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

Phase 1

Active, not recruiting

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

Interventions: Procedure: Biopsy Procedure
Drug: Birinapant
Procedure: Computed Tomography
Radiation: Intensity-Modulated Radiation Therapy
Procedure: Magnetic Resonance Imaging
Procedure: Positron Emission Tomography

Registration Number: NCT03803774

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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 inhibitor of apoptosis (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: 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 Fas-associated death domain (FADD) and/or Baculoviral IAP Repeat containing 2 and Baculoviral IAP Repeat containing 3 (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 inhibitor of apoptosis 1/2 (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 programmed death-ligand 1 (PD-L1), cluster of differentiation 8 (CD8) T-cell tumor infiltration, TNFalphatumor necrosis factor (TNF)alpha, 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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 13

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (IMRRT, birinapant)	Biopsy Procedure	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.
Treatment (IMRRT, birinapant)	Birinapant	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.
Treatment (IMRRT, birinapant)	Computed Tomography	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.
Treatment (IMRRT, birinapant)	Intensity-Modulated Radiation Therapy	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.
Treatment (IMRRT, birinapant)	Magnetic Resonance Imaging	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.
Treatment (IMRRT, birinapant)	Positron Emission Tomography	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.

Primary Outcome Measures

Name	Time	Method
Incidence of Dose-limiting Toxicities (DLTs) and Grades 1-5 Serious and/or Non-serious Toxicities Related (Except for Unrelated and Unlikely) to Intervention	Up to 42 days post-treatment	Adverse events will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. A DLT is defined as any of the following adverse events possibly attributed to the combination of birinapant and radiotherapy that occur within 42 days after treatment. Any grade 5 toxicities. Any grade ≥ 4 hematologic toxicity, except lymphopenia. Any grade ≥ 3 non-hematologic toxicity except for nausea or vomiting managed with supportive care over 2 weeks. ≥ grade 3 prolonged (\> 7 days) serum amylase or lipase elevation, aspartate aminotransferase elevation, and/or alanine aminotransferase elevation. Any grade toxicity that mandates discontinuation of birinapant treatment for more than 2 weeks. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event.
Maximum Tolerated Dose (MTD) of Birinapant	Up to 42 days	MTD is defined as the dose level at which no more than 1 of up to 6 participants experience dose limiting- toxicity (DLT) during 42 days after the start of therapy, and the dose below that at which at least 2 (of =\< 6) participants have DLT as a result of the drug. A DLT is defined as any of the following adverse events possibly attributed to the combination of birinapant and radiotherapy that occur within 42 days after treatment. Any grade 5 toxicities. Any grade ≥ 4 hematologic toxicity except lymphopenia. Any grade ≥ 3 non-hematologic toxicity except for nausea or vomiting managed with supportive care over 2 weeks. ≥ grade 3 prolonged (\> 7 days) serum amylase or lipase elevation, aspartate aminotransferase elevation, and/or alanine aminotransferase elevation. Any grade toxicity that mandates discontinuation of birinapant treatment for more than 2 weeks. Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Secondary Outcome Measures

Name	Time	Method
Response Rate	From the start of the treatment until response assessment by positron emission tomography (PET)-computed tomography (CT), assessed at 3 months post-treatment	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 maximum tolerated dose (MTD) level, including the expansion cohort and will be presented along with a 95% two-sided confidence interval. Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesion. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions; and the appearance of one or more new lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Fas-associated Protein With Death Domain (FADD) Copy Gain in Tumor Tissue and/or in Blood Associated With Response	At baseline	The association between FADD copy gain in tumor tissue and/or in blood will be evaluated for any association with response.
BIRC2 Copy Gain in Tumor Tissue and/or in Blood Associated With Response	At baseline	BIRC2 copy gain in tumor tissue and/or in blood will be evaluated for any association with response.
Baculoviral Inhibitor of Apoptosis (IAP) Repeat Containing 2 and Baculoviral IAP Repeat Containing 2/3 (BIRC2/3) Copy Gain in Tumor Tissue and/or in Blood	At baseline	Baculoviral inhibitor of apoptosis (IAP) Repeat containing 2 and Baculoviral IAP Repeat containing 2/3 (BIRC2/3) copy gain in tumor tissue and/or in blood.
Feasibility of Detecting Effects of Birinapant and Re-irradiation on Pilot Pharmacodynamic Markers in Tumor Tissue	Up to cycle 1, day 4	Will determine the feasibility of detecting effects of birinapant and re-irradiation on pilot pharmacodynamic markers in tumor tissue.
Feasibility of Detecting Effects of Birinapant and Re-irradiation on Pilot Pharmacodynamic Markers Microwestern for Decrease in Drug Targets Inhibitor of Apoptosis 1/2 (IAP1/2)	Up to cycle 1, day 4	Will determine the feasibility of detecting effects of birinapant and re-irradiation on pilot pharmacodynamic markers microwestern for decrease in drug targets IAP1/2.
Change in Caspase 3 Levels	Baseline up to cycle 1, day 4	A change (i.e., increase) in apoptosis/necroptosis marker caspase 3 will be evaluated.
Change in Mixed Lineage Kinase Domain-like (MLKL) Levels	Baseline up to cycle 1, day 4	A change (i.e., increase) in apoptosis/necroptosis marker mixed lineage kinase domain-like (MLKL) levels will be evaluated.
Overall Survival (OS)	Up to 24 months post-treatment	OS is the time between the first day of treatment to the day of death. Estimates of OS will be determined at the maximum tolerated dose (MTD) level, including the expansion cohort, and will be presented along with a 95% two-sided confidence interval.
Progression-free Survival (PFS)	From start of treatment to time of progression or death, whichever occurs first, assessed up to 24 months post-treatment	PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Estimates of PFS will be determined at the maximum tolerated dose (MTD) level, including the expansion cohort and will be presented along with a 95% two-sided confidence interval. Response was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions; and the appearance of one or more new lesions.
Local-regional Control	Up to 24 months post-treatment	Estimates of local control will be determined at the maximum tolerated dose (MTD) level, including the expansion cohort and will be presented along with a 95% two-sided confidence interval.

Trial Locations

Locations (33): HaysMed
🇺🇸
Hays, Kansas, United States
The University of Kansas Cancer Center - Olathe
🇺🇸
Olathe, Kansas, United States
Mercy Hospital Pittsburg
🇺🇸
Pittsburg, Kansas, United States
University Health Truman Medical Center
🇺🇸
Kansas City, Missouri, United States
NYU Langone Hospital - Long Island
🇺🇸
Mineola, New York, United States
University of Alabama at Birmingham Cancer Center
🇺🇸
Birmingham, Alabama, United States
Los Angeles General Medical Center
🇺🇸
Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
🇺🇸
Los Angeles, California, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
🇺🇸
Orange, California, United States
UM Sylvester Comprehensive Cancer Center at Coral Gables
🇺🇸
Coral Gables, Florida, United States
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
🇺🇸
Deerfield Beach, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
🇺🇸
Miami, Florida, United States
UM Sylvester Comprehensive Cancer Center at Plantation
🇺🇸
Plantation, Florida, United States
Moffitt Cancer Center-International Plaza
🇺🇸
Tampa, Florida, United States
Moffitt Cancer Center - McKinley Campus
🇺🇸
Tampa, Florida, United States
Moffitt Cancer Center
🇺🇸
Tampa, Florida, United States
University of Kansas Clinical Research Center
🇺🇸
Fairway, Kansas, United States
University of Kansas Cancer Center
🇺🇸
Kansas City, Kansas, United States
Lawrence Memorial Hospital
🇺🇸
Lawrence, Kansas, United States
University of Kansas Cancer Center-Overland Park
🇺🇸
Overland Park, Kansas, United States
Salina Regional Health Center
🇺🇸
Salina, Kansas, United States
University of Kansas Health System Saint Francis Campus
🇺🇸
Topeka, Kansas, United States
University of Kansas Hospital-Westwood Cancer Center
🇺🇸
Westwood, Kansas, United States
University of Kentucky/Markey Cancer Center
🇺🇸
Lexington, Kentucky, United States
NCI - Center for Cancer Research
🇺🇸
Bethesda, Maryland, United States
University of Kansas Cancer Center - North
🇺🇸
Kansas City, Missouri, United States
University of Kansas Cancer Center - Lee's Summit
🇺🇸
Lee's Summit, Missouri, United States
University of Kansas Cancer Center at North Kansas City Hospital
🇺🇸
North Kansas City, Missouri, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
🇺🇸
New York, New York, United States
Wake Forest Baptist Health - Wilkes Medical Center
🇺🇸
Wilkesboro, North Carolina, United States
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
Ohio State University Comprehensive Cancer Center
🇺🇸
Columbus, Ohio, United States
Huntsman Cancer Institute/University of Utah
🇺🇸
Salt Lake City, Utah, United States