Epacadostat in Treating Patients with Resectable Solid Tumors
This phase Ib trial studies how epacadostat reacts in the body and how well it works in treating patients with solid tumors that can be removed by surgery. Epacadostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
- Subjects must meet the inclusion criteria listed in the master protocol.
- White blood cell (WBC) > 3,000/mcL.
- Absolute neutrophil count > 1,500/mcL.
- Platelets > 100 x 10^9/L.
- Hemoglobin >= 9 g/dL or < 5.6 mmol/L. * NOTE: transfusion is acceptable to meet this criterion.
- Total bilirubin < 1.5 x upper limit of normal (ULN) or normal direct bilirubin if the patient has Gilberts. * NOTE: If total bilirubin exceeds the ULN, conjugated bilirubin must be checked, and subjects should be excluded if the value is >= 2.0 x ULN.
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase ALT (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN.
- Alkaline phosphatase (ALP) < 5 x ULN, in subjects with 1) bone metastases and 2) no hepatic parenchymal metastases on screening radiographic examinations may.
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN.
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN.
- Creatinine < 1.5 x ULN OR measured or calculated creatinine clearance (glomerular filtration rate can also be used in place of creatinine or creatinine clearance [CrCl]) >= 50 mL/min for subjects with creatinine levels >= 1.5 x institutional ULN.
- Women of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to registration. Patients that are pregnant or breast feeding are excluded. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
- Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 months after completion of study. * Should a woman become pregnant or suspect while she or her partner is participating in this study, she should inform her treating physician immediately.
- Subject meets any exclusion criteria listed in the master protocol.
- Pregnant or nursing women or subjects expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment.
- Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg [> 10 mg] daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days before the first dose of study treatment. * NOTE: Use of inhaled or topical steroids or systemic corticosteroids < 10 mg is permitted.
- Subjects who have any active or inactive autoimmune disease or syndrome (i.e., rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease) that has required systemic treatment in the past 2 years or who are receiving systemic therapy for an autoimmune or inflammatory disease (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). NOTE: Exceptions include subjects with vitiligo or resolved childhood asthma/atopy, hypothyroidism stable on hormone replacement, controlled asthma, type I diabetes, Grave's disease, or Hashimoto's disease, or with medical monitor approval.
- Evidence of interstitial lung disease or active, noninfectious pneumonitis including symptomatic and/or pneumonitis requiring treatment.
- Active infection requiring systemic therapy.
- Presence of a gastrointestinal condition that may affect drug absorption.
- Uncontrolled human immunodeficiency viral (HIV; HIV 1/2 antibodies) infection. * NOTE: Patients who are HIV-positive are eligible if: ** CD4+ cell count greater or equal to 250 cells/mm^3 ** If patient is on antiretroviral therapy, there must be minimal interactions or overlapping toxicity of the antiretroviral therapy with the experimental cancer treatment ** No history of non-malignancy acquired immunodeficiency syndrome (AIDS)-defining conditions other than historical low CD4+ cell counts ** Probable long-term survival with HIV if cancer were not present.
- Patients who have a positive test for hepatitis B virus surface antigen (HBVs Ag) and HBV deoxyribonucleic acid (DNA) positive or hepatitis C antibody (HCV Ab)/ribonucleic acid (RNA) (HCV RNA) indicating acute or chronic infection are ineligible (baseline testing required).
- Receipt of live attenuated vaccine within 30 days before the first dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed.
- Subjects receiving monoamine oxidase inhibitors (MAOIs) or drug which has significant MAOI activity (meperidine, linezolid, methylene blue) within the 21 days before screening.
- Subjects receiving coumarin-based anticoagulants (e.g. Coumadin).
- Any history of serotonin syndrome (SS) after receiving serotonergic drugs.
- History or presence of an abnormal electrocardiogram (ECG) that, in the investigator's opinion, is clinically meaningful. Screening corrected QT (QTc) interval > 480 milliseconds is excluded. In the event that a single QTc is > 480 milliseconds, the subject may enroll if the average QTc for the 3 ECGs is < 480 milliseconds. For subjects with an intraventricular conduction delay (QRS interval > 120 milliseconds), the corrected JT (JTc) interval may be used in place of the QTc with sponsor approval. The JTc must be < 340 milliseconds if JTc is used in place of the QTc. Subjects with left bundle branch block are excluded. * NOTE: QTc prolongation due to pacemaker may enroll if the JTc is normal.
- Use of any UGT1A9 inhibitor from screening through follow-up period, including the following: diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid.
Locations & Contacts
Contact: Nilofer Saba Azad
Trial Objectives and Outline
I. To explore the mechanism of action and the immunologic correlates associated with administration of epacadostat therapy in subjects with resectable solid malignancies, with a particular focus in changes in CD8+ T cells, on tumor tissue.
I. To assess the safety and tolerability of epacadostat in the pre-surgical setting graded according to Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
II. To evaluate pathological response rate of solid tumor malignancies in subjects with resectable solid malignancies receiving neo-adjuvant therapy with epacadostat and the correlation with biomarkers either in the tumor specimens either in the bloods samples.
III. To measure the baseline serum levels of tryptophan levels and serum kynurenine/tryptophan ratio and to measure their changes after treatment.
I. To evaluate changes in expression of IDO in peripheral blood cells and tumor biopsies pre- and post-therapy.
II. To assess the ratio of effector T cells: regulatory T cells in peripheral blood and tumor biopsies pre- and post therapy (immunohistochemistry).
III. To evaluate inflammatory T cell signature changes in peripheral blood and tumor biopsies pre- and post therapy.
IV. To evaluate changes in number of regulatory T-cells (Tregs), classical dendritic cells (cDCs), plasmacytoid dendritic cells (pDCs), NK and myeloid-derived suppressor cells (MDSCs) cells in peripheral blood and tumor biopsies pre- and post-therapy (flow cytometry).
V. To identify gene expression changes in malignant tissue after therapy, and to perform complete gene set analysis to elucidate affected pathways.
VI. To explore changes in other immune markers pre and after treatment.
Patients receive epacadostat orally (PO) twice daily (BID) on days 1-14. Within 1 week after last dose, patients undergo standard of care surgery.
After completion of study treatment, patients are followed up within 6-8 weeks after surgery, then every 12 weeks for up to 6 months.
Trial Phase & Type
Johns Hopkins University / Sidney Kimmel Cancer Center
Nilofer Saba Azad
Secondary IDs NCI-2018-03651, CRMS-67892, IRB00156271
Clinicaltrials.gov ID NCT03471286