Birinapant and Intensity Modulated Re-Irradiation Therapy in Treating Patients With Locally Recurrent Head and Neck Squamous Cell Carcinoma

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of birinapant when given together with intensity modulated re-irradiation therapy (IMRRT) in treating patients with head and neck squamous cell carcinoma that has come back at or near the same place as the original (primary) tumor (locally recurrent). Birinapant may stop the growth of tumor cells by blocking IAP, a protein needed for tumor cell survival. IMRRT uses thin beams of radiation of different intensities that are aimed at the tumor from many angles. This type of re-irradiation therapy reduces the damage to healthy tissue near the tumor. Giving birinapant with IMRRT may lower the chance of head and neck squamous cell carcinoma growing or spreading.

Detailed Description
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PRIMARY OBJECTIVE: I. Determine the toxicities and maximum tolerated dose (MTD) of birinapant concurrent with intensity modulated re-irradiation therapy (IMRRT). SECONDARY OBJECTIVES: I. Determine the objective response rate of patients with locoregionally recurrent head and neck squamous cell carcinoma (HNSCC) treated with re-irradiation and birinapant. II. Determine the local-regional control, progression free survival (PFS), and overall survival. III. Determine if FADD and/or BIRC2/3 copy gain in tumor tissue or in the blood are associated with improved response, locoregional control (LCR), progression-free survival and overall survival. IV. Determine the feasibility of detecting effects of birinapant and re-irradiation on pilot pharmacodynamic markers in tumor tissue, by using microwestern to assess decrease in drug targets IAP1/2 and increase in apoptosis/necroptosis markers caspase 3 and mixed lineage kinase domain like pseudokinase gene (MLKL). EXPLORATORY OBJECTIVES: I. Explore if mutational load detected with whole exome sequencing of tumor tissue influences objective response rate. II. Explore if PD-L1, CD8 T-cell tumor infiltration, TNFalpha, and other immune related biomarkers in tumor tissue are associated with objective response rate. III. Explore the pharmacokinetics of birinapant in combination with radiotherapy in blood samples. IV. Explore whether specific germline single-nucleotide polymorphisms (SNPs) are associated with response to birinapant and reirradiation. OUTLINE: This is a dose-escalation study of birinapant. Beginning on day 1, patients undergo IMRRT 5 days a week (Monday-Friday). Patients also receive birinapant intravenously (IV) over 30 minutes on days 2 and 9 of each cycle. Treatment repeats every 3 weeks for up to 2 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 28 days, and at 3, 6, 9, 12, 18, and 24 months until confirmation of disease progression.

Official Title
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Birinapant and Intensity Modulated Re-Irradiation Therapy (IMRRT) for Locoregionally Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC)

Conditions
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Locally Recurrent Head and Neck Squamous Cell Carcinoma, Nasopharyngeal Squamous Cell Carcinoma, Sinonasal Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Birinapant
* Radiation: Intensity-Modulated Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed locally recurrent HNSCC, including nasopharyngeal or sinonasal cancer for whom re-irradiation for local control is considered standard of care Patients with human papillomavirus (HPV)-negative or HPV-positive head and neck cancer are eligible Patients who have had prior treatment with immune therapies are eligible Patients must have received curative-intent platinum- and/or cetuximab-based chemoradiotherapy or radiotherapy alone Patients must have completed their last treatment dose with chemotherapy or immunotherapy at least 4 weeks (6 weeks for nitrosoureas or mitomycin C) before enrolling on study Patients must have completed their last treatment dose with radiotherapy at least 6 months before enrolling on study Patients who have had major surgery must be fully recovered and require a recovery period of at least 4 weeks prior to enrolling on study Age >= 18 years Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Hemoglobin >= 9 g/dL (transfusion permitted) Absolute neutrophil count >= 1,500/mcL Platelets >= 100,000/mcL Total bilirubin within 1.5 x the upper limit of normal (ULN) institutional limits Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal Serum creatinine =< 1.5 x upper limit of normal (ULN), OR: Creatinine clearance >= 50 mL/min according to Cockcroft Gault formula or other institutional methods Patients must have a corrected QT interval by Fridericia (QTcF) =< 480 msec International normalized ratio (INR) =< 1.5 and no clinically significant bleeding event within the past six months Ability to understand and the willingness to sign a written informed consent document Patients must have measurable disease, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 The effects of birinapant on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) beginning at study entry and for the duration of study participation. Male study participants should use an additional barrier method of contraception for 30 days following the last dose of birinapant. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately Exclusion Criteria: Eligibility for curative-intent surgery, unless the patient is considered a poor surgical candidate related to resectability, functional outcome, or prefers non-surgical therapy More than 2 lines of palliative systemic therapy (platinum-, taxane- or cetuximab-based chemotherapy or immunotherapy) Patients who are receiving any other investigational agents Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events History of allergic reactions attributed to compounds of similar chemical or biologic composition to birinapant Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study because birinapant may have potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with birinapant, breastfeeding should be discontinued prior to enrollment. A negative pregnancy test is required for women of childbearing potential. Women who are postmenopausal (age-related amenorrhea >= 12 consecutive months, or who had undergone hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If necessary, to confirm postmenopausal status, a follicle stimulating hormone (FSH) level may be included at screening Human immunodeficiency virus (HIV) positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with birinapant Patients requiring the use of anti-tumor necrosis factor (anti TNF) therapies, such as infliximab, or patients who have received treatment with anti-TNF therapies within 5 half-lives of the drug (48 days for infliximab, 55 days for golimumab, 70 days for certolizumab and adalimumab, and 16 days for etanercept) Patients with previous exposure to birinapant

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (IMRRT, birinapant)<br>Beginning on day 1, patients undergo IMRRT 5 days a week (Monday-Friday). Patients also receive birinapant IV over 30 minutes on days 2 and 9 of each cycle. Treatment repeats every 3 weeks for up to 2 cycles in the absence of disease progression or unacceptable toxicity. | Drug: Birinapant<br>* Given IV<br>* Other names: TL32711;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo IMRRT<br>* Other names: Radiation, Intensity-Modulated Radiotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (DLTs) and other toxicities | Will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Will be evaluated by reporting the DLTs obtained at each dose level, and reporting toxicities noted in tabular form. | Up to 28 days post-treatment | 
| Maximum tolerated dose (MTD) | Defined as the dose level at which no more than 1 of up to 6 patients experience DLT during 42 days after the start of therapy, and the dose below that at which at least 2 (of =< 6) patients have DLT as a result of the drug. Will be evaluated by reporting the DLTs obtained at each dose level, and reporting toxicities noted in tabular form. | Up to 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | Overall response is the best response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Estimates of response rates will be determined at the MTD level, including the expansion cohort and will be presented along with a 95% two-sided confidence interval. | From the start of the treatment until response assessment by positron emission tomography (PET)-computed tomography (CT), assessed at 3 months post-treatment | 
| Local-regional control | Estimates of local control will be determined at the MTD level, including the expansion cohort and will be presented along with a 95% two-sided confidence interval. | Up to 24 months post-treatment | 
| Progression-free survival (PFS) | Estimates of PFS will be determined at the MTD level, including the expansion cohort and will be presented along with a 95% two-sided confidence interval. | From start of treatment to time of progression or death, whichever occurs first, assessed up to 24 months post-treatment | 
| Overall survival (OS) | Estimates of OS will be determined at the MTD level, including the expansion cohort and will be presented along with a 95% two-sided confidence interval. | Up to 24 months post-treatment | 
| FADD copy gain in tumor tissue or in blood | The association between results according to whether or not they have a copy gain will be presented for OS and PFS, by comparing Kaplan-Meier curves with a two-tailed log-rank test. In addition, as exploratory analyses, the association between FADD copy gain and BIRC2 copy gain will be individually evaluated for any association with response. | At baseline | 
| BIRC2/3 copy gain in tumor tissue or in blood | The association between results according to whether or not they have a copy gain will be presented for OS and PFS, by comparing Kaplan-Meier curves with a two-tailed log-rank test. In addition, as exploratory analyses, the association between FADD copy gain and BIRC2 copy gain will be individually evaluated for any association with response. | At baseline | 
| Feasibility of detecting effects of birinapant and re-irradiation on pilot pharmacodynamic markers in tumor tissue | Will determine the feasibility of detecting effects of birinapant and re-irradiation on pilot pharmacodynamic markers in tumor tissue, including microwestern for decrease in drug targets IAP1/2. | Up to cycle 1, day 4 | 
| Change in caspase 3 levels | Increase in apoptosis/necroptosis marker caspase 3 will be evaluated. | Baseline up to cycle 1, day 4 | 
| Change in MLKL levels | Increase in apoptosis/necroptosis marker MLKL will be evaluated. | Baseline up to cycle 1, day 4 |