Mercaptopurine for the Treatment of Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC), Uterine/Cutaneous Leiomyomas, and Kidney Cancer

Mercaptopurine (6-MP) for the Treatment of Manifestations of Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Metastatic Renal Cell Carcinoma; Stage III Renal Cell Cancer AJCC v8; Stage IV Renal Cell Cancer AJCC v8; Advanced Renal Cell Carcinoma; Hereditary Leiomyomatosis and Renal Cell Carcinoma; Metastatic Kidney Carcinoma; Advanced Kidney Carcinoma; Skin Leiomyoma; Uterine Corpus Leiomyoma
• Intervention / Treatment: Other: Questionnaire Administration; Procedure: Biospecimen Collection; Procedure: Magnetic Resonance Imaging; Procedure: Computed Tomography; Drug: Mercaptopurine; Procedure: Biopsy Procedure; Procedure: Skin Biopsy

Detailed Description

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.

EXPLORATORY OBJECTIVES:

I. Associate changes in serum thiopurine metabolites (6-methylmercaptopurine [6-MMP] and 6-thioguanine [6-TG]) with efficacy endpoints for kidney cancer, cutaneous leiomyoma, and uterine fibroids.

II. Generate in vitro and in vivo models of cutaneous leiomyomas and kidney cancer that may be useful to predict clinical activity to treatment with 6-MP or purine restriction.

III. Bank clinical specimens (urine, tissue, blood) and tissue for future HLRCC research.

OUTLINE: This is a phase I dose-escalation study followed by a phase II study.

Patients receive 6-MP orally (PO) once daily (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 computed tomography (CT) or magnetic resonance imaging (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).

After completion of study treatment, patients are followed up within 45 days and then every 12 months for 2 years.

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA / Jonsson Comprehensive Cancer Center
      • Principal Investigator: Brian Shuch
      • Contact: Brian Shuch; Email: Bshuch@mednet.ucla.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18

• 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

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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).

Other: Questionnaire Administration; Ancillary studies; Procedure: Biospecimen Collection; Undergo collection of blood; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Drug: Mercaptopurine; Given PO; Other Names: 6-MP; Purinethol; 3H-Purine-6-thiol; 6 MP; 6 Thiohypoxanthine; 6 Thiopurine; 6-Mercaptopurine; 6-Mercaptopurine Monohydrate; 6-Purinethiol; 6-Thiopurine; 6-Thioxopurine; 6H-Purine-6-thione, 1,7-dihydro- (9CI); 7-Mercapto-1,3,4,6-tetrazaindene; Alti-Mercaptopurine; Azathiopurine; Bw 57-323H; Flocofil; Ismipur; Leukerin; Leupurin; Mercaleukim; Mercaleukin; Mercaptina; Mercaptopurinum; Mercapurin; Mern; NCI-C04886; Puri-Nethol; Purimethol; Purine, 6-mercapto-; Purine-6-thiol (8CI); Purine-6-thiol, monohydrate; Purinethiol; U-4748; WR-2785; Procedure: Biopsy Procedure; Undergo tumor biopsy; Other Names: Bx; BIOPSY_TYPE; Biopsy; Procedure: Skin Biopsy; Undergo skin biopsy; Other Names: Biopsy of Skin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD)	Will be determined using Common Terminology Criteria for Adverse Events version 5.0 grading.	Up to cycle 2 (Cycles = 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best overall response (Kidney Cancer Cohort)	Will be assessed per Response Evaluation Criteria in Solid Tumors. A descriptive summary will report the proportion of patients with complete response, partial response, stable disease, or progressive disease. Patients who are unevaluable will be summarized separately.	Up to 2 years after completion of study treatment
Progression-free survival (PFS) (Kidney Cancer Cohort)	Kaplan-Meier survival curves will be generated to estimate the distribution of PFS, including median survival and confidence intervals. Landmark analyses will be conducted at 1-year and 2-year time points to estimate the proportion of patients remaining progression-free at these intervals, providing both longitudinal and milestone-based insights into disease control.	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)	Will be assessed via pelvic magnetic resonance imaging. A descriptive summary will report maximal volume reduction from baseline, including the proportion of patients achieving partial or complete response, stable disease, or progression, based on predefined thresholds. Mean and median volume changes will be calculated, and overall response rates will be summarized.	Up to 1 year
Changes in Pictorial Blood Loss Assessment Chart (PBAC) scores (Uterine Fibroids Cohort)	Will be summarized from baseline to follow-up. Response will be defined as a ≥ 50% reduction in PBAC score. The proportion of responders and non-responders will be reported, along with changes in mean and median scores.	Baseline up to 1 year
Changes in symptom severity (SSS) and health-related quality of life (HRQoL) domains (Uterine Fibroids Cohort)	Will be assessed using the Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QOL) questionnaire. Response will be defined as a ≥ 10-point improvement in SSS and ≥ 20-point improvement in HRQoL scores. Descriptive statistics will summarize changes from baseline, and response rates will be reported.	Baseline up to 1 year
Changes in leiomyoma pain with/without ice provocation (Cutaneous Leiomyomas Cohort)	A descriptive summary of the Visual Analogue Scale will be provided from baseline to follow-up scans both with and without ice provocation. The number of responders (improvement in 2 points or 30% reduction) and non-responders will be reported. Similarly, changes in the Brief Pain Inventory-Short Form (BPI-SF) pain severity (average of the 4 questions) will identify the number of responders (2-point reduction or 30% improvement) and non-responders.	Baseline up to 1 year
Changes in leiomyoma-associated interference (Cutaneous Leiomyomas Cohort)	Will be evaluated using BPI-SF interference scores across all time points. Descriptive statistics will summarize changes from baseline to each follow-up, as well as from baseline to maximal improvement. Response rates will be calculated based on predefined thresholds (≥ 2-point or ≥ 30% improvement), and changes in mean and median scores will be reported.	Baseline up to 1 year
Changes in Patient-Reported Global Change (Cutaneous Leiomyomas Cohort)	The Patient's Global Impression of Change (PGIC) will be analyzed descriptively to assess perceived improvement in overall skin symptoms. The maximal PGIC score change from baseline will be summarized, and PGIC scores will be visualized across visits using spider plots to illustrate individual and cohort-level trends over time.	Baseline up to 1 year

Collaborators and Investigators

• Sponsor: Jonsson Comprehensive Cancer Center
• Collaborators: The V Foundation; Phase One Foundation
• Investigators: Principal Investigator: Brian Shuch, UCLA / Jonsson Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2026
• Primary Completion (Estimated): December 1, 2034
• Study Completion (Estimated): December 1, 2035

Study Registration Dates

• First Submitted: July 15, 2026
• First Submitted That Met QC Criteria: July 15, 2026
• First Posted (Actual): July 21, 2026

Study Record Updates

• Last Update Posted (Actual): July 21, 2026
• Last Update Submitted That Met QC Criteria: July 15, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Connective Tissue Diseases; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Urologic Neoplasms; Carcinoma; Kidney Neoplasms; Neoplasms, Connective and Soft Tissue; Neoplasms, Connective Tissue; Skin and Connective Tissue Diseases; Carcinoma, Renal Cell; Myofibroma; Hereditary leiomyomatosis and renal cell cancer; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Purines; Diagnostic Techniques, Surgical; Chemistry Techniques, Analytical; Spectrum Analysis; Sulfhydryl Compounds; Mercaptopurine; Biopsy; Specimen Handling; Magnetic Resonance Spectroscopy; azathiopurine
• Other Study ID Numbers: 25-2484; NCI-2026-04727 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No