proof of Concept Study
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 16
- 试验地点
- 1
- 主要终点
- Safety and Adverse Events (AEs)
研究概览
简要总结
The goal of our study is to explore how treatments affect the bone immune microenvironment and determine the best treatment options for patients with metastatic kidney cancer to the bone. This could prevent skeletal complications and improve patient outcomes.
详细描述
Primary Objectives:
- To assess safety of obtaining biopsy within close time frame of cabozantinib treatment.
- To evaluate the success rate of obtaining serial biopsies of bone metastases. Success is defined as viable single cell sequencing of bone biopsy samples at baseline and after 8 weeks of treatment.
- To quantify the fold change in M1:M2 macrophage population in serial biopsies from renal cell carcinoma bone metastases.
Secondary Objectives:
- To compare the M1:M2 macrophage population at baseline and on therapy in paired bone versus non-bone metastatic sites.
- To compare CD8+, Granzyme+ cells on multiplex immunofluorescence at baseline and on therapy in paired bone versus non-bone metastatic sites.
- To describe serum marker changes over time while on therapy for bone metastasis including bone alkaline phosphatase, osteopontin, procollagen type I amino-terminal propeptide (PINP), and beta-isomer of carboxy-terminal telopeptide of type I collagen (â-CTX) and association with response and progression.
- To describe overall response rate (proportion of participants who achieve a best response of complete response or partial response using RECIST 1.1 criteria), time until progression (time from initiation of systemic treatment to the date of documented disease progression), and progression-free survival (time between the first date of systemic treatment to first date of documented progression or death due to any cause).
- To describe incidence of skeletal related events defined as a composite of pathologic fracture, spinal cord compression, radiation or surgery to bone, and hypercalcemia of malignancy.
2.3 Exploratory Objective:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •To be eligible for the study, the subject must meet all of the inclusion and none of the
排除标准
- •Signed Written Informed Consent
- •Ability to understand and the willingness to sign a written informed consent document.
- •Participants must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal participant care.
- •Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and serial biopsy schedule.
- •Participants must be willing to consent to PA-17-0577, a protocol led by Dr. Jianjun Gao, that allows for tissue sample collection and analysis
- •Type of Participant and Target Disease Characteristics
- •Histological confirmation of RCC with a clear-cell component, including participants who may also have sarcomatoid or rhabdoid features
- •Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) RCC
- •No prior systemic therapy with nivolumab or cabozantinib or previous systemic treatment for metastatic disease.
- •ECOG performance status ≤2 (Karnofsky ≥60%) (See Tables 1 and 2 in section 14 for reference)
- •Presence of both a bone metastasis and visceral or soft tissue metastatic lesion amenable to biopsies
- •Patients must have adequate organ and marrow function as defined below:
- •absolute neutrophil count ≥1,000/mcL
- •platelets ≥100,000/mcL
- •total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (Except participants with Gilbert Syndrome who must have a total bilirubin < 3.0 x ULN)
- •AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN
- •GFR ≥30 mL/min (using the Cockcroft-Gault formula)
- •For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
- •Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
- •Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. Treated CNS metastases are defined as having no ongoing requirement for corticosteroids for at least 2 weeks prior to enrollment and no evidence of progression or hemorrhage after treatment completed at least 4 weeks prior to enrollment clinical examination and brain imaging (MRI or CT).
- •Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
- •Patients are eligible to receive standard of care nivolumab and cabozantinib treatment and must be prescribed this regimen at treating physician's determination.
- •Age and Reproductive Status
- •Males and females aged 18 years or greater. Because there is inadequate dosing or adverse event data in patients <18 years of age, children are excluded from this study.
- •The effects of cabozantinib and nivolumab on the developing human fetus are unknown. For this reason and because tyrosine kinase inhibitors and immune checkpoint inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation (refer to MDA Policy CLN 1114) and for 4 months after the last dose of cabozantinib and 4 months after the last dose of nivolumab. This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:
- •Postmenopausal (no menses in greater than or equal to 12 consecutive months).
- •History of hysterectomy or bilateral salpingo-oophorectomy
- •Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy).
- •History of bilateral tubal ligation or another surgical sterilization procedure.
- •In addition, females < 55 years-of-age must have a serum follicle stimulating (FSH) level > 40 mIU/mL to confirm menopause).
- •Approved methods of birth control are as follows: Hormonal contraception (i.e., birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
- •Males who are sexually active with women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of study treatment and 7 months after the last dose of study treatment (ie, 90 days [duration of sperm turnover] plus the time required for the investigational drug to undergo approximately five half-lives).
- •Azoospermic males are exempt from contraceptive requirements. WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements, and still must undergo pregnancy testing as described in this section. Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise on the use of highly effective methods of contraception which have a failure rate of < 1% when used consistently and correctly.
- •Exclusion Criteria:
- •Any active CNS metastases greater than 0.5cm in size. Participants with treated CNS metastases demonstrated stability for at least 28 days are allowed to enroll.
- •Any impending pathologic fracture or cord compression requiring urgent surgical or site-directed therapy. Participants may be eligible if they undergo initial surgery with tissue collection and have adequately recovered and have received clearance for systemic treatment from orthopedic surgeon or neurosurgery. The tissue collected at the time of initial surgery may be used as the baseline tissue collection. An alternative bone metastasis must be available for biopsy after treatment to be considered eligible.
- •Any active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
- •Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. Transient short-term use of systemic corticosteroids for allergic conditions (e.g., contrast allergy) is also allowed.
- •Any tumor invading the GI tract or any evidence of endotracheal or endobronchial tumor within 30 days prior to randomization
- •Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
- •Known medical condition (e.g., a condition associated with diarrhea or acute diverticulitis, aortic aneurysm, aortic dissection) that, in the investigator's opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results
- •History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, bowel obstruction, or gastric outlet obstruction within the past 6 months prior to enrollment
- •Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of cabozantinib (e.g., malabsorptive disorder, ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or small bowel resection)
- •Serious, non-healing wound or ulcer within 2 weeks prior to study enrollment. May be eligible if cleared by surgical team.
- •Evidence of active bleeding or bleeding susceptibility; or medically significant hemorrhage within prior 3 months prior to study enrollment. Microscopic hematuria is allowed.
- •History of cerebrovascular accident (CVA) including transient ischemic attack within the last 6 months prior to enrollment unstable cardiac arrhythmia within 6 months prior to enrollment
- •Prolongation of the Fridericia corrected QT (QTcF) interval defined as > 450 msec for males and > 470 msec for females, where QTcF = QT / 3√RR with triplicate measurements
- •Poorly controlled hypertension (defined as systolic blood pressure (SBP) of > 150 mmHg or diastolic blood pressure (DBP) of > 90 mmHg), despite antihypertensive therapy
- •History of any of the following cardiovascular conditions within 3 months of study enrollment: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery by-pass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure (CHF), as defined by the New York Heart Association (NYHA)
- •Any radiologic or clinical evidence of pancreatitis within 30 days prior to enrollment
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研究组 & 干预措施
Treatment with Cabozantinib [PO] + Nivolumab [IV] Q4W
Experimental
Participants standard of care treatment stage begins when the patient has completed the baseline paired core biopsies.
干预措施: Cabozantinib (Drug)
Treatment with Cabozantinib [PO] + Nivolumab [IV] Q4W
Experimental
Participants standard of care treatment stage begins when the patient has completed the baseline paired core biopsies.
干预措施: Nivolumab (Drug)
结局指标
主要结局
Safety and Adverse Events (AEs)
时间窗: Through study completion; an average of 1 year
Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0
次要结局
未报告次要终点
研究者
研究点 (1)
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