Clinical Trials /

Cisplatin, Intensity-Modulated Radiation Therapy, and Pembrolizumab in Treating Patients With Stage III-IV Head and Neck Squamous Cell Carcinoma

NCT02775812

Description:

This phase I trial studies the side effects and best dose of pembrolizumab when given together with cisplatin and intensity-modulated radiation therapy, in treating patients with stage III-IV squamous cell carcinoma of the head and neck. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as cisplatin, 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. Intensity-modulated radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Giving pembrolizumab with cisplatin and intensity-modulated radiation therapy may work better in treating patients with squamous cell carcinoma of the head and neck.

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

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Cisplatin</span>, Radiation Therapy, and <span class="go-doc-concept go-doc-intervention">Pembrolizumab</span> in Treating Patients With Stage III-IV <span class="go-doc-concept go-doc-disease">Head and Neck Squamous Cell Carcinoma</span>

Title

  • Brief Title: Cisplatin, Radiation Therapy, and Pembrolizumab in Treating Patients With Stage III-IV Head and Neck Squamous Cell Carcinoma
  • Official Title: A Phase I and Expansion Cohort Study of Adjuvant Cisplatin, Intensity-Modulated Radiotherapy, and Pembrolizumab in High-Risk Head and Neck Squamous Cell Carcinoma (HNSCC)
  • Clinical Trial IDs

    NCT ID: NCT02775812

    ORG ID: NCI-2016-00667

    NCI ID: NCI-2016-00667

    Trial Conditions

    Stage III Hypopharyngeal Squamous Cell Carcinoma

    Stage III Laryngeal Squamous Cell Carcinoma

    Stage III Oral Cavity Squamous Cell Carcinoma

    Stage III Oropharyngeal Squamous Cell Carcinoma

    Stage IVA Hypopharyngeal Squamous Cell Carcinoma

    Stage IVA Laryngeal Squamous Cell Carcinoma

    Stage IVA Oral Cavity Squamous Cell Carcinoma

    Stage IVA Oropharyngeal Squamous Cell Carcinoma

    Stage IVB Hypopharyngeal Squamous Cell Carcinoma

    Stage IVB Laryngeal Squamous Cell Carcinoma

    Stage IVB Oral Cavity Squamous Cell Carcinoma

    Stage IVB Oropharyngeal Squamous Cell Carcinoma

    Trial Interventions

    Drug Synonyms Arms
    Cisplatin Abiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone's Chloride, Peyrone's Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, Platosin Treatment (cisplatin, pembrolizumab, IMRT)

    Trial Purpose

    This phase I trial studies the side effects and best dose of pembrolizumab when given
    together with cisplatin and radiation therapy, in treating patients with stage III-IV
    squamous cell carcinoma of the head and neck. Monoclonal antibodies, such as pembrolizumab,
    may block tumor growth in different ways by targeting certain cells. Drugs used in
    chemotherapy, such as cisplatin, 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. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors.
    Giving pembrolizumab with cisplatin and radiation therapy may work better in treating
    patients with squamous cell carcinoma of the head and neck.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To determine the recommended phase II dose (RP2D) for the combination of pembrolizumab
    and standard, adjuvant cisplatin-radiotherapy in patients with high-risk, human
    papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), based upon
    dose-limiting toxicity (DLT).

    SECONDARY OBJECTIVES:

    I. To describe 1-year disease -free survival (DFS), overall survival (OS), local-regional
    failure (LRF), and rate of distant metastases following treatment with adjuvant
    cisplatin-radiotherapy and pembrolizumab.

    II. To describe the toxicity of the combination of cisplatin-radiotherapy and pembrolizumab
    according to Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4,
    including immune-related adverse events (AEs).

    III. To describe the relationship between baseline programmed cell death 1 ligand 1 (PD-L1)
    expression 1-year disease-free survival (DFS).

    IV. To describe baseline immune-inflammatory biomarkers in both tumor and tumor-infiltrating
    lymphocytes (TILs), and correlate them with 1-year DFS.

    V. To describe baseline and change in expression of peripheral immune-inflammatory
    biomarkers, including a panel of candidate tumor antigen (TA)-specific memory T cells, and
    correlate with 1-year DFS.

    OUTLINE:

    Patients receive cisplatin intravenously (IV) over 1-2 hours once weekly for weeks 1-6 and
    pembrolizumab IV over 30 minutes every 3 weeks in weeks 9, 12, 15, 18, and 21. Patients also
    undergo intensity-modulated radiation therapy (IMRT) in weeks 1-6. Patients may also receive
    pembrolizumab IV over 30 minutes in weeks 3, 6, 24, and 27.

    After completion of study treatment, patients are followed up at months 6, 9, 12, 15, 18,
    21, 24, 30, and 36.

    Trial Arms

    Name Type Description Interventions
    Treatment (cisplatin, pembrolizumab, IMRT) Experimental Patients receive cisplatin IV over 1-2 hours once weekly for weeks 1-6 and pembrolizumab IV over 30 minutes every 3 weeks in weeks 9, 12, 15, 18, and 21. Patients also undergo IMRT in weeks 1-6. Patients may also receive pembrolizumab IV over 30 minutes in weeks 3, 6, 24, and 27. Cisplatin

    Eligibility Criteria

    Inclusion Criteria:

    - STEP 1 (REGISTRATION)

    - Pathologically (histologically or cytologically) proven diagnosis of head and neck
    squamous cell carcinoma (HNSCC) involving the oral cavity (excluding lips),
    oropharynx (p16 negative), hypopharynx or larynx

    - Patients must have undergone gross total surgical resection of high-risk oral cavity,
    oropharynx (p16 negative), larynx, or hypopharynx squamous cell carcinoma (SCC)
    within 63 days prior to registration; Note: Patients may have a biopsy under general
    anesthesia in an operating room followed by definitive ablative cancer surgery
    representing gross total resection; the gross total resection has to be done within
    63 days prior to registration; if, however, patients have ablative resection but
    demonstrate rapid gross recurrence or are determined to have gross persisting disease
    requiring re-resection to achieve gross total resection, then the patient is not
    eligible

    - Patients must have at least one of the following high risk pathologic features:

    - Extracapsular nodal extension

    - Invasive cancer at the primary tumor resection margin (tumor on ink); Note:
    Patients who have a positive margin and undergo re-resection with final negative
    margin are eligible only if they can be enrolled within 63 days of initial gross
    total resection AND extracapsular nodal extension was also present; patients who
    have a positive margin and undergo re-resection with final negative margin and
    do not have extracapsular nodal extension, are NOT eligible

    - Pathologic stage III or IV HNSCC, including no distant metastases, based on the
    following minimum diagnostic workup:

    - General history/physical examination by a radiation oncologist and/or medical
    oncologist within 84 days prior to registration

    - Examination by an ear nose and throat (ENT) or head & neck surgeon prior to
    surgery; a laryngopharyngoscopy (mirror and/or fiberoptic and/or direct
    procedure), if appropriate, is recommended but not required; intra-operative
    examination is acceptable documentation

    - Pre-op Imaging of the head and neck: a neck computerized tomography (CT) (with
    contrast) or CT/positron emission tomography (PET) (with contrast) and/or an
    magnetic resonance imaging (MRI) of the neck (T1 with gadolinium and T2) within
    84 days prior to surgery; Note: This imaging data (diagnostic pre-operative scan
    showing gross disease) is to be submitted in Digital Imaging and Communications
    in Medicine (DICOM) format via transfer of images and data (TRIAD); the report
    is to be uploaded into Rave

    - Chest imaging with either a CT scan (with or without contrast) or CT/PET (with
    or without contrast) that includes the chest within 120 days prior to
    registration ; Note: if the CT/PET with or without contrast is done within 84
    days prior to surgery, it fulfills the chest imaging requirement

    - For patients with oropharyngeal cancer only: the institution will do p16 testing, and
    if p16 is negative, this tissue must be submitted for central review for confirmation
    before Step 2 registration Note: If the institution finds that the patient is p16
    positive, the patient is excluded from this trial on the basis of distinct biology,
    prognosis, and low- or intermediate-risk rather than high-risk status

    - Zubrod performance status of 0-1 within 28 days prior to registration

    - Absolute neutrophil count (ANC): >= 1,500 /mm^3

    - Platelets: >= 100,000 / mm^3

    - Hemoglobin: >= 8.0 g/dL (Note: The use of transfusion or other intervention to
    achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable)

    - Serum creatinine =< the institutional upper limit of normal (ULN) OR

    - Creatinine clearance (CrCl) >= 50 ml/min within 14 days prior to registration as
    determined by 24-hour collection or estimated by Cockraft-Gault formula

    - Serum total bilirubin: =< 1.5 X ULN OR

    - Direct bilirubin: =< ULN for patients with total bilirubin levels > 1.5 ULN

    - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
    alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5
    X ULN

    - International normalized ratio (INR) or prothrombin time (PT): =< 1.5 X ULN unless
    patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic
    range of intended use of anticoagulants

    - Activated Partial Thromboplastin Time (aPTT): =< 1.5 X ULN unless patient is
    receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of
    intended use of anticoagulants

    - The following assessments are required within 14 days prior to registration: sodium
    (Na), potassium (K), chlorine (Cl), glucose, calcium (Ca), magnesium (Mg), and
    albumin; Note: Patients with an initial magnesium < 0.5 mmol/L (1.2 mg/dl) may
    receive corrective magnesium supplementation but should continue to receive either
    prophylactic weekly infusion of magnesium and/or oral magnesium supplementation (eg,
    magnesium oxide) at the investigator's discretion

    - For women of childbearing potential, a negative serum pregnancy test within 14 days
    of registration

    - Female patients of childbearing potential and men receiving pembrolizumab who are
    sexually active with women of childbearing potential must be willing to use an
    adequate method of contraception for the course of the study through 120 days after
    the last dose of pembrolizumab Note: Abstinence is acceptable if this is the usual
    lifestyle and preferred contraception for the patient

    - Patients with feeding tubes are eligible for the study

    - The patient or a legally authorized representative must provide study-specific
    informed consent prior to study entry, including consent for mandatory tumor tissue,
    serum, and blood submission for immune correlatives (all patients) and p16 analysis
    (oropharyngeal cases only)

    - STEP 2 (REGISTRATION)

    - For patients with oropharyngeal cancer only: p16 negative, confirmed by central
    pathology review

    Exclusion Criteria:

    - Definitive clinical or radiologic evidence of metastatic disease

    - Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
    for a minimum of 1095 days (3 years); noninvasive cancers (for example, carcinoma in
    situ of the breast, oral cavity, or cervix) are permitted even if diagnosed and
    treated < 3 years ago

    - Patients with simultaneous primaries or bilateral tumors are excluded, with the
    exception of patients with bilateral tonsil cancers or patients with T1-2, N0, M0
    differentiated thyroid carcinoma, who are eligible

    - Prior systemic therapy, including cytotoxic chemotherapy, biologic/targeted therapy,
    or immune therapy for the study cancer; Note: Prior cytotoxic chemotherapy or
    biologic/targeted therapy for a different cancer is allowable; however, a prior
    anti-programmed cell death (PD)-1, anti-PD-L1, or anti-programmed cell death 1 ligand
    2 (PD-L2) agent is not permitted

    - Prior radiotherapy to the region of the study cancer that would result in overlap of
    radiation therapy fields

    - Severe, active co-morbidity defined as follows:

    - Unstable angina and/or congestive heart failure requiring hospitalization within
    6 months prior to registration

    - Transmural myocardial infarction within 6 months prior to registration

    - Acute bacterial or fungal infection requiring intravenous antibiotics at the
    time of registration; Note: If the infection resolves and the patient is on oral
    (p.o.) and still within, the required registration timeframe, then the patient
    is eligible

    - Chronic obstructive pulmonary disease exacerbation or other respiratory illness
    requiring hospitalization or precluding study therapy at the time of
    registration

    - Idiopathic pulmonary fibrosis or other severe interstitial lung disease that
    requires oxygen therapy or is thought to require oxygen therapy within 1 year
    prior to registration

    - Known history of, or any evidence of active, non-infectious pneumonitis

    - Acquired immune deficiency syndrome (AIDS) based upon current Center for Disease
    Control and Prevention (CDC) definition; note: human immunodeficiency virus
    (HIV) testing is not required for entry into this protocol; the need to exclude
    patients with AIDS from this protocol is necessary because the cisplatin and
    IMRT involved in this protocol may be significantly immunosuppressive

    - A diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
    other form of immunosuppressive therapy within 7 days prior to the first dose of
    t pembrolizumab

    - Known history of active TB (bacillus tuberculosis)

    - Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
    hepatitis C (e.g., hepatitis c virus [HCV] ribonucleic acid [RNA] [qualitative]
    is detected); Note: Patients who have been curatively treated for hepatitis C
    and have no detectable viral load are eligible

    - Active autoimmune disease that has required systemic treatment in the past 2
    years (i.e. with use of disease modifying agents, corticosteroids or
    immunosuppressive drugs); replacement therapy (eg thyroxine, insulin, or
    physiologic corticosteroid replacement therapy for adrenal or pituitary
    insufficiency, etc.) is not considered a form of systemic treatment

    - Grade 3-4 electrolyte abnormalities (CTCAE, v. 4):

    - Serum calcium (ionized or adjusted for albumin) < 7 mg/dl (1.75 mmol/L) or > 12.5
    mg/dl (>3.1 mmol/L) despite intervention to normalize levels

    - Glucose < 40 mg/dl (< 2.2 mmol/L) or > 250 mg/dl (> 14mmol/L)

    - Magnesium < 0.9 mg/dl (< 0.4 mmol/L) or > 3 mg/dl (> 1.23 mmol/L) despite
    intervention to normalize levels

    - Potassium < 3.0 mmol/L or > 6 mmol/L despite intervention to normalize levels

    - Sodium < 130 mmol/L or > 155 mmol/L despite intervention to normalize levels

    - Patients who are pregnant, nursing, or expecting to conceive or father children
    within the projected duration of the trial, starting with the pre-screening or
    screening visit through 120 days after the last dose of pembrolizumab

    - A known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

    - Hypersensitivity to pembrolizumab or any of its excipients;

    - Patients who have received a live vaccine within 30 days of planned start of study
    therapy; Note: Seasonal influenza vaccines for injection are generally inactivated
    flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist)
    are live attenuated vaccines, and are not allowed

    - Patients for whom it is not in the best interest to participate in the study, in the
    opinion of the treating investigator

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    DLT in patients with high-risk head and neck squamous cell carcinoma treated with adjuvant cisplatin, IMRT, and pembrolizumab

    Secondary Outcome Measures

    Change in expression of peripheral immune-inflammatory biomarkers

    DFS

    Distant metastases

    Immune-inflammatory biomarkers

    Incidence of acute toxicities by NCI CTCAE version 4.0

    Incidence of late toxicities by NCI CTCAE version 4.0

    Levels of PDL1 assessed in tumor tissue by light microscopy

    LRF

    OS

    Trial Keywords