Clinical Trials /

Leflunomide in Previously Treated Metastatic Triple Negative Cancers

NCT03709446

Description:

Triple negative breast cancer (TNBC) represents about 15% of breast cancers and is characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR), and HER-2 non-amplification. Women with TNBC tend to be younger, African American, and BRCA-1 germline carriers. The hallmark of this subtype is early metastatic recurrences with a peak frequency 1-2 years. Prognosis for metastatic TNBC is especially poor with median survival of about 1 year as compared to about 2-4 years with other types of metastatic breast cancer. The primary objective of the phase I part of this study is to determine the safety, tolerability and maximum tolerated dose of leflunomide in women with previously treated TNBC. The primary objective of the phase 2 part of this study is to determine the efficacy of leflunomide in patients with TNBC. Leflunomide, which will be taken daily by mouth, is an inhibitor of dihydroorotate dehydrogenase (DHODH). This proposal will test if DHODH is a novel target for a particular subset of women with metastatic TNBC.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase I/II Trial of Leflunomide in Previously Treated Metastatic Triple Negative Cancers
  • Official Title: A Phase I/II Trial of Leflunomide in Women With Previously Treated Metastatic Triple Negative Cancers

Clinical Trial IDs

  • ORG STUDY ID: GCO 18-1832
  • NCT ID: NCT03709446

Conditions

  • Breast Neoplasms
  • Breast Diseases
  • Metastatic Triple Negative Breast Cancer

Interventions

DrugSynonymsArms
LeflunomideAravaLeflunomide

Purpose

Triple negative breast cancer (TNBC) represents about 15% of breast cancers and is characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR), and HER-2 non-amplification. Women with TNBC tend to be younger, African American, and BRCA-1 germline carriers. The hallmark of this subtype is early metastatic recurrences with a peak frequency 1-2 years. Prognosis for metastatic TNBC is especially poor with median survival of about 1 year as compared to about 2-4 years with other types of metastatic breast cancer. The primary objective of the phase I part of this study is to determine the safety, tolerability and maximum tolerated dose of leflunomide in women with previously treated TNBC. The primary objective of the phase 2 part of this study is to determine the efficacy of leflunomide in patients with TNBC. Leflunomide, which will be taken daily by mouth, is an inhibitor of dihydroorotate dehydrogenase (DHODH). This proposal will test if DHODH is a novel target for a particular subset of women with metastatic TNBC.

Trial Arms

NameTypeDescriptionInterventions
LeflunomideExperimentalWomen with metastatic triple negative breast cancer. Leflunomide tablet orally daily
  • Leflunomide

Eligibility Criteria

        Inclusion Criteria:

          -  Women with histologically confirmed TNBC on the pre-trial metastatic biopsy.

          -  Age ≥ 18.

          -  ≤ 2 prior chemotherapies for metastatic disease.

          -  Prior immunotherapy is permitted and does not count as chemotherapy.

          -  The use denosumab or zoledronic is permitted.

          -  History of previously treated brain metastases with ≥ 4 weeks after definitive surgery
             and gamma knife/whole brain radiation and not taking steroids.

          -  ≥ 4 weeks from last oral or IV chemotherapy, small molecule inhibitor, a biologic
             agent, surgery or radiation.

          -  Performance status 0-2.

          -  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) ≤ ULN

               -  Creatinine ≤ ULN

               -  A negative serum or urine pregnancy test within 3 days of receiving Day 1 Cycle 1
                  of leflunomide.

          -  Women of child-bearing potential and men must agree to use adequate contraception
             before study entry, for the duration of study participation and for 90 days following
             completion of therapy. Should a woman become pregnant or suspect she is pregnant while
             participating in this study, she should inform her treating physician immediately.

          -  Recommended methods of birth control are: The consistent use of an approved hormonal
             contraception such as an intrauterine device (IUD), Double barrier methods (Diaphragm
             with spermicidal gel or condoms with contraceptive foam), Sexual abstinence (no sexual
             intercourse) or Sterilization. The use of hormonal forms of birth control is
             controversial in TNBC and as such women enrolled in the trial are permitted to use
             birth control pills or depot Provera, only after a documented discussion by the
             treating physician as too the uncertain risks of hormonal birth control methods in the
             TNBC population. A female of child-bearing potential is any woman (regardless of
             sexual orientation, having undergone a tubal ligation, or remaining celibate by
             choice) who meets the following criteria: Has not undergone a hysterectomy or
             bilateral oophorectomy; or Has not been naturally postmenopausal for at least 12
             consecutive months (i.e., has had menses at any time in the preceding 12 months).

          -  Ability to understand and the willingness to sign a written informed consent.

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks before entering the
             study or those who have not recovered from adverse events due to agents administered
             more than 4 weeks earlier.

          -  Patients may not be receiving any other investigational agents.

          -  The known history human immunodeficiency virus, acute and chronic Hepatitis B or C, or
             acute or previously treated tuberculosis.

          -  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.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to leflunomide or teriflunomide.

          -  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 must not be pregnant or nursing due to the potential for congenital
             abnormalities and the potential of this regimen to harm nursing infants.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:3 months
Safety Issue:
Description:3+3 escalation schema. treated at each dose level until Dose-limiting Toxicity (DLT) (defined as any grade 3 or higher toxicity seen during the first cycle of leflunomide). If 2/3 patients experience a DLT, one dose level will be defined as the MTD. If 1/3 experiences a DLT, three additional patients will be enrolled. If ≤ 2/6 patients experience a DLT, the next cohort of 3 patients will be treated with the next dose level. If ≥ 3/6 experience a DLT, the next lower dose level will define the MTD. If at the 50 mg dose/day if 0/3 or ≤ 2/6 patients experience a DLT, then that dose will define the MTD

Secondary Outcome Measures

Measure:Number of side effects
Time Frame:3 years
Safety Issue:
Description:Number of side effects using NCI CTCAE v.4.03
Measure:Objective Response Rate
Time Frame:3 years
Safety Issue:
Description:Objective Response Rate (proportion of patients with the best overall response of CR or PR) in those who have measurable disease by RECIST
Measure:Progression-free survival (PFS)
Time Frame:3 years
Safety Issue:
Description:PFS of women with phosphatase and tensin homolog (PTEN) wild-type and PTEN null expression breast cancers. PFS is defined as the duration of time from the start of treatment to the first occurrence of disease progression or death from any cause, whichever occurs first.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Charles L Shapiro MD

Trial Keywords

  • Breast Neoplasms
  • Breast Diseases
  • Leflunomide
  • Teriflunomide
  • Phosphatase and tensin homolog

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