The purpose of this study is to test the hypothesis that a combined Immuno-Oncology (IO)
strategy would see efficacy in a virally driven cancer like Nasopharyngeal Carcinoma (NPC).
Hence, this is a combination study of nivolumab and ipilimumab in Epstein-Barr virus (EBV)
driven nasopharyngeal carcinoma.
Nasopharyngeal carcinoma (NPC) is endemic in Southern China and South-east Asia. Due to the
peculiar chemosensitive nature of this disease and the low investment in drug development in
Asia, there has been a paucity of new therapies for this disease. While response rates to
repeated lines of chemotherapy average around 30%, the duration of disease control remains
dismal and hence there is an unmet need to develop new therapies for this disease. These
response rates are fairly similar to current monotherapy use of anti-PD1 agents in this
group. Of specific interest, combined IO strategies have appear to add significantly to
response rates in selected tumors such as melanoma, small cell lung cancer, and now Epidermal
Growth Factor Receptor (EGFR) mutant lung cancers. It is hypothesized that a combined IO
strategy would have similar if not better responses in a virally driven cancer like NPC.
Hence this is a single arm study exploring the activity of a combination of nivolumab and
ipilimumab in EBV driven nasopharyngeal carcinoma (NPC). The primary endpoint is best overall
response rate. Secondary endpoints will examine clinical benefit rate at 18 weeks, toxicities
of the combination, and immunological correlates.
Inclusion Criteria:
- Patients must have histologically or cytologically confirmed NPC with Epstein-Barr
Encoded RNA (EBER) positive tumour cells and/or elevated serum EBV DNA viral titres.
- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional
techniques or as >10 mm with spiral CT scan, MRI, or calipers by clinical exam.
- No more than 1 line of previous chemotherapy and/or targeted therapy or patients who
do not tolerate chemotherapy. Pts who progress within 1 year of chemoradiation for
locally advanced disease are allowed on study.
- Age > 21
- Life expectancy > 3 months
- Eastern Cooperative Oncology Group (ECOG) 0-1
- Patients must have normal organ and marrow function as defined below:
- White Blood Cells (WBC) ≥ 2000/μL
- Neutrophils ≥ 1500/μL
- Platelets ≥ 100 x103/μL
- Hemoglobin > 9.0 g/dL
- Serum creatinine ≤ 1.5 x Upper Limit of Normal (ULN) or creatinine clearance
(CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):
- Female CrCl = [(140 - age in years) x weight in kg x 0.85] ÷ (72 x serum
creatinine in mg/dL)
- Male CrCl = [(140 - age in years) x weight in kg x 1.00] ÷ (72 x serum
creatinine in mg/dL)
- Aspartate Transaminase/Alanine Transaminase (AST/ALT) ≤ 3 x ULN
- Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have
total bilirubin < 3.0 mg/dL)
- Measurable levels of circulating EBV DNA
- Women of childbearing potential (WOCBP) must use appropriate method(s) of
contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30
days plus the time required for nivolumab/ipilimumab to undergo five half-lives) after
the last dose of investigational drug
- Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the
start of nivolumab/ipilimumab
- Women must not be breastfeeding
- Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year. Men receiving nivolumab/ipilimumab and who are
sexually active with WOCBP will be instructed to adhere to contraception for a period
of 31 weeks after the last dose of investigational product. Women who are not of
childbearing potential (ie, who are postmenopausal or surgically sterile as well as
azoospermic men do not require contraception
- Ability to understand and the willingness to sign a written informed consent document.
- Any surgery must be more than 28 days before start of study drug and any surgical
wounds must be completely healed
Exclusion Criteria:
- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier.
- Patients who are receiving any other investigational agents.
- Patients are excluded if they have active brain metastases or leptomeningeal
metastases. Subjects with brain metastases are eligible if metastases have been
treated and there is no magnetic resonance imaging (MRI) evidence of progression for
[lowest minimum is 4 weeks or more] after treatment is complete and within 28 days
prior to the first dose of IO administration. There must also be no requirement for
immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone
equivalents) for at least 2 weeks prior to study drug administration.
- Patients should be excluded if they are positive test for hepatitis B virus surface
antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating
acute or chronic infection.
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to nivolumab or ipilimumab.
- Prior use of anti-PD1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or
any drug specifically targeted T-cell costimulatory checkpoint pathways
- 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.
- Pregnant women are excluded from this study because ipilimumab has the potential for
teratogenic or abortifacient effects. Because there is an unknown but potential risk
for adverse events in nursing infants secondary to treatment of the mother with
nivolumab or ipilimumab, breastfeeding should be discontinued if the mother is treated
with nivolumab or ipilimumab.
- Patients should be excluded if they have known history of testing positive for human
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
- Patients should be excluded if they have an active, known or suspected autoimmune
disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes
mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone
replacement, psoriasis not requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger
- Patients should be excluded if they have a condition requiring systemic treatment with
either corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration. Inhaled or
topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents
are permitted in the absence of active autoimmune disease.
- As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab
combinations, drugs with predisposition to hepatoxicity should be used with caution in
patients treated with nivolumab-containing regimen.
- Patient should be excluded if they have history or active interstitial lung disease
(pneumonitis).
- Prior organ allograft or allogeneic bone marrow transplantation
- Allergies and Adverse Drug Reaction
- History of allergy to study drug components
- History of severe hypersensitivity reaction to any monoclonal antibody
- Prisoners or subjects who are involuntarily incarcerated
- Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness
- Inability to comply with restrictions and prohibited activities/treatments in this
study
- Subjects with concomitant second malignancies (except adequately treated
non-melanomatous skin cancers, in situ cervical cancers, localized prostate cancer or
in situ breast cancer) are excluded unless a complete remission was achieved at least
3 years prior to study entry and no additional therapy is required or anticipated to
be required
