Clinical Trials /

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

NCT03803774

Description:

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). 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.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-00175
  • SECONDARY ID: NCI-2019-00175
  • SECONDARY ID: 10184
  • SECONDARY ID: 10184
  • NCT ID: NCT03803774
  • NCT ALIAS: NCT03809208

Conditions

  • Recurrent Head and Neck Squamous Cell Carcinoma

Interventions

DrugSynonymsArms
BirinapantTL32711Treatment (IMRRT, birinapant)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (IMRRT, birinapant)ExperimentalBeginning 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.
  • Birinapant

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of dose-limiting toxicities (DLTs) and other toxicities
Time Frame:Up to 28 days post-treatment
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description: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.
Measure:Local-regional control
Time Frame:Up to 24 months post-treatment
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:Up to 24 months post-treatment
Safety Issue:
Description: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.
Measure:FADD copy gain in tumor tissue or in blood
Time Frame:At baseline
Safety Issue:
Description: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.
Measure:BIRC2/3 copy gain in tumor tissue or in blood
Time Frame:At baseline
Safety Issue:
Description: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.
Measure:Feasibility of detecting effects of birinapant and re-irradiation on pilot pharmacodynamic markers in tumor tissue
Time Frame:Up to cycle 1, day 4
Safety Issue:
Description: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.
Measure:Change in caspase 3 levels
Time Frame:Baseline up to cycle 1, day 4
Safety Issue:
Description:Increase in apoptosis/necroptosis marker caspase 3 will be evaluated.
Measure:Change in MLKL levels
Time Frame:Baseline up to cycle 1, day 4
Safety Issue:
Description:Increase in apoptosis/necroptosis marker MLKL will be evaluated.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

November 18, 2019