Leflunomide in Previously Treated Metastatic Triple Negative Cancers

• ClinicalTrials.gov Identifier: NCT03709446
• Recruitment Status: Recruiting
• First Posted: October 17, 2018
• Last Update Posted: June 7, 2022
• Sponsor: Joseph Sparano
• Information provided by (Responsible Party): Joseph Sparano, Icahn School of Medicine at Mount Sinai

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Breast Neoplasms; Breast Diseases; Metastatic Triple Negative Breast Cancer	Drug: Leflunomide	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 54 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Trial of Leflunomide in Women With Previously Treated Metastatic Triple Negative Cancers
• Actual Study Start Date: April 16, 2019
• Estimated Primary Completion Date: October 2023
• Estimated Study Completion Date: October 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Leflunomide; Women with metastatic triple negative breast cancer. Leflunomide tablet orally daily	Drug: Leflunomide; Single agent leflunomide; Other Name: Arava

Outcome Measures

Primary Outcome Measures :

1. Maximum Tolerated Dose (MTD) [ Time Frame: 3 months ]
   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
2. Clinical Benefit Rate (CBR) [ Time Frame: 6 months ]
   Response and progression to be evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST). CBR = Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) for at least 6 months duration

Secondary Outcome Measures :

1. Number of side effects [ Time Frame: 3 years ]
   Number of side effects using NCI CTCAE v.4.03
2. Objective Response Rate [ Time Frame: 3 years ]
   Objective Response Rate (proportion of patients with the best overall response of CR or PR) in those who have measurable disease by RECIST
3. Progression-free survival (PFS) [ Time Frame: 3 years ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Contacts

Contact: Rita Vaccaro, RN; 212-659-5549; rita.vaccaro@mssm.edu

Locations

United States, New York

Mt Sinai Chelesa; Recruiting

New York, New York, United States, 10011

Mt Sinai West; Recruiting

New York, New York, United States, 10019

Icahn School of Medicine at Mount Sinai; Recruiting

New York, New York, United States, 10029

Sponsors and Collaborators

Joseph Sparano

Investigators

• Principal Investigator: Joseph Sparano, MD; Icahn School of Medicine at Mount Sinai

More Information

• Responsible Party: Joseph Sparano, Professor, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT03709446
• Other Study ID Numbers: GCO 18-1832
• First Posted: October 17, 2018
• Last Update Posted: June 7, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Joseph Sparano, Icahn School of Medicine at Mount Sinai:

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

Additional relevant MeSH terms:

Triple Negative Breast Neoplasms; Breast Neoplasms; Breast Diseases; Neoplasms; Neoplasms by Site; Skin Diseases; Leflunomide; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs