A Study Using Nivolumab, in Combination With Chemotherapy Drugs to Treat Nasopharyngeal Carcinoma (NPC)

Stage IV Nasopharyngeal Carcinoma AJCC v8 Clinical Trial

Official title:

A Phase 2 Study Using Chemoimmunotherapy With Gemcitabine, Cisplatin and Nivolumab in Newly Diagnosed Nasopharyngeal Carcinoma (NPC)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06064097
• Other study ID #: NCI-2023-07208
• Secondary ID: NCI-2023-07208AR
• Status: Recruiting
• Phase: Phase 2
• Start date: January 17, 2025
• Est. completion date: August 31, 2026

Study information

• Verified date: May 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial tests effects of nivolumab in combination with chemotherapy drugs prior to radiation therapy patients with nasopharyngeal carcinoma (NPC). 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 gemcitabine and cisplatin, 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. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Researchers want to find out what effects, good and/or bad, adding nivolumab to chemotherapy has on patients with newly diagnosed NPC. In addition, they want to find out if children with NPC may be treated with less radiation therapy and whether this decreases the side effects of therapy.

Description:

PRIMARY OBJECTIVE:

I. To evaluate safety of combining chemotherapy (cisplatin and gemcitabine) with an anti-PD1 immune checkpoint inhibitor (nivolumab) in children, adolescents and young adults with nasopharyngeal carcinoma (NPC) by determining the rate of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher immune related adverse events (irAEs).

SECONDARY OBJECTIVES:

I. To estimate the 2-year event-free survival (EFS) of children, adolescents and young adults with NPC who are treated with induction chemoimmunotherapy (CIT), followed by consolidation chemoradioimmunotherapy (CRIT, cisplatin, nivolumab and response-adjusted, dose de-escalated radiation therapy), and nivolumab maintenance therapy.

II. To evaluate the objective response rate (ORR) including complete responders and partial responders (complete response [CR] + partial response [PR]) of neoadjuvant CIT.

III. To evaluate feasibility of combining chemotherapy (cisplatin and gemcitabine) with an anti-PD1 immune checkpoint inhibitor (nivolumab) in children, adolescents and young adults with nasopharyngeal carcinoma (NPC).

IV. To evaluate the cumulative incidence of local and distant relapse.

EXPLORATORY OBJECTIVES:

I. To estimate 5-year EFS and overall survival (OS) of children with NPC who are treated with induction CIT followed by consolidation CRIT, and nivolumab maintenance therapy.

II. To compare response assessed by fludeoxyglucose F18 (FDG) positron emission tomography (PET) versus magnetic resonance imaging (MRI).

III. To determine treatment outcomes for patients treated with radiation per protocol versus (vs) deviation.

IV. To evaluate outcomes comparing patients receiving intensity modulated radiation therapy (IMRT) to proton therapy.

V. To objectively measure both acute and long-term toxicity including immune related adverse events and radiation late effects.

VI. To evaluate swallowing dysfunction using patient reported outcome (PRO) measures for children and adults throughout the protocol for up to 5 years.

VII. To evaluate quality of life (QOL) using Patient-Reported Outcomes Measurement Information System (PROMIS) multidimensional questionnaire throughout the protocol for up to 5 years.

VIII. To correlate the lymphocyte to monocyte ratio on complete blood counts (CBCs) with treatment response and outcomes.

IX. To collect and bank specimens (including tumor, blood and stool) for future research studies.

OUTLINE:

INDUCTION THERAPY: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1 of each cycle, gemcitabine IV over 30 minutes on days 1 and 8 of each cycle, and cisplatin IV over 3-6 hours on day 1 of each cycle. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION THERAPY: Patients receive nivolumab IV over 30 minutes on day 1 of each cycle and cisplatin IV over 3-6 hours on day 1 of cycles 1-2. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive concurrent radiation therapy on trial.

MAINTENANCE THERAPY: Patients receive nivolumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

Patients also undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening and as clinically indicated on trial. Patients undergo MRI, FDG PET, and computed tomography (CT) throughout the trial and chest x-ray during follow-up. Patients also undergo dental x-ray imaging on the trial. Patients may optionally undergo tissue biopsy, blood and stool sample collection during screening and on trial.

After completion of study treatment, patients are followed up every 3 months for 12 months, every 6 months until 24 months off therapy, and then yearly until 5 years off therapy.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: August 31, 2026
• Est. primary completion date: August 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 21 Years

Eligibility

Inclusion Criteria:

• Patients must be = 21 years of age at the time of study enrollment

• Newly diagnosed American Joint Committee on Cancer (AJCC) stage II-IV nasopharyngeal carcinoma (NPC)

• Patients must have had histologic verification of the malignancy at original diagnosis

• Although submission of tumor tissue for the molecular characterization initiative is not required for eligibility, it is strongly recommended

• Patients must have had histologic verification of the malignancy at original diagnosis

• Although submission of tumor tissue for the molecular characterization initiative is not required for eligibility, it is strongly recommended

• Patients must have a Lansky (for patients = 16 years of age) or Karnofsky (for patients > 16 years of age) performance status score of = 60%

• Peripheral absolute neutrophil count (ANC) = 1000/uL (within 7 days prior to start of protocol therapy)

• Platelet count = 100,000/uL (transfusion independent) (within 7 days prior to start of protocol therapy)

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) = 60 mL/min/1.73 m^2 or (within 7 days prior to start of protocol therapy)

• A serum creatinine based on age/gender (within 7 days prior to start of protocol therapy) Age: Maximum serum creatinine (mg/dL)

1 month to < 6 months: 0.4 mg/dL (male); 0.4 mg/dL (female) 6 months to < 1 year: 0.5 mg/dL (male); 0.5 mg/dL (female)

1 to < 2 years: 0.6 mg/dL (male); 0.6 mg/dL (female) 2 to < 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female) 6 to < 10 years 1 mg/dL (male); 1 mg/dL (female) 10 to <13 years: 1.2 mg/dL (male); 1.2 mg/dL (female) 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)

= 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female)

• Total bilirubin = 1.5 x upper limit of normal (ULN) for age, and (within 7 days prior to start of protocol therapy)

• Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) = 135 U/L* (within 7 days prior to start of protocol therapy)

• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L

• Shortening fraction of = 27% by echocardiogram, or

• Ejection fraction of = 50% by radionuclide angiogram

• No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if there is clinical indication for determination

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months and T-cell count above the lower limit of normal are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. 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

Exclusion Criteria:

• Patients who received prior radiotherapy to the head or neck

• Patients who received prior chemotherapy or radiation for the treatment of any cancer in the last 3 years. These patients must also be in remission

• Patients with a diagnosis of immunodeficiency

• Patients with an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive agents). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

• Note: Patients with well-controlled asthma and no need for systemic steroids for the treatment of asthma in the last 12 months will not be excluded

• Patients with a condition requiring systemic treatment with either corticosteroids (> 0.25 mg/kg (10 mg) daily prednisone equivalent) within 14 days or other immunosuppressive medications within 30 days of enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses > 0.25 mg/kg (10 mg) daily prednisone equivalent, are permitted in the absence of active autoimmune disease

• Patients with a history of (non-infectious) pneumonitis that required steroids or current pneumonitis

• Patients with detectable viral load of human immunodeficiency virus (HIV), hepatitis B or hepatitis C, or active tuberculosis

• Patients who have undergone solid organ or allogeneic hematopoietic transplant at any time

• Due to risks of fetal and teratogenic adverse events as seen in animal studies, a negative pregnancy test must be obtained in females of childbearing potential, defined as females who are post-menarchal. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Females of childbearing potential that are sexually active must agree to either practice 2 medically accepted highly-effective methods of contraception at the same time or abstain from heterosexual intercourse from the time of signing the informed consent through 5 months after the last dose of nivolumab, 6 months after the last dose of gemcitabine, and 14 months after the last dose of cisplatin, whichever is longer

• Males of childbearing potential that are sexually active must agree to either practice a medically accepted highly-effective methods of contraception or abstain from heterosexual intercourse from the time of signing the informed consent through 3 months after the last dose of gemcitabine, and 11 months after the last dose of cisplatin, whichever is longer

• Lactating females are not eligible unless they have agreed not to breastfeed their infants starting with the first dose of study therapy through 5 months after the last dose of nivolumab

• All patients and/or their parents or legal guardians must sign a written informed consent

• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Related Conditions & MeSH terms

• Carcinoma
• Nasopharyngeal Carcinoma
• Stage II Nasopharyngeal Carcinoma AJCC v8
• Stage III Nasopharyngeal Carcinoma AJCC v8
• Stage IV Nasopharyngeal Carcinoma AJCC v8

Intervention

Procedure:
• Biopsy
Undergo tissue biopsy
• Biospecimen Collection
Undergo blood and stool sample collection
• Chest Radiography
Undergo chest x-ray

Drug:
• Cisplatin
Given IV

Procedure:
• Computed Tomography
Undergo CT
• Echocardiography
Undergo ECHO

Other:
• Electronic Health Record Review
Ancillary studies
• Fluciclovine F18
Given IV

Drug:
• Gemcitabine
Given IV

Procedure:
• Magnetic Resonance Imaging
Undergo MRI
• Multigated Acquisition Scan
Undergo MUGA

Biological:
• Nivolumab
Given IV

Procedure:
• Positron Emission Tomography
Undergo PET

Other:
• Quality-of-Life Assessment
Ancillary studies
• Questionnaire Administration
Ancillary studies

Radiation:
• Radiation Therapy
Receive radiation therapy

Procedure:
• X-Ray Imaging
Undergo dental x-ray

Locations

Country	Name	City	State
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Saint Jude Children's Research Hospital	Memphis	Tennessee
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Kaiser Permanente-Oakland	Oakland	California
United States	Nemours Children's Hospital	Orlando	Florida
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	EFS	Will be assessed using Kaplan-Meier estimates.	At 5 years
Other	Overall survival	Will be assessed using Kaplan-Meier estimates.	From date of enrollment to death due to any cause or date of last follow-up, assessed at 5 years
Other	Proportion of patients who achieve complete response	Will be assessed by retrospective central review by the proportion of patients who achieve complete response by magnetic resonance imaging using RECIST 1.1 criteria and the proportion of patients who achieve complete metabolic response using Positron Emission Tomography Response Criteria In Solid Tumors criteria at the end of induction and the end of maintenance based on central review will be presented. A two-way table of response assessments according to the two modalities will be constructed and McNemar's test will be performed to evaluate the concordance.	At the end of induction and maintenance
Other	Protocol deviation related to radiation therapy delivery	Will be assessed by retrospective central review. The effect of deviation, categorized as present or absent by the central reviewer, on the hazard of EFS will be estimated by Cox proportional hazard model. The hazard ratio will be reported along with 95% confidence interval.	Up to 5 years
Other	EFS in patients receiving intensity modulated radiation therapy with those who receive proton therapy	Will be assessed using a log-rank test.	Up to 5 years
Other	Incidence of grade 3 or higher adverse events	Will be assessed during protocol therapy. The incidence of these events will be reported for each toxicity term. Furthermore, the irAE and toxicity related to radiation will be summarized by toxicity term and will be presented separately for the on-protocol therapy period and long-term follow-up.	Up to 5 years
Other	Swallowing dysfunction	Will be assessed using modified Functional Oral Intake Scale (FOIS) and pediatric Eating Assessment Tool (EAT)-10. The EAT-10 consists of 10 items scored from 0 (no impairment) to 4 (severe impairment). Total scores range from 0 to 40; higher scores indicate greater self-perceived impairment. Modified FOIS is an ordinal scale is a rating scale with 7 points for adults and 5 points in pediatrics. It is used to describe the feeding status and patients with dysphagia. Level 1 indicates inability to take anything by mouth while the highest point indicates full oral feeding. Will summarize responses from the modified FOIS and pediatric EAT-10 descriptively for each of these time points. A two-sided Wilcoxon rank-sum test will be performed to test the null hypothesis of equal score between two groups (who receive 54Gy versus 59.4Gy) at the end of the CRIT. Will evaluate the potential impact of other factors, as appropriate, such as baseline scores or disease stages for this analysis.	At baseline, during induction prior to start of chemoradioimmunotherapy (CRIT), each cycle throughout CRIT, within 3 months after maintenance and yearly at follow up, up to 5 years
Other	Quality of life	Will be assessed using Patient-Reported Outcomes Measurement Information System (PROMIS). PROMIS includes multiple measures such as physical function mobility, anxiety, depressive symptoms, fatigue, etc. PROMIS use a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation of that population. Higher T-score indicates more of the concept being measured. The numerical T scores of each domain will be summarized descriptively at every time point.	At baseline, during induction prior to start of CRIT, each cycle throughout CRIT, within 3 months after maintenance and yearly at follow up, up to 5 years
Other	Lymphocyte-to-monocyte ratio (LMR)	Will be assessed the ratio calculated by dividing the absolute lymphocyte count by the absolute monocyte count from a complete blood count with differential analysis performed. Lymphocyte and monocyte counts will be collected at the following time points: baseline, pre-radiation/consolidation, and post-radiation pre-maintenance. Cox proportional hazards regression will be used to evaluate the association between baseline LMR and EFS. The hazard ratio will be reported with a 95% confidence interval. In addition, the LMR will be summarized descriptively by the evaluation time points.	At baseline, pre-radiation/consolidation, and post-radiation pre-maintenance
Primary	Incidence of grade 3 or higher immune-related adverse events (irAE) during induction chemoimmunotherapy (CIT)	Will be assessed by Common Terminology Criteria for Adverse Events. IrAEs include diarrhea (noninfectious), colitis (noninfectious), pneumonitis (noninfectious), myocarditis, elevated alanine aminotransferase, elevated aspartate aminotransferase, pancreatitis, elevated blood bilirubin, hypophysitis and hyperthyroid considered possibly, probably, or definitely related to nivolumab.	Until the end of consolidation therapy
Secondary	Event-free survival (EFS)	EFS along with the 95% confidence intervals will be estimated using the Kaplan-Meier method. The EFS will be reported separately for patients with non-metastatic disease and those with metastatic disease (if there are enough patients with metastatic disease enrolled).	From date of enrollment to the earliest occurrence of date of relapse, disease progression, second malignant neoplasm or death due to any cause, assessed at 2 years
Secondary	Objective response rate	Will be defined as the rate of responders among evaluable patients using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.	At the end of induction CIT
Secondary	Feasibility success of the induction regimen	Will be defined as the completion of three cycles of induction without delay of greater than 30 days for radiation initiation due to toxicity in 80% of patients.	At the end of induction CIT
Secondary	Cumulative incidence of local or distant relapse	Defined as a function of time since enrollment will be estimated by the method of Gray.	Up to 5 years