What side effects are associated with this type of intervention?

Common treatments for breast disease, particularly breast cancer, include chemotherapy, hormone therapy, and targeted therapy. Chemotherapy can cause side effects such as alopecia, nausea, vomiting, diarrhea, fatigue, and neuropathy. Hormone therapies, like aromatase inhibitors, may lead to hot flashes, joint pain, and osteoporosis. Targeted therapies, such as those involving monoclonal antibodies, can result in infusion reactions, fatigue, and gastrointestinal issues. Specifically, for treatments similar to Leflunomide, which targets DHODH, side effects may include gastrointestinal disturbances, liver enzyme abnormalities, and potential immunosuppression.

What prior FDA approvals exist?

FDA-approved treatments for breast disease, particularly breast cancer, include a variety of hormone therapies, chemotherapies, and targeted therapies. Hormone therapies like tamoxifen and aromatase inhibitors target estrogen receptors. Chemotherapies such as doxorubicin and paclitaxel are commonly used. Targeted therapies include HER2 inhibitors like trastuzumab and pertuzumab. While Leflunomide, a DHODH inhibitor, is being studied for its efficacy in triple-negative breast cancer, there are no specific FDA-approved DHODH inhibitors for breast cancer treatment as of now.

What other types of research exist?

Promising novel alternatives to Leflunomide for breast disease patients, particularly those with TNBC, include PARP inhibitors (e.g., Olaparib, Talazoparib), immune checkpoint inhibitors (e.g., Pembrolizumab, Atezolizumab), and antibody-drug conjugates (e.g., Sacituzumab Govitecan). These therapies have shown significant efficacy in clinical trials and are being integrated into treatment protocols for breast cancer.

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DHODH Inhibitor

Leflunomide for Triple Negative Breast Cancer

Phase 1 & 2

Recruiting

Led By Joseph Sparano, MD

Research Sponsored by Charles L Shapiro MD

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Adequate organ and marrow function as defined below: leukocytes ≥ 3,000/mcL, Absolute neutrophil count ≥ 1,000/mcL, platelets ≥ 100,000/mcl, total bilirubin within institutional upper limit of normal (≤ ULN), AST (SGOT)/ALT (SPGT) ≤ 3 x ULN (3xULN if liver mets), Creatinine ≤ ULN, A negative serum or urine pregnancy test within 3 days of receiving Day 1 Cycle 1 of leflunomide.

Age ≥ 18.

Must not have

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Patients with untreated brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 6 years

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing the safety and effectiveness of leflunomide, a daily oral medication, in women with aggressive triple negative breast cancer. The drug aims to block a substance that helps cancer cells grow. The study focuses on women who have already tried other treatments.

Who is the study for?

This trial is for women with metastatic triple-negative breast cancer or ER+, HER2- negative breast cancer who have undergone previous treatments. They must be over 18, not pregnant, willing to use contraception, and have a performance status of 0-2. Participants should not have had chemotherapy or radiotherapy within the last 4 weeks and must have recovered from any prior treatment side effects.

What is being tested?

The study is testing Leflunomide's safety and effectiveness in treating metastatic TNBC. It's taken orally daily and targets DHODH, an enzyme that may play a role in this type of cancer. The trial has two phases: Phase I determines the maximum tolerated dose; Phase II assesses how well it works against TNBC.

What are the potential side effects?

Potential side effects of Leflunomide include risk of infection due to immune system suppression, liver issues (as indicated by blood tests), diarrhea, hair loss, high blood pressure, skin reactions like rash or dry skin, and respiratory infections like pneumonia.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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Your blood and organ function tests must show certain levels within normal ranges, and you must have a negative pregnancy test before starting the study drug leflunomide.

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I am 18 years old or older.

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I can take care of myself and perform daily activities.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I do not have any severe illnesses that could interfere with the study.

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I do not have untreated brain metastases.

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I haven't had chemotherapy or radiotherapy in the last 2 weeks and have recovered from any side effects from treatments over 4 weeks ago.

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I have a history of HIV, Hepatitis B or C, or tuberculosis.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 6 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~6 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and 6 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Clinical Benefit Rate (CBR)

Maximum Tolerated Dose (MTD)

Secondary study objectives

Number of side effects

Objective Response Rate

Progression-free survival (PFS)

Side effects data

From 2015 Phase 4 trial • 400 Patients • NCT01172639

33%

Upper respiratory tract infection

26%

Abdominal pain

23%

Nausea

19%

Gastroenteritis

16%

Hairloss

14%

Liver function disturbance

12%

Tendinopathy

12%

Arthralgia

Eczema

Vertigo

Hypertension

Increased transpiration

Arthrosis

Back pain

Agitation

Tooth extraction

Paresthesia

Pruritus

Sjogren's disease

Venous insufficiency

Palpitations

Anaemia

Influenza infection

Fatigue

Muscle cramps

Headache

Bronchitis

General malaise

Arthritis

Flushes

Endometrioid adenocarcinoma

Pyrosis

Intervertebral disc disorder

Rotator cuff lesion

Bladder infection

Eye infection

Insomnia

Diarrhoea

Angina

Kidney cancer malignant

Pneumonia

Cough

Genital infection

100%

80%

60%

40%

20%

Study treatment Arm

CoBRA Slim Low Risk Group

Tight Step Up Low Risk Group

CoBRA Classic High Risk Group

CoBRA Slim High Risk Group

CoBRA Avant-garde High Risk Group

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: LeflunomideExperimental Treatment1 Intervention

Women with HER2-negative metastatic and/or locally advanced, inoperable breast cancer. Leflunomide tablet orally daily

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Leflunomide

2003

Completed Phase 4

~1670

0 / 7Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for breast disease, particularly breast cancer, include hormone therapies, chemotherapy, and targeted therapies. Hormone therapies, such as tamoxifen and aromatase inhibitors, work by blocking hormone receptors or decreasing hormone production, which is crucial for hormone receptor-positive breast cancers. Chemotherapy drugs, like doxorubicin, kill rapidly dividing cancer cells by damaging their DNA. Targeted therapies, such as HER2 inhibitors, specifically target cancer cell proteins to inhibit their growth. Leflunomide, an inhibitor of dihydroorotate dehydrogenase (DHODH), disrupts pyrimidine synthesis, which is essential for DNA replication in rapidly dividing cells. Understanding these mechanisms helps patients and doctors choose the most effective treatment based on the cancer's specific characteristics.

Combination endocrine therapy in the management of breast cancer.