NCI Protocol
SARC Protocol #:SARC023TITLE:A Phase I/II Trial of ganetespib in combination with the mTOR inhibitorsirolimus for patients with recurrent or refractory sarcomas includingunresectable or metastatic malignant peripheral nerve sheath tumorsSponsor:SARC (Sarcoma Alliance for Research through Collaboration)Funding:Department of DefenseSupporter:Synta PharmaceuticalsConfidentiality StatementThe information contained in this document, especially the unpublished data, hasbeen generated by [SARC, Children’s National Medical Center, and SyntaPharmaceuticals] and therefore provided to you in confidence as an investigator,potential investigator or consultant, for review by you, your staff and applicableIndependent Ethics Committee/Institutional Review Board. It is understood thatthis information will not be disclosed to others without written authorization fromSARC except to the extent necessary to obtain informed consent from those personsto whom the drug may be administered.IND #119061Version # / Version DateVersion 7/ Version Date 13JAN2016ConfidentialCopyright SARC (Sarcoma Alliance for Research through Collaboration)
Principal Investigator:AeRang Kim, MD, PhDChildren’s National Medical Center111 Michigan Ave, NWWashington, DC al.orgCo-Principal Investigator: Brigitte Widemann, MDNational Cancer InstitutePediatric Oncology Branch10 Center Drive, room 1-5750Bethesda, MD 20892-1101Phone: 301-496-7387Fax: 301-480-8871E-mail: widemanb@mail.nih.govStatistician:Seth Steinberg, PhDHead, Biostatistics and Data Management SectionCenter for Cancer Research6116 Executive Blvd, Room 702Bethesda, MD 20892-8325Phone: 301-496-9502Fax: 301-402-1259E-mail: steinbes@mail.nih.govSARC Operations Office:24 Frank Lloyd Wright DriveLobby A, Suite 3100; PO Box 406Ann Arbor, MI 48105Telephone: (734) 930-7600Fax: (734) 930-7557Email: sarc@sarctrials.orgMedical Monitor/DoD IndependentResearch Monitor:SARC Medical OfficerScott Okuno, MDMayo Clinic200 1st St SWRochester, MN 55905Phone: 507-284-4849Email: okuno.scott@mayo.eduConfidentialCopyright SARCSARC023 Version 7 13JAN2016Page 2 of 97
Roles and Responsibilities of Study Personnel:AeRang Kim, MD, PhD: Principal Investigator of the studyBrigitte Widemann, MD: Co-Principal Investigator of the studyKaren Cichowski, PhD: Scientific Investigator and preclinical collaboratorScot Okuno, MD: SARC Medical Officer, providing SARC oversight to the conduct of thisstudy and ongoing medical monitoringDenise Reinke, MS, NP, MBA: President, SARC and CEOVesna Milacic, PhD: Director of Research Project ManagementRachel Luchs, BS: Research Project ManagerEva Dombi, MD: Associate Investigator; Volumetric MRI analysis of MPNSTs on protocolJohn Perenetesis, MD: Associate Investigator; Clinical and preclinical collaboratorSeth Steinberg, PhD: Study StatisticianPam Wolters, PhD: Associate Investigator, pain outcome analysisStaci Martin, PhD: Associate Investigator; pain outcome analysisConfidentialCopyright SARCSARC023 Version 7 13JAN2016Page 3 of 97
GLOSSARY OF ABBREVIATIONSALPALT (SGPT)Alanine aminotransferaseANCAbsolute neutrophil countAST (SGOT)Aspartate aminotransferaseAUCArea under the curveCBRClinical benefit rateCIConfidence intervalCRComplete ResponseDLTDose Limiting ToxicityDoDDepartment of DefenseECOGEastern Cooperative Oncology GroupEGFREpidermal growth factor receptorEIAEDSCYP3A4-Enzyme inducing anti-epileptic drugseIF2 Eukaryotic translational initiation factor 2 Alkaline phosphataseEndoplasmic reticulumFluorescence in situ hybridizationGlucose 6-phosphate dehydrogenaseHepatocellular CarcinomaHeat shock proteinIntraperitonealLower Limit of NormalLeft Ventricular Ejection FractionMalignant Peripheral Nerve Sheath TumorMagnetic Resonance ImagingCopyright SARCSARC023 Version 7 13JAN2016Page 4 of 97
GLOSSARY OF ABBREVIATIONSMUGANCIMUGAMultiple Gated Acquisition scanNational Cancer Institute Multiple Gated Acquisition scanNCI-CTCNCINational Cancer Institute-Common Toxicity Criteria National CancerInstituteNCI-CTCAENCICTCNational Cancer Institute-Common Terminology Criteria for AdverseEvents National Cancer Institute-Common Toxicity CriteriaORRNCI-CTCAEObjective Response Rate National Cancer Institute-Common TerminologyCriteria for Adverse EventsOSORRPDOSProgressive disease or Pharmacodynamic Overall SurvivalPFSPDProgression Free Survival Progressive Disease or PharmacodynamicPSPFSPerformance Status Progression Free SurvivalPRPSPartial Response Performance StatusRECISTPRResponse Evaluation Criteria in Solid Tumors Partial ResponseSDRECISTStable Disease Response Evaluation Criteria in Solid TumorsSFSDTNMSFTTPTNMTTPConfidentialOverall Survival Objective Response RateShortening Fraction Stable Diseaseprimary tumor/regional lymph nodes/distant metastasis Shortening FractionTime to Tumor Progression primary tumor/regional lymph nodes/distantmetastasisTime to Tumor ProgressionCopyright SARCSARC023 Version 7 13JAN2016Page 5 of 97
SCHEMADays 1, 8, 15Days 1-28Day 28TreatmentGanetespib IV over 1 hourSirolimus once dailyEnd of CyclePatients will receive 28 day cycles of Ganetespib Sirolimus until disease progression orunacceptable toxicity for up to 1 year (13 cycles).Response evaluations (using WHO criteria) will be performed after every 2 treatment cycles(prior to each odd cycle 3, 5, 7, etc.).ConfidentialCopyright SARCSARC023 Version 7 13JAN2016Page 6 of 97
SynopsisPrimary Objective1. Phase I: To assess the safety, tolerability, and maximum tolerated/ recommendeddose of ganetespib when administered in combination with sirolimus in patientswith refractory sarcomas or unresectable or metastatic sporadic orneurofibromatosis type 1 (NF1) associated MPNST.2. Phase II: To determine the clinical benefit of ganetespib in combination withsirolimus for patients with unresectable or metastatic sporadic orneurofibromatosis type 1 (NF1) associated MPNST.Secondary Objectives1. Phase I: To describe the plasma pharmacokinetic profile of ganetespib andsirolimus when administered in combination therapy2. Phase I/II: To determine changes in pharmacodynamic parameters includingphospho-S6, phosphorylated eIF2 alpha, Akt Phosphorylation, Hsp70, and G6PDin tumor tissue and peripheral blood mononuclear cells at baseline and duringtreatment and correlate with changes in clinical or radiologic outcome.3. Phase I/II: To assess patient-reported pain severity and the impact of pain ondaily activities before and during treatment with ganetespib and sirolimus and tocorrelate with changes in clinical or radiologic outcome.4. Phase I/II: To evaluate the utility of three-dimensional MRI (3D-MRI) analysis incomparison to 1-dimensional and 2-dimensional measurements as a method tomore sensitively monitor response.Hypothesis and RationalePreviously, no targeted agents have been able to cause tumor regression in a geneticallyengineered MPNST mouse model or human MPNST. Recently published data from theCichowski laboratory demonstrated using Hsp90 inhibitors to enhance endoplasmic reticulumstress coupled with the mTOR inhibitor sirolimus led to dramatic tumor shrinkage in a transgenicMPNST mouse model, which correlated with profound damage to the endoplasmic reticulumand cell death. Ganetespib is a novel, injectable, small molecule inhibitor of Hsp90 and iscurrently being investigated in adults with a broad range of tumor types with a favorable safetyprofile and promising early results. Ganetespib has been studied in preclinical in vivo modelswith a variety of targeted agents with no marked apparent pharmacological interactions.Sirolimus is a commercially available orally administered mTOR inhibitor and is the activemetabolite of temsirolimus, which is FDA approved agent for advanced metastatic renal cellcarcinoma. Sirolimus has been studied and tolerated in combination with multiple cytotoxic andtargeted agents in a variety of tumor types. Based on strong preclinical rationale, we hypothesizethat ganetespib in combination with sirolimus will cause tumor regression in patients withrefractory MPNSTs.ConfidentialCopyright SARCSARC023 Version 7 13JAN2016Page 7 of 97
Trial DesignWe propose a multi-institutional open label phase I/II trial of ganetespib in combination withsirolimus in patients with refractory sarcoma including MPNST. The primary objective of theinitial component is to determine the safety, tolerability and recommended dose of this novelcombination in a limited dose escalation phase I trial. Hsp90 inhibitors and mTOR inhibitorshave also both demonstrated benefit in a variety of preclinical bone and soft tissue sarcomamodels. We hypothesize that these agents that work on separate and potentially synergisticpathways will also be beneficial for other refractory bone and soft tissue sarcomas. Thus, thephase I component will be open to patients with refractory sarcomas, which will also expediteenrollment. Ganetespib will be given intravenously over one hour on days 1, 8, and 15 every 28days. Sirolimus will be given orally daily continuously (28 days 1 cycle). Upon determinationof the recommended dosing, the primary objectives of the phase II portion will be to determinethe clinical benefit rate (CR, PR, or stable disease 4 months using WHO criteria) of ganetespibin combination with sirolimus for patients with refractory MPNST. Secondary objectivesinclude determination of the pharmacokinetic profile of these agents in combination andpharmacodynamic markers in tumor tissue and peripheral blood mononuclear cells, patientreported pain outcomes, and volumetric MRI analysis of tumor measurement.Maximum Total Number of SubjectsPhase I: 3 to 6 patients per cohort with 1 dose escalations (potential for 2 de-escalations). Thus aminimum of 6 patients to a maximum of 18 patients are required.Phase II: 10 patients in first stage with an additional 10 patients in the second stage for a total of20 patients. The maximum number of evaluable patients for entire study will be 38.Target PopulationIndividuals 16 years of age with unresectable or metastatic histologically confirmed sporadicor NF1 associated high grade MPNST who have experienced progression after one or more priorregimens of cytotoxic chemotherapy. Phase I component will also be open to patients with otherrefractory or relapsed sarcomas.Anticipated Length of Study (patient enrollment period, overall length including follow-up)Patients will be able to remain on treatment for up to 1 year (13 cycles) as long as they do notexperience progressive disease or unacceptable toxicity. It is expected that 15-25 patients will beenrolled per year, and enrollment is expected to be completed in approximately 2.5 yearsStudy Drug (s)Ganetespib intravenousSirolimus 2 mg oral tabletsDosing and AdministrationGanetespib will be administered intravenously over 1 hour on days 1, 8, 15 every 28 daysSirolimus will be administered once daily continuously1 cycle 28 daysConfidentialCopyright SARCSARC023 Version 7 13JAN2016Page 8 of 97
Efficacy EvaluationsResponse evaluations (WHO) with appropriate imaging studies (MRI/CT) will be performed atbaseline and prior to odd cycles (3, 5, 7, etc.).Safety Evaluations/ConcernsHistory and physical examinations and laboratory evaluations will be routinely performed duringtreatment study. For the phase I component: The recommended doses will be based on toxicitiesobserved over the first treatment cycle. Dose modifications and management plans are specifiedin the protocol.Correlative Studies Pharmacokinetic samples will be collected in all phase I patients (mandatory) and in upwardsof 10 patients in the phase II component for data and experience at the recommended dose.Detailed pharmacokinetic sampling will occur at steady state during cycle 1. Correlative studies evaluating pharmacodynamic parameters on Hsp inhibition (Hsp70),mTOR inhibition (phospho-S6 and Akt Phosphorylation), UPR activation (EIF2 phosphorylation), and oxidative stress (G6PD) will be explored in tumor tissue andperipheral blood mononuclear cells at baseline and during treatment. The patient-reported pain evaluation will consist of two validated scales. The NumericalRating Scale-11 (NRS-11) will be used to assess pain severity, and the Pain InterferenceScale from the Brief Pain Inventory will be used to assess the impact of pain on dailyactivities. These tests will be given prior to treatment and then prior to cycle 3, 5, 9, and 13when disease evaluation is performed.Brief Statistical DesignIn the phase I component, a conventional 3 3 dose-escalation design is used. The initial startingdose of ganetespib is 150 mg/m2, approximately 1 dose level below the recommended phase 2weekly dose, in combination with the recommended adult dose of sirolimus of 4 mg once daily.This will be followed by one dose escalation of the ganetespib to 200 mg/m2 weekly(recommended phase 2 dose) and sirolimus recommended adult dose. The Maximum tolerateddose (MTD)/Recommended dose will be defined as the dose level immediately below the level atwhich 33% of patients in a cohort experience a dose-limiting toxicity (DLT) based ontoxicities observed in the first treatment cycle.In the phase II component, the primary endpoint will be clinical benefit rate, which will bedefined as a CR, PR, or stable disease 4 cycles. An evaluable patient will be classified as aresponder (success) for the primary endpoint if the patient achieves a PR, CR or stable disease at 4 months. The target clinical benefit rate will be 25%, and a clinical benefit rate 5% will beconsidered uninteresting. Using a Simon’s optimal two-stage phase II design, the first stage willrequire 10 patients, with no further accrual if 0 of 10 respond. If 1/10 patients respond, accrualwill continue until a total of 20 patients have been enrolled. If 3/20 patients respond, thisConfidentialCopyright SARCSARC023 Version 7 13JAN2016Page 9 of 97
combination will be considered of sufficient activity. Assuming the number of successes isbinomially distributed, this design has a one sided alpha of 0.07 and a power of 88% fordetecting a true success probability of at least 25% versus the null hypothesis success rate of 5%or less.ConfidentialCopyright SARCSARC023 Version 7 13JAN2016Page 10 of 97
TABLE OF CONTENTSSCHEMA . 61.OBJECTIVES . 141.1Primary Objective . 141.2. Secondary Objectives. 142.BACKGROUND . 142.1Malignant peripheral nerve sheath tumors . 142.2Refractory bone and soft tissue sarcomas . 172.3Study Agents: Ganetespib and Sirolimus . 172.4Rationale . 232.5Preliminary results of current study (March 2015) . 252.6Study Design . 262.7Correlative Studies Background . 273.PATIENT SELECTION . 29Eligibility Criteria . 293.1Inclusion Criteria . 303.2Exclusion Criteria . 323.3Inclusion of Women and Minorities . 344.REGISTRATION PROCEDURES . 344.1General Guidelines. 344.2Registration Process . 355.TREATMENT PLAN . 355.1Agent Administration. 355.2Criteria for starting subsequent cycles . 365.3Dose Escalation Schema [Phase I component]- Completed . 365.3.1 Inter-patient Escalation . 365.3.2 Criteria for Dose Escalation. 375.3.3 Definition of Dose Limiting Toxicity (DLT) (Criteria for entire study) . 375.3.3.1 Non-hematological DLT . 375.3.3.2 Hematological DLT . 385.3.4 Intra-Patient Escalation . 385.3.5 Definition of Maximum Tolerated Dose (MTD) . 385.4Dosing for Phase II component. 385.5General Concomitant Medication and Supportive Care Guidelines . 395.5.1 Concomitant Cancer and other Therapy . 395.5.2 Supportive Care . 395.5.3 Management for Surgery . 405.6Duration of Therapy. 405.7Duration of Follow Up . 415.8Criteria for Removal from Study Treatment . 41ConfidentialCopyright SARCSARC023 Version 7 13JAN2016Page 11 of 97
5.96.Off Study Criteria . 41DOSING MODIFICATIONS/ MANAGEMENT FOR SPECIFIC SIDE EFFECTS . 416.1 Dose modifications for non-hematological toxicity . 416.2 Dose modifications for hematological toxicity . 426.3 Ganetespib dose level modifications . 426.4 Sirolimus dose level modification . 426.5 Management of Specific Side Effects . 426.5.1 Management of hypersensitivity reactions to ganetespib infusions . 426.5.2 Management of stomatitis/oral mucositis/mouth ulcers . 436.5.3 Management of hyperlipidemia and hyperglycemia . 446.5.4Management of non-infectious pneumonitis. 457.ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS . 467.1Adverse Event and Laboratory Abnormalities . 477.2Handling of Safety Parameters . 518.PHARMACEUTICAL INFORMATION . 528.1Ganetespib. 528.2Sirolimus . 579.CORRELATIVE/SPECIAL STUDIES . 609.1Laboratory Correlative Studies . 609.1.1 Mandatory . 609.1.1.1 Pharmacokinetics . 609.1.1.2 Pain (Appendix V) . 609.1.1.3 Volumetric MRI analysis . 609.1.2 Optional. 619.1.2.1 Pharmacokinetics . 619.1.2.2 Pharmacodynamics . 6110.STUDY EVALUATIONS AND STUDY CALENDAR . 6110.1 SCREENING STUDIES . 6110.2 ON STUDY EVALUATIONS . 6210.3 OFF STUDY EVALUATIONS . 6310.4 STUDY EVALUATIONS . 6411.MEASUREMENT OF EFFECT. 6611.1 Antitumor Effect – Solid Tumors . 6612.DATA REPORTING / REGULATORY CONSIDERATIONS . 7012.1 Data Reporting . 7012.2 Multi-institutional guidelines . 7212.3 Data and Participating Institution Monitoring . 7412.4 Human Subjects Protection . 74ConfidentialCopyright SARCSARC023 Version 7 13JAN2016Page 12 of 97
13.STATISTICAL CONSIDERATIONS. 7613.1 Study Design/Endpoints. 7613.2 Definitions. 7713.3 Sample Size/Accrual Rate. 7813.4 Analysis of Secondary Endpoints . 78REFERENCES . 80APPENDIX I: PERFORMANCE STATUS CRITERIA . 85APPENDIX II: DRUG INTERACTION TABLE . 86APPENDIX III: PATIENT DIARY . 87APPENDIX IV: DOCUMENTATION OF FINDINGS OF NF1 . 91APPENDIX V: PAIN QUESTIONNAIRE . 95APPENDIX VI: DRUGS WITH RISK OF TORSADES DE POINTES . 96ConfidentialCopyright SARCSARC023 Version 7 13JAN2016Page 13 of 97
1. OBJECTIVES1.1Primary Objective1. Phase I: To assess the safety, tolerability, and maximum tolerated dose (MTD)/recommended dose of ganetespib when administered in combination withsirolimus in patients with refractory or relapsed sarcomas including unresectableor metastatic sporadic or neurofibromatosis type 1 (NF1) associated MPNST.2. Phase II: To determine the clinical benefit of ganetespib in combination withsirolimus for patients with unresectable or metastatic sporadic or NF1 associatedMPNST.1.2.Secondary Objectives1. Phase I: To describe the plasma pharmacokinetic profile of ganetespib andsirolimus when administered in combination therapy2. Phase I/II: To determine changes in pharmacodynamic parameters includingphospho-S6, phosphorylated eIF2 alpha, Akt Phosphorylation, Hsp70, and G6PDin tumor tissue and peripheral blood mononuclear cells at baseline and duringtreatment and correlate with changes in clinical or radiologic outcome.3. Phase I/II: To assess patient-reported pain severity and the impact of pain ondaily activities before and during treatment with ganetespib and sirolimus and tocorrelate with changes in clinical or radiologic outcome.4. Phase I/II: To evaluate the utility of three-dimensional MRI (3D-MRI) analysis incomparison to 1-dimensional and 2-dimensional measurements as a method tomore sensitively monitor response.2. BACKGROUND2.1Malignant peripheral nerve sheath tumorsMalignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas arising fromperipheral nerve or show nerve sheath differentiation and are associated with a high risk oflocal recurrence and metastasis 1. MPNSTs account for 10% of all soft tissue sarcomas, andcarry the highest risk for sarcoma specific death among all the soft tissue sarcoma histologies2. At present, complete surgical resection is the only curative treatment for MPNST 3,4.MPNSTs are at high risk for local recurrence (32-65%) 5 and metastasis (40%) 6. The mostfrequent sites of metastasis of MPNSTs are lung, liver, brain, soft tissue, bone, lymph nodes,and retroperitoneum 7. The outcome for unresectable, recurrent, or metastatic MPNST isdismal.Neurofibromatosis Type 1 and MPNSTApproximately half of all MPNSTs arise from individuals with NF1 8. NF1 is a commonautosomal dominant tumor predisposition syndrome. The gene responsible for NF1 encodesfor a protein called neurofibromin, which includes a GTPase activating protein that regulateshydrolysis of Ras-GTP to Ras-GDP 9,10. Patients with NF1 have decreased levels ofConfidentialCopyright SARCSARC023 Version 7 13JAN2016Page 14 of 97
neurofibromin, which can lead to dysregulated Ras and tumorigenesis 11. MPNSTs are themost common NF1-associated malignancy. The lifetime risk of MPNST in NF1 is 8-13%compared to 0.001% in the general population 7,8. The majority of NF1-associated MPNSTsarise within pre-existing plexiform neurofibromas 12. This may lead to difficulty and delay indiagnosing MPNSTs in patients with NF1 because the clinical indicators of malignancy suchas mass, pain, and edema may also be features of active, benign plexiform neurofibromas.NF1 associated MPNSTs are frequently more located in the trunk 13,14 as opposed toextremity location seen more commonly in sporadic MPNSTs, tend to be large ( 5cm) 15,and may have a greater propensity to metastasize 7. These may be potential reasons whyNF1-assoicated MPNSTs appear to have a worse outcome than sporadic MPNSTs. Geneexpression profiling of NF1 associated (n 25) and sporadic (n 17) MPNSTs did not identifya molecular signature that could reliably distinguish between both groups 16,17.TreatmentThe only known curative approach to MPNSTs is complete surgical resection with widenegative margins 3,4. Thus, early diagnosis of MPNST is crucial, which may be difficult inpatients with NF1 for the reasons stated above. Radiotherapy is used in situations where thesarcoma is not amenable to surgical resection, but extremely high doses are needed, and thelocal control rate is only 30-60%. Clinical trials have shown that external beam radiation orbrachytherapy in addition to limb sparing surgery can improve local control in patients withsoft tissue sarcomas 18,19. Thus adjuvant radiotherapy is recommended to improve localcontrol in intermediate and high grade lesions 5 cm after a marginal excision 1,19. The roleof chemotherapy for MPNSTs has not been defined to date. In retrospective reviews, NF1associated MPNSTs have been described to have much lower response to chemotherapy thansporadic MPNSTs 3,15.There is a current DoD sponsored, SARC coordinated phase II clinical trial evaluating theresponse rate of high grade unresectable MPNST to standard
NCI-CTCNCI National Cancer Institute-Common Toxicity Criteria National Cancer Institute NCI-CTCAENCI-CTC National Cancer Institute-Common Terminology Criteria for Adverse Events National Cancer Institute-Common Toxicity Criteria ORRNCI-CTCAE Objective Response Rate National Cancer Institute-Common Ter
NCI GUIDELINES FOR AUDITING CLINICAL . TRIALS FOR THE NCI NATIONAL CLINICAL TRIAL S NETWORK (NCTN) PROGRAM INCLUDING NCI . Audit Information System (AIS) . 5.3 Review of
NCI-AD NCI-AD (Quick) Overview National Report Methodology National Report Structure Selected findings from 2016-17 NCI-AD National Report Q&A Note: This webinar is being recorded and will be posted on our website, https://nciad.org
EGP Exterior Gateway Protocol OSPF Open Shortest Path First Protocol IE-IRGP Enhanced Interior Gateway Routing Protocol VRRP Virtual Router Redundancy Protocol PIM-DM Protocol Independent Multicast-Dense Mode PIM-SM Protocol Independent Multicast-Sparse Mode IGRP Interior Gateway Routing Protocol RIPng for IPv6 IPv6 Routing Information Protocol PGM
Nas Zahir, PhD (NCI Division of Cancer Biology) Claudia Fischbach -Teschl, PhD (Cornell University) Franziska Michor, PhD (Dana-Farber Cancer Institute) Jann N. Sarkaria, MD (Mayo Clinic - Rochester) 12 th Joint NCI BSA/NCAB Meeting
NCI BUILDING SYSTEMS, INC. 5020 Weston Parkway Suite 400 Cary, North Carolina 27513 NOTICE OF ANNUAL MEETING OF STOCKHOLDERS TO BE HELD MAY 23, 2019 The Annual Meeting of Stockholders of NCI Building Systems, Inc. will be held at the Umstead Hotel and Spa, located at 100 Woodland Pond Drive,
I NCI-MICCAI Challenge on Multimodal Brain Tumor Segmentation Proceedings of NCI-MICCAI BRATS 2013 September 22 nd, Nagoya, Japan
The National Cancer Institute Common Terminology Criteria, Version 4.0 for Adverse Events (NCI CTCAE) is a descriptive terminology which can be utilized for Adverse Event (AE) reporting (including an abnormal laboratory . Records toxicity grade value using a standard toxicity scale (such as the NCI CTCAE). If value is from aFile Size: 810KB
o Additif alimentaire. 41 Intrants alimentaires: o Matière première : matière unique ou principale soumise à la transformation Unique : blé en minoterie, betterave ou canne en sucrerie Principale en volume : lait pour le yaourt, eau pour les boissons gazeuses Principale en valeur : sucre pour les boissons gazeuses 1. Chapitre introductif 1.4- Intrants et produits des IAA. 42 o Ingrédient .
