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.
Title
- Brief Title: 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
Drug | Synonyms | Arms |
---|
Leflunomide | Arava | Leflunomide |
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
Name | Type | Description | Interventions |
---|
Leflunomide | Experimental | Women with metastatic triple negative breast cancer. Leflunomide tablet orally daily | |
Eligibility Criteria
Inclusion Criteria:
- Women with histologically confirmed ER ≤ 10% and or PR ≤ 10% TNBC on the pre-trial
metastatic biopsy.
- Age ≥ 18.
- ≤ 3 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) ≤ 2 x 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 ≥ 2 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: | Recruiting |
Lead Sponsor: | Charles L Shapiro MD |
Trial Keywords
- Breast Neoplasms
- Breast Diseases
- Leflunomide
- Teriflunomide
- Phosphatase and tensin homolog
Last Updated
March 17, 2020