Cetuximab & Nivolumab in Patients With Recurrent/Metastatic Head & Neck Squamous Cell Carcinoma

Study Overview
=================
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.

Official Title
-----------------
A Phase I/II Study of Concurrent Cetuximab and Nivolumab in Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma

Conditions
-----------------
Squamous Cell Carcinoma of the Oropharynx, Squamous Cell Carcinoma of the Larynx, Squamous Cell Carcinoma of the Oral Cavity, Squamous Cell Carcinoma of the Hypopharynx, Squamous Cell Carcinoma of the Paranasal Sinus, Head and Neck Squamous Cell Carcinoma, Squamous Cell Cancer, Head and Neck Carcinoma

Intervention / Treatment
-----------------
* Drug: Nivolumab
* Drug: Cetuximab


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I - Affiliate Sites Only<br>Nivolumab and dose escalation of Cetuximab. Dose Level 1: 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. Dose Level -1: 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 250 mg/m^2; Nivolumab 240 mg. | Drug: Nivolumab<br>* Nivolumab intravenously (IV) at 240 mg as outlined in the treatment arms.<br>* Other names: Opdivo;Drug: Cetuximab<br>* Cetuximab intravenously (IV) at 500 mg/m^2 or 250 mg/m^2 as outlined in the treatment arms.<br>* Other names: Erbitux;|
| Experimental: Phase I - Moffitt Site Only<br>Nivolumab and dose escalation of Cetuximab. Dose Level 1: 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. Dose Level -1: 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 250 mg/m^2; Nivolumab 240 mg. | Drug: Nivolumab<br>* Nivolumab intravenously (IV) at 240 mg as outlined in the treatment arms.<br>* Other names: Opdivo;Drug: Cetuximab<br>* Cetuximab intravenously (IV) at 500 mg/m^2 or 250 mg/m^2 as outlined in the treatment arms.<br>* Other names: Erbitux;|
| Experimental: Phase II - Affiliate Sites Only<br>Nivolumab and Cetuximab at recommended Phase II dose (RP2D). | Drug: Nivolumab<br>* Nivolumab intravenously (IV) at 240 mg as outlined in the treatment arms.<br>* Other names: Opdivo;Drug: Cetuximab<br>* Cetuximab intravenously (IV) at 500 mg/m^2 or 250 mg/m^2 as outlined in the treatment arms.<br>* Other names: Erbitux;|
| Experimental: Phase II - Moffitt Site Only<br>Nivolumab and Cetuximab at recommended Phase II dose (RP2D). | Drug: Nivolumab<br>* Nivolumab intravenously (IV) at 240 mg as outlined in the treatment arms.<br>* Other names: Opdivo;Drug: Cetuximab<br>* Cetuximab intravenously (IV) at 500 mg/m^2 or 250 mg/m^2 as outlined in the treatment arms.<br>* Other names: Erbitux;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Up to 12 months | 
| 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. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 48 months | 
| 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). | at 12 months | 
| 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. | Up to 48 months |