临床试验/NCT03149822

NCT03149822已完成1 期

Phase I/II Study of Pembrolizumab and Cabozantinib in Patients With Metastatic Renal Cell Carcinoma

University of Colorado, Denver5 个研究点分布在 1 个国家目标入组 45 人开始时间: 2017年9月28日最近更新: 2025年3月13日

适应症

干预措施

试验速览

阶段: 1 期
状态: 已完成
发起方: University of Colorado, Denver
入组人数: 45
试验地点: 5
主要终点: Efficacy of Pembrolizumab and Cabozantinib Based on Objective Response Rate

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

This is a phase I/II open-label study designed to evaluate the combination of pembrolizumab and cabozantinib in subjects with locally advanced, recurrent, or metastatic renal cell carcinoma. Sequential dose escalation of cabozantinib with standard dose pembrolizumab will occur in the phase I dose escalation part of the study to determine the recommended phase 2 dose (RP2D). Subsequently, subjects will receive cabozantinib at the RP2D in combination with pembrolizumab in the phase II dose expansion part of the study.

详细描述

Primary Objectives

To determine the efficacy based on objective response rate [ORR = complete response (CR) + partial response (PR)] of pembrolizumab and cabozantinib when administered in combination in subjects with locally advanced or metastatic renal cell carcinoma..

Secondary Objectives

To characterize dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) for the combination.
To assess other measures of anti-tumor activity of the combination of pembrolizumab and cabozantinib in subjects with locally advanced or metastatic renal cell carcinoma.

研究设计

研究类型: Interventional
分配方式: Non Randomized
干预模型: Sequential
主要目的: Treatment
盲法: None

盲法说明

Open-Label

入排标准

年龄范围: 18 Years 至 100 Years（Adult, Older Adult）
性别: All
接受健康志愿者: 否

入选标准

•Subjects must have histological or cytological documentation of renal cell carcinoma
•Subjects must have locally advanced, recurrent, or metastatic disease.
•Be willing and able to provide written informed consent/assent for the trial.
•Stated willingness to complywith all study procedures and be available for the duration of the trial.
•Be ≥ 18 years of age on day of signing informed consent.
•Have measurable or evaluable disease based on RECIST 1.
•Recovery to baseline or ≤ Grade 1 CTCAE v.4.0 from toxicities related to any prior treatments, unless AE(s) are clinically non-significant and/or stable on supportive therapy.
•Confirmed availability of representative archival tumor specimens in paraffin blocks (preferred) or ≥ 10 unstained slides, with an associated pathology report.
•Acceptable samples include core needle biopsies for deep tumor tissue or excisional, incisional, or punch biopsies for cutaneous, subcutaneous, or mucosal lesions.
•Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is therefore not acceptable.
•A subject with insufficient or unavailable archival tissue may be eligible, upon discussion with the Principal Investigator, if the subject is willing to consent to undergo a pretreatment core, punch, or excisional/incisional biopsy sample collection of the tumor.
•Have a performance status of 0 or 1 on the ECOG Performance Scale.
•Demonstrate adequate organ function as defined by desired lab values.
•Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
•Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 - Contraception, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
•Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate method of contraception as outlined in Section 5.7.1- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

排除标准

•Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
•Has a diagnosis of immunodeficiency or is receiving systemic steroiderapy equivalent to ≥ 10 mg/day of prednisone, or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
•Has a known history of active TB (Bacillus Tuberculosis)
•Has had prior treatment with pembrolizumab.
•Has had prior treatment with cabozantinib.
•Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
•Note: Subjects with stable, treated hypothyroidism or adrenal insufficiency may qualify for the study
•Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
•Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
•Subjects with hypertension managed with medication are an exception to this criterion and may qualify for the study.
•Subjects with ≤ Grade 2 endocrinopathy (e.g. hypothyroidism or adrenal insufficiency managed with medication) are an exception to this criterion and may qualify for the study.
•Has had major surgery within 4 weeks or minor surgery within 2 weeks prior to study Day
•Subjects must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
•Prior treatment with immune checkpoint inhibitors is allowed, provided that no treatment-related Grade ≥ 3 adverse events (other than Grade 3 endocrinopathy managed with replacement therapy) were observed and at least a minimum of 28 days have elapsed between the last dose of prior treatment and the proposed Cycle 1 Day
•Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer, carcinoma in situ or superficial bladder cancer, low-grade prostate cancer, intraductal papillary mucinous neoplasm (IPMN), and other low grade cancers that is suitable for active surveillance in the opinion of the investigator.
•Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Active CNS metastases will be defined as brain lesions that 1) require intervention with surgery, stereotactic radiosurgery (SRS), or whole brain radiotherapy (WBRT) or 2) require anti-epileptic therapy, systemic steroid treatment, or intrathecal therapy. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks after completion of focal therapy for brain metastases and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
•Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is allowed.
•Has history of solid organ transplantation.
•Has history of osteonecrosis of the jaw.
•Has history of reversible posterior leukoencephalopathy syndrome.
•Has history of wound dehiscence or complications requiring medical intervention within 6 months of study entry.
•Has history of (non-infectious) pneumonitis that required steroids or active, non- infectious pneumonitis.
•Has an active infection requiring systemic therapy with IV antibiotics.
•Has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
•Cardiovascular disorders:
•Symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmias.
•Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment.
•Stroke (including TIA), myocardial infarction, or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 3 months before randomization.
•Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
•Tumors invading the GI-tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction.
•Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 6 months before randomization. Complete healing of an intra-abdominal abscess must be confirmed before study initiation.
•Has clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon within 3 months before randomization.
•Known endobronchial disease manifestation. Patients with suspected endobronchial disease on imaging who have no evidence of endobronchial disease on bronchoscopy are allowed. Patients with treated endobronchial disease are also allowed provided they are stable.
•Lesions invading major pulmonary blood vessels.
•Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
•Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
•Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
•Has an inability to swallow tablets or capsules.
•Has a previously identified allergy or hypersensitivity to components of the study treatment formulations.
•Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
•Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
•Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

研究组 & 干预措施

Phase 1: Pembrolizumab 200 mg plus Cabozantinib 40mg

Experimental

Pembrolizumab 200 mg intravenous (IV) infusion on day 1 of each 21-day cycle in combination with cabozantinib 40 mg orally once daily until disease progression, unacceptable toxicity, or consent withdrawal.

干预措施: Cabozantinib (Drug)

Phase 1: Pembrolizumab 200 mg plus Cabozantinib 40mg

Experimental

干预措施: Pembrolizumab (Drug)

Phase 1: Pembrolizumab 200 mg plus Cabozantinib 60mg

Experimental

Pembrolizumab 200 mg intravenous (IV) infusion on day 1 of each 21-day cycle in combination with cabozantinib 60 mg orally once daily until disease progression, unacceptable toxicity, or consent withdrawal.

干预措施: Cabozantinib (Drug)

Phase 1: Pembrolizumab 200 mg plus Cabozantinib 60mg

Experimental

干预措施: Pembrolizumab (Drug)

Phase 2: Pembrolizumab 200 mg plus Cabozantinib at the RP2D

Experimental

Pembrolizumab 200 mg intravenous (IV) infusion on day 1 of each 21-day cycle in combination with cabozantinib at the RP2D orally once daily for up to 35 cycles, until disease progression, unacceptable toxicity, or consent withdrawal. All participants who stop pembrolizumab after 35 cycles with SD or better may be eligible for up to an additional 17 cycles (approximately 1 year) of pembrolizumab treatment if they progress after stopping pembrolizumab from the initial treatment phase.

干预措施: Cabozantinib (Drug)

Phase 2: Pembrolizumab 200 mg plus Cabozantinib at the RP2D

Experimental

干预措施: Pembrolizumab (Drug)

结局指标

主要结局

Efficacy of Pembrolizumab and Cabozantinib Based on Objective Response Rate

时间窗: Beginning of study to end of study, up to 5 years

Measured through the complete response (CR) + partial response (PR)\] of pembrolizumab and cabozantinib when administered in combination in subjects with locally advanced or metastatic renal cell carcinoma. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

次要结局

Dose Limiting Toxicities(Throughout Cycle 1, up to 21 days)
Maximally Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D)(Throughout Cycle 1, up to 21 days)
Disease Control Rate (DCR), AKA Clinical Benefit Rate (CBR)(Beginning of study to end of study, or death, whichever comes first, up to 5 years)
Progression-Free Survival(Beginning of study to end of study, or death, whichever comes first, up to 5 years)
Duration of Response(Time of first response as measured by RECIST 1.1 to time of progression or death, whichever comes first, up to 5 years)
Overall Survival(Beginning of study to end of study, or death, whichever comes first, up to 5 years)

研究者

发起方

University of Colorado, Denver

申办方类型

Other

责任方

Sponsor

研究点 (5)

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