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

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.

• Biopsy Procedure (Procedure), also known as Biopsy, BIOPSY_TYPE, Bx: Undergo biopsy
• Birinapant (Drug), also known as TL32711: Given IV
• Computed Tomography (Procedure), also known as CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography: Undergo CT scan
• Intensity-Modulated Radiation Therapy (Radiation), also known as IMRT, Intensity modulated radiation therapy (procedure), Intensity Modulated RT, Intensity-Modulated Radiotherapy, Radiation, Intensity-Modulated Radiotherapy: Undergo IMRRT
• Magnetic Resonance Imaging (Procedure), also known as Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI: Undergo MRI
• Positron Emission Tomography (Procedure), also known as Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure), Positron Emission Tomography Scan, Positron-Emission Tomography, PT: Undergo PET scan

Primary outcomes

• 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 outcomes

• 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.
• 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.
• 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.
• 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.
• 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.

Other outcomes

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) [An average of 611 days.]: Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• Incidence of Dose-limiting Toxicities (DLTs) and Grades 1-5 Serious and/or Non-serious Toxicities Related (Except for Unrelated and Unlikely) to Intervention (Primary), Number, toxicities: Birinapant 5.6 mg/m^2 & Intensity Modulated Re-Irradiation Therapy (IMRRT) 2 Gray(Gy) 0; Birinapant 11 mg/m^2 & Intensity Modulated Re-Irradiation Therapy (IMRRT) 2 Gray(Gy) 0; Birinapant 17 mg/m^2 & Intensity Modulated Re-Irradiation Therapy (IMRRT) 2 Gray(Gy) 0; Birinapant 24 mg/m^2 & Intensity Modulated Re-Irradiation Therapy (IMRRT) 2 Gray(Gy) 0
• Maximum Tolerated Dose (MTD) of Birinapant (Primary), Number, mg/m^2: All Participants 24
• Response Rate (Secondary)
• Local-regional Control (Secondary)
• Progression-free Survival (PFS) (Secondary)
• Overall Survival (OS) (Secondary)
• Fas-associated Protein With Death Domain (FADD) Copy Gain in Tumor Tissue and/or in Blood Associated With Response (Secondary)
• BIRC2 Copy Gain in Tumor Tissue and/or in Blood Associated With Response (Secondary)
• 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 (Secondary)
• Feasibility of Detecting Effects of Birinapant and Re-irradiation on Pilot Pharmacodynamic Markers in Tumor Tissue (Secondary)
• 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) (Secondary)
• Change in Caspase 3 Levels (Secondary)
• Change in Mixed Lineage Kinase Domain-like (MLKL) Levels (Secondary)
• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) (Other pre specified), Count of participants, Participants: Birinapant 5.6 mg/m^2 & Intensity Modulated Re-Irradiation Therapy (IMRRT) 2 Gray(Gy) 3; Birinapant 11 mg/m^2 & Intensity Modulated Re-Irradiation Therapy (IMRRT) 2 Gray(Gy) 3; Birinapant 17 mg/m^2 & Intensity Modulated Re-Irradiation Therapy (IMRRT) 2 Gray(Gy) 3; Birinapant 24 mg/m^2 & Intensity Modulated Re-Irradiation Therapy (IMRRT) 2 Gray(Gy) 2

Adverse events

Time frame: An average of 611 days.

Serious adverse events by term

Other adverse events by term

23 more terms not shown.

• Study Protocol and Statistical Analysis Plan (PDF, 2022-12-15)

• Vassiliki Saloura, Principal investigator, National Cancer Institute LAO