Mercaptopurine (6-MP) for the Treatment of Manifestations of Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC)
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Maximum tolerated dose (MTD)
研究概览
简要总结
This phase I/II trial studies the side effects and best dose of mercaptopurine, and to see how well it works in treating patients with hereditary leiomyomatosis and renal cell carcinoma (HLRCC). HLRCC is a rare inherited disorder that increases the risk of developing benign (not cancer) tumors of the skin and the uterus (leiomyomas) and malignant (cancer) tumors of the uterus (leiomyosarcoma) and the kidney. Mercaptopurine is in a class of medications called purine antagonists. It works by stopping the growth of cancer cells.
详细描述
PRIMARY OBJECTIVE:
I. To identify the safety, side effects, and best dose of mercaptopurine (6-MP).
SECONDARY OBJECTIVES:
I. To assess clinical activity in treating metastatic fumarate hydratase (FH) Deficient Kidney Cancer.
II. To assess how treatment impacts uterine fibroid clinical symptoms. III. To determine the change in menstrual bleeding. IV. To evaluate changes in pain due to leiomyomas. V. To evaluate the overall improvement in leiomyoma symptoms.
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
- •Disease-causing, germline FH mutation including variants considered either:
- •a) Pathogenic/likely pathogenic OR
- •b) variants of unknown significance (VUS) with immunohistochemical staining showing loss of FH or high 2-SC expression in tumor tissue
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1
- •Thiopurine S-methyltransferase (TPMT) and NUDT15 homozygous, wild-type genotype
- •TPMT*1/TPMT*1 and NUDT15*1/ NUDT15*1
- •Calculated creatinine clearance ≥ 30 milliliters per minute (mL/min) per the Cockcroft and Gault formula OR serum creatinine < 1.5 x upper limit of normal (ULN)
- •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x ULN (< 5 x ULN if liver metastases are present)
- •Total bilirubin < 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin up to 3.0 mg/dL)
- •Albumin ≥ 2.2 mg/dL
- •White blood cells (WBC) > 2,000/mm^3
- •Hemoglobin (Hb) ≥ 9
- •Neutrophils > 1,500/mm^3
- •Platelets > 100,000/mm^3
- •Inclusion into ≥ 1 of the following symptomatic, disease states listed below:
- •Inclusion allows entry into that cohort for efficacy assessments. Patients can be in ≥ 1 cohort if they have more than one disease manifestation fitting the below criteria. If a patient fits inclusion/exclusion into one cohort and has disease manifestations that are excluded from another cohort, they can still participate in the trial but will not be assessed for efficacy for that specific disease manifestation
- •KIDNEY CANCER COHORT: Advanced, metastatic kidney cancer disease
- •KIDNEY CANCER COHORT: Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
- •KIDNEY CANCER COHORT: ≥ 1 lines of systemic therapy (not considering adjuvant)
- •UTERINE FIBROIDS COHORT: Age ≥ 18
- •UTERINE FIBROIDS COHORT: Female biologic sex
- •UTERINE FIBROIDS COHORT: Any pre-menopausal patient
- •UTERINE FIBROIDS COHORT: Fibroid-associated symptoms including symptomatic menorrhagia and/or pelvic pain/pressure
- •UTERINE FIBROIDS COHORT: Estimated ≤ 15-week uterus by bimanual exam OR by radiographic parameters (≤ 10 cm max dimension of largest fibroid or estimated weight ≤ 400 g)
- •UTERINE FIBROIDS COHORT: Be willing to use non hormonal contraception if needed
- •CUTANEOUS LEIOMYOMAS COHORT: ≥ 5 cutaneous leiomyomas
- •CUTANEOUS LEIOMYOMAS COHORT: Leiomyoma-associated pain or paresthesia causing weekly pain ≥ 4/10 on a pain scale
排除标准
- •Absolute contraindication to the use of contrast-enhanced imaging for efficacy assessment. If moderate allergy, patients could be allowed if pre-medication can be given to limit adverse reactions. (*Not relevant for skin-only cohort)
- •Presence of untreated brain metastases. Treated brain metastases must be stable for 4 weeks after treatment, have no clinical symptoms, and not be on corticosteroids > 10 mg/day of prednisone-equivalent > 2 weeks prior to treatment. Patients with known leptomeningeal metastases are excluded
- •Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (> 10 mg daily prednisone equivalent) or immunosuppressive medications within 14 days prior to first dose of study drug. An exception is allowed for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
- •History of myocarditis or congestive heart failure (as defined by New York Heart Association Functional Classification III or IV), as well as unstable angina, serious uncontrolled cardiac arrhythmia, uncontrolled infection, or myocardial infarction 6 months prior to study entry
- •Known medical condition that, in the investigator's opinion, would increase the risk associated with study participation or interfere with the interpretation of safety results
- •Individuals who are pregnant; negative serum pregnancy tests in patients of childbearing potential and consent to an effective contraceptive method (if needed Centers for Disease Control and Prevention [CDC] guidelines provided) until a minimum of 30 days after cessation of therapy
- •Individuals who wish to continue actively breast-feeding must agree to not breastfeed during the study or for 180 days after the last dose of study treatment
- •An untreated non-renal malignancy with the following exceptions:
- •low risk prostate cancer on active surveillance (National Comprehensive Cancer Network [NCCN] very low/low risk)
- •non-melanoma skin cancer
- •Any prior treated, non-renal malignancy except for those meeting the following characteristics:
- •Treated stage I or II cancer from which the patient is currently in complete remission
- •Stage III cancer in remission for > 2 years and is not receiving any current treatment
- •A hematologic malignancy from which the patient is considered to be in complete remission
- •UTERINE FIBROIDS COHORT: Hormonal management ≤ 2 months of starting treatment. Including gonadotrophin releasing hormone (GnRH) analog, progestins or estrogen (pills or intrauterine devices), or ulipristal acetate
- •UTERINE FIBROIDS COHORT: GnRH analog usage ≤ 12 months of starting treatment
- •UTERINE FIBROIDS COHORT: History of uterine artery embolization
- •UTERINE FIBROIDS COHORT: Prior radiofrequency ablation to a target lesion
- •UTERINE FIBROIDS COHORT: History of MR guided focused ultrasound
- •UTERINE FIBROIDS COHORT: Myomectomy ≤ 1 year of starting therapy
- •UTERINE FIBROIDS COHORT: Concern for gynecologic malignancy
- •UTERINE FIBROIDS COHORT: Any Federation of Gynecology and Obstetrics (FIGO) 1 or FIGO 2 myomas requiring immediate treatment
- •UTERINE FIBROIDS COHORT: Planning pregnancy in the next 6 months
- •UTERINE FIBROIDS COHORT: History of endometrial ablation
- •UTERINE FIBROIDS COHORT: Hormonal intrauterine device (IUD) in place
- •CUTANEOUS LEIOMYOMAS COHORT: Willingness/ability to have all cutaneous lesions completely removed
研究组 & 干预措施
Treatment (6-MP)
Patients receive 6-MP PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 26 cycles/2 years (for kidney cohort) or up to 13 cycles/1 year (for skin or uterine cohorts) in the absence of disease progression or unacceptable toxicity. Patients may also undergo CT or MRI throughout the study (kidney and uterine cohorts only), tumor biopsy on study (kidney cohort only), skin biopsy on study (skin cohort only), and blood sample collection throughout the study (all cohorts).
干预措施: Questionnaire Administration (Other)
Treatment (6-MP)
Patients receive 6-MP PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 26 cycles/2 years (for kidney cohort) or up to 13 cycles/1 year (for skin or uterine cohorts) in the absence of disease progression or unacceptable toxicity. Patients may also undergo CT or MRI throughout the study (kidney and uterine cohorts only), tumor biopsy on study (kidney cohort only), skin biopsy on study (skin cohort only), and blood sample collection throughout the study (all cohorts).
干预措施: Skin Biopsy (Procedure)
Treatment (6-MP)
Patients receive 6-MP PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 26 cycles/2 years (for kidney cohort) or up to 13 cycles/1 year (for skin or uterine cohorts) in the absence of disease progression or unacceptable toxicity. Patients may also undergo CT or MRI throughout the study (kidney and uterine cohorts only), tumor biopsy on study (kidney cohort only), skin biopsy on study (skin cohort only), and blood sample collection throughout the study (all cohorts).
干预措施: Biopsy Procedure (Procedure)
Treatment (6-MP)
Patients receive 6-MP PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 26 cycles/2 years (for kidney cohort) or up to 13 cycles/1 year (for skin or uterine cohorts) in the absence of disease progression or unacceptable toxicity. Patients may also undergo CT or MRI throughout the study (kidney and uterine cohorts only), tumor biopsy on study (kidney cohort only), skin biopsy on study (skin cohort only), and blood sample collection throughout the study (all cohorts).
干预措施: Biospecimen Collection (Procedure)
Treatment (6-MP)
Patients receive 6-MP PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 26 cycles/2 years (for kidney cohort) or up to 13 cycles/1 year (for skin or uterine cohorts) in the absence of disease progression or unacceptable toxicity. Patients may also undergo CT or MRI throughout the study (kidney and uterine cohorts only), tumor biopsy on study (kidney cohort only), skin biopsy on study (skin cohort only), and blood sample collection throughout the study (all cohorts).
干预措施: Computed Tomography (Procedure)
Treatment (6-MP)
Patients receive 6-MP PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 26 cycles/2 years (for kidney cohort) or up to 13 cycles/1 year (for skin or uterine cohorts) in the absence of disease progression or unacceptable toxicity. Patients may also undergo CT or MRI throughout the study (kidney and uterine cohorts only), tumor biopsy on study (kidney cohort only), skin biopsy on study (skin cohort only), and blood sample collection throughout the study (all cohorts).
干预措施: Magnetic Resonance Imaging (Procedure)
Treatment (6-MP)
Patients receive 6-MP PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 26 cycles/2 years (for kidney cohort) or up to 13 cycles/1 year (for skin or uterine cohorts) in the absence of disease progression or unacceptable toxicity. Patients may also undergo CT or MRI throughout the study (kidney and uterine cohorts only), tumor biopsy on study (kidney cohort only), skin biopsy on study (skin cohort only), and blood sample collection throughout the study (all cohorts).
干预措施: Mercaptopurine (Drug)
结局指标
主要结局
Maximum tolerated dose (MTD)
时间窗: Up to cycle 2 (Cycles = 28 days)
Will be determined using Common Terminology Criteria for Adverse Events version 5.0 grading.
次要结局
- Best overall response (Kidney Cancer Cohort)(Up to 2 years after completion of study treatment)
- Progression-free survival (PFS) (Kidney Cancer Cohort)(From study enrollment to documented disease progression or death from any cause, assessed up to 2 years after completion of study treatment)
- Tumor volume changes (Uterine Fibroids Cohort)(Up to 1 year)
- Changes in Pictorial Blood Loss Assessment Chart (PBAC) scores (Uterine Fibroids Cohort)(Baseline up to 1 year)
- Changes in symptom severity (SSS) and health-related quality of life (HRQoL) domains (Uterine Fibroids Cohort)(Baseline up to 1 year)
- Changes in leiomyoma pain with/without ice provocation (Cutaneous Leiomyomas Cohort)(Baseline up to 1 year)
- Changes in leiomyoma-associated interference (Cutaneous Leiomyomas Cohort)(Baseline up to 1 year)
- Changes in Patient-Reported Global Change (Cutaneous Leiomyomas Cohort)(Baseline up to 1 year)