Leflunomide in Patients With PTEN-null Advanced Solid Malignancies

Study Overview
=================
Brief Summary
-----------------
Leflunomide in patients with PTEN-null advanced solid tumors. Objectives are to determine the safety and tolerability and the MTD of leflunomide in patients with PTEN-null advanced solid malignancies and to assess preliminary evidence of clinical activity of leflunomide in patients with PTEN-null advanced solid malignancies.

Official Title
-----------------
A Phase IA/IB Trial of Leflunomide in Patients With PTEN-null Advanced Solid Malignancies

Conditions
-----------------
PTEN-null Advanced Solid Tumors

Intervention / Treatment
-----------------
* Drug: Leflunomide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 Advanced or metastatic solid tumor with lack of PTEN expression as determined by immunohistochemistry. Lack of PTEN expression is defined as the absence of staining in the tumor (<5%), with strong positive staining of adjacent normal endometrium or stromal cells, using the monoclonal DAKO antibody 6H2.1.9 Patients must have measurable disease per RECIST 1.1 criteria (Appendix C). Patients must have progressed on, be refractory or intolerant of standard therapy for their cancer, if such a standard therapy exists. Patients with treated brain metastases are eligible if follow-up brain imaging at least 4 weeks after after CNS directed therapy shows no evidence of progression. Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS directed therapy is not required and is unlikely to be required during the first cycle of therapy. ≥ 4 weeks from last systemic therapy, surgery or radiation. ECOG performance status 0-2. Patients with HIV on effective anti-retroviral therapy with an undetectable viral load within 6 months are eligible for this trial. 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 GFR (Cockroft-Gault) ≥ 50 mL/min/1.73m2 Negative serum or urine pregnancy test within 3 days prior to C1D1 of leflunomide therapy. 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 Ability to understand and the willingness to sign a written informed consent Exclusion Criteria: Patients with primary CNS tumors are not eligible. Patients who have had chemotherapy or radiotherapy within 4 weeks before entering the study or those who have not recovered from grade ≥ 2 adverse events due to agents administered more than 4 weeks earlier. Adverse events such as alopecia, hypothyroidism, and neuropathy are allowed. Other adverse events may be allowed by permission of the principal investigator. Patients may not be receiving any other investigational agents. A known history of acute or chronic Hepatitis B or C, due to the known potential hepatotoxicity of leflunomide. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Leflunomide<br>Leflunomide, 20-50mg PO daily | Drug: Leflunomide<br>* Leflunomide, 20-50mg PO daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Dose-limiting toxicities | Grade 3 or higher non-hematologic toxicity, Any death not clearly due to the underlying disease, Cases defined by Hy's law, Grade 4 neutropenia or thrombocytopenia > 7 days, Grade 3 thrombocytopenia with clinically significant bleeding, Febrile neutropenia | 1 month | 
| Number of Dose-limiting toxicities | Grade 3 or higher non-hematologic toxicity Any death not clearly due to the underlying disease Cases defined by Hy's law Grade 4 neutropenia or thrombocytopenia > 7 days Grade 3 thrombocytopenia with clinically significant bleeding Febrile neutropenia | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose | A standard 3+3 design is used to define the MTD. Dose level 0 will only be utilized in the presence of ≥2/6 DLTs in dose level 1 or for a dose reduction if a patient does not tolerate dose level one. Standard dosing for rheumatoid arthritis is 100mg daily for 3 days loading dose followed by 20mg daily maintenance dose, which can be reduced to 10mg in the event of intolerance. | 2 years | 
| Overall Response Rate | Overall Response Rate for dose expansion cohort. Overall response rate is defined as the proportion of patients achieving a best response of complete response or partial response using RECIST v1.1 | 2 years |