Epacadostat and Pembrolizumab in Treating Patients with Locally Advanced or Metastatic Sarcoma
This phase II trial studies how well epacadostat and pembrolizumab work in treating patients with sarcoma that has spread to nearby tissues, lymph nodes or other places in the body. Epacadostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving epacadostat and pembrolizumab may work better in treating patients with sarcoma.
- Be willing and able to provide written informed consent/assent for the trial
- Be willing to comply with treatment protocol
- Subjects must have a histologically confirmed metastatic and/or locally advanced sarcoma
- Adequate performance status: Eastern Cooperative Oncology Group (ECOG) 0 or 1/Karnofsky performance status (KPS) 100-70%
- Subjects must have at least one prior line of systemic therapy (e.g. chemotherapy, immunotherapy, targeted or biological therapy) for their sarcoma; an exception to this criterion will be made for patients with sarcoma histological subtypes for which there is no known standard systemic therapy (e.g., chondrosarcoma); any patient that refuses standard chemotherapy for the treatment of their disease is also considered eligible; prior adjuvant therapy will not count provided it was completed more than 6 months previously
- Presence of measurable disease per RECIST v1.1; target lesions must not be chosen from a previously irradiated field unless there has been radiographically and/or pathologically documented tumor progression in that lesion prior to enrollment
- All subjects must agree to pre-treatment tumor biopsy; subjects in whom biopsy is technically not feasible or in whom would result in unacceptable risk, in the opinion of the investigator, may be exempted from the biopsy requirement with discussion with the principal investigator
- Absolute neutrophil count (ANC) >= 1,000/mcL within 21 days of treatment initiation
- Platelets >= 75,000 / mcL within 21 days of treatment initiation
- Hemoglobin >= 8 g/dL or >= 5.0 mmol/L within 21 days of treatment initiation
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or corrected creatinine [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN within 21 days of treatment initiation
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN within 21 days of treatment initiation
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases within 21 days of treatment initiation
- Albumin >= 2.5 mg/dL within 21 days of treatment initiation
- International normalized ratio or prothrombin time =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as prothrombin time (PT) or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants within 21 days of treatment initiation
- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants within 21 days of treatment initiation
- Women of childbearing potential must have a negative serum pregnancy test at screening and =< 72 hours prior to day 1 of study treatment
- Male and female subjects of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of study medication; Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- Uncontrolled intercurrent illness including current active infection requiring systemic therapy or symptomatic congestive heart failure within 6 months
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
- Evidence of clinically significant immunosuppression such as the following: * Primary immunodeficiency state such as severe combined immunodeficiency disease * Concurrent opportunistic infection * Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid doses > 10 mg/day of prednisone or equivalent within 7 days prior to enrollment; however, in the setting of non-immune mediated indications for steroid use, chronic/active low dose steroid use may be permitted at the discretion of the principal investigator; the dose of steroid allowed in this setting is also at the discretion of the principal investigator; (use of inhaled or topical steroids is permitted)
- History or evidence of symptomatic autoimmune disease (e.g., pneumonitis, glomerulonephritis, vasculitis, or other), or history of active autoimmune disease that has required systemic treatment (i.e., use of corticosteroids, immunosuppressive drugs or biological agents used for treatment of autoimmune diseases) in past 2 years prior to enrollment; replacement therapy (e.g., thyroxine for hypothyroidism, insulin for diabetes or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment for autoimmune disease
- Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) disease
- Has known active hepatitis B (e.g., hepatitis B virus polymerase chain reaction [PCR] is detected) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
- Patients who have received a live vaccine within 30 days of the start date of the planned study therapy; 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; note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
- Has a known history of active TB (Bacillus tuberculosis)
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 2 weeks of the first dose of treatment
- Has had a prior chemotherapy, immunotherapy, biological therapy, targeted small molecule therapy, or radiation therapy within 3 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to previously administered agent * Note: subjects with =< grade 2 neuropathy, alopecia or hypothyroidism are an exception to this criterion and may qualify for the study * Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy events due to a previously administered agent
- Presence of a gastrointestinal condition that may affect drug absorption
- Known allergy or reaction to any component of either study drug formulation
- Women who are pregnant or breast feeding
- Subjects expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of study treatment(s)
- Inability to comply with protocol required procedures
- Subjects receiving monoamine oxidase inhibitors (MAOIs) or drug which has significant MAOI activity (meperidine, linezolid, methylene blue) within the 21 days before screening
- 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 the approval of the principal investigator; 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
- History of prior therapy with an IDO1 inhibitor in combination with an anti-PD-1/anti-PD-L1 agent/any other drug specifically targeting checkpoint pathways; patients who have received prior therapy with single agent anti-PD-1/anti-PD-L1 therapy or single agent IDO1 inhibitor will be eligible for this study
- Presence of any other concurrent active malignancy
Locations & Contacts
Contact: Sandra Pierina D'Angelo
Trial Objectives and Outline
I. To evaluate the efficacy of epacadostat in combination with pembrolizumab in patients with advanced sarcoma, as assessed by the best objective response rate (complete response + partial response) by 24 weeks using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
I. To assess the safety of epacadostat in combination with pembrolizumab in patients with advanced sarcoma using Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.03 criteria for toxicity assessment.
II. To determine the progression free survival (PFS) rate at 24 weeks by RECIST 1.1 and immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) and overall survival (OS) for patients treated with epacadostat in combination with pembrolizumab.
III. To evaluate the efficacy of epacadostat in combination with pembrolizumab in patients with advanced sarcoma, as assessed by the best objective response rate (complete response + partial response) by 24 weeks by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).
I. To determine the baseline characteristics of sarcoma tumors (pre-treatment biopsy sample) evaluated in this study including the level of IDO1, kynurenine and PD-1/PD-L1 expression, presence of tumor infiltrating lymphocytes (TILs) and tumor antigens, gene expression profile, and the T-cell receptor clonality in tumor-infiltrating lymphocytes (TIL).
II. To assess the potential effect of epacadostat and pembrolizumab on selected biomarker expression measured in pre- and post-treatment tumor tissue and the association between these biomarkers (baseline level of expression and the change in biomarker level of expression following treatment) and clinical outcome, including characterization of IDO-1 expression, PD-1/PD-L1 expression, kynurenine expression, tumor-infiltrating lymphocytes (TILs) and tumor antigens, gene expression profiling, and characterization of T-cell receptor clonality in tumor-infiltrating lymphocytes (TIL).
III. To evaluate associations between selected biomarkers measured in serial peripheral blood and with clinical efficacy, including immunophenotyping and functional analyses, evaluation of serum levels of chemokines, cytokines and other immune mediators, and characterization of T-cell receptor clonality in peripheral blood.
IV. To evaluate the association between baseline tumor mutational burden and neoantigen production with clinical efficacy of the study therapy.
Patients receive epacadostat orally (PO) twice daily (BID) on days 1-21 and pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 12 weeks and for up to 12 months.
Trial Phase & Type
Memorial Sloan Kettering Cancer Center
Sandra Pierina D'Angelo
Secondary IDs NCI-2018-00155
Clinicaltrials.gov ID NCT03414229