{ "FullStudy":{ "Rank":217918, "Study":{ "ProtocolSection":{ "IdentificationModule":{ "NCTId":"NCT01515137", "OrgStudyIdInfo":{ "OrgStudyId":"05-045" }, "Organization":{ "OrgFullName":"University of Pittsburgh", "OrgClass":"OTHER" }, "BriefTitle":"Study of TARCEVA (Erlotinib) as Adjuvant Treatment for Locally Advanced Head and Neck Squamous Cell Carcinoma", "OfficialTitle":"Phase II Study of TARCEVA (Erlotinib) as Adjuvant Treatment for Locally Advanced Head and Neck Squamous Cell Carcinoma With Evaluation of Neoadjuvant Biomarker Modulation With TARCEVA vs. TARCEVA Plus Sulindac" }, "StatusModule":{ "StatusVerifiedDate":"January 2016", "OverallStatus":"Completed", "ExpandedAccessInfo":{ "HasExpandedAccess":"No" }, "StartDateStruct":{ "StartDate":"November 2005" }, "PrimaryCompletionDateStruct":{ "PrimaryCompletionDate":"September 2014", "PrimaryCompletionDateType":"Actual" }, "CompletionDateStruct":{ "CompletionDate":"September 2014", "CompletionDateType":"Actual" }, "StudyFirstSubmitDate":"January 12, 2012", "StudyFirstSubmitQCDate":"January 20, 2012", "StudyFirstPostDateStruct":{ "StudyFirstPostDate":"January 23, 2012", "StudyFirstPostDateType":"Estimate" }, "LastUpdateSubmitDate":"January 28, 2016", "LastUpdatePostDateStruct":{ "LastUpdatePostDate":"January 29, 2016", "LastUpdatePostDateType":"Estimate" } }, "SponsorCollaboratorsModule":{ "ResponsibleParty":{ "ResponsiblePartyType":"Sponsor" }, "LeadSponsor":{ "LeadSponsorName":"University of Pittsburgh", "LeadSponsorClass":"OTHER" }, "CollaboratorList":{ "Collaborator":[ { "CollaboratorName":"OSI Pharmaceuticals", "CollaboratorClass":"INDUSTRY" } ] } }, "OversightModule":{ "OversightHasDMC":"Yes" }, "DescriptionModule":{ "BriefSummary":"This trial was originally designed and powered to compare biomarker modulation in the neo-adjuvant setting (erlotinib versus erlotinib plus sulindac versus placebo) with clinical response to erlotinib in the adjuvant setting. Since implementing the trial in late 2005, The investigators have encountered significant obstacles to implementing the adjuvant therapy phase of the trial.\n\nBarriers included:\n\ndisease recurrence\npatient refusal to take the agent\npatient refusal to travel to Pittsburgh for clinical evaluations.\n\nGiven the institutional challenges to implement and complete the adjuvant portion, the investigators have decided to change the primary endpoint to a biomarker modulation endpoint. To achieve this goal, the investigators determined that they needed 39 paired tissue specimens (see statistical justification below).\n\nThe central hypothesis to be tested in this study is that persistent activation of parallel and/or downstream pathways contributes to tumor progression in the setting of EGFR blockade. While not all head and neck squamous cell carcinoma (HNSCC) patients will respond to EGFR targeting, the optimal strategy to identify those subjects whose tumors are sensitive to EGFR inhibition remains unknown.\n\nThe primary objective is centered around the concept of tumor biomarkers which may be modulated by EGFR and Cox-2 inhibitors and may serve as future therapeutic targets for therapy. To this end patients on this trial will be randomly assigned to one of three arms to receive either Tarceva, Tarceva plus sulindac, or a placebo in the 2 week pre-operative period. A panel of biomarkers will be obtained by biopsy prior to pre-operative therapy and again at surgery. Biomarkers will be examined for modulation in the 2-week pre-operative period, for group differences, for treatment effects and for further understanding of protein signaling pathways.\n\nSample size for the primary objective\n\nModification of Statistical Design:\n\nThe primary endpoint is the difference between pre (biopsy) and post (surgery). There are 3 hypotheses of interest: (1) placebo vs erlotinib alone, (2) placebo versus erlotinib plus sulindac, and (3) erlotinib vs erlotinib + sulindac. With a randomization in a 3:5:5 ratio, we have 88% power, alpha = .01 for an omnibus test to show between-group differences of 1 log exist. This requires 39 patients. Basically, 39 patients will provide the ability to detect a one log difference between any 2 of the 3 groups in pre-post change.", "DetailedDescription":"Head and neck squamous cell carcinoma (HNSCC) constitutes 3 percent of all malignancies and is the sixth most common malignancy worldwide. There will be an estimated 38,000 new cases and 11,000 deaths in the United States in 2004 and approximately 500,000 cases worldwide yearly [1]. Squamous cell carcinoma accounts for at least 95 percent of all head and neck cancers. Surgical treatment remains the standard of therapy for patients with resectable HNSCC. For patients with high risk of local or distant relapse, radiation therapy (RT) alone, or in combination with chemotherapy, is given after surgery to improve loco-regional control and overall survival.\n\nNeoadjuvant chemotherapy for patients with respectable HNSCC remains an experimental option for these patients. A two-week delay in definitive surgical resection in patients with operable HNSCC is not thought to impact the clinical outcome of these patients and in many cases may be needed to complete all of the preoperative work-up. As a result, a study design involving a two-week preoperative course of therapy in patients with operable HNSCC should not be a concern.\n\nEGFR as a therapeutic target in HNSCC\n\nEpidermal growth factor receptor (EGFR) is a 170-Kda transmembrane protein that is thought to be important in the proliferation and survival of cancer cells [2]. Overexpression of EGFR has been found in several malignancies, including head and neck, lung, breast, prostate, bladder, and pancreatic cancer [3-7]. In HNSCC, EGFR and its ligand TGF are overexpressed in 80-90% of tumors compared to normal mucosa; [8] the coexpression of receptor and ligand implicates an autocrine regulatory pathway in HNSCC carcinogenesis. The clinical relevance of EGFR overexpression as an independent prognostic factor in HNSCC has been well demonstrated. High tumor EGFR levels are correlated with advanced stage,[9] increased tumor size, [9] decreased survival,[10-13] increased recurrence,[10] and decreased sensitivity to radiation treatment [14]. A recent study suggests that high serum EGFR levels may even correlate with higher head and neck tumor grade [15]. The overexpression of EGFR and ligand in partially and fully transformed HNSCC tissue, its correlation with poor clinical outcome, and the aberrant function of the EGFR network in HNSCC provide compelling evidence of a relationship between EGFR and the development and progression of HNSCC, and suggest a role for EGFR as a target for cancer therapy.\n\nEGFR has been targeted at the extracellular domain by blocking ligand binding, at the intracellular domain by inhibiting tyrosine kinase activity, and at the genetic level by targeting production of the receptor itself. EGFR-specific monoclonal antibodies interfere with ligand binding, while conjugation of an EGFR ligand or antibody to a bacterially derived toxin enables the delivery of a cytotoxic agent to the cell surface. Many of the EGFR-targeting agents are undergoing clinical evaluation in HNSCC. In general, clinical responses in HNSCC patients with advanced disease have only been observed when these agents have been combined with cytotoxic chemotherapy or radiation therapy. Clinical trials using EGFR inhibitors as adjuvant therapy for HNSCC are currently underway." }, "ConditionsModule":{ "ConditionList":{ "Condition":[ "Head and Neck Squamous Cell Carcinoma" ] }, "KeywordList":{ "Keyword":[ "Head and Neck", "Locally Advanced Head and Neck Squamous Cell Carcinoma" ] } }, "DesignModule":{ "StudyType":"Interventional", "PhaseList":{ "Phase":[ "Phase 1" ] }, "DesignInfo":{ "DesignAllocation":"Randomized", "DesignInterventionModel":"Parallel Assignment", "DesignPrimaryPurpose":"Treatment", "DesignMaskingInfo":{ "DesignMasking":"Single", "DesignWhoMaskedList":{ "DesignWhoMasked":[ "Participant" ] } } }, "EnrollmentInfo":{ "EnrollmentCount":"47", "EnrollmentType":"Actual" } }, "ArmsInterventionsModule":{ "ArmGroupList":{ "ArmGroup":[ { "ArmGroupLabel":"Arm A erlotinib plus sulindac", "ArmGroupType":"Experimental", "ArmGroupDescription":"erlotinib (150 mg PO QD) plus sulindac (150 mg PO BID) (Arm A),", "ArmGroupInterventionList":{ "ArmGroupInterventionName":[ "Drug: Erlotinib plus sulindac" ] } },{ "ArmGroupLabel":"Arm B erlotinib", "ArmGroupType":"Experimental", "ArmGroupDescription":"erlotinib (150 mg PO QD) (Arm B)", "ArmGroupInterventionList":{ "ArmGroupInterventionName":[ "Drug: Erlotinib" ] } },{ "ArmGroupLabel":"Arm C", "ArmGroupType":"Experimental", "ArmGroupDescription":"placebo (for Erlotinib) QD (Arm C).", "ArmGroupInterventionList":{ "ArmGroupInterventionName":[ "Drug: Placebo" ] } } ] }, "InterventionList":{ "Intervention":[ { "InterventionType":"Drug", "InterventionName":"Erlotinib", "InterventionDescription":"Erlotinib (150 mg PO QD) plus sulindac (150 mg PO BID) (Arm A), Erlotinib (150 mg PO QD) (Arm B) or placebo (for Erlotinib) QD (Arm C).", "InterventionArmGroupLabelList":{ "InterventionArmGroupLabel":[ "Arm B erlotinib" ] }, "InterventionOtherNameList":{ "InterventionOtherName":[ "Tarceva" ] } },{ "InterventionType":"Drug", "InterventionName":"Erlotinib plus sulindac", "InterventionDescription":"Erlotinib (150 mg PO QD) plus sulindac (150 mg PO BID) (Arm A), Erlotinib (150 mg PO QD) (Arm B) or placebo (for Erlotinib) QD (Arm C).", "InterventionArmGroupLabelList":{ "InterventionArmGroupLabel":[ "Arm A erlotinib plus sulindac" ] }, "InterventionOtherNameList":{ "InterventionOtherName":[ "Tarceva" ] } },{ "InterventionType":"Drug", "InterventionName":"Placebo", "InterventionDescription":"Erlotinib (150 mg PO QD) plus sulindac (150 mg PO BID) (Arm A), Erlotinib (150 mg PO QD) (Arm B) or placebo (for Erlotinib) QD (Arm C).", "InterventionArmGroupLabelList":{ "InterventionArmGroupLabel":[ "Arm C" ] }, "InterventionOtherNameList":{ "InterventionOtherName":[ "Tarceva" ] } } ] } }, "OutcomesModule":{ "PrimaryOutcomeList":{ "PrimaryOutcome":[ { "PrimaryOutcomeMeasure":"Phase II Study of TARCEVA (Erlotinib) as Adjuvant Treatment for Locally Advanced Head and Neck Squamous Cell Carcinoma with Evaluation of Neoadjuvant Biomarker Modulation with TARCEVA vs. TARCEVA Plus Sulindac", "PrimaryOutcomeDescription":"Primary objective centered around concept of tumor biomarkers which may be modulated by EGFR & Cox-2 inhibitors & may serve as future therapeutic targets for therapy. Patients on this trial to be randomly assigned to 1 of 3 arms in the 2 week pre-operative period. A panel of biomarkers will be obtained by biopsy prior to pre-operative therapy and again at surgery. Biomarkers will be examined for modulation in the 2-week pre-operative period, for group differences, for treatment effects and for further understanding of protein signaling pathways.", "PrimaryOutcomeTimeFrame":"10 years" } ] } }, "EligibilityModule":{ "EligibilityCriteria":"Inclusion Criteria:\n\nHistologically or cytologically confirmed, previously untreated HNSCC.\nClinical stage II, III or IVA disease without distant metastasis, as defined by the American Joint Committee on Cancer Staging System, Sixth edition (See Appendix I).\nPrimary tumors of the oral cavity, oropharynx, hypopharynx, or larynx will be included. Primary tumors of the sinuses, paranasal sinuses, or nasopharynx, or unknown primary tumors are NOT allowed.\nMacroscopic complete resection of the primary tumor must be planned.\nPatients will be willing to receive postoperative therapy with platinum and radiation if qualified based on criteria listed in treatment plan.\nAge 18 years.\nECOG performance status 0-1 (See Appendix II).\n\nAdequate hematologic, renal and hepatic function, as defined by:\n\nAbsolute neutrophil count (ANC) greater than 1,500/ul, platelets greater than 100,000/ul.\nCreatinine less than 1.5 x institutional upper limit of normal (ULN).\nBilirubin less than 1.5 x ULN, AST or ALT 2.5 x ULN.\nHave signed written informed consent.\n\nExclusion Criteria:\n\nSubjects who fail to meet the above criteria.\nPregnancy or breastfeeding. Women of childbearing potential (WOCBP) must practice acceptable methods of birth control to prevent pregnancy.\nSubjects with a ECOG performance status of 2 or worse.\nEvidence of distant metastasis.\nAny other malignancy active within 5 years except for non-melanoma skin cancer or carcinoma in situ of the cervix, DCIS or LCIS of the breast.\nPrior history of HNSCC.\nPrior therapy targeting the EGFR pathway.\nKnown severe hypersensitivity to sulindac or other non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin.\nAny unresolved chronic toxicity greater than grade 2 from previous anticancer therapy (except alopecia), according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE).\nIncomplete healing from previous major surgery.\nAcute hepatitis, known HIV, or active uncontrolled infection.\nHistory of uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable angina, myocardial infarction within prior 6 months, untreated known coronary artery disease, uncontrolled congestive heart failure, and cardiomyopathy with decreased ejection fraction.\nAny preexisting active interstitial lung disease (patients with chronic stable radiographic changes who are asymptomatic are NOT excluded).\nTreatment with anticoagulants, except when used to maintain the patency of a central venous line.\nUncontrolled peptic or gastric ulcer disease, or gastrointestinal bleeding within prior 6 months.\nActive alcohol abuse or other illness that carries a likelihood of inability to comply with study treatment and follow-up.\nTreatment with a non-approved or investigational drug within 30 days prior to Day 1 of study treatment.", "HealthyVolunteers":"No", "Gender":"All", "MinimumAge":"18 Years", "StdAgeList":{ "StdAge":[ "Adult", "Older Adult" ] } }, "ContactsLocationsModule":{ "OverallOfficialList":{ "OverallOfficial":[ { "OverallOfficialName":"Jennifer Grandis, MD", "OverallOfficialAffiliation":"University of Pittsburgh", "OverallOfficialRole":"Principal Investigator" } ] }, "LocationList":{ "Location":[ { "LocationFacility":"University of Pittsburgh Cancer Institute", "LocationCity":"Pittsburgh", "LocationState":"Pennsylvania", "LocationZip":"15232", "LocationCountry":"United States" } ] } } }, "DerivedSection":{ "MiscInfoModule":{ "VersionHolder":"April 22, 2020" }, "InterventionBrowseModule":{ "InterventionMeshList":{ "InterventionMesh":[ { "InterventionMeshId":"D000013467", "InterventionMeshTerm":"Sulindac" },{ "InterventionMeshId":"D000069347", "InterventionMeshTerm":"Erlotinib Hydrochloride" } ] }, "InterventionAncestorList":{ "InterventionAncestor":[ { "InterventionAncestorId":"D000000970", "InterventionAncestorTerm":"Antineoplastic Agents" },{ "InterventionAncestorId":"D000047428", "InterventionAncestorTerm":"Protein Kinase Inhibitors" },{ "InterventionAncestorId":"D000004791", "InterventionAncestorTerm":"Enzyme Inhibitors" },{ "InterventionAncestorId":"D000045504", "InterventionAncestorTerm":"Molecular Mechanisms of Pharmacological Action" },{ "InterventionAncestorId":"D000000894", "InterventionAncestorTerm":"Anti-Inflammatory Agents, Non-Steroidal" },{ "InterventionAncestorId":"D000018712", "InterventionAncestorTerm":"Analgesics, Non-Narcotic" },{ "InterventionAncestorId":"D000000700", "InterventionAncestorTerm":"Analgesics" },{ "InterventionAncestorId":"D000018689", "InterventionAncestorTerm":"Sensory System Agents" },{ "InterventionAncestorId":"D000018373", "InterventionAncestorTerm":"Peripheral Nervous System Agents" },{ "InterventionAncestorId":"D000045505", "InterventionAncestorTerm":"Physiological Effects of Drugs" },{ "InterventionAncestorId":"D000000893", "InterventionAncestorTerm":"Anti-Inflammatory Agents" },{ "InterventionAncestorId":"D000018501", "InterventionAncestorTerm":"Antirheumatic Agents" },{ "InterventionAncestorId":"D000016861", "InterventionAncestorTerm":"Cyclooxygenase Inhibitors" } ] }, "InterventionBrowseLeafList":{ "InterventionBrowseLeaf":[ { "InterventionBrowseLeafId":"M14833", "InterventionBrowseLeafName":"Sulindac", "InterventionBrowseLeafAsFound":"Sulindac", "InterventionBrowseLeafRelevance":"high" },{ "InterventionBrowseLeafId":"M398", "InterventionBrowseLeafName":"Erlotinib Hydrochloride", "InterventionBrowseLeafAsFound":"Erlotinib", "InterventionBrowseLeafRelevance":"high" },{ "InterventionBrowseLeafId":"M24407", "InterventionBrowseLeafName":"Protein Kinase Inhibitors", "InterventionBrowseLeafRelevance":"low" },{ "InterventionBrowseLeafId":"M2799", "InterventionBrowseLeafName":"Anti-Inflammatory Agents, Non-Steroidal", "InterventionBrowseLeafRelevance":"low" },{ "InterventionBrowseLeafId":"M2798", "InterventionBrowseLeafName":"Anti-Inflammatory Agents", "InterventionBrowseLeafRelevance":"low" },{ "InterventionBrowseLeafId":"M2613", "InterventionBrowseLeafName":"Analgesics", "InterventionBrowseLeafRelevance":"low" },{ "InterventionBrowseLeafId":"M19370", "InterventionBrowseLeafName":"Analgesics, Non-Narcotic", "InterventionBrowseLeafRelevance":"low" },{ "InterventionBrowseLeafId":"M19188", "InterventionBrowseLeafName":"Antirheumatic Agents", "InterventionBrowseLeafRelevance":"low" },{ "InterventionBrowseLeafId":"M17792", "InterventionBrowseLeafName":"Cyclooxygenase Inhibitors", "InterventionBrowseLeafRelevance":"low" } ] }, "InterventionBrowseBranchList":{ "InterventionBrowseBranch":[ { "InterventionBrowseBranchAbbrev":"Infl", "InterventionBrowseBranchName":"Anti-Inflammatory Agents" },{ "InterventionBrowseBranchAbbrev":"ANeo", "InterventionBrowseBranchName":"Antineoplastic Agents" },{ "InterventionBrowseBranchAbbrev":"ARhu", "InterventionBrowseBranchName":"Antirheumatic Agents" },{ "InterventionBrowseBranchAbbrev":"Analg", "InterventionBrowseBranchName":"Analgesics" },{ "InterventionBrowseBranchAbbrev":"All", "InterventionBrowseBranchName":"All Drugs and Chemicals" } ] } }, "ConditionBrowseModule":{ "ConditionMeshList":{ "ConditionMesh":[ { "ConditionMeshId":"D000002277", "ConditionMeshTerm":"Carcinoma" },{ "ConditionMeshId":"D000002294", "ConditionMeshTerm":"Carcinoma, Squamous Cell" },{ "ConditionMeshId":"D000077195", "ConditionMeshTerm":"Squamous Cell Carcinoma of Head and Neck" } ] }, "ConditionAncestorList":{ "ConditionAncestor":[ { "ConditionAncestorId":"D000009375", "ConditionAncestorTerm":"Neoplasms, Glandular and Epithelial" },{ "ConditionAncestorId":"D000009370", "ConditionAncestorTerm":"Neoplasms by Histologic Type" },{ "ConditionAncestorId":"D000009369", "ConditionAncestorTerm":"Neoplasms" },{ "ConditionAncestorId":"D000018307", "ConditionAncestorTerm":"Neoplasms, Squamous Cell" },{ "ConditionAncestorId":"D000006258", "ConditionAncestorTerm":"Head and Neck Neoplasms" },{ "ConditionAncestorId":"D000009371", "ConditionAncestorTerm":"Neoplasms by Site" } ] }, "ConditionBrowseLeafList":{ "ConditionBrowseLeaf":[ { "ConditionBrowseLeafId":"M4116", "ConditionBrowseLeafName":"Carcinoma", "ConditionBrowseLeafAsFound":"Carcinoma", "ConditionBrowseLeafRelevance":"high" },{ "ConditionBrowseLeafId":"M4132", "ConditionBrowseLeafName":"Carcinoma, Squamous Cell", "ConditionBrowseLeafAsFound":"Squamous Cell Carcinoma", "ConditionBrowseLeafRelevance":"high" },{ "ConditionBrowseLeafId":"M1689", "ConditionBrowseLeafName":"Squamous Cell Carcinoma of Head and Neck", "ConditionBrowseLeafAsFound":"Head and Neck Squamous Cell Carcinoma", "ConditionBrowseLeafRelevance":"high" },{ "ConditionBrowseLeafId":"M10903", "ConditionBrowseLeafName":"Neoplasms, Glandular and Epithelial", "ConditionBrowseLeafRelevance":"low" },{ "ConditionBrowseLeafId":"M10898", "ConditionBrowseLeafName":"Neoplasms by Histologic Type", "ConditionBrowseLeafRelevance":"low" },{ "ConditionBrowseLeafId":"M19035", "ConditionBrowseLeafName":"Neoplasms, Squamous Cell", "ConditionBrowseLeafRelevance":"low" },{ "ConditionBrowseLeafId":"M7931", "ConditionBrowseLeafName":"Head and Neck Neoplasms", "ConditionBrowseLeafRelevance":"low" } ] }, "ConditionBrowseBranchList":{ "ConditionBrowseBranch":[ { "ConditionBrowseBranchAbbrev":"BC04", "ConditionBrowseBranchName":"Cancers and Other Neoplasms" },{ "ConditionBrowseBranchAbbrev":"All", "ConditionBrowseBranchName":"All Conditions" } ] } } } } } }