Birinapant and Intensity Modulated Re-Irradiation Therapy for Local-Regionally Recurrent Head and Neck Squamous Cell Carcinoma

Oral Cancer Clinical Trial

Official title:

A Phase I Study of Birinapant and Intensity Modulated Re-Irradiation Therapy (IMRRT) for Local-Regionally Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03809208
• Other study ID #: 190041
• Secondary ID: 19-C-0041
• Status: Recruiting
• Phase: Phase 1
• Start date: April 15, 2019
• Est. completion date: October 31, 2021

Study information

• Verified date: March 19, 2019
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Elizabeth Q Akoth
• Phone: (240) 858-3154
• Email: elizabeth.akoth[@]nih.gov
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background:

Head and neck cancer is a group of cancers that start in the mouth, nose, throat, larynx and sinuses. The usual treatment is surgery, radiation, chemotherapy, or a combination of those. Approximately 50% of HPV-negative head and neck cancer patients that have been treated with any of these modalities will have a recurrence. For these patients, current treatment options include surgery and re-irradiation with chemotherapy, which can reduce symptoms and may stop the tumor from growing but in the majority of cases, only for a few months. In this trial, researchers want to see if they can cure or significantly lower the chance of head and neck cancer growing back or spreading by adding the new agent birinapant to re-irradiation.

Objective:

To test the safety of birinapant and re-irradiation at different doses in patients with head and neck cancer.

Eligibility:

Adults age 18 and older with head and neck cancer who are candidates for re-irradiation.

Design:

Participants will be screened with a review of their medical record. Participants will have exams and procedures that are part of their usual care. Participants will also have a test of heart activity before treatment.

Participants will have urine pregnancy tests, if female.

Participants will have blood and tumor samples taken 2 times and stored for research. The study lasts 6 weeks.

Participants will get radiation for 5 days a week (Monday Friday) for all 6 weeks.

Participant will get the study drug on 4 Tuesdays. They will get it in an arm vein over 30 minutes each time.

About 4 weeks after the study ends, participants will have a follow-up visit. They will have a physical exam, health questions, and blood tests.

Participants may have scans 4 times over the next 2 years. Participants will get an email or phone call every 6 months.

Sponsoring Institute: National Cancer Institute

Description:

Background:

• Head and neck squamous cell carcinomas (HNSCC) affect 52,000 new patients and cause approximately 11,000 deaths in the U.S. annually.

• The Cancer Genome Atlas recently uncovered amplifications of chromosome 11q13/22 in approximately 30% of HNSCC.

• The 11q13/22 loci harbor genes Fas Associated Death Domain (FADD) and Baculovirus Inhibitor of apoptosis Repeat Containing (BIRC2/cIAP1). A mutually exclusive subset harboring mutation of caspase 8 (CASP8) affects an additional 10% of HPV- cases. Further, deletions in Tumor Necrosis Factor Associated Factor 3 and overexpression of BIRC3 (cIAP2) are detected in 20% of HPV+ HNSCC.

• These genes encode proteins that form critical components of the Tumor Necrosis Factor Receptor/Death Domain Receptor signaling complex, which is deregulated and implicated in cell survival and therapeutic resistance in cancer.

• Based on pre-clinical studies, birinapant plus radiation demonstrates anti-tumor activity and improved survival, but the dose, schedule and tolerability in human studies needs to be determined.

Objectives:

-The primary objective is to determine the toxicities and maximum tolerated dose (MTD) of birinapant concurrent with IMRRT

Eligibility:

-Patients must have histologically or cytologically confirmed locally recurrent HNSCC for whom re-irradiation for local control is considered standard of care.

Design:

-Birinapant dose levels include 5.6, 11, 17 and 24mg/m2 IV on days 2 and 9 of each cycle. The primary endpoints are acute toxicities and the MTD for 2/3 week and weekly administration schedule of birinapant plus re-IMRT. Secondary clinical endpoints include overall response by PET- CT and RECIST criteria at 2 months post treatment, delayed toxicities, duration of local and regional control, progression free survival (PFS), Overall Survival (OS), and Whole ExomeSequencing of tumor biopsies. Exploratory endpoints are FADD and BIRC2 copy number.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 34
• Est. completion date: October 31, 2021
• Est. primary completion date: October 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

• INCLUSION CRITERIA:

• Patients must have histologically or cytologically confirmed locally recurrent HNSCC for whom re-irradiation for local control is considered standard of care. Patients with potentially reactive benign nodes will not be excluded.

• Patients with 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.

• 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 greater than or equal to 18 years.

• ECOG performance status less than or equal to 2 (see Appendix A).

• Patients must have normal organ and marrow function as defined below:

• Hemoglobin greater than or equal to 10 g/dL (transfusion permitted)

• Absolute neutrophil count greater than or equal to 1,500/mcL

• Platelets greater than or equal to 75,000/mcL

• Total bilirubin within 1.5 x the upper limit of normal (ULN) institutional limits

• AST(SGOT)/ALT(SGPT) less than or equal to 2.5 (SqrRoot) institutional upper limit of normal

• Creatinine clearance greater than or equal to 60 mL/min/1.73 m squared for patients with creatinine levels above institutional normal.

• Patients must have a QTc less than or equal to 480 msec.

• Ability to understand and the willingness to sign a written informed consent document.

• Patients must have measurable disease.

EXCLUSION CRITERIA:

• Eligibility for curative-intent surgery.

• More than 2 lines of palliative systemic therapy (platinum-, taxane- or cetuximabbased 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.

• 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, and16 days for etanercept).

• Patients with previous exposure to birinapant.

Related Conditions & MeSH terms

• Carcinoma, Squamous Cell
• Facial Cancer
• Head and Neck Neoplasms
• Head Cancer
• Mouth Neoplasms
• Neck Cancer
• Oral Cancer
• Squamous Cell Carcinoma of Head and Neck
• Upper AerodigestiveTract Cancer

Intervention

Drug:
• Birinapant
Birinapant will be administered IV on days 2 and 9 of each cycle in combination with IMRRT.

Radiation:
• Intensity modulated re-irradiation therapy (IMMRT)
IMMRT will take place starting on Day 1 of cycle 1 continuing for 5 days a week x 6 weeks.

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center	Bethesda	Maryland
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (2)

Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015 Jan 29;517(7536):576-82. doi: 10.1038/nature14129. — View Citation

Eytan DF, Snow GE, Carlson S, Derakhshan A, Saleh A, Schiltz S, Cheng H, Mohan S, Cornelius S, Coupar J, Sowers AL, Hernandez L, Mitchell JB, Annunziata CM, Chen Z, Van Waes C. SMAC Mimetic Birinapant plus Radiation Eradicates Human Head and Neck Cancers with Genomic Amplifications of Cell Death Genes FADD and BIRC2. Cancer Res. 2016 Sep 15;76(18):5442-5454. doi: 10.1158/0008-5472.CAN-15-3317. Epub 2016 Jul 28. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose	Maximum tolerated dose of birinapant administered concurrently with IMRRT	While on therapy and 2 years post-therapy
Primary	Brinipart toxicities	Toxicities of birinapant administered concurrently with IMRRT	While on therapy and 2 years post-therapy

External Links

•   NIH Clinical Center Detailed Web Page