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Entolimod in Treating Patients With Stage III-IV Squamous Cell Head and Neck Cancer Receiving Cisplatin and Radiation Therapy

Primary Purpose

Mucositis, Recurrent Squamous Cell Carcinoma of the Hypopharynx, Recurrent Squamous Cell Carcinoma of the Larynx

Status
Withdrawn
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
entolimod
intensity-modulated radiation therapy
cisplatin
pharmacological study
laboratory biomarker analysis
Sponsored by
Roswell Park Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Mucositis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Histologically proven diagnosis of squamous cell carcinoma (stage III - IV) of the nasopharynx, oropharynx, oral cavity, paranasal sinuses, larynx, hypopharynx; the tumor must be human papillomavirus (HPV) negative or the patient should have a greater than 10 packs year smoking history; OR need for post-operative concurrent chemoradiotherapy (extracapsular extension, positive surgical margin, more than 1 lymph node positive, stage III - IV disease, perineural invasion, vascular tumor embolus) for histologically proven squamous cell carcinoma of the paranasal sinuses, nasopharynx, larynx, hypopharynx, with extension to structures of the oropharynx
  • Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
  • Induction chemotherapy (up to 3 cycles of cetuximab/taxanes/platinum based regimens) is allowed
  • Patients or their legal representatives must be able to comprehend and provide written informed consent
  • Absolute neutrophil count => 1,500/uL
  • Platelets >= 100,000/uL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit normal (ULN)
  • Calculated creatinine clearance >= 60 mL/min (Cockcroft-Gault equation)
  • 12-Lead Electrocardiogram (ECG) with normal tracing or non-clinically significant changes that do not require medical intervention
  • Bazett's corrected QT (QTcB) interval < 470 msec at any timepoint prior to receiving the first dose of study drug (mean of replicate values, correction per institutional standard) and no history of Torsades des Pointes or other symptomatic QTcB abnormality
  • Absence of orthostatic hypotension
  • Patients must be sufficiently recovered from induction chemotherapy to allow initiation therapy

Exclusion Criteria:

  • Women of childbearing potential who do not have a negative serum pregnancy test performed within 7 days prior to the start of study drug
  • Male and female patients of child-bearing potential who do not agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 90 days after last investigational drug dose received
  • Contraindication to full course chemoradiotherapy with cisplatin
  • Previous treatment with a toll-like receptor 5 (TLR5) agonist
  • Presence of neutralizing antibodies to CBLB502
  • Patients with an active infection or with a fever >= 38.5ºC within 3 days of the first scheduled day of dosing; patients who are registered but develop a fever of >= 38.5ºC may remain in the study if the fever abates prior to the expiration of the screening procedures; if the screening procedures have expired, the patient may be re-screened once afebrile
  • Patients with a history of significant cardiovascular, neurological, endocrine, gastrointestinal, respiratory or inflammatory illness that could preclude their participation in the study, pose an undue medical hazard or interfere with the interpretation of the study results, including, but not limited to, patients with congestive heart failure (New York Heart Association [NYHA] class 3 or class 4); unstable angina; cardiac arrhythmia; recent (within the preceding 6 months) myocardial infarction or stroke; hypertension requiring > 2 medications for adequate control; diabetes mellitus with > 2 episodes of ketoacidosis in the preceding 12 months; chronic obstructive pulmonary disease (COPD) requiring > 2 hospitalizations in the preceding 12 months
  • Patients with a history of, or known autoimmune disease, but not limited to systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, ankylosing spondylitis, sarcoidosis, vasculitis, Wegener's granulomatosis, Hashimoto's thyroiditis, ulcerative colitis, Crohn's disease, Goodpasture's disease, multiple sclerosis, etc.
  • Patients with any other medical, psychiatric or social condition that would preclude their participation in the study, pose an undue medical hazard, interfere with the conduct of the study or interfere with interpretation of the study results
  • Patients taking sucralfate, palifermin or amifostine
  • Patients receiving hematopoietic growth factors
  • Patients currently taking, or who have taken within 30 days of the initiation of protocol therapy, any immunomodulatory therapy, including pharmacologic doses of glucocorticoids (topical and inhalation glucocorticoids are permitted), azathioprine, methotrexate, interferon-alpha, interferon-beta, interluekin-2, etanercept, infliximab, tacrolimus, cyclosporine, mycophenolic acid, etc
  • Patients with a history of hypersensitivity reactions to any of the components of CBLB502 or cisplatin
  • Women who are pregnant or lactating or who are planning on becoming pregnant during the study or for 90 days after completion of the study
  • Patients who have received an investigational therapy within 4 weeks of signing the informed consent for the current study
  • Patients with a history of, patients who were treated for, or patients who are suspected of having, hepatitis B, and hepatitis C or human immunodeficiency virus (HIV); patients suspected of having any of these conditions should undergo appropriate evaluations prior to being enrolled in the study
  • Surgery with significant defect or flap in the oral cavity
  • Poor dentition or ill-fitting dental appliances (can be enrolled if this can be corrected by a dentist prior to start of radiation therapy)
  • Presence of other medical conditions causing mucositis (e.g., rheumatologic, gastroesophageal reflux, etc.)

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    Treatment (entolimod, IMRT, cisplatin)

    Arm Description

    Patients undergo IMRT 5 times per week for 7 weeks, receive cisplatin IV once weekly for 7 weeks, and entolimod SC on days 1, 8, 15, 22, 29, 36, and 43.

    Outcomes

    Primary Outcome Measures

    Adverse events defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related graded according to Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0
    Summarized descriptively by time point (mean, standard deviation). All safety analyses will be presented by dose cohort and overall as well as examined for relation to demographic parameters (i.e., gender, weight, body surface area [BSA]) and covariance or dependence on PK, PD, or presence of anti-entolimod antibodies at baseline and/or the development of entolimod antibodies.
    PK of entolimod when administered in combination with cisplatin and radiation therapy
    A population PK model will be developed utilizing the PK time points collected and used to estimate individual areas under the curve (AUCs) or clearance (CL) of entolimod. The effect of patient factors, such as demographics and ECOG status, on entolimod PK will be evaluated by the model to help explain the interpatient variability in PK. Entolimod AUC, as well as the observed Crnax, will then be tested for association changes in cytokine levels, such as G-CSF, IL-6, IL-8, IL- 10 and TNF-alpha.
    The percentage of patients with mucositis, measured using the World Health Organization (WHO) mucositis global severity score and the oral mucositis daily questionnaire (OMDQ)
    The percentage of patients with mucositis will be tabulated overall and by dose level.

    Secondary Outcome Measures

    Full Information

    First Posted
    November 13, 2012
    Last Updated
    December 10, 2013
    Sponsor
    Roswell Park Cancer Institute
    Collaborators
    National Cancer Institute (NCI), Cleveland BioLabs, Inc.
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    1. Study Identification

    Unique Protocol Identification Number
    NCT01728480
    Brief Title
    Entolimod in Treating Patients With Stage III-IV Squamous Cell Head and Neck Cancer Receiving Cisplatin and Radiation Therapy
    Official Title
    A Phase I Study of CBLB502 in the Treatment of Patients With Poor Prognosis Advanced Squamous Cell Carcinomas of the Head and Neck Receiving Chemoradiotherapy
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    December 2013
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    Financial Sponsor requested termination
    Study Start Date
    January 2014 (undefined)
    Primary Completion Date
    October 2015 (Anticipated)
    Study Completion Date
    undefined (undefined)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Roswell Park Cancer Institute
    Collaborators
    National Cancer Institute (NCI), Cleveland BioLabs, Inc.

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    This phase I trial studies the side effects and best dose of entolimod in treating patients with stage III-IV or recurrent head and neck cancer. Biological therapies, such as entolimod, may stimulate the immune system in different ways and stop tumor cells from growing. Entolimod may also prevent side effects caused by chemotherapy with cisplatin and radiation therapy. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving entolimod together with cisplatin and radiation therapy may kill more tumor cells
    Detailed Description
    PRIMARY OBJECTIVES: I. To define the Phase II dose of CBLB502 (entolimod) when given as weekly injections during irradiation with cisplatin, for patients with poor prognosis advanced squamous cell carcinomas of the head and neck receiving chemoradiotherapy. SECONDARY OBJECTIVES: I. To describe the adverse event (AE) profile and the dose limiting toxicities of CBLB502 when administered weekly in combination with cisplatin and radiation therapy. II. To determine the maximally tolerated dose (if observed) of CBLB502 in combination with cisplatin and radiation therapy. III. To describe the pharmacokinetics (PK) of CBLB502 when administered in combination with cisplatin. IV. To describe the pharmacodynamics (PD) of CBLC502 by examining plasma levels of various cytokines, including filgrastim (granulocyte-colony stimulating factor [G-CSF]), interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-α). V. To describe any clinical activity of CBLB502 in the form of mitigation of mucositis. VI. To describe the response rate to chemoradiotherapy in combination with CBLB502. OUTLINE: This is a dose-escalation study of entolimod. Patients undergo intensity-modulated radiation therapy (IMRT) 5 times per week for 7 weeks, receive cisplatin intravenously (IV) once weekly for 7 weeks, and entolimod subcutaneously (SC) on days 1, 8, 15, 22, 29, 36, and 43. After completion of study treatment, patients are followed up for 3 months.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Mucositis, Recurrent Squamous Cell Carcinoma of the Hypopharynx, Recurrent Squamous Cell Carcinoma of the Larynx, Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity, Recurrent Squamous Cell Carcinoma of the Nasopharynx, Recurrent Squamous Cell Carcinoma of the Oropharynx, Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Recurrent Verrucous Carcinoma of the Larynx, Recurrent Verrucous Carcinoma of the Oral Cavity, Stage III Squamous Cell Carcinoma of the Hypopharynx, Stage III Squamous Cell Carcinoma of the Larynx, Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage III Squamous Cell Carcinoma of the Nasopharynx, Stage III Squamous Cell Carcinoma of the Oropharynx, Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Stage III Verrucous Carcinoma of the Larynx, Stage III Verrucous Carcinoma of the Oral Cavity, Stage IV Squamous Cell Carcinoma of the Hypopharynx, Stage IV Squamous Cell Carcinoma of the Nasopharynx, Stage IVA Squamous Cell Carcinoma of the Larynx, Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage IVA Squamous Cell Carcinoma of the Oropharynx, Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Stage IVA Verrucous Carcinoma of the Larynx, Stage IVA Verrucous Carcinoma of the Oral Cavity, Stage IVB Squamous Cell Carcinoma of the Larynx, Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage IVB Squamous Cell Carcinoma of the Oropharynx, Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Stage IVB Verrucous Carcinoma of the Larynx, Stage IVB Verrucous Carcinoma of the Oral Cavity, Stage IVC Squamous Cell Carcinoma of the Larynx, Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage IVC Squamous Cell Carcinoma of the Oropharynx, Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Stage IVC Verrucous Carcinoma of the Larynx, Stage IVC Verrucous Carcinoma of the Oral Cavity, Tongue Cancer

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Treatment (entolimod, IMRT, cisplatin)
    Arm Type
    Experimental
    Arm Description
    Patients undergo IMRT 5 times per week for 7 weeks, receive cisplatin IV once weekly for 7 weeks, and entolimod SC on days 1, 8, 15, 22, 29, 36, and 43.
    Intervention Type
    Drug
    Intervention Name(s)
    entolimod
    Other Intervention Name(s)
    CBLB502, TLR5 agonist CBLB502, toll-like receptor 5 agonist CBLB502
    Intervention Description
    Given SC
    Intervention Type
    Radiation
    Intervention Name(s)
    intensity-modulated radiation therapy
    Other Intervention Name(s)
    IMRT
    Intervention Description
    Undergo IMRT
    Intervention Type
    Drug
    Intervention Name(s)
    cisplatin
    Other Intervention Name(s)
    CACP, CDDP, CPDD, DDP
    Intervention Description
    Given IV
    Intervention Type
    Other
    Intervention Name(s)
    pharmacological study
    Other Intervention Name(s)
    pharmacological studies
    Intervention Description
    Correlative studies
    Intervention Type
    Other
    Intervention Name(s)
    laboratory biomarker analysis
    Intervention Description
    Correlative studies
    Primary Outcome Measure Information:
    Title
    Adverse events defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related graded according to Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0
    Description
    Summarized descriptively by time point (mean, standard deviation). All safety analyses will be presented by dose cohort and overall as well as examined for relation to demographic parameters (i.e., gender, weight, body surface area [BSA]) and covariance or dependence on PK, PD, or presence of anti-entolimod antibodies at baseline and/or the development of entolimod antibodies.
    Time Frame
    Up to 3 months after completion of study treatment
    Title
    PK of entolimod when administered in combination with cisplatin and radiation therapy
    Description
    A population PK model will be developed utilizing the PK time points collected and used to estimate individual areas under the curve (AUCs) or clearance (CL) of entolimod. The effect of patient factors, such as demographics and ECOG status, on entolimod PK will be evaluated by the model to help explain the interpatient variability in PK. Entolimod AUC, as well as the observed Crnax, will then be tested for association changes in cytokine levels, such as G-CSF, IL-6, IL-8, IL- 10 and TNF-alpha.
    Time Frame
    Predose, and at 2, 4, 6, 8, and 12 (+/- 2) hours postdose on Day 1
    Title
    The percentage of patients with mucositis, measured using the World Health Organization (WHO) mucositis global severity score and the oral mucositis daily questionnaire (OMDQ)
    Description
    The percentage of patients with mucositis will be tabulated overall and by dose level.
    Time Frame
    Up to 3 months after completion of study treatment

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Histologically proven diagnosis of squamous cell carcinoma (stage III - IV) of the nasopharynx, oropharynx, oral cavity, paranasal sinuses, larynx, hypopharynx; the tumor must be human papillomavirus (HPV) negative or the patient should have a greater than 10 packs year smoking history; OR need for post-operative concurrent chemoradiotherapy (extracapsular extension, positive surgical margin, more than 1 lymph node positive, stage III - IV disease, perineural invasion, vascular tumor embolus) for histologically proven squamous cell carcinoma of the paranasal sinuses, nasopharynx, larynx, hypopharynx, with extension to structures of the oropharynx Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 Induction chemotherapy (up to 3 cycles of cetuximab/taxanes/platinum based regimens) is allowed Patients or their legal representatives must be able to comprehend and provide written informed consent Absolute neutrophil count => 1,500/uL Platelets >= 100,000/uL Total bilirubin within normal institutional limits Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit normal (ULN) Calculated creatinine clearance >= 60 mL/min (Cockcroft-Gault equation) 12-Lead Electrocardiogram (ECG) with normal tracing or non-clinically significant changes that do not require medical intervention Bazett's corrected QT (QTcB) interval < 470 msec at any timepoint prior to receiving the first dose of study drug (mean of replicate values, correction per institutional standard) and no history of Torsades des Pointes or other symptomatic QTcB abnormality Absence of orthostatic hypotension Patients must be sufficiently recovered from induction chemotherapy to allow initiation therapy Exclusion Criteria: Women of childbearing potential who do not have a negative serum pregnancy test performed within 7 days prior to the start of study drug Male and female patients of child-bearing potential who do not agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 90 days after last investigational drug dose received Contraindication to full course chemoradiotherapy with cisplatin Previous treatment with a toll-like receptor 5 (TLR5) agonist Presence of neutralizing antibodies to CBLB502 Patients with an active infection or with a fever >= 38.5ºC within 3 days of the first scheduled day of dosing; patients who are registered but develop a fever of >= 38.5ºC may remain in the study if the fever abates prior to the expiration of the screening procedures; if the screening procedures have expired, the patient may be re-screened once afebrile Patients with a history of significant cardiovascular, neurological, endocrine, gastrointestinal, respiratory or inflammatory illness that could preclude their participation in the study, pose an undue medical hazard or interfere with the interpretation of the study results, including, but not limited to, patients with congestive heart failure (New York Heart Association [NYHA] class 3 or class 4); unstable angina; cardiac arrhythmia; recent (within the preceding 6 months) myocardial infarction or stroke; hypertension requiring > 2 medications for adequate control; diabetes mellitus with > 2 episodes of ketoacidosis in the preceding 12 months; chronic obstructive pulmonary disease (COPD) requiring > 2 hospitalizations in the preceding 12 months Patients with a history of, or known autoimmune disease, but not limited to systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, ankylosing spondylitis, sarcoidosis, vasculitis, Wegener's granulomatosis, Hashimoto's thyroiditis, ulcerative colitis, Crohn's disease, Goodpasture's disease, multiple sclerosis, etc. Patients with any other medical, psychiatric or social condition that would preclude their participation in the study, pose an undue medical hazard, interfere with the conduct of the study or interfere with interpretation of the study results Patients taking sucralfate, palifermin or amifostine Patients receiving hematopoietic growth factors Patients currently taking, or who have taken within 30 days of the initiation of protocol therapy, any immunomodulatory therapy, including pharmacologic doses of glucocorticoids (topical and inhalation glucocorticoids are permitted), azathioprine, methotrexate, interferon-alpha, interferon-beta, interluekin-2, etanercept, infliximab, tacrolimus, cyclosporine, mycophenolic acid, etc Patients with a history of hypersensitivity reactions to any of the components of CBLB502 or cisplatin Women who are pregnant or lactating or who are planning on becoming pregnant during the study or for 90 days after completion of the study Patients who have received an investigational therapy within 4 weeks of signing the informed consent for the current study Patients with a history of, patients who were treated for, or patients who are suspected of having, hepatitis B, and hepatitis C or human immunodeficiency virus (HIV); patients suspected of having any of these conditions should undergo appropriate evaluations prior to being enrolled in the study Surgery with significant defect or flap in the oral cavity Poor dentition or ill-fitting dental appliances (can be enrolled if this can be corrected by a dentist prior to start of radiation therapy) Presence of other medical conditions causing mucositis (e.g., rheumatologic, gastroesophageal reflux, etc.)
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Anurag Singh
    Organizational Affiliation
    Roswell Park Cancer Institute
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Learn more about this trial

    Entolimod in Treating Patients With Stage III-IV Squamous Cell Head and Neck Cancer Receiving Cisplatin and Radiation Therapy

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