Durvalumab, Tremelimumab and Hypofractionated Radiation Therapy in Treating Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Study Overview
=================
Brief Summary
-----------------
This phase I/II trial studies the side effects of durvalumab, tremelimumab and hypofractionated radiation therapy in treating patients with head and neck squamous cell carcinoma that has come back (recurrent) or that has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Giving durvalumab, tremelimumab, and hypofractionated radiation therapy may work better in treating patients with recurrent or metastatic head and neck squamous cell carcinoma.

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. To demonstrate safety and tolerability of durvalumab and tremelimumab and palliative radiation therapy in patients with recurrent metastatic squamous cell carcinomas of the head and neck previously exposed to an anti PD-1 or PDL-1 monoclonal antibody. SECONDARY OBJECTIVES: I. Measure objective response rates based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. criteria in patients receiving the durvalumab, tremelimumab and palliative radiation therapy (RT) combination. II. Determine overall and progression free survival in patients enrolled in the study. OUTLINE: Patients receive tremelimumab intravenously (IV) over 1 hour and durvalumab IV over 1 hour on day 1, week 1. Treatment repeats every 4 weeks for up to 4 cycles or every 6 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes on day 1, week 16. Treatment repeats every 4 weeks for up to 9 cycles or every 6 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo hypofractionated radiation therapy using either hypofractionated, image-guided radiotherapy (HIGRT) or stereotactic body radiation therapy (SBRT) over 3 fractions every other day (QOD) during week 3. After completion of study treatment, patients are followed up at 30 days, 2, 3, 4, 6, 8, and 10 months, and then every 12 months.

Official Title
-----------------
Durvalumab (MEDI4736), Tremelimumab and Palliative Hypofractionated Image Guided Radiation Therapy (HIGRT) in Patients With Recurrent/Metastatic Squamous Cell Carcinomas of the Head and Neck Previously Treated With Immune Checkpoint Inhibitors

Conditions
-----------------
Metastatic Head and Neck Squamous Cell Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
-----------------
* Biological: Durvalumab
* Other: Laboratory Biomarker Analysis
* Radiation: Stereotactic Body Radiation Therapy
* Biological: Tremelimumab
* Procedure: Hypofractionated Image-Guided Radiation Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically proven recurrent/metastatic squamous cell carcinoma arising from a previous head and neck primary site, and located within the head and neck region, lung mediastinum, lymph nodes, soft tissue metastases or bone, and who are not candidates for curative intent therapy An actual body weight > 40kg Demonstrated disease progression during, or after discontinuation, of the most recent line of systemic therapy Have received any number lines of prior systemic therapy (including systemic therapy in the curative intent setting, and including a platinum containing regimen) Have received an anti-PD1 or anti PDL1 monoclonal antibody Have a target lesion/s deemed suitable by the treating physicians for hypofractionated radiation therapy (HIGRT or SBRT) with the intent of palliation or prevention of symptoms; this lesion must be: a) 1-3 non overlapping sites in the head and neck region OR b) metastatic lesions outside the head and neck (H&N) region in the lung mediastinum, soft tissue metastases, lymph nodes or bone (a minimum of 1 and a maximum 5 lesions will be irradiated), provided there is no significant overlap between the lesions; patients should have RECIST 1.1 criteria measurable disease in addition to the lesion/s treated with radiation; if the site/s of radiation were previously radiated to high dose RT (> 50 Gy), there should be > 6 month time interval between the last dose of radiation and the start of radiation Have the ability to tolerate required radiotherapy-related procedures (e.g.: lie flat and hold position for treatment) as determined by the treating physician Be willing and able to provide written informed consent for the trial and comply with the study visit requirements Have measurable disease based on RECIST 1.1. (in addition to the lesion/s that will be treated with hypofractionated radiation therapy) Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale Hemoglobin >= 9.0 g/dL (should be performed within 10 days of treatment initiation) Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500 per mm^3) (should be performed within 10 days of treatment initiation) Platelet count >= 100 x 10^9/L (>= 100,000 per mm^3) (should be performed within 10 days of treatment initiation) Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) (should be performed within 10 days of treatment initiation); this will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be =< 5 x ULN (should be performed within 10 days of treatment initiation) Serum creatinine clearance (CL) > 60 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance (should be performed within 10 days of treatment initiation) Evidence of post-menopausal status OR negative urinary or serum pregnancy test for female pre-menopausal patients; women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause; the following age-specific requirements apply: Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy, or hysterectomy) Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female subjects of childbearing potential should be willing to use 1 method of highly effective birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 180 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 180 days after the last dose of study therapy Patient is >= 5 years free of another primary malignancy, except: a) if the other malignancy is basal cell carcinoma or cervical carcinoma in situ or b) if the other primary malignancy is not considered clinically significant and is requiring no active intervention Exclusion Criteria: Has a body weight =< 40kg at the time of enrollment Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment Has a target lesion/s for radiotherapy that is > 5 cm (> 50 cc) in greatest dimension Has a target lesion/s in a region that previously received high dose radiation therapy (RT) (> 50 Gy) demonstrating any of the following: carotid artery encasement (> 180 degrees) unprotected carotid artery (i.e. skin is directly over the carotid without intervening soft tissue, especially after prior neck dissection without a vascularized free flap) (a&b due to risk of carotid blow out) skin infiltration by tumor (due to risk of fistula) located in the larynx/hypopharynx primaries (due airway threat) treated with high dose radiation therapy (> 50 Gy) within 6 months or less of trial enrollment Any prior grade >= 3 immune-related adverse event (irAE) while receiving a prior immunotherapy agent, or any unresolved irAE > grade 1 Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab; the following are exceptions to this criterion: Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication) Has received a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier Has received prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy Has known brain metastases or spinal cord compression unless the patient is stable (asymptomatic; no evidence of new or emerging brain metastases; and stable and off steroids for at least 14 days prior to start of study treatment); following radiotherapy and/or surgery of the brain metastases patients must wait 4 weeks following the intervention and before initiating study treatment with imaging to confirm stability Has an active autoimmune disease requiring systemic treatment within the past 2 years or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement will not be excluded from the study Has evidence of current interstitial lung disease (ILD) or pneumonitis or a prior history of ILD or pneumonitis requiring oral or intravenous glucocorticoids Has an active infection requiring systemic therapy Requires therapeutic anticoagulation or has known active bleeding diathesis Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 180 days after the last dose of trial treatment Has received prior therapy with an anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) Has evidence of acute or chronic hepatitis B or hepatitis C Has received a live vaccine within 30 days prior to the first dose of trial treatment Has a mean QT interval corrected for heart rate (QTc) >= 470ms calculated from 3 electrocardiograms (ECGs) using Fridericia's Correction Has a history of primary immunodeficiency or an allogeneic organ transplant Has a history of hypersensitivity to durvalumab or tremelimumab excipient Known history of previous clinical diagnosis of tuberculosis Uncontrolled intercurrent illness including, but not limited to symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, seizures

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (tremelimumab, durvalumab, HIGRT, SBRT)<br>Patients receive tremelimumab IV over 1 hour and durvalumab IV over 1 hour on day 1, week 1. Treatment repeats every 4 weeks for up to 4 cycles or every 6 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes on day 1, week 16. Treatment repeats every 4 weeks for up to 9 cycles or every 6 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo hypofractionated radiation therapy using either HIGRT or SBRT over 3 fractions QOD during week 3. | Biological: Durvalumab<br>* Given IV<br>* Other names: MEDI4736;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Radiation: Stereotactic Body Radiation Therapy<br>* Undergo SBRT<br>* Other names: Stereotactic Ablative Body Radiation Therapy;Biological: Tremelimumab<br>* Given IV<br>* Other names: Ticilimumab;Procedure: Hypofractionated Image-Guided Radiation Therapy<br>* Undergo HIGRT<br>* Other names: Hypofractionated Image-Guided Radiotherapy;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Adverse Effects Graded According to Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0 | Toxicities will be summarized as the number and percentage of patients with each type of toxicity, per Criteria for Adverse Events version 4.0 | From the start of study treatment up to 3 months after last study treatment, up to 38 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Up to 2 years | 
| Progression-free Survival | Survival estimates will be calculated using the Kaplan-Meier method. Progression free survival is measured in months. PFS is defined as the amount of time between treatment initiation and when the disease progresses per RECIST 1.1 criteria | From the date of study enrollment for up to 2 years | 
| Overall Survival | Survival estimates will be calculated using the Kaplan-Meier method. Overall survival is measured in months. OS is defined as the amount of time between treatment initiation and when the patient is deceased. | From the date of study enrollment for up to 2 years |