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Treatment Agent: EC-18

Synopsis: The purpose of Stage 1 of this research study is to measure the safety of the study drug EC-18 at different dosages in patients being treated with chemoradiation for cancers of the mouth, oropharynx, hypopharynx and nasopharynx.

Sometimes it is not known which way of treating patients is best. To find out, researchers need to compare different treatments. People are put into groups and each group given a different treatment. The results are compared to see if one is better. To try to make sure the groups are the same to start with, each patient is assigned to a group by chance (randomly). Stage 1 of this study, is called a “dose-finding” stage. This means that the dose level of the study drug EC-18 may be different for each patient. Twenty-four (24) patients will be equally randomized (divided) into 4 groups to receive a dosage of either EC-18 500 mg, EC-18 1000 mg, EC-18 2000 mg or placebo. A placebo is a medication which looks exactly like the investigational drug but has no active ingredient.  You, your study doctor and study staff will not know what dosage you are receiving or if you are receiving placebo. All the softgels look the same whether study medication or placebo.

The purpose of this study is to find out good and/or bad effects of the investigational drug, Imprime PGG, when given together with pembrolizumab in the treatment of your type of cancer. An investigational drug is one that is not approved by the United States Food and Drug Administration (FDA). Imprime PGG is a glucan. Glucans are molecules that are not normally present in your body. Imprime PGG when given with pembrolizumab may help the immune system to fight your type of cancer. Pembrolizumab is already approved by the FDA when given alone for the treatment of advanced metastatic melanoma, non-small cell lung cancer, and in recurrent or metastatic SCCHN for patients with disease progression on or after platinum-containing chemotherapy. The combination of these drugs used in this study is also investigational.

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• Signed informed consent
• Male or female age 21 years or older
• Pathologically confirmed diagnosis of squamous cell carcinoma of the mouth, oropharynx, hypopharynx or nasopharynx
• Planned to receive IMRT with daily fractions of 2.0 Gy to 2.2 Gy to a cumulative dose of at least 60 Gy and a maximum of 72 Gy
• Radiation fields to include at least two mucositis sites at risk (buccal mucosa, floor of mouth, ventral and lateral tongue, soft palate) in which both sites receive a minimum cumulative dose of 55 Gy
• Planned to receive concomitant single agent chemotherapy with cisplatin given either weekly or tri-weekly
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
• Screening Laboratory Values Hemoglobin ≥ 9g/dL White blood cell count ≥ 3,500 cells/mm3 Absolute neutrophil count ≥ 1,500 cells/mm3 Total bilirubin ≤ 2 times upper limit of normal Serum AST and ALT ≤ 2.5 times upper limit of normal Serum creatinine concentration ≤ 2mg/mL Pregnancy test: negative for females of childbearing potential
• Subjects of childbearing potential must consent to utilize a medically accepted means of contraception throughout the active dosing period with study medication and for a minimum of 30 days following the administration of the last dose of study medication.

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Unable to provide informed consent or, in the opinion of the Principal Investigator, comply with the protocol.

• Prior radiation therapy to the head and neck
• Metastatic disease
• Presence of active infectious disease excluding oral candidiasis
• Presence of oral mucositis or any oral lesion that would confound the assessment of oral mucositis
• Active systemic disease or condition known to impact the risk or course of oral mucositis including chronic immunosuppression and known seropositivity for HIV
• Use of any investigational agent within 30 days of the first radiation dose
• Active alcohol abuse syndrome
• Subjects with a history of hepatitis of any etiology or hepatic insufficiency
• Pregnant or nursing at the time of signing informed consent
• Known sensitivity to any study medication
• Unwilling or unable to complete study diary
• Any other condition or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for the study or unable to comply with the protocol

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Treatment Agent: GC4419

Synopsis: The main purpose of this study is to further investigate whether fewer people getting radiation therapy and chemotherapy for head and neck cancer will get severe oral mucositis if they get GC4419 along with chemoradiation.  This study will also investigate how many people get the most severe oral mucositis, how long it lasts, and how long it takes to occur.  The safety of GC4419 will also be assessed in this study.  To do this, the effects of GC4419 will be compared against a placebo (a substance that copies the appearance of the investigational drug but contains no active ingredient).  This study will also investigate whether GC4419 has any effect on your cancer.

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• squamous cell carcinoma of the head and neck
• treatment plan to receive IMRT delivered as single daily fractions of 2.0 to 2.2 Gy with a cumulative radiation dose of 60-72 Gy
• Treatment plan to receive standard cisplatin monotherapy
• Age 18 years or older
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Adequate hematologic, renal and liver function
• Negative serum pregnancy test
• Use of effective contraception

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• Tumor of the lips, larynx, hypopharynx, nasopharynx, sinuses, or salivary glands
• Metastatic disease
• Prior radiotherapy to the region of the study cancer or adjacent anatomical
• Prior induction chemotherapy
• Receiving any approved or investigational anti-cancer agent other than those provided for in this study
• Concurrent participation in another interventional clinical study
• Inability to eat soft solid food at baseline
• Malignant tumors other than HNC within the last 5 years
• Active infectious disease excluding oral candidiasis
• Presence of oral mucositis at baseline
• Known history of HIV or active hepatitis B/C
• Female patients who are pregnant or breastfeeding
• Known allergies or intolerance to cisplatin and similar platinum-containing compounds
• Requirement for concurrent treatment with nitrates or other drugs that may create a risk for a precipitous decrease in blood pressure

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Treatment Agent: Pembrolizumab

Synopsis: The purpose of this study is to:

• Test the safety of the study drug, pembrolizumab (MK-3475)
• Test how your cancer responds to one of the following:

• Pembrolizumab plus radiation therapy (RT) with or without cisplatin after surgery
• RT with or without cisplatin after surgery.  

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• Has histologically confirmed new diagnosis of resectable, non-metastatic, squamous cell carcinoma that is either: Stage III Human Papillomavirus (HPV) positive oropharyngeal primary that is tumor size (T) 4, lymph node involvement (N) 0-2, no distant metastases (M0); Stage III or IVA oropharyngeal HPV negative; or Stage III or IVA larynx/hypopharynx/oral cavity primaries
• Is eligible for primary surgery based on investigator decision and per local practice
• 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
• Male participants must refrain from donating sperm throughout the study period and for up to 180 days after the last dose of study therapy
• Female participant that is not pregnant or breastfeeding
• Has evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI), based on RECIST version 1.1
• Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
• Has results from testing of HPV status for oropharyngeal cancer defined as p16
• 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

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• Has Stage T4B and/or N3 LA HNSCC and/or distant metastases
• 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 (HNC)
• Female participant who has a positive urine pregnancy test within 72 hours prior to study start or within 24 hours prior to the start of radiotherapy with or without cisplatin
• Has received prior therapy with an anti-programmed cell death receptor 1(PD-1), anti-programmed cell death receptor ligand 1(PD-L1), or anti-programmed cell death receptor ligand 2 (PD-L2) agent or with an agent directed to another co-inhibitory T-cell receptor
• Has received prior radiotherapy treatment or systemic anti-cancer therapy including investigational agents for the HNC under study prior to study start
• Has received a live vaccine within 30 days prior to the first dose of study therapy
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study therapy
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study therapy
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. in situ cervical cancer or breast carcinoma) that have undergone potentially curative therapy
• Has radiographically detectable (even if asymptomatic and/or previously treated) central nervous system metastases and/or carcinomatous meningitis
• Has Grade ≥2 audiometric hearing loss
• Has Grade ≥2 neuropathy
• Has Grade 3-4 bleeding due to the underlying malignancy
• Has received major surgery or has not recovered adequately from the toxicity and/or complications from the intervention prior to study start
• Has had previous allogeneic tissue/solid organ transplant
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients, radiotherapy, cisplatin or their analogs
• Has an active autoimmune disease that has required systemic treatment in past 2 years
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has a known history of or is positive for Hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C (defined as Hepatitis C virus [HCV] ribonucleic acid is detected).
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the investigator
• Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study

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