Clinical trial NCT03803774: Birinapant and Intensity Modulated Re-Irradiation Therapy in Treating Patients With Locally Recurrent Head and Neck Squamous Cell Carcinoma
Official title: Birinapant and Intensity Modulated Re-Irradiation Therapy (IMRRT) for Locoregionally Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Locally Recurrent Head and Neck Squamous Cell Carcinoma
Nasopharyngeal Squamous Cell Carcinoma
Sinonasal Squamous Cell Carcinoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2019-01-15
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence of Dose-limiting Toxicities (DLTs) and Grades 1-5 Serious and/or Non-serious Toxicities Related (Except for Unrelated and Unlikely) to Intervention
timeFrame: Up to 42 days post-treatment
measure: Maximum Tolerated Dose (MTD) of Birinapant
timeFrame: Up to 42 days
Secondary outcomes:
measure: Response Rate
timeFrame: From the start of the treatment until response assessment by positron emission tomography (PET)-computed tomography (CT), assessed at 3 months post-treatment
measure: Local-regional Control
timeFrame: Up to 24 months post-treatment
measure: Progression-free Survival (PFS)
timeFrame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 24 months post-treatment
measure: Overall Survival (OS)
timeFrame: Up to 24 months post-treatment
measure: Fas-associated Protein With Death Domain (FADD) Copy Gain in Tumor Tissue and/or in Blood Associated With Response
timeFrame: At baseline
measure: BIRC2 Copy Gain in Tumor Tissue and/or in Blood Associated With Response
timeFrame: At baseline
measure: 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
timeFrame: At baseline
measure: Feasibility of Detecting Effects of Birinapant and Re-irradiation on Pilot Pharmacodynamic Markers in Tumor Tissue
timeFrame: Up to cycle 1, day 4
measure: 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)
timeFrame: Up to cycle 1, day 4
measure: Change in Caspase 3 Levels
timeFrame: Baseline up to cycle 1, day 4
measure: Change in Mixed Lineage Kinase Domain-like (MLKL) Levels
timeFrame: Baseline up to cycle 1, day 4
Other outcomes:
measure: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
timeFrame: An average of 611 days.
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham Cancer Center
state: Alabama
city: Los Angeles
country: United States
facility: Los Angeles General Medical Center
state: California
city: Los Angeles
country: United States
facility: USC / Norris Comprehensive Cancer Center
state: California
city: Orange
country: United States
facility: UC Irvine Health/Chao Family Comprehensive Cancer Center
state: California
city: Coral Gables
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Coral Gables
state: Florida
city: Deerfield Beach
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Deerfield Beach
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine-Sylvester Cancer Center
state: Florida
city: Plantation
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Plantation
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center-International Plaza
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center - McKinley Campus
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Fairway
country: United States
facility: University of Kansas Clinical Research Center
state: Kansas
city: Hays
country: United States
facility: HaysMed
state: Kansas
city: Kansas City
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Lawrence
country: United States
facility: Lawrence Memorial Hospital
state: Kansas
city: Olathe
country: United States
facility: The University of Kansas Cancer Center - Olathe
state: Kansas
city: Overland Park
country: United States
facility: University of Kansas Cancer Center-Overland Park
state: Kansas
city: Pittsburg
country: United States
facility: Mercy Hospital Pittsburg
state: Kansas
city: Salina
country: United States
facility: Salina Regional Health Center
state: Kansas
city: Topeka
country: United States
facility: University of Kansas Health System Saint Francis Campus
state: Kansas
city: Westwood
country: United States
facility: University of Kansas Hospital-Westwood Cancer Center
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky/Markey Cancer Center
state: Kentucky
city: Bethesda
country: United States
facility: NCI - Center for Cancer Research
state: Maryland
city: Kansas City
country: United States
facility: University Health Truman Medical Center
state: Missouri
city: Kansas City
country: United States
facility: University of Kansas Cancer Center - North
state: Missouri
city: Lee's Summit
country: United States
facility: University of Kansas Cancer Center - Lee's Summit
state: Missouri
city: North Kansas City
country: United States
facility: University of Kansas Cancer Center at North Kansas City Hospital
state: Missouri
city: Mineola
country: United States
facility: NYU Langone Hospital - Long Island
state: New York
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center at NYU Langone
state: New York
city: Wilkesboro
country: United States
facility: Wake Forest Baptist Health - Wilkes Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
Study officials:
affiliation: National Cancer Institute LAO
name: Vassiliki Saloura
role: PRINCIPAL_INVESTIGATOR
References: