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Head and Neck Clinical Trials

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Merck MK-3475-412-00

Pembrolizumab or Placebo in Combination with Chemoradiation (CRT) in Subjects with Locally Advanced HNSCC (Head and Neck Squamous Cell Carcinoma)

  • Physician & Study Coordinator
  • Synopsis
  • Inclusion Criteria
  • Exclusion Criteria
  • Study Coordinator

    Jillian Timer, RN, BSN
    484-503-4156 

    Jillian.timer@sluhn.org
  • Treatment Agent: MK-3475

    Synopsis: The purpose of this study is to evaluate and compare the safety, tolerability and anti-tumor activity of the research study drug pembrolizumab (MK-3475) in combination with chemoradiation (CRT) to placebo in combination with CRT in subjects with locally advanced head and neck squamous cell carcinoma. This is a research study to test a drug, Keytruda® (pembrolizumab) that has been approved for use in certain types of melanoma, lung cancer, and recurrent/metastatic head and neck squamous cell cancer. Keytruda® or placebo will be administered along with cisplatin and radiotherapy in this study. Cisplatin is a type of chemotherapy drug and is marketed in the United States as Platinol®.

      • Has a pathologically proven new diagnosis of oropharyngeal p16 positive, oropharyngeal p16 negative, or larynx/hypopharynx/oral cavity (independent of p16) squamous cell carcinoma. Participants with oral cavity tumors need to have unresectable disease.
      • Has provided adequate tissue for Programmed Cell Death Receptor Ligand 1 (PD-L1) biomarker analysis from a core or excisional biopsy
      • Has evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography scan or magnetic resonance imaging, based on RECIST version 1.1
      • Is eligible for definitive CRT and not considered for primary surgery based on investigator decision
      • Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days prior to receiving the first dose of study therapy
      • Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study therapy
      • Female and male participants of reproductive potential must agree to use adequate contraception throughout the study period and for up to 180 days after the last dose of study therapy
      • Is currently participating or has participated in a study with an investigational agent or using an investigational device within 4 weeks of the first dose of study therapy
      • Has received prior therapy with an anti-Programmed Cell Death Receptor 1 (PD-1), anti-PD-L1, anti-Programmed Cell Death Receptor Ligand 2 (PD-L2) agent or with an agent directed to another co-inhibitory T-cell receptor or has previously participated in clinical studies with pembrolizumab
      • Has received a live vaccine within 30 days prior to the first dose of study therapy
      • Has cancer outside of the oropharynx, larynx, and hypopharynx or oral cavity, such as nasopharyngeal, sinus, other para-nasal, or other unknown primary head and neck cancer
      • Has had prior systemic therapy, targeted therapy, radiotherapy treatment or radical surgery for head and neck cancer under study
      • Has not recovered from major surgery prior to starting study therapy
      • Has known active Hepatitis B or C
      • Has known history of Human Immunodeficiency Virus (HIV)
      • Has 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 study therapy
      • Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
      • Has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic treatment.
      • Has history of a diagnosed and/or treated hematologic or primary solid tumor malignancy, unless in remission for at least 5 years prior to randomization
      • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
      • Has had previous allogeneic tissue/solid organ transplant
      • Has active infection requiring systemic therapy
      • Has a history of severe hypersensitivity reaction to pembrolizumab, cisplatin or radiotherapy or their analogs
      • Is pregnant or breast feeding or expecting to conceive or father children throughout the study period and for up to 180 days after the last dose of study therapy

NRG-HN003

A Phase I and Expansion Cohort Study of Adjuvant Cisplatin, Intensity-Modulated Radiotherapy, and MK-3475 (Pembrolizumab) in High-risk Head and Neck Squamous Cell Carncinoma (HNSCC)

  • Physician & Study Coordinator
  • Synopsis
  • Inclusion Criteria
  • Exclusion Criteria
  • Study Coordinator

    Jillian Timer, RN, BSN

    484-503-4156

    Jillian.timer@sluhn.org

  • Treatment Agent: Cisplatin, MK-3475

    Synopsis: This study tests the timing of the dose of pembrolizumab paired with the timing of the radiation and chemotherapy to see which combination is safer in people. The purpose of this study is to test the safety and schedule of adding full-dose pembrolizumab to radiation therapy and cisplatin chemotherapy. Pembrolizumab is FDA approved for treating patients with melanoma and lung cancer, and it is FDA approved for treating patients with head and neck cancer that has returned after treatment with chemotherapy (such as cisplatin). However, pembrolizumab is not part of the usual treatment of high-risk head and neck cancer, and the combination of pembrolizumab with radiation therapy and chemotherapy is investigational in this disease setting. Pembrolizumab may or may not increase the side effects of radiation therapy and chemotherapy. In this study, your doctor will carefully evaluate the side effects that you experience when pembrolizumab is added to the usual treatment.

  • 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
    • 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