A Phase II Study of Cabozantinib (XL184) for Plexiform Neurofibromas in Subjects With Neurofibromatosis Type 1 in Children and Adults
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 45
- 试验地点
- 12
- 主要终点
- The Change in Tumor Size Based on Radiographic Assessment
研究概览
简要总结
This study, "A Phase II Study of Cabozantinib (XL l84) for Plexiform Neurofibromas in Subjects with Neurofibromatosis Type I in Children and Adults diagnosed with Neurofibromatosis Type 1 (NF1) and have a type of tumor called a plexiform neurofibroma (PN). Neurofibromas are tumors that develop from the cells and tissues that cover the nerves. Plexiform neurofibromas can be disfiguring, painful, and life-threatening. These types of tumors typically do not respond well to most treatment approaches such as chemotherapy, radiation, and surgery because of their slow growth and location near vital structures of the body such as nerves, blood vessels, and the airway.
The primary objective is to determine the response rate of NF1 patients with plexiform neurofibromas treated with Cabozantinib therapy using MRI scans. The objective response rate to cabozantinib is defined as ≥ 20% reduction in tumor volume at the end of 12 cycles.
详细描述
There are two cohorts: Cohort A is for patients ≥ 16 years of age and Cohort B is for patients 3 - 15 years of age. Cohort A is closed to enrollment but this study will open to Cohort B patients. This phase II open label study will evaluate adults and children with NF1 and plexiform neurofibromas treated with cabozantinib (XL184). This study will enroll subjects who either meet clinical diagnostic criteria or have an identified pathogenetic NF1 mutation. Subjects on study must have clinically significant plexiform neurofibroma defined as potentially life-threatening, impinging on vital structures or significantly impairing the quality of life from pain or other symptoms. Patients must not have lesions suspicious for malignant tumors such as MPNSTs (malignant peripheral nerve sheath tumors) and suspicious tumors must be proven negative by histopathology prior to enrollment on study. Since Cohort A is closed to accrual, this study will be open to Cohort B, patients 3 - 15 years of age that meet eligibility criteria.
For Cohort A, the study will be a Simon two-stage study design. It will be a single-arm open-label study of cabozantinib and the primary endpoint is the objective response rate (ORR) to cabozantinib at 1 year. In the first stage, 9 evaluable subjects will be accrued. If there is at least 1 response, accrual will continue to the second stage and an additional 8 evaluable subjects will be enrolled. To allow for 25% unevaluable subjects, a maximum of 24 subjects will be enrolled. Radiographic response will be evaluated as the primary endpoint with 20% volumetric MRI response of the target lesion being the threshold criteria for tumor response. A target lesion will be selected at time of enrollment and tumor evaluations will occur serially while on study.
For Cohort B, a minimum of 17 evaluable subjects will be enrolled. To allow for up to 25% unevaluable subjects, a minimum of 24 subjects will be enrolled. Based on preliminary response data and minimal toxicity in Cohort A, a 2-stage design is not felt to be necessary for Cohort B.
In Cohort A, all subjects will start cabozantinib at 40 mg. The published maximum tolerated dose (MTD) for Cabozantinib is 140 mg and the current recommended dose in Phase 3 clinical trials for subjects with medullary thyroid cancer is 100 mg. Doses of 40 mg and 60 mg continue to show efficacy in on-going phase 2 and phase 3 trials with reduced toxicity. Subjects who tolerate 40 mg for 2 cycles will escalate to 60 mg. The rationale for this is that the majority of subjects who develop toxicity do so after >2 weeks on drug as cabozantinib has a long half-life. Subjects who experience dose-limiting toxicity at 40 mg will dose reduce to 20 mg when their toxicities resolve. Subjects without toxicity at 40mg will increase to 60mg. Subjects who experience toxicity at 60 mg will dose reduce to 40 mg. This dosing schema is designed to maximize safety and tolerability in this new population of patients.
In Cohort B, subjects will start at 30 mg/m2/day dosing. Dose will be escalated at cycle 3 if tolerated to 40 mg/m2. Subjects who experience DLT at 40 mg/m2/day will dose reduce to 30 mg/m2/day. Subjects who experience DLT at 30 mg/m2/day will dose reduce to 23 mg/m2day. Actual dosing will be based on the dosing nomogram.
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
- 3 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Clinical or molecular diagnosis of Neurofibromatosis Type 1
- •Plexiform neurofibroma that is progressive OR causing significant morbidity.
- •Measurable disease amenable to volumetric MRI imaging defined as lesion seen on at least 3 consecutive MRI slices and at least 3 mL in volume. Select tumors <3 cm may be eligible on review.
- •Central review or MRI required prior to enrollment.
- •Age ≥ 3 years of age at the time of study entry. Subjects ≥ 16 years will be enrolled in Cohort A. Subjects 3 - 15 years will be enrolled in Cohort B.
- •Performance Level Karnofsky ≥ 50%. Subjects unable to walk because of paralysis, but up in a wheel chair will be considered ambulatory for purpose of assessing performance score.
- •Complete resection of plexiform neurofibroma is not feasible or if subject refuses surgery.
- •Fully recovered from acute toxic effects of all prior chemotherapy or radiotherapy.
- •No myelosuppressive chemotherapy within 4 weeks of study entry.
- •At least 7 days since completion of hematopoietic growth factors.
- •At least 14 days since completion of biologic agent.
- •At least 4 weeks since receiving any investigational drug.
- •Physiologic or stress doses of steroids allowed in patients with endocrine deficiencies.
- •At least 6 months from radiation therapy to index tumor and at least 6 weeks from radiation to areas outside of index plexiform neurofibroma.
- •At least 3 months from major surgery or at least 1 month from minor surgery. No major surgery anticipated within 3 months of enrollment.
- •Adequate bone marrow function.
- •Adequate renal function.
- •Adequate liver function.
- •Blood pressure within upper limit of normal.
排除标准
- •Active optic glioma or other low-grade glioma requiring treatment with chemotherapy or radiation therapy.
- •Malignant glioma, malignant peripheral nerve sheath tumor, or other malignancy requiring treatment in the last 12 months.
- •Dental braces or prosthesis that interferes with volumetric analysis of the neurofibroma(s).
- •Unable to swallow tablets.
- •Women who are pregnant or breast-feeding.
- •Subjects of reproductive potential who have not agreed to use effective contraception.
- •Subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs).
- •Subject requires anticoagulants. Low dose aspirin, low-dose warfarin, and prophylactic low molecular weight heparin are permitted.
- •Concomitant treatment of strong CYP3A4 inducers or inhibitors.
- •History of noncompliance to medical regimens
- •A known history of HIV seropositivity or known immunodeficiency. HIV testing will not be required as part of this trial, unless HIV is clinically suspected.
- •Impairment of gastrointestinal function or gastrointestinal disease that may affect the absorption of cabozantinib. (e.g. ulcerative disease, malabsorption syndrome, or small bowel resection). Nasogastric tube (NG) tube is allowed.
- •Any of the following within 28 days before the first dose of study treatment:
- •intra-abdominal tumor/metastases invading GI mucosa
- •active peptic ulcer disease
- •inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
- •malabsorption syndrome
- •Any of the following within 6 months before the first dose of study treatment:
- •abdominal fistula
- •gastrointestinal perforation
- •bowel obstruction or gastric outlet obstruction
- •intra-abdominal abscess. Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating study treatment even if abscess occurred more than 6 months before the first dose of study treatment.
- •Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy
- •Patients who have an uncontrolled infection.
- •Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
- •Hemoptysis of ≥0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment
- •Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
- •Radiographic evidence of cavitating pulmonary lesion(s).
- •Concurrent severe and/or uncontrolled medical disease which could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration)
- •Cardiovascular disorders including:
- •Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening
- •Concurrent uncontrolled hypertension defined as sustained BP > 140 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days before the first dose of study treatment
- •Any history of congenital long QT syndrome
- •Baseline heart-rate corrected QT (QTc) interval >470 msec in women and >450 msec in men
- •Concomitant treatment with medications that prolong the QT interval and have a known risk of Torsades de Pointes is not contraindicated, but should be avoided if possible and will require more frequent EKG monitoring.
- •Any of the following within 6 months before the first dose of study treatment:
- •unstable angina pectoris
- •clinically-significant cardiac arrhythmias
- •stroke (including transient ischemic attack (TIA), or other ischemic event)
- •myocardial infarction
- •thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter (e.g. vena cava filter) are not eligible for this study)
- •Other clinically significant disorders such as:
- •Active infection requiring systematic treatment within 28 days before the first dose of study treatment
- •Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment
- •History of organ transplant
- •Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment
- •Complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of study treatment irrespective of time from surgery.
研究组 & 干预措施
Experimental Agent XL184 (Cabozantinib)
Cohort A (≥ 16 years - closed to accrual): Starting cabozantinib of 40 mg daily by mouth per cycle. Duration of each cycle is 28 days. Subjects will dose escalate after 2 cycles to 60 mg based on dose tolerability. Subjects who do not tolerate 40 mg will dose reduce to 20 mg. Doses will be capped at 60 mg.
Cohort B (3 - 15 years). The starting cabozantinib dose is 30 mg/m2/day by mouth per cycle. Duration of each cycle is 28 days. Subjects will dose escalate after 2 cycles to 40 mg/m2/day based on dose tolerability. Subjects who do not tolerate 30 mg/m2/day will dose reduce to 23 mg/m2/day. Doses will be capped at 60 mg/day max daily dose
Each cohort will enroll up to 24 evaluable subjects with a target minimum of 17 evaluable subjects per cohort.
干预措施: Cabozantinib (Drug)
结局指标
主要结局
The Change in Tumor Size Based on Radiographic Assessment
时间窗: baseline to 12 Months
We will estimate the objective response rate (ORR) as defined by 20% volumetric MRI response of the target lesion to cabozantinib at 12 months in adolescents and adults with Neurofibromatosis type 1 (NF1) plexiform neurofibromas by volumetric MRI imaging.
次要结局
- Number of Participants With Adverse Events(baseline to 24 months)
研究者
Bruce Korf, MD
Principal Investigator
University of Alabama at Birmingham