Testing the Addition of an Anti-cancer Immune Therapy Drug (Nivolumab) to the Usual Chemotherapy Treatment (Cisplatin or Carboplatin With Gemcitabine) for Recurrent or Metastatic Nasopharyngeal Cancer

Not Recruiting

Trial ID: NCT04458909


This phase III trial compares the effect of adding nivolumab to the usual chemotherapy (cisplatin or carboplatin with gemcitabine) versus standard chemotherapy alone in treating patients with nasopharyngeal cancer that has come back (recurrent) or spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as cisplatin, carboplatin, and gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab with the usual chemotherapy may work better than the standard chemotherapy alone in treating patients with nasopharyngeal cancer.

Official Title

An Open-Label, Phase III Study of Platinum-Gemcitabine With or Without Nivolumab in the First-Line Treatment of Recurrent or Metastatic Nasopharyngeal Carcinoma

Stanford Investigator(s)

A. Dimitrios Colevas, MD
A. Dimitrios Colevas, MD

Professor of Medicine (Oncology) and, by courtesy, of Otolaryngology - Head & Neck Surgery (OHNS) and of Radiation Oncology (Radiation Therapy)


Inclusion Criteria:

   - Pathologically (histologically or cytologically) proven diagnosis of NPC that has
   recurred at locoregional and/or distant sites. For locoregional recurrence, the
   disease must not be amenable to potentially curative surgery or re-irradiation. The
   following histological types are accepted: (a) Keratinizing - squamous cell carcinoma;
   (b) Non-keratinizing - undifferentiated or poorly differentiated

   - Measurable disease by the RECIST 1.1 criteria. Lesion(s) that have been irradiated
   previously can be counted as measurable as long as radiological progression has been
   demonstrated prior to enrollment

   - History/physical examination by a medical oncologist or clinical oncologist within 14
   days prior to registration

   - Zubrod/Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 within 14
   days prior to registration

   - Contrast enhanced magnetic resonance imaging (MRI) or computed tomography (CT) of the
   nasopharynx and neck within 30 days prior to registration

   - Contrast enhanced CT scan of the chest, abdomen, and pelvis within 30 days prior to

   - Absolute neutrophil count (ANC) >= 1500 cells/mm^3 (within 14 days prior to

   - Platelets >= 100,000 cells/mm^3 (within 14 days prior to registration)

   - Hemoglobin >= 9.0 g/dL (transfusion is accepted. Erythropoietin dependency not
   accepted) (within 14 days prior to registration)

   - Total bilirubin =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN for
   patients with total bilirubin levels > 1.5 x ULN. Patients with known Gilbert's
   syndrome are not excluded (within 14 days prior to registration)

   - Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
   ULN (=< 3 x ULN for patients with liver metastases) (within 14 days prior to

   - Serum creatinine =< 1.5 x ULN OR calculated creatinine clearance (CrCl) based on
   Cockcroft-Gault equation >= 30 mL/min for patients with serum creatinine levels > 1.5
   x ULN. In this protocol, cisplatin or carboplatin may be used at the discretion of the
   investigator - except for patients with CrCl between 30-50 mL/min, for whom
   carboplatin should be used instead of cisplatin (within 14 days prior to registration)

   - For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
   load must be undetectable, and patients must be receiving anti-viral therapy at
   enrollment. Patients must agree to continue anti-viral therapy throughout the study
   period as directed by their treating physicians

      - Known positive test for hepatitis B virus surface antigen (HBsAg) indicating
      acute or chronic infection would make the patient ineligible unless the viral
      load becomes undetectable on anti-viral therapy

      - Patients who are immune to hepatitis B (anti-Hepatitis B surface antibody
      positive) are eligible (i.e., patients immunized against hepatitis B)

      - In some centers, hepatitis B core antibody (anti-HBc) is done routinely before
      chemotherapy for some cancer patients. This is because patients who are
      HBsAg-negative but positive for anti-HBc should have undetectable HBV viral load
      at enrollment and receive prophylactic anti-viral therapy throughout the study
      (American Society of Clinical Oncology 2015 guideline, Hwang 2015). In this
      protocol, anti-HBc should be performed based on institutional standards

   - Patients with a history of hepatitis C virus (HCV) infection must have been treated
   and cured. For patients with HCV infection who are currently on treatment they are
   eligible if they have an undetectable HCV viral load

      - Note: Known positive test for hepatitis C virus ribonucleic acid (HCV RNA)
      indicating acute or chronic infection would make the patient ineligible unless
      the viral load becomes undetectable on suppressive therapy

   - For women of childbearing potential (WOCBP), negative serum or urine pregnancy test
   within 14 days prior to registration. For WOCBP randomized to Arm 1, an additional
   negative serum or urine pregnancy is required within 24 hours prior to starting
   nivolumab treatment

      - Women of childbearing potential (WOCBP) is defined as any female who has
      experienced menarche and who has not undergone surgical sterilization
      (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause
      is defined clinically as 12 months of amenorrhea in a woman over 45 in the
      absence of other biological or physiological causes

   - Women of childbearing potential (WOCBP) and men who are sexually active with WOCBP
   must be willing to use an adequate method of contraception. Women must use an
   effective oral contraception and the male partner must use condom) during and after

   - The patient or a legally authorized representative must provide written informed
   consent prior to study entry

Exclusion Criteria:

   - Diagnosed with another invasive malignancy (except non-melanomatous skin cancer)
   unless disease free for more than 3 years. Note: Patients with basal cell carcinoma of
   the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast
   carcinoma, cervical cancer in situ) who have undergone potentially curative therapy
   are not excluded

   - Any prior systemic anti-cancer agents (including chemotherapy and investigational
   agents) for the purpose of treating locoregional and/or distant recurrence of NPC

   - Patients who have received neoadjuvant (induction) and/or adjuvant chemotherapy for
   primary NPC with chemotherapy (any drug regimens including those containing platinum
   and/or gemcitabine) at or within 6 months prior to registration are excluded (counting
   from the last day of the chemotherapy for the primary NPC, prior to enrolling into the
   current study). The following subgroups of patients are NOT excluded:

      - Patients who have received neoadjuvant (induction) and/or adjuvant chemotherapy
      for primary (non-metastatic/non-recurrent) NPC more than 6 months prior to
      registration, counting from the last day of the chemoradiotherapy for the primary
      NPC, prior to enrolling into the current study

      - For prior RT with radical intent: Patients who have prior radiotherapy (RT) to
      the primary and locoregional disease (i.e. non-recurrent disease) with or without
      concurrent cisplatin or carboplatin monotherapy are not excluded as long as they
      have not received any neoadjuvant/adjuvant chemotherapy within 6 months prior to
      registration (counting from the last day of the chemotherapy), and that the last
      RT fraction (with radical intent) has been given more than 3 months prior to

      - For RT with palliative intent: Prior radiotherapy (RT) at or within 30 days prior
      to registration, this includes RT given with palliative intent (with or without
      concurrent cisplatin or carboplatin alone) to recurrent/ metastatic sites in
      patients with recurrent/metastatic NPC. The re-irradiated sites must not be the
      only sites of measurable recurrent disease

      - Prior chemotherapy for cancers other than NPC is allowed as long as the last
      course of chemotherapy was administered more than 3 years prior to registration
      and the patient has remained disease-free for more than 3 years

   - Prior therapy for any indication, with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
   or with an agent directed to another stimulatory or co-inhibitory T-cell receptor
   (e.g. CTLA-4, OX-40, CD137)

   - History of severe (grade 3-4) hypersensitivity reaction to any monoclonal antibody
   including nivolumab and/or any of its excipients

   - Severe, active co-morbidity defined as follows:

      - Unstable angina and/or congestive heart failure requiring hospitalization within
      the last 6 months

      - Myocardial infarction within the last 6 months

      - Acute bacterial or fungal infection requiring intravenous antibiotics at the time
      of registration

      - Chronic obstructive pulmonary disease exacerbation or other respiratory illness
      requiring hospitalization or precluding study therapy within 30 days of

      - Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

      - History of (non-infectious) pneumonitis that required steroids or has current
      pneumonitis requiring steroids and/or immunosuppressive therapy

      - History of active TB (Bacillus tuberculosis, not known to be multi-drug
      resistant) as defined by the need to receive systemic treatment within the last 2
      years or any known history of multi-drug resistant TB. Note: Patients who had a
      distant history of treated TB (not known to be multi-drug resistant) at 5 or more
      years from enrollment and have no current symptoms suggestive of active TB, are
      not excluded from this study. Note: Testing for prior exposure to TB is not
      required in this study since TB is endemic in parts of Asia

      - Prior solid organ transplant or bone marrow transplant

      - History of active primary immunodeficiency including, but not limited to acquired
      immune deficiency syndrome (AIDS) based upon current Centers for Disease Control
      and Prevention (CDC) definition; Note: Human immunodeficient virus (HIV) testing
      is not required for entry into this protocol. The need to exclude patients with
      AIDS from this protocol is necessary because the treatment involved in this
      protocol may be immunosuppressive

      - Condition requiring systemic treatment with either corticosteroids (> 10 mg daily
      prednisone or equivalents) or other immunosuppressive medications within 14 days
      of registration. Inhaled or topical steroids and adrenal replacement doses < 10
      mg daily prednisone equivalents are permitted in the absence of active autoimmune
      disease. Steroid premedication for the prophylaxis of CT contrast-related
      allergies is allowed. The use of dexamethasone as an anti-emetic premedication
      prior to chemotherapy is also allowed

      - Active autoimmune disease requiring systemic treatment (i.e. disease modifying
      agents, corticosteroids, or immunosuppressive drugs) within the past 2 years.
      These include but are not limited to patients with a history of immune-related
      neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy,
      Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as
      systemic lupus erythematosus (SLE), rheumatoid arthritis, connective tissue
      diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative
      colitis, hepatitis; and patients with a history of toxic epidermal necrolysis
      (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded
      because of the risk of recurrence or exacerbation of disease

      - Note: Patients are permitted to enroll if they have vitiligo; type I diabetes
      mellitus; hypothyroidism, pituitary or adrenal insufficiency requiring only
      hormone replacement; psoriasis not requiring systemic treatment, or conditions
      not expected to recur in the absence of an external trigger (precipitating event)

   - Patients who are pregnant or breastfeeding and unwilling to discontinue breastfeeding

   - Known history of grade 3-4 allergic reaction and/or hepatic toxicity to cisplatin,
   carboplatin, or gemcitabine

      - NOTE: For patients with known history of grade 3-4 renal toxicity to cisplatin or
      known history of clinically significant hearing loss (grade 2 or above)
      attributed to cisplatin, or other intolerances to cisplatin that are of clinical
      significance, carboplatin can be used in this study and therefore these patients
      are NOT excluded from enrollment

   - Known central nervous system (CNS) metastases and/or carcinomatous meningitis.
   Patients with base of skull involvement by NPC are not excluded unless their disease
   is directly invading the brain parenchyma and is associated with clinical symptoms
   (headaches, nausea and vomiting, neurological abnormalities on physical examination)
   and/or cerebral edema on radiological imaging

   - Patients who have received a live vaccine within 30 days prior to the first dose of
   study treatment. Examples of live vaccines include, but are not limited to, the
   following: measles, mumps, rubella, varicella/zoster, 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

   - History or current evidence of any condition, therapy, or laboratory abnormality that
   might confound the results of the study, interfere with the subject's participation
   for the full duration of the study, or is not in the best interest of the subject to
   participate, in the opinion of the treating investigator


drug: Carboplatin

drug: Cisplatin

drug: Gemcitabine

biological: Nivolumab

other: Questionnaire Administration

Not Recruiting

Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Elizabeth Winters

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