Overview

The investigators propose a phase II randomized-controlled study on using durvalumab in combination with induction chemotherapy followed by concurrent chemoradiation and adjuvant durvalumab, compared to induction chemotherapy followed by concurrent chemoradiation for previously untreated locoregionally advanced stage III to IVA NPC. In parallel, the investigators will also perform collateral tumor and serum biomarker studies which will be correlated with the treatment response. The investigators will collect fresh tumour biopsies at pretreatment, then serially after induction chemotherapy and after concurrent chemoradiation to investigate the change in microenvironment of the tumour and the surrounding inflammatory cells before and after durvalumab. In addition, the investigators will also measure the change in number and intensity of PD-L1-positive circulating tumour cells (CTC) before and after durvalumab and evaluate their correlation with treatment response.

Eligibility

Inclusion Criteria:

1. Patients must have pathologically confirmed, previously untreated stage III-IVA nasopharyngeal carcinoma (staged by American Joint Committee on Cancer/Union International for Cancer Control 8th edition staging classification) who plan to receive radical chemoradiation +/- durvalumab.
2. Fresh frozen tumour and archived formalin-fixed paraffin-embedded (FFPE) nasopharyngeal tumour specimens must be available for PD-L1 expression and/other biomarker correlation studies.
3. Age between 18-75 years. (The age limit set at 75 years because a previous Hong Kong study showed that elderly patient >70 years had poor tolerance to radiotherapy and worse survival for their NPC. Please refer to Sze et al. Radical radiotherapy for nasopharyngeal carcinoma in elderly patients: The importance of co-morbidity assessment Oral Oncology 2012;48:162-167.)
4. Eastern Cooperative Oncology Group Performance Status of 0 or 1
5. All eligible patients must be magnetic resonance imaging of T1, T2 and T1-contrast enhanced sequences of the head and neck region and PET-CT scan within 60 days of study entry
6. Modified Charlson Comorbidity Score <2
7. Adult Comorbidity Evaluation (ACE)-27 Index <2
8. Pre-existing peripheral neuropathy ≤1
9. Baseline creatinine clearance >60ml/min, calculated by Cockcroft-Gault Formula or derived by collection of 24-hour urine.

   Males

             Creatinine Clearance (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine
             (mg/dL)
             Females:
             Creatinine Clearance (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine
             (mg/dL)
         10. Adequate serum hematological function defined as:
               -  Absolute neutrophil count ≥1.5 × 109/l
               -  Hemoglobin ≥9.0 g/dl
               -  Platelet ≥100 × 109/l
         11. Adequate serum biochemical functions defined as:
               -  Alanine transferase ≤3 × upper limit of normal range (ULT)
               -  Aspartate transferase ≤3 × ULT
               -  Total bilirubin ≤2 x ULT
               -  Albumin ≥2.8 g/dl
         12. For women of childbearing potential, a negative serum or urine pregnancy test within
             14 days prior to the start of treatment for their NPC. Women will be considered
             postmenopausal if they are amenorrheic for 12 months without an alternative medical
             cause. The following age-specific requirements apply:
               -  Women <50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of exogenous hormonal
                  treatments and if they have luteinizing hormone and follicle-stimulating hormone
                  levels in the post-menopausal range for the institution or underwent surgical
                  sterilization (bilateral oophorectomy or hysterectomy).
               -  Women ≥50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of all exogenous hormonal
                  treatments, had radiation-induced menopause with last menses >1 year ago, had
                  chemotherapy-induced menopause with last menses >1 year ago, or underwent
                  surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
                  hysterectomy).
         13. Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the informed consent form (ICF) and in this
             protocol. Written informed consent and any locally required authorization (eg, Health
             Insurance Portability and Accountability Act in the US, European Union [EU] Data
             Privacy Directive in the EU) obtained from the patient/legal representative prior to
             performing any protocol-related procedures, including screening evaluations.
         14. Body Weight >30kg
         15. Patient 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.
         16. Must have a life expectancy of at least 12 weeks.
        Exclusion Criteria:
          1. Is currently participating in or has participated in a study of an investigational
             agent or using an investigational device within 4 weeks of the first dose of treatment
             or 5 half-lives, whichever is shorter.
          2. Has a diagnosis of severe active scleroderma, lupus, other rheumatologic or autoimmune
             disease within the past 3 months before study recruitment. Patients with a documented
             history of clinically severe autoimmune disease or a syndrome requiring systemic
             steroids or immunosuppressive agents will not be allowed on this study. Subjects with
             vitiligo or resolved childhood asthma/atopy are an exception to this rule. Subjects
             that require intermittent use of bronchodilators or local steroid injections are not
             excluded from the study. Subjects with hypothyroidism stable on hormone replacement
             are not excluded from this study.
          3. Has had a prior monoclonal antibody within 4 weeks or 5 half-lives, whichever is
             shorter, prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
             baseline) from adverse events due to agents administered more than 4 weeks earlier.
          4. Has had prior chemotherapy or targeted small molecule therapy (including sorafenib or
             other anti-vascular endothelial growth factor inhibitor) within 3 weeks prior to
             administration of the study drug or who has not recovered (i.e., ≤Grade 1 or at
             baseline) from adverse events due to a previously administered agent. *Note: Subjects
             with permanent ≤Grade 2 toxicities (e.g. neuropathy) or toxicities corrected through
             routine medical management (e.g. thyroid replacement for 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. *Note: Subjects with
             ≤Grade 2 amylase or lipase elevations abnormalities that have no corresponding
             clinical manifestations (e.g. manifestation of pancreatitis), are an exception to this
             criterion and may qualify for the study.
          5. Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, indolent lymphomas, or in situ cervical cancer that has undergone potentially
             curative therapy
          6. Has known carcinomatous meningitis (also known as leptomeningeal carcinomatosis).
          7. Has an active infection requiring intravenous systemic therapy or hospital admission.
          8. Has a history or current evidence of any condition, therapy, or laboratory
             abnormality, including psychiatric or substance abuse disorder, that might confound
             the results of the trial, interfere with the subject's participation for the full
             duration of the trial, or is not in the best interest of the subject to participate,
             in the opinion of the treating investigator.
          9. Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the screening visit through 31 weeks
             after the last dose of trial treatment.
         10. Has a known history of Human Immunodeficiency Virus (HIV) (HIV type 1/2 antibodies).
             Routine checking for Anti-HIV type 1 or Anti-HIV type 2 is not mandatory.
         11. Untreated hepatitis B infection. Patients with chronic hepatitis B infection (defined
             as HBsAg positive) are eligible if they have started anti-viral therapy for at least 1
             month and is continuing anti-viral treatment throughout the whole duration of this
             study.
         12. Has received a live vaccine 30 days prior to the first dose of trial treatment.
         13. Has experienced Grade 4 toxicity on treatment with prior radiation.
         14. Has experienced Grade 3-4 intracranial toxicity (hypophysitis or central nervous
             system toxicity) with either prior intracranial radiation, anti programmed cell
             death-1 (PD-1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor
             therapy.
         15. Is taking > 4mg/day of dexamethasone or its equivalent at the start of immunotherapy
             or has required > 4mg/day of dexamethasone or its equivalent for 3 consecutive days
             within 1 week of starting treatment.
         16. Allergies and adverse drug reaction to the following: History of allergy to study drug
             components; History of severe hypersensitivity reaction to any monoclonal antibody.
         17. Prior systemic therapy utilizing an anti CTLA-4 or PD-1/PD-L1 agent or other forms of
             immunotherapy.
         18. Has had prior radiation therapy
         19. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
             criteria
               1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
                  consultation with the Study Physician.
               2. Patients with irreversible toxicity not reasonably expected to be exacerbated by
                  treatment with durvalumab may be included only after consultation with the Study
                  Physician
         20. Major surgical procedure (as defined by the Investigator within 28 days prior to the
             first dose of IP. Local surgery of isolated lesions for palliative intent is
             acceptable.
         21. History of allogenic organ transplantation.
         22. History of leptomeningeal carcinomatosis
         23. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470ms
             calculated from 3 ECGs (within 15 minutes at 5 minutes apart).
         24. Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab. The following are exceptions to this criterion:
               1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
                  articular injection)
               2. Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of
                  prednisone or its equivalent
               3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication)