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
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|ClinicalTrials.gov Identifier: NCT04458909|
Recruitment Status : Active, not recruiting
First Posted : July 7, 2020
Last Update Posted : February 13, 2023
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|Condition or disease||Intervention/treatment||Phase|
|Metastatic Nasopharyngeal Carcinoma Metastatic Nasopharyngeal Keratinizing Squamous Cell Carcinoma Metastatic Nasopharyngeal Nonkeratinizing Carcinoma Metastatic Nasopharyngeal Undifferentiated Carcinoma Nasopharyngeal Nonkeratinizing Carcinoma Recurrent Nasopharyngeal Carcinoma Recurrent Nasopharyngeal Keratinizing Squamous Cell Carcinoma Recurrent Nasopharyngeal Undifferentiated Carcinoma Stage IV Nasopharyngeal Carcinoma AJCC v8 Stage IVA Nasopharyngeal Carcinoma AJCC v8 Stage IVB Nasopharyngeal Carcinoma AJCC v8||Drug: Carboplatin Drug: Cisplatin Drug: Gemcitabine Biological: Nivolumab Other: Questionnaire Administration||Phase 3|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||316 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|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|
|Actual Study Start Date :||September 8, 2020|
|Estimated Primary Completion Date :||May 9, 2028|
|Estimated Study Completion Date :||May 9, 2028|
Experimental: Arm I (nivolumab, gemcitabine, cisplatin, carboplatin)
Patients receive nivolumab IV over 30 minutes on day 1, gemcitabine IV over 30 minutes on days 1 and 8, and cisplatin IV over 30-60 minutes or carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. After 4 weeks, patients then receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
Other: Questionnaire Administration
Active Comparator: Arm II (gemcitabine, cisplatin, carboplatin)
Patients receive gemcitabine and cisplatin or carboplatin as in Arm I.
Other: Questionnaire Administration
- Overall survival (OS) [ Time Frame: From randomization until death due to any cause or last follow-up. Analysis occurs after 200 deaths have been reported, assessed up to 8 years ]Overall survival rates for both treatment arms will be estimated using the Kaplan-Meier method. The comparison of OS distributions between treatment arms will be done using a log-rank test.
- Locoregional failure [ Time Frame: From randomization until local or regional progression, death, or last follow-up, assessed up to 8 years ]Rates estimated by cumulative incidence method and arms compared by cause-specific log-rank test.
- Distant metastases [ Time Frame: From randomization until distant progression, death, or last follow-up, assessed up to 8 years ]Rates estimated by cumulative incidence method and arms compared by cause-specific log-rank test.
- Progression-free survival (PFS) [ Time Frame: From randomization until progression or death due to any cause, or last follow-up, assessed up to 8 years ]Rates estimated using the Kaplan-Meier method and between-arm differences compared using the log-rank test.
- Tumor response [ Time Frame: From randomization to last follow-up, assessed up to 8 years ]Will be assessed by Response Evaluation Criteria in Solid Tumors 1.1. The Objective Response Rate (ORR), defined as the proportion of confirmed complete and partial response, will be calculated with their respective 95% confidence intervals (CI). An estimate of the difference in ORR between the experimental and control arms along with the 95% CI, will also be provided. The between-arm difference in ORR will be assessed using a chi-square test for proportions based on normal approximation. The confidence intervals will be also based on a normal approximation.
- Incidence of adverse events (AEs) [ Time Frame: From start of treatment to last follow-up, assessed up to 8 years ]Will be assessed by Common Terminology Criteria for Adverse Events version 5.0. Counts of all AEs by grade will be provided by the treatment arm. Counts and frequencies will be provided for the worst grade AE experienced by the patient's treatment arm. The number of patients with at least 1 grade 3 or higher AE will be compared between the treatment arms. All comparisons will be tested using a chi-Square test, or Fisher's exact test if cell frequencies are < 5, with a significance level of 0.05. Toxicity analyses will be based on an as-treated population, including all patients who received at least one dose of the assigned trial treatment.
- Patient-reported symptomatic toxicities [ Time Frame: From randomization to 2 years ]Will be assessed by Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE). The proportion of patients with scores >= 1 and >= 3 will be compared between groups using a Chi-square test, or Fisher's exact test if cell frequencies are < 5, using a significance level of 0.05. Analysis of changes in patient reported outcomes over time will be analyzed by fitting generalized estimating equation (GEE) models using a logit link (dichotomizing the symptom scores as 0 versus [vs.] > 1 and 0-2 vs. 3-4) with the time of assessment, treatment arm, and treatment-by-time interaction terms in the model.
- Quality of life [ Time Frame: From randomization to 2 years ]Will be assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30).
- Fatigue [ Time Frame: From randomization to 2 years ]Will be assessed by Multidimensional Fatigue Inventory (MFI-20).
- Progression-free survival by PD-L1 Combined Positive Score (CPS)/Tumor Proportion Score (TPS) cut-off [ Time Frame: From randomization until progression or death due to any cause, or last follow-up, assessed up to 8 years ]Will be assessed based on PD-L1 CPS/TPS cut-off.
- Overall survival by PD-L1 CPS/TPS cut-off [ Time Frame: From randomization until death due to any cause or last follow-up, assessed up to 8 years ]Will be assessed based on PD-L1 CPS/TPS cut-off.
- Change in quality of life [ Time Frame: From randomization to 2 years ]Will be measured by EORTC QLQ-C30 between and within arms over time.
- Change in fatigue [ Time Frame: From randomization to 2 years ]Will be measured by MFI-20 between and within arms over time.
- Translational research studies [ Time Frame: From randomization to last follow-up, assessed up to 8 years ]
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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 registration
- Absolute neutrophil count (ANC) >= 1500 cells/mm^3 (within 14 days prior to registration)
- 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 registration)
- 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 treatment
- The patient or a legally authorized representative must provide written informed consent prior to study entry
- 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 registration
- 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 registration
- 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
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): NCT04458909
|Principal Investigator:||Brigette B Ma||NRG Oncology|
|Responsible Party:||National Cancer Institute (NCI)|
|Other Study ID Numbers:||
NCI-2020-04581 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-HN007 ( Other Identifier: NRG Oncology )
NRG-HN007 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
|First Posted:||July 7, 2020 Key Record Dates|
|Last Update Posted:||February 13, 2023|
|Last Verified:||November 2022|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Yes|
|Plan Description:||NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Carcinoma, Squamous Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Squamous Cell
Head and Neck Neoplasms
Neoplasms by Site
Molecular Mechanisms of Pharmacological Action