Quad Shot Radiotherapy in Combination With Immune Checkpoint Inhibition

Quad-Shot Radiotherapy in Combination With Immune Checkpoint Inhibition for Advanced/Recurrent Head and Neck Cancer

This is a single-arm, non-randomized pilot study to evaluate the efficacy and tolerability of combination quad-shot palliative radiotherapy with immunotherapy for advanced/recurrent/metastatic head and neck cancer.

Primary Objective: Measure the overall response rate for immunotherapy given with quad-shot radiotherapy. Secondary Objective(s) Measure the response rate at the target lesion. Measure the response rate at non-target sites in patients with non-target sites. Evaluate the durability of response at the target lesion. Evaluate progression-free survival. Evaluate overall survival. Assess the tolerability of the combination of quad-shot radiotherapy with immunotherapy in order to assess the feasibility of this treatment regimen. Exploratory Objective: Evaluate the effect of quad- shot administration on increasing the immune activation by treatment with pembrolizumab and investigate possible mechanisms. OUTLINE: Patients receive standard of care pembrolizumab intravenously (IV) over 30 minutes every 3 weeks. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo quad-shot radiation therapy twice daily (BID) on 2 consecutive days between cycles 2-3 or 3-4, 6-7, and 11-12 of pembrolizumab treatment and in the last week of pembrolizumab treatment. After completion of study treatment, patients are followed up at 1 and 2 months for adverse events monitoring. Patients will be followed until death for monitoring survival study endpoints. Frequency of visits will be established by the treating physician and will be done in person or over the phone.

Advanced Head and Neck Squamous Cell Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma, Metastatic Head-and-neck Squamous-cell Carcinoma, Stage III Cutaneous Squamous Cell Carcinoma of the Head and Neck, Locally Advanced Head and Neck Squamous Cell Carcinoma, Stage IV Cutaneous Squamous Cell Carcinoma of the Head and Neck

Systemic therapy (ICI) and radiotherapy will be administered according to the standard of care, according to the treating medical oncologist and radiation oncologist, respectively

Each cycle of quad-shot radiotherapy will be comprised of 14.8 Gy in 4 fractions (3.7 Gy per fraction) delivered twice daily (at least 6 hours apart) over two consecutive days. All patients will receive 1 cycle of quad-shot radiotherapy between ICI cycles 2-3. Subsequent cycles may occur between immunotherapy cycles 6-7 and 11-12, if more than 1 cycle can be safely delivered and the patient has experienced less than a partial response at protocol-specified tumor assessments (after C5 and C10). The eligibility for subsequent cycles will be at the discretion of the treating radiation oncologist. Therefore, the total prescription dose will be: 14.8 Gy in 4 fractions for those that complete 1 cycle (all patients will receive 1 cycle) 19.6 Gy in 8 fractions for those that complete 2 cycles 44.4 Gy in 12 fractions for those that complete 3 cycles

Overall response will be measured according to RECIST 1.1 criteria to determine the percentage of participants with either a partial or complete response and the corresponding 95% Clopper-Pearson exact confidence interval. The best overall response is the best response recorded from the start of the treatment across all time points.

Response rate will be measured as the following: Complete: Disappearance (or decrease to the point at which measurement is not possible) of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial: At least a 30% decrease in the sum of diameters of target lesions. Progressive Disease: Greater than 20% increase in the sum of the longest diameters (SLD) taking as reference the smallest SLD recorded since the treatment started (nadir) and minimum 5 mm increase over the nadir. When sum becomes very small, increases within measurement error (2-3 mm) can lead to 20% increase. Stable Disease: Greater than 20% increase in the sum of the longest diameters (SLD) taking as reference the smallest SLD recorded since the treatment started (nadir) and minimum 5 mm increase over the nadir. When sum becomes very small, increases within measurement error (2-3 mm) can lead to 20% increase.

Response rate will be measured using RECIST 1.1: Complete: Disappearance (or decrease to the point at which measurement is not possible) of all non-target lesions. All lymph nodes must be non-pathological in size (< 10 mm short axis). Partial: Non-complete response/Non-progressive disease: Persistence of 1 or more non-target lesion(s). Progressive Disease: Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Stable Disease: Greater than 20% increase in the sum of the longest diameters (SLD) taking as reference the smallest SLD recorded since the treatment started (nadir) and minimum 5 mm increase over the nadir. When sum becomes very small, increases within measurement error (2-3 mm) can lead to 20% increase.

For the duration of response, among participants investigators will estimate both the mean duration and the corresponding 95% confidence intervals for the mean and inter-quartile range for the median.

For the duration of response, among participants investigators will estimate the median duration and the corresponding 95% confidence intervals for the mean and inter-quartile range for the median.

For progression-free survival investigators will estimate Kaplan Meier survival curves and the median time to progression-free survival.

For time to event measure of overall survival investigators will estimate Kaplan Meier survival curves and the median time to overall survival.

Tolerability of intervention will be assessed using Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Event (PRO CTCAE). Investigators will estimate the percentage of patients with different adverse events using a 95% Clopper Pearson exact confidence level.

Inclusion Criteria: Advanced, recurrent or metastatic head and neck squamous cell carcinoma, as defined by clinical or pathological diagnosis of any of the following: Locally advanced head and neck squamous cell carcinoma not suitable for curative local treatment. Locally recurrent head and neck squamous cell carcinoma not suitable for curative local treatment within or outside a previously irradiated tissue. Metastatic head and neck squamous cell carcinoma. Target site in the head and neck region amenable to quad-shot palliative radiotherapy, for which palliative radiotherapy is recommended, as determined by the treating radiation oncologist. Age 18 years or greater at time of registration. ECOG Performance Status of 0-2. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Ability to understand and the willingness to sign an IRB-approved informed consent document (either directly or via a legally authorized representative). Willingness to provide blood and saliva samples for exploratory research purposes. Organ and Marrow Function as defined below: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, hemoglobin ≥ 9.0 g/dL, serum bilirubin ≤ 1.5 x ULN (institutional upper limit of normal), AST and ALT ≤ 2.5 x ULN (institutional upper limit of normal), serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: MALES: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) (divided by) 72 x serum creatinine (mg/dL). FEMALES: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 (divided by) 72 x serum creatinine (mg/dL) Exclusion Criteria: Radiation therapy to the planned quad-shot radiotherapy target region within 30 days of registration. Prior radiotherapy to the head and neck that precludes safe delivery of study radiotherapy, as determined by the treating radiation oncologist. Active medical conditions that are contraindications to study radiotherapy (i.e. scleroderma), as determined by the treating radiation oncologist. Pregnant or lactating women are excluded from this study because radiotherapy is contraindicated in pregnancy and because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with immunotherapy. Participation in another clinical study with an investigational product during the last 3 months. Any previous treatment with a PD1 or PD-L1 inhibitor. Any anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) within the last 30 days. Note: this excludes palliative radiotherapy to the non-target site. Mean QT interval corrected for heart rate (QTc) ≥470 ms except for patients with pacemaker who have a paced ventricular rhythm. Current or prior use of immunosuppressive medication within 30 days, with exceptions of intranasal and inhaled corticosteroids, a brief, non-sustained corticosteroids treatment for incidental problems such as allergies (at the discretion of the treating physician) or sustained systemic corticosteroids treatment at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid except for short course of prednisone that is prescribed for acute allergic situations or for prevention of an allergy to contrast substance utilized for imaging studies. Any unresolved toxicity (>CTCAE grade > 2) from previous anti-cancer therapy. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy). Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1. Active or prior documented autoimmune disease within the past 2 years, NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis). History of primary immunodeficiency. History of allogeneic organ transplant. History of hypersensitivity to any excipient in pembrolizumab. History of pneumonitis or interstitial lung disease. Subjects with uncontrolled seizures. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent. Known history of active tuberculosis. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving pembrolizumab. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.