{ "FullStudy":{ "Rank":217715, "Study":{ "ProtocolSection":{ "IdentificationModule":{ "NCTId":"NCT01517776", "OrgStudyIdInfo":{ "OrgStudyId":"HIT-HGG-CilMetro" }, "SecondaryIdInfoList":{ "SecondaryIdInfo":[ { "SecondaryId":"2009-011898-33", "SecondaryIdType":"EudraCT Number" } ] }, "Organization":{ "OrgFullName":"Martin-Luther-Universität Halle-Wittenberg", "OrgClass":"OTHER" }, "BriefTitle":"Cilengitide and Metronomic Temozolomide for Relapsed or Refractory High Grade Gliomas or Diffuse Intrinsic Pontine Gliomas in Children and Adolescents", "OfficialTitle":"Cilengitide and Metronomic Temozolomide for Relapsed or Refractory High Grade Gliomas or Diffuse Intrinsic Pontine Gliomas in Children and Adolescents - A Phase II Study HIT-HGG-CilMetro - A Clinical Phase II Trial of the HIT-HGG Study Group -", "Acronym":"HGG-CilMetro" }, "StatusModule":{ "StatusVerifiedDate":"June 2015", "OverallStatus":"Terminated", "WhyStopped":"due to an altered benefit/risk assessment.", "ExpandedAccessInfo":{ "HasExpandedAccess":"No" }, "StartDateStruct":{ "StartDate":"January 2012" }, "PrimaryCompletionDateStruct":{ "PrimaryCompletionDate":"March 2014", "PrimaryCompletionDateType":"Actual" }, "CompletionDateStruct":{ "CompletionDate":"April 2014", "CompletionDateType":"Actual" }, "StudyFirstSubmitDate":"January 11, 2012", "StudyFirstSubmitQCDate":"January 20, 2012", "StudyFirstPostDateStruct":{ "StudyFirstPostDate":"January 25, 2012", "StudyFirstPostDateType":"Estimate" }, "DispFirstSubmitDate":"May 26, 2015", "DispFirstSubmitQCDate":"June 26, 2015", "DispFirstPostDateStruct":{ "DispFirstPostDate":"July 21, 2015", "DispFirstPostDateType":"Estimate" }, "LastUpdateSubmitDate":"June 26, 2015", "LastUpdatePostDateStruct":{ "LastUpdatePostDate":"July 21, 2015", "LastUpdatePostDateType":"Estimate" } }, "SponsorCollaboratorsModule":{ "ResponsibleParty":{ "ResponsiblePartyType":"Principal Investigator", "ResponsiblePartyInvestigatorFullName":"Christof Kramm", "ResponsiblePartyInvestigatorTitle":"Principal investigator (", "ResponsiblePartyInvestigatorAffiliation":"Martin-Luther-Universität Halle-Wittenberg" }, "LeadSponsor":{ "LeadSponsorName":"Martin-Luther-Universität Halle-Wittenberg", "LeadSponsorClass":"OTHER" }, "CollaboratorList":{ "Collaborator":[ { "CollaboratorName":"Merck KGaA, Darmstadt, Germany", "CollaboratorClass":"INDUSTRY" } ] } }, "OversightModule":{ "OversightHasDMC":"Yes" }, "DescriptionModule":{ "BriefSummary":"The primary objective of this study is to evaluate the efficacy of a combined treatment with cilengitide and metronomic oral temozolomide as measured by 6 months overall survival (OS) after diagnosis of relapse or tumour progression in children and adolescents with relapsed or refractory high-grade malignant glioma and diffuse intrinsic pontine glioma.\n\nSecondary objectives include:\n\nTo evaluate the safety and toxicity of the study treatment by common toxicity criteria (CTC; version 4.0).\n\nTo assess\n\nthe response rates at 6 months (continuous complete response = CCR, complete response = CR, partial response = PR, stable disease = SD, progressive disease = PD) and\nprogression-free survival (PFS) at 6 months, and\nresponse rates, OS, and PFS at 12 months after relapse diagnosis or diagnosis of tumor progression. Response will be presented including histopathological variants.\nTo assess the pharmacokinetics of cilengitide administered as part of the study treatment.\n\nIndication and study population for this trial:\n\nTreatment of relapsed or refractory high grade gliomas and diffuse intrinsic pontine gliomas in paediatric patients ≥ 3 years and < 18 years of age.\n\nPatients included in the study receive\n\nCilengitide 1800 mg/m² i.v. twice weekly\nTemozolomide 75 mg/m²/d p.o. for 6 weeks, followed by 1 week rest with a mandatory platelet-count dependent dose adaptation rule: mandatory blood counts twice weekely: Platelets ≥ 100 000/µl (≥ 100 Gpt/l): 75 mg/m², platelets ≥ 50 000 - < 100 000/µl (≥ 50 - <100 Gpt/l): 50 mg/m², platelets < 50 000/µl (<50 Gpt/l): stop temozolomide until platelet recovery ≥ 100 000/µl (≥100 Gpt/l)\nStudy treatment in the individual patient is scheduled for 1 year unless tumor progression or excessive toxicity occurs. However, study treatment may be extended beyond 1 year upon individual decision.", "DetailedDescription":"Indication:\n\nTreatment of relapsed or refractory high grade gliomas and diffuse intrinsic pontine gliomas in paediatric patients ≥ 3 years and < 18 years of age.\n\nBackground and rationale:\n\nRelapsed or refractory high-grade gliomas or diffuse intrinsic pontine gliomas (in the following both addressed as high grade gliomas = HGG) in children and adolescents represent a very bad prognosis group for which a recommended standard salvage therapy is currently not available.\n\nThe combination of cilengitide and metronomic temozolomide will be investigated in the present trial as new treatment strategy for these patients.\n\nMetronomic temozolomide was shown to act via inhibition of tumour angiogenesis and as a cytotoxic agent. Cilengitide might act via tumour angiogenesis and also inhibits tumour cell migration.\n\nFor both drugs, safe doses with only low toxicity had been defined in phase I trials for paediatric patients with recurrent or refractory brain tumours (Cilengitide: 1800 mg/m² twice weekly; metronomic Temozolomide: 75-80 mg/m²/d in a 6 week schedule followed by one week rest) In a phase II trial for adult patients with relapsed glioblastoma cilengitide as single agent showed a trend towards higher efficacy with 2000 mg twice weekly as compared to 500 mg twice weekly. Furthermore, in a phase II trial of newly diagnosed adult glioblastoma patients, signs of clinical activity of cilengitide in combination with radiotherapy and conventional temozolomide was seen in the methylated MGMT gene promoter subgroup. Based on these findings, a large randomized phase III trial investigating cilengitide in combination with standard therapy (temozolomide and radiation) in this subgroup was started recently.\n\nMetronomic temozolomide was also shown to be still effective in glioma patients suffering from relapse after temozolomide standard therapy. Interestingly, the mode of action appears to be widely independent of the MGMT status, probably due to MGMT depletion by continuous treatment.\n\nIn conclusion, for both drugs signs of clinical activity have been shown in relapsed glioblastoma patients, even after failure of temozolomide standard therapy.\n\nStudy design:\n\nProspective, non-randomized phase II trial.\n\nStudy population:\n\nPatients 3 years and < 18 years of age with high grade glioma or diffuse intrinsic pontine glioma relapsed after or refractory to standard therapy recruited by approved trial sites\n\nSample size:\n\nIt is planned to include 33 patients.\n\nTherapy:\n\nPatients included in the study receive\n\nCilengitide 1800 mg/m² i.v. twice weekly\nTemozolomide 75 mg/m²/d p.o. for 6 weeks, followed by 1 week rest with a mandatory platelet-count dependent dose adaptation rule: mandatory blood counts twice weekely: Platelets ≥ 100 000/µl (≥ 100 Gpt/l): 75 mg/m², platelets ≥ 50 000 - < 100 000/µl (≥ 50 - <100 Gpt/l): 50 mg/m², platelets < 50 000/µl (<50 Gpt/l): stop temozolomide until platelet recovery ≥ 100 000/µl (≥100 Gpt/l)\nStudy treatment in the individual patient is scheduled for 1 year unless tumor progression or excessive toxicity occurs. However, study treatment may be extended beyond 1 year upon individual decision.\n\nBiometry:\n\nStatistical analysis and sample size calculation:\n\nThe feasibility and efficacy of the HIT-HGG-CilMetro therapy will be assessed by a single stage analysis. Sample size calculation is based on the 6 month overall survival rate. This survival rate was found to be 44% in a historical study population from the HIT-GBM data base. An overall survival rate of 59% in the present study is considered to be of clinical relevance. Based on a one sided one sample χ2-test and a significance level α=5% a sample size of 33 patients is planned. This sample size implies a power of 50%.\n\nSchedule:\n\nThe study is scheduled to start on January 1, 2012. The recruitment period for the trial will last 24 months until December 31, 2013. Individual follow-up for at least 1 year after study entry is required for this protocol. The study will be finished 30 days after completion of study treatment of the last patient enrolled, i.e. the expected end of the trial will be January 31, 2015.\n\nLong-term follow-up is strongly recommended and will be organised via the HIT-HGG Study Office.\n\nIf the start of the study is delayed, given dates will change accordingly.\n\nFinancial support:\n\nMerck KGaA, Darmstadt, Germany, provides a grant for the conduct of the trial, supplies Cilengitide free of charge and agrees to perform the laboratory assessments for pharmacokinetics." }, "ConditionsModule":{ "ConditionList":{ "Condition":[ "Gliomas" ] }, "KeywordList":{ "Keyword":[ "High grade glioma", "Glioblastoma multiforme", "Anaplastic astrocytoma", "Diffuse intrinsic pontine glioma", "Relapse", "refractory tumour disease", "Relapsed or refractory high grade gliomas and diffuse intrinsic pontine gliomas" ] } }, "DesignModule":{ "StudyType":"Interventional", "PhaseList":{ "Phase":[ "Phase 2" ] }, "DesignInfo":{ "DesignInterventionModel":"Single Group Assignment", "DesignPrimaryPurpose":"Treatment", "DesignMaskingInfo":{ "DesignMasking":"None (Open Label)" } }, "EnrollmentInfo":{ "EnrollmentCount":"28", "EnrollmentType":"Actual" } }, "ArmsInterventionsModule":{ "ArmGroupList":{ "ArmGroup":[ { "ArmGroupLabel":"Cilengitide and metronomic temozolomide", "ArmGroupType":"Experimental", "ArmGroupDescription":"Cilengitide 1800 mg/m² i.v. twice weekly and Temozolomide 75 mg/m²/d p.o. for 6 weeks, followed by 1 week rest with a mandatory platelet-count dependent dose adaptation rule", "ArmGroupInterventionList":{ "ArmGroupInterventionName":[ "Drug: Cilengitide", "Drug: Temozolomide" ] } } ] }, "InterventionList":{ "Intervention":[ { "InterventionType":"Drug", "InterventionName":"Cilengitide", "InterventionDescription":"Cilengitide 1800 mg/m² i.v. twice weekly with a mandatory platelet-count dependent dose adaptation rule", "InterventionArmGroupLabelList":{ "InterventionArmGroupLabel":[ "Cilengitide and metronomic temozolomide" ] }, "InterventionOtherNameList":{ "InterventionOtherName":[ "EMD 121974" ] } },{ "InterventionType":"Drug", "InterventionName":"Temozolomide", "InterventionDescription":"Temozolomide 75 mg/m²/d p.o. for 6 weeks, followed by 1 week rest with a mandatory platelet-count dependent dose adaptation rule", "InterventionArmGroupLabelList":{ "InterventionArmGroupLabel":[ "Cilengitide and metronomic temozolomide" ] }, "InterventionOtherNameList":{ "InterventionOtherName":[ "Temodal" ] } } ] } }, "OutcomesModule":{ "PrimaryOutcomeList":{ "PrimaryOutcome":[ { "PrimaryOutcomeMeasure":"Efficacy of a combined treatment with cilengitide and temozolomide as measured by 6 months overall survival after diagnosis of relapsed or refractory high grade glioma or diffuse intrinsic pontine glioma in children and adolescents", "PrimaryOutcomeDescription":"Evaluation of overall survival after 6 months", "PrimaryOutcomeTimeFrame":"6 months" } ] }, "SecondaryOutcomeList":{ "SecondaryOutcome":[ { "SecondaryOutcomeMeasure":"Safety and toxicity of the study treatment", "SecondaryOutcomeDescription":"Evaluation of safety and toxicity of the study treatment by NCI Common Toxicity Criteria (CTC; version 4.0) for up to 30 days after the end of study treatment which may last up to 52 weeks.\n\nToxic events defined as CTC grade 4 toxicities and deaths caused by therapy (CTC grade 5) excluding haematological toxicities (CTC grade 1-4)will be immediately assessed after documentation, and probability for such a toxic event statistically evaluated to ensure that this probability is within the predefined range (p1=15%).", "SecondaryOutcomeTimeFrame":"Up to 52 weeks of treatment and subsequently 30 days after end of treatment" },{ "SecondaryOutcomeMeasure":"Response rates (RR) at 6 months, progression-free survival (PFS) at 6 months, and RR, overall survival (OS), and PFS at 12 months after relapse diagnosis or diagnosis of tumor progression", "SecondaryOutcomeDescription":"Evaluation of RR (continuous complete response = CCR, complete response = CR, partial response = PR, stable disease = SD, progressive disease = PD) by MRI and PFS (defined as survival from date of first progression/relapse to first documented date of second progression/relapse) after 6 and 12 months.\n\nEvaluation of OS after 12 months", "SecondaryOutcomeTimeFrame":"Response rates and progression-free survival at 6 and 12 months, overall survival at 12 months (Trial subjects will be followed up for at least 1 year and 30 days after study entry)" },{ "SecondaryOutcomeMeasure":"Peak plasma levels of cilengitide [ng/ml] on day 1 of week 1 and day 4 of week 6", "SecondaryOutcomeDescription":"Assessment of cilengitide serum levels [ng/ml] by a validated liquid chromatograpy tandem mass spectrometry assay on day 1 of week (before, immediately after, and 2, 4, 7 hours after cilengitide administration) and day 4 of week 6 (2 hours after cilengitide administration)", "SecondaryOutcomeTimeFrame":"Day 1 of treatment week 1: Immediately before and immediately after as well as 2, 4, and 7 hours after end of cilengitide administration; day 4 of treatment week 6: 2 hours after end of cilengitide adminstration" } ] } }, "EligibilityModule":{ "EligibilityCriteria":"Inclusion Criteria:\n\nDiagnosis of high-grade malignant glioma confirmed by central neuropathological review (last MRI diagnosis not older than 4 weeks) - including glioblastoma multiforme (WHO IV), anaplastic astrocytoma (WHO III), anaplastic oligodendroglioma (WHO III), anaplastic oligoastrocytoma (WHO III), anaplastic pilocytic astrocytoma (WHO III), anaplastic ganglioglioma (WHO III), anaplastic pleomorphic xanthoastrocytoma (analogous to WHO III), giant cell glioblastoma (WHO IV), and gliosarcoma (WHO IV) - or diagnosis of diffuse intrinsic pontine glioma confirmed by central neuroradiological review - refractory to standard treatment, or relapsed or progressive after first-line therapy.\nPatient aged 3 years and older but under 18 years at time of relapse diagnosis\nWritten informed consent of the patient (mandatory from 15 years of age) or the parents (mandatory till 18 years of age).\n\nExclusion Criteria:\n\nKnown hypersensitivity or contraindication to any study drugs\nOther (simultaneous) malignancies\nPregnancy and / or lactation\nPatients who are sexually active refusing to use effective contraception (oral contraception, intrauterine devices, barrier method of contraception in conjunction with spermicidal jelly or surgical sterile)\nCurrent or recent (within 30 days prior to start of trial treatment) treatment with another investigational drug or participation in another investigational trial\nSevere concomitant diseases (e.g. immune deficiency syndrome) or HIV infection\nSevere psychological disease or neurological damage without possibility to communicate\nClinical signs of intracranial pressure\nIntracerebral hemorrhage or history of intracerebral hemorrhage\n\nRequirements for laboratory test results not older than 2 weeks before patient´s inclusion:\n\nPlatelets < 100 000/µl (< 100 Gpt/l) PT, INR and PTT above normal range Absulute neutrophil count ≤ 1 500/µl (< 1,5 Gpt/l) Hemoglobin < 10g/dl (< 6,4 mmol/L) Serum creatinine ≥ 1,5 x upper limit of normal range or creatinine clearance rate ≤ 60 ml/min/m2 (corrected for body surface area) Total bilirubin ≥ 1,5 x upper limit of normal range SGOT (ASAT) and SGPT (ALAT) ≥ 2,5 x upper limit of normal range Alkaline phosphatase ≥ 2,5 x upper limit of normal range\n\nHereditary Intrinsic Platelet Disorders\nOngoing irradiation or chemotherapy (within the last 4 weeks)\nEstimated life expectancy of less than 2 months", "HealthyVolunteers":"No", "Gender":"All", "MinimumAge":"3 Years", "MaximumAge":"17 Years", "StdAgeList":{ "StdAge":[ "Child" ] } }, "ContactsLocationsModule":{ "OverallOfficialList":{ "OverallOfficial":[ { "OverallOfficialName":"Christof M. Kramm, MD", "OverallOfficialAffiliation":"University Children´s Hospital, Halle, Germany", "OverallOfficialRole":"Study Chair" } ] }, "LocationList":{ "Location":[ { "LocationFacility":"University Children´s Hospital", "LocationCity":"Halle", "LocationState":"Saxonia-Anhalt", "LocationZip":"06120", "LocationCountry":"Germany" } ] } } }, "ResultsSection":{ "MoreInfoModule":{} }, "AnnotationSection":{ "AnnotationModule":{} }, "DerivedSection":{ "MiscInfoModule":{ "VersionHolder":"April 22, 2020" }, "InterventionBrowseModule":{ "InterventionMeshList":{ "InterventionMesh":[ { "InterventionMeshId":"D000077204", "InterventionMeshTerm":"Temozolomide" } ] }, "InterventionAncestorList":{ "InterventionAncestor":[ { "InterventionAncestorId":"D000018906", "InterventionAncestorTerm":"Antineoplastic Agents, Alkylating" },{ "InterventionAncestorId":"D000000477", "InterventionAncestorTerm":"Alkylating Agents" },{ "InterventionAncestorId":"D000045504", "InterventionAncestorTerm":"Molecular Mechanisms of Pharmacological Action" },{ "InterventionAncestorId":"D000000970", "InterventionAncestorTerm":"Antineoplastic Agents" } ] }, "InterventionBrowseLeafList":{ "InterventionBrowseLeaf":[ { "InterventionBrowseLeafId":"M1692", "InterventionBrowseLeafName":"Temozolomide", "InterventionBrowseLeafAsFound":"Temozolomide", "InterventionBrowseLeafRelevance":"high" },{ "InterventionBrowseLeafId":"M2401", "InterventionBrowseLeafName":"Alkylating Agents", "InterventionBrowseLeafRelevance":"low" } ] }, "InterventionBrowseBranchList":{ "InterventionBrowseBranch":[ { "InterventionBrowseBranchAbbrev":"ANeo", "InterventionBrowseBranchName":"Antineoplastic Agents" },{ "InterventionBrowseBranchAbbrev":"All", "InterventionBrowseBranchName":"All Drugs and Chemicals" } ] } }, "ConditionBrowseModule":{ "ConditionMeshList":{ "ConditionMesh":[ { "ConditionMeshId":"D000005910", "ConditionMeshTerm":"Glioma" } ] }, "ConditionAncestorList":{ "ConditionAncestor":[ { "ConditionAncestorId":"D000018302", "ConditionAncestorTerm":"Neoplasms, Neuroepithelial" },{ "ConditionAncestorId":"D000017599", "ConditionAncestorTerm":"Neuroectodermal Tumors" },{ "ConditionAncestorId":"D000009373", "ConditionAncestorTerm":"Neoplasms, Germ Cell and Embryonal" },{ "ConditionAncestorId":"D000009370", "ConditionAncestorTerm":"Neoplasms by Histologic Type" },{ "ConditionAncestorId":"D000009369", "ConditionAncestorTerm":"Neoplasms" },{ "ConditionAncestorId":"D000009375", "ConditionAncestorTerm":"Neoplasms, Glandular and Epithelial" },{ "ConditionAncestorId":"D000009380", "ConditionAncestorTerm":"Neoplasms, Nerve Tissue" } ] }, "ConditionBrowseLeafList":{ "ConditionBrowseLeaf":[ { "ConditionBrowseLeafId":"M7603", "ConditionBrowseLeafName":"Glioma", "ConditionBrowseLeafAsFound":"Glioma", "ConditionBrowseLeafRelevance":"high" },{ "ConditionBrowseLeafId":"M7602", "ConditionBrowseLeafName":"Glioblastoma", "ConditionBrowseLeafRelevance":"low" },{ "ConditionBrowseLeafId":"M3142", "ConditionBrowseLeafName":"Astrocytoma", "ConditionBrowseLeafRelevance":"low" },{ "ConditionBrowseLeafId":"M19030", "ConditionBrowseLeafName":"Neoplasms, Neuroepithelial", "ConditionBrowseLeafRelevance":"low" },{ "ConditionBrowseLeafId":"M18428", "ConditionBrowseLeafName":"Neuroectodermal Tumors", "ConditionBrowseLeafRelevance":"low" },{ "ConditionBrowseLeafId":"M18971", "ConditionBrowseLeafName":"Neuroectodermal Tumors, Primitive", "ConditionBrowseLeafRelevance":"low" },{ "ConditionBrowseLeafId":"M10901", "ConditionBrowseLeafName":"Neoplasms, Germ Cell and Embryonal", "ConditionBrowseLeafRelevance":"low" },{ "ConditionBrowseLeafId":"M10898", "ConditionBrowseLeafName":"Neoplasms by Histologic Type", "ConditionBrowseLeafRelevance":"low" },{ "ConditionBrowseLeafId":"M10903", "ConditionBrowseLeafName":"Neoplasms, Glandular and Epithelial", "ConditionBrowseLeafRelevance":"low" },{ "ConditionBrowseLeafId":"M10908", "ConditionBrowseLeafName":"Neoplasms, Nerve Tissue", "ConditionBrowseLeafRelevance":"low" },{ "ConditionBrowseLeafId":"T2531", "ConditionBrowseLeafName":"Glioma", "ConditionBrowseLeafAsFound":"Glioma", "ConditionBrowseLeafRelevance":"high" },{ "ConditionBrowseLeafId":"T1878", "ConditionBrowseLeafName":"Diffuse Intrinsic Pontine Glioma", "ConditionBrowseLeafAsFound":"Diffuse Intrinsic Pontine Glioma", "ConditionBrowseLeafRelevance":"high" },{ "ConditionBrowseLeafId":"T2530", "ConditionBrowseLeafName":"Glioblastoma", "ConditionBrowseLeafRelevance":"low" },{ "ConditionBrowseLeafId":"T365", "ConditionBrowseLeafName":"Anaplastic Astrocytoma", "ConditionBrowseLeafRelevance":"low" },{ "ConditionBrowseLeafId":"T4119", "ConditionBrowseLeafName":"Neuroepithelioma", "ConditionBrowseLeafRelevance":"low" } ] }, "ConditionBrowseBranchList":{ "ConditionBrowseBranch":[ { "ConditionBrowseBranchAbbrev":"BC04", "ConditionBrowseBranchName":"Cancers and Other Neoplasms" },{ "ConditionBrowseBranchAbbrev":"All", "ConditionBrowseBranchName":"All Conditions" },{ "ConditionBrowseBranchAbbrev":"Rare", "ConditionBrowseBranchName":"Rare Diseases" } ] } } } } } }