Head and Neck Carcinoma, Head and Neck Squamous Cell Carcinoma, Squamous Cell Cancer, Squamous Cell Carcinoma of the Hypopharynx, Squamous Cell Carcinoma of the Larynx, Squamous Cell Carcinoma of the Oral Cavity, Squamous Cell Carcinoma of the Oropharynx, Squamous Cell Carcinoma of the Paranasal Sinus
Conditions
Brief summary
The purpose of this study is to find out if the combination of two established anti-cancer therapies are beneficial in participants with Head and Neck Squamous Cell Carcinoma (HNSCC). Specifically, investigators want to determine if the combination of Cetuximab and nivolumab can help people with advanced cases of HNSCC. Both cetuximab and nivolumab have been used separately to treat HNSCC and are Food and Drug Administration (FDA) approved in this type of cancer.
Detailed description
PHASE I: Participants will be enrolled sequentially and treated at Dose Level 1, or Dose Level -1, every 2 weeks for 12 cycles or until discontinuation. Each cycle is 4 weeks. Cetuximab is given alone in lead-in period at Day -14 before Cycle 1 only. In all subsequent doses starting Cycle 1 Day 1, nivolumab and cetuximab will be given concurrently. Dose limiting toxicity (DLT) assessment will be performed during Cycle 1 and will start with the initiation of the combination of cetuximab and nivolumab (4 weeks). PHASE II: Once the maximum tolerated dose (MTD) or the recommended phase II dose of cetuximab is determined in Phase I, accrual to the phase II will begin. FOLLOW-UP: Participants will be followed for 2 years from End of Treatment. The imaging studies will be performed every 8 weeks (2 cycles) of the treatments during Cycle 1-6 and then every 12 weeks during Cycle 7-12 as per standard of care. Patient will be followed by treating physicians as per standard of care.
Interventions
DRUGNivolumab
Nivolumab intravenously (IV) at 240 mg as outlined in the treatment arms.
DRUGCetuximab
Cetuximab intravenously (IV) at 500 mg/m\^2 or 250 mg/m\^2 as outlined in the treatment arms.
Sponsors
H. Lee Moffitt Cancer Center and Research Institute
James and Esther King Biomedical Research Program
Eli Lilly and Company
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must have histologically or cytologically confirmed squamous cell carcinoma of oral cavity, oropharynx, paranasal sinuses, nasal cavity, hypopharynx, or larynx. Squamous cell carcinoma of unknown primary in cervical lymph node can be included only if p16 status is positive. * Must have recurrent or metastatic HNSCC stage III/IV that is not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy).Patients with persistent disease following radiation therapy administered with a chemotherapy sensitizer may also be included. * Must have progressed on at least one prior line of chemotherapy, targeted therapy, palliative radiation, and/or biological therapy regimen for their recurrent and/or metastatic HNSCC. However, if patients are likely to be intolerant to standard first-line systemic chemotherapy, the patients are eligible to enroll to this study as the first-line therapy. Additionally, patients with persistent disease or platinum-refractory recurrent disease may enroll in this study as a first-line therapy. * Must NOT have any systemic therapy for recurrent and/or metastatic disease except if given as a part of a multimodality treatment (i.e. re-irradiation and systemic therapy for curable intent of locally recurrent disease). * Must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as outlined in RECIST version 1.1. * Must be ≥ 18 years of age. * Life expectancy of greater than 3 months. * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. * Must have normal organ function: Absolute neutrophil count \> 1,500/μL; Hemoglobin \> 9 g/dL; Platelets \> 100,000/μL; Total bilirubin ≤ 1.5 mg/dL X institutional upper limits of normal (ULN); AST (SGOT)/ALT (SGPT) \< 3 X institutional ULN (or 5.0 X the ULN in the setting of liver metastasis); Serum creatinine of ≤ 1.5 X ULN or creatinine clearance \> 40 mL/minute (using Cockcroft/Gault formula): Female creatinine clearance = (140 - age in years) x weight in kg x 0.8572 x serum creatinine in mg/ dL; Male creatinine clearance = (140 - age in years) x weight in kg x 1.0072 x serum creatinine in mg/dL. * Participants, if sexually active, must be postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods). Female participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to enrollment. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Have experienced grade 3 or above skin toxicity from prior Epidermal growth factor receptor (EGFR) inhibiting therapy. * Have experienced grade 3 or above toxicity from prior anti-PD1 therapy. * Have p16 negative squamous cell carcinoma of unknown primary in cervical lymph node. * Patients with primary nasopharynx or salivary gland cancers. * Patients who have had chemotherapy, biological therapy or definitive radiation within 4 weeks of the study enrollment or those who have not recovered from adverse events to ≤ Grade 1 due to agents administered more than 4 weeks earlier. * Had undergone any major surgery within 4 weeks of study enrollment. * Had undergone any palliative radiation within 2 weeks of study enrollment. * Have had other investigational agents within 4 weeks or 5 half-lives, whichever is shorter, of the study enrollment. * Have known leptomeningeal metastases or untreated or symptomatic brain metastases. Treated, asymptomatic brain metastasis can be included. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, autoimmune disease requiring systemic steroids, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Have a 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. * Have clinically relevant coronary artery disease or history of myocardial infarction in the last 12 months or high risk of uncontrolled arrhythmia or uncontrolled cardiac insufficiency. * Have uncontrolled or poorly controlled hypertension (\>180 mmHg systolic or \> 130 mmHg diastolic) at the time of enrollment. * Prior treatment with a combination of cetuximab and a PD-1/PD-L1 inhibitor. Prior treatment with cetuximab or a PD-1/PD-L1 inhibitor is allowed as long as not previously given in combination. * A history of allergic reactions attributed to compounds of chemical or biologic composition similar to those of cetuximab and/or nivolumab. * Pregnant or breast-feeding. * Known active HIV, Hep B, or Hep C infection. If not clinically indicated, the patients do not need to be tested.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Maximum Tolerated Dose | Up to 12 months | Maximum Tolerated Dose (MTD).. The target Dose Limiting Toxicity (DLT) rate is \<25%. The MTD will be defined as the dose of cetuximab and nivolumab in which \<1 of 3 patients experience a DLT or \<2 of 6 patients experience a DLT with the next higher dose having at least 2 patients experiencing a DLT. The MTD is the highest dose at which at most 1 of 6 patients has a DLT. This study will utilize the Cancer Therapy Evaluation Program CTCAE version 4.1 for toxicity and event reporting. Dose-limiting toxicities will be observed until patients have completed Cycle 1 (4 weeks). |
| Phase II: Overall Survival (OS) | Up to 24 months | One year overall survival of concurrent cetuximab and nivolumab in patients with recurrent and/or metastatic HNSCC. OS: The length of time from the start of treatment until death by any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Up to 48 months | Complete Response (CR): The disappearance of all measurable lesions. Partial Response (PR): At least a 30% decrease in the sum of the longest diameters of measureable lesions, taking as reference the baseline sum longest diameter. Progressive Disease (PD): At least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s). Stable Disease (SD): Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease. To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval of 6 weeks. |
| Progression Free Survival (PFS) | at 12 months | Progressive Disease (PD): At least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s). |
| Number of Study Treatment Related Adverse Events | Up to 48 months | Related adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) V4.1. An adverse event (AE) is defined as any untoward medical occurrence, including an exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a pharmaceutical product. A serious adverse event (SAE) is defined as any AE that results in death, is immediately life-threatening, results in persistent or significant disability/incapacity, requires or prolongs patient hospitalization, is a congenital anomaly/birth defect, or is to be deemed serious for any other reason if it is an important medical event when based on appropriate medical judgement that may jeopardize the patient and may require medical or surgical intervention to prevent one of the other outcomes listed in the above definitions. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORChristine H. Chung, M.D.
H. Lee Moffitt Cancer Center and Research Institute
Participant flow
Pre-assignment details
Participants in lead-in were included in Cohort A for outcome measure data.
Participants by arm
| Arm | Count |
|---|---|
| Phase I - Lead in Lead-in Day -14 before Cycle 1 only: Cetuximab 500 mg/m\^2; Nivolumab - none. Cycle 1 Day 1 and all subsequent doses every 2 weeks (Q2W): Cetuximab 500 mg/m\^2; Nivolumab 240 mg.
Nivolumab: Nivolumab intravenously (IV) at 240 mg as outlined in the treatment arms. | 3 |
| Phase II - Cohort A Patients who had progressed on at least one prior line of treatment for their recurrent and/or metastatic HNSCC
Participants were treated with Nivolumab and Cetuximab at recommended Phase II dose (RP2D). Nivolumab: Nivolumab intravenously (IV) at 240 mg as outlined in the treatment arms. Cetuximab: Cetuximab intravenously (IV) at 500 mg/m\^2 or 250 mg/m\^2 as outlined in the treatment arms. | 44 |
| Phase II - Cohort B Patients who have not had any prior treatment for their recurrent and/or metastatic HNSCC
Participants were treated with Nivolumab and Cetuximab at recommended Phase II dose (RP2D). Nivolumab: Nivolumab intravenously (IV) at 240 mg as outlined in the treatment arms. Cetuximab: Cetuximab intravenously (IV) at 500 mg/m\^2 or 250 mg/m\^2 as outlined in the treatment arms. | 48 |
| Total | 95 |
Baseline characteristics
| Characteristic | Phase I - Lead in | Phase II - Cohort A | Phase II - Cohort B | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 20 Participants | 16 Participants | 37 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 24 Participants | 32 Participants | 58 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 41 Participants | 45 Participants | 89 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 3 Participants | 39 Participants | 42 Participants | 84 Participants |
| Region of Enrollment United States | 3 participants | 44 participants | 48 participants | 95 participants |
| Sex: Female, Male Female | 1 Participants | 7 Participants | 15 Participants | 23 Participants |
| Sex: Female, Male Male | 2 Participants | 37 Participants | 33 Participants | 72 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 35 / 44 | 33 / 48 |
| other Total, other adverse events | 3 / 3 | 43 / 44 | 45 / 48 |
| serious Total, serious adverse events | 3 / 3 | 19 / 44 | 19 / 48 |
Outcome results
Primary
Phase II: Overall Survival (OS)
One year overall survival of concurrent cetuximab and nivolumab in patients with recurrent and/or metastatic HNSCC. OS: The length of time from the start of treatment until death by any cause.
Time frame: Up to 24 months
Population: Evaluable participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Lead in | Phase II: Overall Survival (OS) | 11.4 months |
| Phase II - Cohort B | Phase II: Overall Survival (OS) | 20.2 months |
Primary
Phase I: Maximum Tolerated Dose
Maximum Tolerated Dose (MTD).. The target Dose Limiting Toxicity (DLT) rate is \<25%. The MTD will be defined as the dose of cetuximab and nivolumab in which \<1 of 3 patients experience a DLT or \<2 of 6 patients experience a DLT with the next higher dose having at least 2 patients experiencing a DLT. The MTD is the highest dose at which at most 1 of 6 patients has a DLT. This study will utilize the Cancer Therapy Evaluation Program CTCAE version 4.1 for toxicity and event reporting. Dose-limiting toxicities will be observed until patients have completed Cycle 1 (4 weeks).
Time frame: Up to 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Lead in | Phase I: Maximum Tolerated Dose | 500 mg/m^2 |
Secondary
Number of Study Treatment Related Adverse Events
Related adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) V4.1. An adverse event (AE) is defined as any untoward medical occurrence, including an exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a pharmaceutical product. A serious adverse event (SAE) is defined as any AE that results in death, is immediately life-threatening, results in persistent or significant disability/incapacity, requires or prolongs patient hospitalization, is a congenital anomaly/birth defect, or is to be deemed serious for any other reason if it is an important medical event when based on appropriate medical judgement that may jeopardize the patient and may require medical or surgical intervention to prevent one of the other outcomes listed in the above definitions.
Time frame: Up to 48 months
Population: Evaluable participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I - Lead in | Number of Study Treatment Related Adverse Events | Grade 1 | 115 events |
| Phase I - Lead in | Number of Study Treatment Related Adverse Events | Grade 2 | 105 events |
| Phase I - Lead in | Number of Study Treatment Related Adverse Events | Grade 3 | 23 events |
| Phase I - Lead in | Number of Study Treatment Related Adverse Events | Grade 4 | 1 events |
| Phase II - Cohort B | Number of Study Treatment Related Adverse Events | Grade 4 | 1 events |
| Phase II - Cohort B | Number of Study Treatment Related Adverse Events | Grade 1 | 228 events |
| Phase II - Cohort B | Number of Study Treatment Related Adverse Events | Grade 3 | 27 events |
| Phase II - Cohort B | Number of Study Treatment Related Adverse Events | Grade 2 | 142 events |
Secondary
Overall Response Rate (ORR)
Complete Response (CR): The disappearance of all measurable lesions. Partial Response (PR): At least a 30% decrease in the sum of the longest diameters of measureable lesions, taking as reference the baseline sum longest diameter. Progressive Disease (PD): At least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s). Stable Disease (SD): Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease. To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval of 6 weeks.
Time frame: Up to 48 months
Population: Participants evaluable for response
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Lead in | Overall Response Rate (ORR) | 22 percentage of participants responded |
| Phase II - Cohort B | Overall Response Rate (ORR) | 37 percentage of participants responded |
Secondary
Progression Free Survival (PFS)
Progressive Disease (PD): At least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s).
Time frame: at 12 months
Population: Evaluable participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Lead in | Progression Free Survival (PFS) | 3.35 months |
| Phase II - Cohort B | Progression Free Survival (PFS) | 6.15 months |