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This phase II trial studies how well durvalumab and epacadostat work in treating patients with Epstein-Barr virus positive nasopharyngeal cancer that cannot be removed by surgery (unresectable), has come back (recurrent), or has spread to other places in the body (metastatic). Epacadostat blocks the enzyme, IDO1, from working. Blocking this enzyme may allow for a stronger immune response against cancer. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body?s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving durvalumab and epacadostat may work better in treating patients with nasopharyngeal cancer compared to durvalumab alone.
Full description
PRIMARY OBJECTIVE:
I. Determine whether adding an IDO inhibitor to PD-L1 antibody therapy improves the probability of remission in nasopharyngeal carcinoma (NPC).
SECONDARY OBJECTIVES:
I. Determine whether adding an IDO inhibitor to PD-L1 antibody therapy improves long-term clinical outcomes in NPC.
II. Determine whether the combination of durvalumab and epacadostat in recurrent and metastatic NPC patients is safe and well tolerated.
EXPLORATORY OBJECTIVES:
I. Identify potential associations between pre-treatment and on-treatment regulatory and effector immune cell populations and clinical outcomes in NPC patients treated with durvalumab and epacadostat.
II. Characterize the oral and fecal microbiome in responding and non-responding patients.
OUTLINE:
Patients receive durvalumab intravenously (IV) over 1 hour on day 1 and epacadostat orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days for 12 months in the absence of disease progression or unacceptable toxicity. Patients with disease progression who are benefiting from treatment in the opinion of the principal investigator may continue durvalumab and epacadostat for up to an additional 12 months from the initiation (or re-initiation) of treatment on study.
After completion of study treatment, patients are followed up every 3 months until start of a new anti-cancer treatment, until 30 days after documented disease progression, until death, or until 36 months from the initiation of treatment on study, whichever comes first.
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Inclusion criteria
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Life expectancy of at least 4 months
Patient is capable of giving signed informed consent and is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
Body weight > 40 kilograms (kg)
Patients must have a histological or cytological diagnosis of Epstein-Barr virus positive (EBV+) nasopharyngeal carcinoma that is not amenable to curative intent therapy (i.e. surgical resection, locoregional radiation therapy, concurrent chemoradiation)
Patients must decline, be ineligible or intolerant to at least 1 standard treatment regimen in the advanced or metastatic setting, if such a therapy exists
Patients must have disease progression within 6 months of completion of platinum-based concurrent chemoradiation or after platinum-based chemotherapy administered for the treatment of recurrent or metastatic disease
If patient has known brain metastases, they must have stable neurologic status for at least 4 weeks without the use of steroids or on stable or decreasing dose of =< 10 mg daily prednisone (or equivalent), and must be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events (AEs) (patients with a history of carcinomatous meningitis are not eligible)
Patients may have had prior chemotherapy or immunotherapy or radiation therapy. Patients should discontinue prior medical therapy at least 5 drug half-lives or 28 days prior to the first dose of treatment on study (whichever is shorter). Patients should complete any prior radiation therapy at least 14 days prior to the initiation of treatment on study. Also, any drug related adverse events identified during prior therapy must be well controlled (typically resolution to =< grade 1, OR resolved upon investigator review prior to initiation of this therapy
No systemic antineoplastic therapy may be received by the patient between the time of the biopsy and the first administration of study treatment
Patient must agree to any protocol mandated biopsies of tumor (deemed accessible, safe and appropriate for biopsy by the investigator?s assessment) and they must allow acquired tissue to be used for biomarker and immunological analysis
For women of childbearing potential, negative serum or urine pregnancy test within 14 days to the first epacadostat, or durvalumab and use of birth control from 30 days prior to the first administration of treatment on study and 120 days following last day administration of treatment on study
Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
Male patients must be surgically sterile, or must agree to use contraception during the study and at least 120 days following the last day of study drug administration
Exclusion criteria
Active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, rheumatoid arthritis, uveitis, etc]). The following are exceptions to this criterion:
Patients with celiac disease controlled by diet alone
Congestive heart failure (New York Heart Association class III to IV)
History or presence of an abnormal electrocardiogram (ECG) that, in the investigator's opinion, is clinically meaningful. Screening corrected QT (QTc) interval > 470 milliseconds is excluded. In the event that a single QTc is > 470 milliseconds, the subject may enroll if the average QTc for the 3 ECGs is < 470 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
Uncontrolled or clinically significant conduction abnormalities (e.g., ventricular tachycardia on anti-arrhythmics are excluded), 1st degree atrioventricular (AV) block or asymptomatic left anterior fascicular block (LAFB)/right bundle branch block (RBBB) are eligible
Uncontrolled, symptomatic ischemia within 6 months of first dose of study treatment or known myocardial infarction in the previous six months
Evidence of interstitial lung disease or any history of autoimmune pneumonitis including symptomatic and/or pneumonitis requiring treatment
Infectious
Evidence of significant active infection (e.g., pneumonia, cellulitis, wound abscess, etc.) requiring systemic therapy at time of study enrollment
Active hepatitis B (hepatitis B surface antigen [HBsAg] reactive) associated the aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevations > 1.5 x upper limit of normal (ULN). Patients who are HBsAg reactive must be on appropriate antiviral therapy while receiving treatment on study
Hepatitis C (hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
Presence of a gastrointestinal condition that may affect drug absorption. Administration of epacadostat through a feeding tube is permitted
Any other current or previous malignancy within the past 2 years that, in the opinion of the principal investigator will interfere with study-specific endpoints
Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician
Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the study physician
History of leptomeningeal carcinomatosis
Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis (TB) testing in line with local practice)
Hepatitis B ? Half of NPC patients have been infected with hepatitis B (Cancer Epidemol Biomarkers Prev. 2015. 24:1766-73, N = 711) and, therefore, inclusion of healthy patients with a history of hepatitis B is a central part of this study. In addition, PD-1 antibodies have been proven to be safe in patients with active hepatitis and hepatocellular carcinoma (e. g. KEYNOTE 224). However, patients with hepatitis B virus (HBV) surface antigen positive (HBSAg) must have AST and total bilirubin < 1.5 x ULN AND
Negative HBV RNA polymerase chain reaction (PCR) OR
On antivirals for HBV AND at least 8 weeks of prior anti-PD1 antibody therapy AND no history of AST or total bilirubin levels > 1.5 x ULN due to PD-1 antibody therapy
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
Known human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) ? Consistent with current guidelines from the NCI / Cancer Therapy Evaluation Program (CTEP), ?HIV infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial? (CTEP protocol template)
Intercurrent illness not otherwise specified
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
Patients receiving systemic steroid therapy for a chronic inflammatory condition. Topical steroids, nasal and inhaled steroids are permitted. Prednisone or equivalent =< 10 mg/day is permitted as hormone replacement; higher dosage prednisone should be stopped at least 14 days prior to cycle 1 day 1 (c1d1)
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
Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
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
Current or prior use of immunosuppressive medication within 14 days (use 28 days if combining durvalumab with a novel agent) before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. The following are exceptions to this criterion:
Absolute neutrophil count (ANC) < 1.0 x 10^9/L
Platelets < 75 x 10^9/L
Hemoglobin < 9 g/dL or < 5.6 mmol/L (transfusion is acceptable to meet this criterion)
Serum creatinine >= 1.5 x institutional upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate can also be used in place of creatinine or creatinine clearance (CrCl)) < 50 mg/min for subjects with creatinine levels > 1.5 x institutional ULN
AST or ALT > 2.5 x institutional ULN
Alkaline phosphatase > 2.5 x ULN
Total bilirubin above 1.5 x the institutional ULN AND conjugated bilirubin >= 2.0 x ULN
International normalized ratio (INR) or prothrombin time (PT) > 1.5 x ULN
Activated partial thromboplastin time (aPTT) > 1.5 x ULN
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Data sourced from clinicaltrials.gov
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