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Nivolumab + Chemoradiation in Stage II-IVB Nasopharyngeal Carcinoma (NPC)

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ClinicalTrials.gov Identifier: NCT03267498
Recruitment Status : Recruiting
First Posted : August 30, 2017
Last Update Posted : April 5, 2019
Sponsor:
Collaborators:
National University Cancer Institute, Singapore
Bristol-Myers Squibb
Information provided by (Responsible Party):
University of California, San Francisco

Brief Summary:
This phase II trial studies how well nivolumab and chemoradiotherapy works in treating patients with stage II-IVB nasopharyngeal cancer. Monoclonal antibodies, such as nivolumab, may block tumor growth in different ways by targeting certain cells. Chemoradiotherapy is the combination of chemotherapy and radiation therapy and may prevent the cancer from spreading when combined with nivolumab. Giving nivolumab and chemoradiotherapy may work better in treating patients with stage II-IVB nasopharyngeal cancer.

Condition or disease Intervention/treatment Phase
Nasopharyngeal Carcinoma Drug: Nivolumab Drug: Cisplatin Radiation: Radiation Therapy Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To establish the feasibility of treatment completion of a combined chemoradiation-nivolumab regimen followed by adjuvant nivolumab.

SECONDARY OBJECTIVES:

I. To determine the overall response rate at 1 year from completion of therapy, as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

II. To determine the locoregional control rate at 1 year post-treatment. III. To determine the distant metastasis rate at 1 year post-treatment. IV. To determine the overall survival rate at 1 year post-treatment. V. To determine the rate of Epstein-Barr virus (EBV) deoxyribonucleic acid (DNA) clearance at end of chemoradiation and at 1 year post-treatment.

VI. To assess patients' quality of life from baseline through 1 year post-treatment.

VII. To determine the acute and late toxicity rates according to Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 5, including immune-related adverse events (AEs).

OUTLINE:

Patients receive nivolumab intravenously (IV) over 60 minutes on day 1 of courses 1-5 and 7-12. Treatment repeats every 14 days for 11 courses in the absence of disease progression or unacceptable toxicity. Beginning at course 2, patients undergo radiation therapy once daily (QD) 5 days per week and receive cisplatin IV over 30-60 minutes on day 1. Treatment repeats every 7 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 100 days, at 1, 3, 6, 9, and 12 months for up to 1 year, and then every 3 months for 1 year.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Single-arm, open label clinical trial of concurrent and adjuvant nivolumab, including a run-in phase to establish basic feasibility of the nivolumab schedule followed by expansion.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Nivolumab in Combination With Chemoradiation for Patients With Stage II-IVB Nasopharyngeal Carcinoma, A Phase II Study With Correlative Biomarkers
Actual Study Start Date : December 12, 2017
Estimated Primary Completion Date : October 15, 2019
Estimated Study Completion Date : October 15, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Nivolumab + chemoradiation
Patients receive nivolumab IV over 60 minutes on day 1 of courses 1-5 and 7-12. Treatment repeats every 14 days for 11 courses in the absence of disease progression or unacceptable toxicity. Beginning at course 2, patients undergo radiation therapy QD 5 days per week and receive cisplatin IV over 30-60 minutes on day 1. Treatment repeats every 7 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
Drug: Nivolumab
Dosage 240mg of Nivolumab will be given intravenously over 60 minutes, every 14 days.
Other Name: Opdivo

Drug: Cisplatin
Dosage 40 mg/m2 of cisplatin will be given intravenously over 30-60 minutes, every 7 days.

Radiation: Radiation Therapy
2.12 Gy/fraction x 33 fractions of radiation therapy will be given, daily Monday - Friday




Primary Outcome Measures :
  1. Feasibility of treatment completion: Rate of completion of all adjuvant immunotherapy, in comparison to the rate of completion of a standard adjuvant cisplatin-based platform. [ Time Frame: Through study completion, maximum of 1 year ]
    The rate of completion of all adjuvant therapy by patients treated at the maximum tolerated dose (MTD) schedule will be determined and compared to a historical control rate of 52%.


Secondary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: From baseline to up to 1 year after completion of treatment ]
    As determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. The ORR is defined as the best overall response (BOR) recorded from the first day of treatment until time of assessment.

  2. Number and frequency of Adverse Events (AEs) [ Time Frame: From baseline to up to 1 year after completion of treatment ]
    As determined by National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 5.0 by investigator assessment

  3. Locoregional Control (LRC) Rate [ Time Frame: From first day of treatment to time of documented relapse, progression or death up to 1 year after completion of treatment ]
    Duration of LRC will be calculated as 1+ the number of days from the first day of treatment to time of documented locoregional clinical or radiographic relapse, progression or death due to any cause.

  4. Distant Metastasis (DM) Rate [ Time Frame: From first day of treatment to time of documented progression at a distant metastatic site, or death up to 1 year after completion of treatment ]
    Time to DM will be calculated as 1+ the number of days from the first day of treatment to documented clinical or radiographic progression at a distant metastatic site, or death due to any cause.

  5. Overall survival rate (OSR) [ Time Frame: From baseline to up to 1 year after completion of treatment ]
    As determined by standard physical examination and radiologic imaging

  6. Rate of Epstein-Barr Virus (EBV) DNA clearance [ Time Frame: Through study completion, maximum of 1 year ]
    From plasma by standardized polymerase chain reaction (PCR) assay

  7. Quality of life as assessed by patient reported outcomes [ Time Frame: From baseline to up to 1 year after completion of treatment ]
    Measured by Functional Assessment of Cancer Therapy - Nasopharyngeal Cancer (FACT-NP)

  8. Acute and late toxicity rates according to CTCAE version 5, including immune-related AEs [ Time Frame: Up to 1 year ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Males and females ≥18 years of age.
  2. Histologically or cytologically confirmed nasopharyngeal carcinoma, stage II-IV by American Joint Committee on Cancer (AJCC) 7th edition, endemic-type (defined as World Health Organization (WHO) type 2a and 2b nonkeratinizing or undifferentiated subtypes, excluding WHO type I keratinizing subtype) performed on a biopsy that occurred within 90 days of registration.
  3. Positron emission tomography-computed tomography (PET-CT) (preferred) or a CT of chest, abdomen, and pelvis within 60 days of registration showing radiographic stage II to IVB nasopharyngeal cancer.
  4. No distant metastasis as verified by one of the study investigators.
  5. Documentation that the patient is a candidate for chemoradiation of their nasopharyngeal cancer by one of the study investigators.
  6. Ability to tolerate radiation therapy (e.g. lie flat and hold position for treatment).
  7. Measurable disease as defined by RECIST v1.1.
  8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
  9. Lack of contraindications to systemic immunotherapy (see list of exclusions below).
  10. Resolution of all acute toxic effects of any prior chemotherapy, radiotherapy or surgical procedures to NCI CTCAE Version 4.0 grade 1.
  11. Adequate hepatic, hematologic, and renal indices permitting administration of cisplatin and nivolumab (within 14 days of registration):

    Hepatic Function:

    Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN); Total bilirubin ≤ 1.5 × ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)

    Adequate bone marrow function:

    White blood cells (WBC) ≥ 2000/μL Neutrophils ≥ 1500/μL Platelet ≥ 100 x103/μL Hemoglobin > 9.0 g/dL

    Adequate renal function:

    Serum creatinine ≤ 1.5 × 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

  12. Women of childbearing potential must have a negative serum pregnancy test within 24 hours prior to the first dose of study treatment and agree to use appropriate highly effective methods of contraception, during the study and for 5 months following completion of study treatment; A "Woman of childbearing potential" 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. In addition, women under the age of 62 must have a documented serum follicle stimulating hormone (FSH) level less than 40 milli-international units per milliliter (mIU/mL).

    Female Subjects:

    Women of child bearing potential are expected to use one of the highly effective methods of contraception listed in the protocol.

    Male Subjects:

    Male subjects must inform their female partners who are women of child bearing potential of the contraceptive requirements and are expected to adhere to using contraception with their partner. Female partners of male subjects, who are women of child bearing potential, are expected to use one of the highly effective methods of contraception listed in the protocol. In addition, male subjects are expected to use a condom as noted in the protocol.

  13. Men with a female partner of childbearing potential must agree to use highly effective methods of contraception or any contraceptive method with a failure rate of less than 1% per year during the study and for 7 months following completion of study treatment.
  14. Ability to sign informed consent.

Exclusion Criteria:

  1. Active second malignancy, i.e. patient known to have potentially fatal hematologic malignancy or another solid primary tumor present for which he/she may be (but not necessarily) currently receiving treatment. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are allowed to enroll in this trial. For example, patients with early-stage skin cancers, prostate cancer under surveillance with non-rising prostate-specific antigen (PSA), or meningioma or thyroid papillary cancers which are under surveillance are eligible. For determinations of a specific clinical condition, please consult with the Principal Investigator.
  2. Active, untreated central nervous system (CNS) metastases;
  3. Prior treatment with any other anti-programmed cell death protein-1 (anti-PD-1), or PD Ligand-1 (PD-L1) or PD Ligand-2 (PD-L2), anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways, or cancer vaccine;
  4. Prior systemic cytotoxic therapy, antineoplastic biologic therapy, or major surgery within 28 days of first dose of study medication;
  5. Severe hypersensitivity reaction to treatment during prior administration of a monoclonal antibody (mAb) or history of allergy to any study drug component;
  6. Has received a live-virus vaccination within 30 days of planned treatment start;
  7. 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.
  8. Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior history of ILD or pneumonitis requiring oral or IV glucocorticoids;
  9. Active, known, or suspected autoimmune disease or any autoimmune condition that has required systemic treatment in the past 2 years (replacement therapies for hormone deficiencies are allowed); 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.
  10. Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, or abdominal carcinomatosis (known risks factors for bowel perforation);
  11. Signs or symptoms of infection within 2 weeks prior to first day of study treatment.
  12. Received therapeutic oral or IV antibiotics within 2 weeks prior to first day of study treatment:

    Patients receiving prophylactic antibiotics (eg, to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible.

  13. Known positive test for human immunodeficiency virus (HIV);
  14. Known active hepatitis B or hepatitis C virus (HBV or HCV):

    Patients with past or resolved HBV infection (defined by a negative hepatitis B surface antigen [HBsAg] test and a positive anti-hepatitis B core antigen (HBc) antibody test) are eligible. HBV DNA must be obtained in these patients prior to first day of study treatment.

    Patients who have been recently discovered to have HBV with positive HBsAg test and positive anti HBc antibody test but who have been started on antiretroviral treatment with nondetectable HBV DNA are eligible. HBV DNA must be obtained in these patients prior to first day of study treatment.

  15. Patients with known active hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection:

    Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.

  16. Prior radiation therapy of any type within 7 days of first dose of study medication;
  17. Prior radiation therapy to head and neck region that would overlap with intended radiation treatment for nasopharyngeal carcinoma;
  18. Medical contraindication to radiation treatment (e.g. active systemic sclerosis, other uncontrolled autoimmune condition)
  19. Treatment with prohibited medications (including concurrent anticancer therapy including chemotherapy, radiation, hormonal treatment [except corticosteroids and megestrol acetate] ≤ 14 days prior to treatment.
  20. Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study;
  21. Active, uncontrolled psychiatric disorders or substance (drug/alcohol) abuse that interfere with patient's safety, ability to provide informed consent, or ability to comply with the protocol.
  22. Persons who are incarcerated or otherwise under compulsory detention by an authority are not eligible.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03267498


Contacts
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Contact: Kyusun Cha 877-827-3222 cancertrials@ucsf.edu
Contact: Sue S Yom, MD, MAS 877-827-3222 cancertrials@ucsf.edu

Locations
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United States, California
Helen Diller Family Comprehensive Center, UCSF Recruiting
San Francisco, California, United States, 94115
Contact: Clinical Trials Office    877-827-3222    cancertrials@ucsf.edu   
Principal Investigator: Sue Yom, M.D.         
Sponsors and Collaborators
University of California, San Francisco
National University Cancer Institute, Singapore
Bristol-Myers Squibb
Investigators
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Principal Investigator: Sue S Yom University of California, San Francisco

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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03267498     History of Changes
Other Study ID Numbers: 162010
NCI-2017-02291 ( Other Identifier: Clinical Trials Reporting Program (CTRP) )
First Posted: August 30, 2017    Key Record Dates
Last Update Posted: April 5, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Nasopharyngeal Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Nasopharyngeal Neoplasms
Pharyngeal Neoplasms
Otorhinolaryngologic Neoplasms
Head and Neck Neoplasms
Neoplasms by Site
Nasopharyngeal Diseases
Carcinoma
Pharyngeal Diseases
Stomatognathic Diseases
Otorhinolaryngologic Diseases
Cisplatin
Nivolumab
Antineoplastic Agents
Antineoplastic Agents, Immunological