Nivolumab in Treating Patients With Recurrent and/or Metastatic Nasopharyngeal Cancer

Multicenter Phase II Study of Nivolumab in Previously Treated Patients With Recurrent and Metastatic Nasopharyngeal Carcinoma

This phase II trial studies how well nivolumab works in treating patients with nasopharyngeal cancer that has returned after a period of improvement (recurrent) and/or has spread to other parts of the body (metastatic). Monoclonal antibodies, such as nivolumab, may block tumor growth in different ways by targeting certain cells.

Study Overview

• Status: Completed
• Conditions: Recurrent Nasopharynx Carcinoma; Stage III Nasopharyngeal Carcinoma AJCC v7; Stage IV Nasopharyngeal Carcinoma AJCC v7; Stage IVA Nasopharyngeal Carcinoma AJCC v7; Stage IVB Nasopharyngeal Carcinoma AJCC v7; Stage IVC Nasopharyngeal Carcinoma AJCC v7; Nasopharyngeal Nonkeratinizing Carcinoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Biological: Nivolumab

Detailed Description

PRIMARY OBJECTIVES:

I. Objective tumor response to nivolumab in patients with previously treated recurrent and/or metastatic nasopharyngeal carcinoma (NPC) based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1.

SECONDARY OBJECTIVES:

I. Tumor response to nivolumab based on immune-related response criteria (IRC). II. Duration of response. III. Progression-free survival and overall survival. IV. Safety and tolerability.

TERTIARY OBJECTIVES:

I. To investigate the effect of nivolumab on tumor burden by analyzing the clearance of plasma Epstein-Barr virus (EBV) deoxyribonucleic acid (DNA) during the first 4-6 weeks of treatment.

II. To investigate the association between treatment outcome and immunological markers: a) Intratumoral expression of programmed cell death 1 (PD-1) and programmed cell death-ligand (PD-L1) in archived NPC tissues (mandatory); b) Serum absolute lymphocyte count at baseline and post-treatment (mandatory); and c) Plasma cytokine levels at baseline and serially during the first 8 weeks of treatment; d) Expression of PD-1 in cluster of differentiation (CD)8+ T cells in tumor infiltrating lymphocytes (TIL) at baseline (optional).

III. To investigate functional magnetic resonance imaging (MRI) sequences as an early predictor of response to nivolumab (optional only at Chinese University of Hong Kong [CUHK]).

OUTLINE:

Patients receive nivolumab intravenously (IV) over approximately 60 minutes on days 1 and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 3 years.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Hong Kong
    • Shatin, Hong Kong, China
      • Chinese University of Hong Kong-Prince of Wales Hospital
• Singapore
  • Singapore, Singapore, 169610
    • National Cancer Centre
  • Singapore, Singapore, 119074
    • National University Hospital Singapore
  • Singapore, Singapore, 308433
    • Johns Hopkins Singapore
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
    • Los Angeles, California, United States, 90033
      • USC / Norris Comprehensive Cancer Center
    • Los Angeles, California, United States, 90033
      • Los Angeles County-USC Medical Center
    • Pasadena, California, United States, 91105
      • Keck Medical Center of USC Pasadena
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
    • South Pasadena, California, United States, 91030
      • City of Hope South Pasadena
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • New Lenox, Illinois, United States, 60451
      • UC Comprehensive Cancer Center at Silver Cross
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Sidney Kimmel Cancer Center
    • Baltimore, Maryland, United States, 21201
      • University of Maryland/Greenebaum Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center P2C
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Ability to understand and the willingness to sign a written informed consent document
• Histologically or cytologically confirmed non-keratinizing nasopharyngeal carcinoma (NPC) that has recurred at locoregional and/or distant sites; NOTE: patients with local recurrence at the bony skull-base as the only site of index disease are excluded; patients with locoregional recurrence without distant metastases must have undergone radical radiotherapy previously
• Measurable disease according to the RECIST criteria (version 1.1), for the evaluation of measurable disease
• Received one or more lines of chemotherapy, which must include prior treatment with a platinum agent and must not be amenable to potentially curative radiotherapy or surgery
• Archived or fresh tumor sample available; willingness to donate blood and tissue for mandatory correlative research studies
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
• Absolute neutrophil count >= 1.5 x 10^9/L
• Platelet count >= 100 x 10^9/L
• Hemoglobin >= 8.0 g/dL
• Serum alanine aminotransferase ([ALT]; serum glutamate-pyruvate transferase [SGPT]), or serum aspartate aminotransferase [AST] where available at the center) < 2.5 x upper limit of normal (ULN), OR < 5 x ULN in the presence of liver metastases
• Serum total bilirubin < 2 x ULN (except patients with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL)
• Serum creatinine < 1.5 x ULN

Exclusion Criteria:

• Any of the following:

  • Chemotherapy =< 4 weeks prior to registration
  • Radiotherapy =< 4 weeks prior to registration
  • Nitrosoureas =< 6 weeks prior to registration or
  • Mitomycin C =< 6 weeks prior to registration
  • Those who have not recovered from adverse events (to grade =< 1 in severity) due to agents administered more than 4 weeks earlier; prior palliative radiotherapy to bone metastases =< 2 weeks prior to registration (i.e. prior palliative radiotherapy to bone metastases is allowed if it is performed > 2 weeks prior to registration)
• Prior investigational agents =< 4 weeks prior to registration
• Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
• Known brain metastases or leptomeningeal metastases; NOTE: symptomatic, and/or if they require immunosuppressive doses of corticosteroids (e.g. > 10 mg/day prednisone or equivalents) for at least 2 weeks prior to study drug administration; patients with treated brain metastases who are deemed clinically stable and without radiological progression on positron emission tomography (PET), MRI or computed tomography (CT) scan performed =< 8 weeks of study entry, are not excluded; NOTE: primary nasopharyngeal cancers that directly invade the skull base and extend into the infratemporal fossa (e) are not regarded as brain metastases and are not excluded
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab
• History of severe hypersensitivity reaction to any monoclonal antibody
• 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

• Any of the following:

  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception NOTE: breastfeeding should be discontinued if the mother is treated with nivolumab; women of childbearing potential and men must use two forms of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; they must adhere to contraception for a period of 31 weeks after the last dose of nivolumab
• For patients with unknown human immunodeficiency virus (HIV) status at the time of enrollment, HIV serology must be tested during screening; patients who are tested positive for HIV could be included if there is an adequate cluster of differentiation 4 (CD4) count (> 350/ul) on a stable regimen of highly active anti-retroviral therapy (HAART) with no detectable or minimal viral burden, and no active infections
• For patients with unknown hepatitis B virus surface antigen (HbsAg) status, must be tested during study screening; patients who are tested positive test for HBsAg are excluded if they have inadequately controlled hepatitis B and/or Child-Pugh Class B or C cirrhosis; however, patients with adequately controlled hepatitis are not excluded from the study if they satisfy all of the following criteria: (i) must be receiving a nucleoside analog anti-viral drug for 3 or more months; and (ii) have a serum hepatitis B virus (HBV) deoxyribonucleic acid (DNA) level of less than 100 IU/ml via polymerase chain reaction quantification assays prior to enrollment
• For patients with unknown hepatitis C virus ribonucleic acid (HCV antibody) status, must be tested during study screening; patients who are tested positive for HCV antibody are excluded from the study if they have inadequately controlled hepatitis C and/or Child-Pugh Class B or C cirrhosis; patients with adequately controlled hepatitis are not excluded from the study as defined by having undetectable level of serum HCV antibody level prior to enrollment; patients who are currently on interferon or other anti-HCV therapy will be excluded from study
• Active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids; NOTE: 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), 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; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
• Patients 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 (precipitating event)
• 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; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if =< 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
• Evidence of active or acute (i.e. current, or recent within 4 weeks prior to registration) diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation; patients with abdominal carcinomatosis, a history of non-recent intra-abdominal abscess, or a history of non-recent GI obstruction should be evaluated for the potential need for additional treatment before coming on study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (nivolumab); Patients receive nivolumab IV over approximately 60 minutes on days 1 and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Confirmed Response Rate (Complete Response or Partial Response) Based on RECIST Version 1.1	Confirmed response rate is defined as either a Complete Response (CR) or Partial Response (PR) based on RECIST version 1.1. > To be consider a CR, there must be a disappearance of all target lesions and each target lymph node must have reduction in short axis to < 1.0 cm.> > To be considered a PR, at least a 30% decrease in PBSD (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the baseline value.> > The confirmed response rate is reported as the number of patients reporting a CR or PR divided by the total number of evaluable patients multiplied by 100 (reported as a percentage).	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Adverse events were collected and recorded according to the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine adverse event patterns. For this outcome measure, we summarize the worst graded adverse event regardless of treatment attribution per patient. All reported adverse events are reported in the Adverse Events section of this report.	Up to 3 years on treatment
Tumor Response to Nivolumab Based on the Immune Response Criteria (IRC)	The Immune Response Criteria (IRC) is a response criteria derived from the WHO criteria.	Up to 3 years
Duration of Response	Duration of response defined as the date at which the patient's objective status is first noted to be either a CR or PR to the date progression is documented, assessed according to RECIST version 1.1.	Up to 3 years
Progression-free Survival (PFS) Based on RECIST Version 1.1	Progression Free Survival is defined as the time from registration to the time of death or progression, whichever occurs first. The distribution of PFS will be estimated using the method of Kaplan-Meier.	Time from registration to the first of either death due to any cause or progression, assessed up to 3 years
Overall Survival (OS)	Overall survival is defined as the time from registration to the time of death. The distribution of survival time will be estimated using the method of Kaplan-Meier.	Time from registration to death due to any cause, assessed up to 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clearance of EBV DNA	Plasma EBV DNA half-life during the first 6 weeks of treatment will be correlated with RECIST-response to nivolumab.	Up to 6 weeks of treatment
Intratumoral Expression of PD-1 and PD-L1	PD-1 and PD-L1 expression will be associated with treatment outcomes. The Chi-Square (or Fisher's Exact test) will be used to assess the association of categorical clinical data with categorical biomarker data. Time-to-event clinical data (PFS, OS) will be correlated with biomarker data using Kaplan-Meier methodology and Cox regression models. Logistic regression models will also be used to predict binary clinical data with baseline biomarker data. Finally, graphical methods and descriptive statistics will be used to summarize the data as well.	Baseline
Change in Serum Absolute Lymphocyte Count	The Chi-Square (or Fisher's Exact test) will be used to assess the association of categorical clinical data with categorical biomarker data. Time-to-event clinical data (PFS, OS) will be correlated with biomarker data using Kaplan-Meier methodology and Cox regression models. Logistic regression models will also be used to predict binary clinical data with baseline biomarker data. Finally, graphical methods and descriptive statistics will be used to summarize the data as well.	Baseline and up to 3 years
Expression of PD-1 in CD8+ T Cells in TIL	The Chi-Square (or Fisher's Exact test) will be used to assess the association of categorical clinical data with categorical biomarker data. Time-to-event clinical data (PFS, OS) will be correlated with biomarker data using Kaplan-Meier methodology and Cox regression models. Logistic regression models will also be used to predict binary clinical data with baseline biomarker data. Finally, graphical methods and descriptive statistics will be used to summarize the data as well.	Baseline
Functional MRI Parameters	Graphical methods and descriptive statistics will be used.	Up to 16 weeks

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Brigette B Ma, Mayo Clinic Cancer Center P2C

Publications and helpful links

General Publications

• Ma BBY, Lim WT, Goh BC, Hui EP, Lo KW, Pettinger A, Foster NR, Riess JW, Agulnik M, Chang AYC, Chopra A, Kish JA, Chung CH, Adkins DR, Cullen KJ, Gitlitz BJ, Lim DW, To KF, Chan KCA, Lo YMD, King AD, Erlichman C, Yin J, Costello BA, Chan ATC. Antitumor Activity of Nivolumab in Recurrent and Metastatic Nasopharyngeal Carcinoma: An International, Multicenter Study of the Mayo Clinic Phase 2 Consortium (NCI-9742). J Clin Oncol. 2018 May 10;36(14):1412-1418. doi: 10.1200/JCO.2017.77.0388. Epub 2018 Mar 27. Erratum In: J Clin Oncol. 2018 Aug 1;36(22):2360.

Study record dates

Study Major Dates

• Study Start (Actual): July 21, 2015
• Primary Completion (Actual): June 16, 2018

Study Registration Dates

• First Submitted: January 12, 2015
• First Submitted That Met QC Criteria: January 12, 2015
• First Posted (Estimate): January 15, 2015

Study Record Updates

• Last Update Posted (Actual): September 13, 2019
• Last Update Submitted That Met QC Criteria: August 16, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Disease Attributes; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Nasopharyngeal Diseases; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Nasopharyngeal Neoplasms; Carcinoma; Nasopharyngeal Carcinoma; Recurrence; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: NCI-2014-02673 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); UM1CA186644 (U.S. NIH Grant/Contract); UM1CA186691 (U.S. NIH Grant/Contract); N01CM00099 (U.S. NIH Grant/Contract); UM1CA186686 (U.S. NIH Grant/Contract); 9742 (Other Identifier: CTEP); MC1471