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

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ClinicalTrials.gov Identifier: NCT03803774
Recruitment Status : Recruiting
First Posted : January 15, 2019
Last Update Posted : June 25, 2019
Sponsor:
Information provided by (Responsible Party):
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. Drugs used in chemotherapy, such as birinapant, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. 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.

Condition or disease Intervention/treatment Phase
Recurrent Head and Neck Squamous Cell Carcinoma Drug: Birinapant Radiation: Intensity-Modulated Radiation Therapy Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

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, including microwestern for decrease in drug targets IAP1/2; increase in apoptosis/necroptosis markers caspase 3 and MLKL.

EXPLORATORY OBJECTIVES:

I. Determine if mutational load detected with whole exome and ribonucleic acid (RNA)-sequencing of tumor tissue influences objective response rate.

II. Determine 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.

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, 12, and 24 months until confirmation of disease progression.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 34 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Birinapant and Intensity Modulated Re-Irradiation Therapy (IMRRT) for Locoregionally Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC)
Actual Study Start Date : January 7, 2019
Estimated Primary Completion Date : July 31, 2020
Estimated Study Completion Date : July 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (IMRRT, 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.
Drug: Birinapant
Given IV
Other Name: TL32711

Radiation: Intensity-Modulated Radiation Therapy
Undergo IMRRT
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy




Primary Outcome Measures :
  1. Incidence of dose-limiting toxicities (DLTs) and other toxicities [ Time Frame: Up to 28 days post-treatment ]
    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.

  2. Maximum tolerated dose (MTD) [ Time Frame: Up to 42 days ]
    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.


Secondary Outcome Measures :
  1. Response rate [ Time Frame: 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 MTD level, including the expansion cohort and will be presented along with a 95% two-sided confidence interval.

  2. Local-regional control [ Time Frame: Up to 24 months post-treatment ]
    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.

  3. Progression-free survival (PFS) [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 24 months post-treatment ]
    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.

  4. Overall survival (OS) [ Time Frame: Up to 24 months post-treatment ]
    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.

  5. FADD copy gain in tumor tissue or in blood [ Time Frame: At baseline ]
    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.

  6. BIRC2/3 copy gain in tumor tissue or in blood [ Time Frame: At baseline ]
    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.

  7. Feasibility of detecting effects of birinapant and re-irradiation on pilot pharmacodynamic markers in tumor tissue [ Time Frame: 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, including microwestern for decrease in drug targets IAP1/2.

  8. Change in caspase 3 levels [ Time Frame: Baseline up to cycle 1, day 4 ]
    Increase in apoptosis/necroptosis marker caspase 3 will be evaluated.

  9. Change in MLKL levels [ Time Frame: Baseline up to cycle 1, day 4 ]
    Increase in apoptosis/necroptosis marker MLKL will be evaluated.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 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
  • 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
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Hemoglobin >= 10 g/dL (transfusion permitted)
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 75,000/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
  • Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Patients must have a corrected QT (QTc) =< 480 msec
  • 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

Exclusion Criteria:

  • Eligibility for curative-intent surgery
  • 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
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03803774


Locations
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United States, Maryland
NCI - Center for Cancer Research Recruiting
Bethesda, Maryland, United States, 20892
Contact: Site Public Contact    800-411-1222      
Principal Investigator: Vassiliki Saloura         
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Site Public Contact    800-293-5066    Jamesline@osumc.edu   
Principal Investigator: Dukagjin M. Blakaj         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Vassiliki Saloura National Cancer Institute LAO

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03803774     History of Changes
Obsolete Identifiers: NCT03809208
Other Study ID Numbers: NCI-2019-00175
NCI-2019-00175 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10184 ( Other Identifier: National Cancer Institute LAO )
10184 ( Other Identifier: CTEP )
First Posted: January 15, 2019    Key Record Dates
Last Update Posted: June 25, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD Sharing Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy pa
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Squamous Cell Carcinoma of Head and Neck
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Head and Neck Neoplasms
Neoplasms by Site