A.P. Chen, MD Director, Developmental Therapeutics Clinic Division of Cancer Treatment and Diagnosis National Cancer Institute

Transcription

1 A.P. Chen, MD Director, Developmental Therapeutics Clinic Division of Cancer Treatment and Diagnosis National Cancer Institute Click to view Biosketch and Presentation Abstract or page down to review presentation

2 CTCAE v 5: Assessing Drug Induced Hepatic Injury Alice Chen, M.D. NCI Core Committee March 18, 2015

3 CTCAE History The Cancer Therapy Evaluation Program (CTEP) of NCI developed the original Common Toxicity Criteria (CTC) in 1983 to aid in the recognition and grading severity of adverse effects of chemotherapy CTCAE v4 was released in May 2009 All AEs were MedDRA terms Categories became SOC CTEP stopped supporting all prior versions of CTCAE as of Sept 2010 Ongoing lifecycle governance was established 2

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6 Process NCI Core Committee (CC) has monitored the comments since publication of v4.0 in 2009 Helpdesk TRI-CTEP s AE contractor Personal communications The CC has met as needed to monitor the comments and use of CTCAE v4 Reviewed the impact of the comment Frequency of use Confusion of grade Clinical significance MedDRA terms Consulted experts Working Group members from v4 NIH members Academic Experts

7 What has not changed in CTCAE v5 SOCs and term placement within SOCs MedDRA Terms 5 grades with no change in the general guidelines for grade definition No deletion of AE terms ULN or LLN will remain instead of actual values 6

8 Changes in CTCAE v5 New AE terms Clarification of Definitions Add, clarify or change grading Editorial Changes Navigational Notes Index

9 Disease Progression Examples of new AEs Though not AE, this was added to allow tracking Bacteremia Reactivation of viral infection Hep B Shingles Epstein-Barr virus Cytomegalovirus Infection reactivation Pregnancy Loss (replaces Fetal death) Budd-Chiari Syndrome Nephrotic Syndrome

10 Examples of changed or revised definitions Spleen Disorder An disorder abnormality of the spleen Diarrhea A disorder characterized by an increase in frequency and/or loose or watery bowel movements Peripheral sensory/motor neuropathy A disorder characterized by damage or dysfunction of the peripheral sensory/motor nerves

11 Examples of added and changed grades Grade 4 myositis Grade 1 Capillary Leak Syndrome Death Neonatal Change grade 5 to grade 4 so patient could continue on study

12 Examples of grade clarifications Allergic reaction added bronchospasm to grade 3 Proteinuria add 3+ proteinuria to grade 2 and 4+ proteinuria to grade 3 Sleep Apnea clarify associated with pulmonary hypertension Diarrhea added limiting instrumental ADL to grade 2 Seizure added new onset seizures (partial or generalized) to grade 3

13 Examples of Navigational Notes Direct to a more definitive AE term Under Enterocolitis directed to consider Colitis if site of abnormality known Direct to a different AE Direct to include another AE AST, ALT, Bilirubin: Consider also reporting Hepatic failure if appropriate Death NOS, Sudden Death or Disease Progression If death is due to a specific AE, report as grade 5 under that AE

14 CTCAE v4: Hepatic Toxicities Hepatobiliary Disorder SOC Bile Duct Stenosis, Biliary Fistula, Cholecystitis Gallbladder (fistula, necrosis, obstruction, pain, perforation) Hepatic (failure, hemorrhage, necrosis, pain) Portal (hypertension, vein thrombosis) Budd-Chiari syndroe Perforation bile duct

15 CTCAE v4: Hepatic Toxicities Infections and Infestations SOC Biliary tract infection Gallbladder infection Hepatic infection Hepatitis viral Hepatitis B reactivation

16 CTCAE v4: Hepatic Toxicities Investigational SOC Activated PTT, INR increased, ALT, AST, Alk Phos, GGT increased Blood bilirubin Fibrinogen decreased Haptoglobin decreased

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18 Other AEs we need to add Other CTCAE changes that would assist in better assessment of drug induced liver injury in drug development? Areas of Discussion Alkaline phos increased GGT increased grade4 in ALT, AST, Bili proposal to map grade 3&4 to grade 2, change definition of grade 1 to > Baseline -2.5 xuln, grade 2 >2.5xULN proposal to map grade 3&4 to grade 2, change definition of grade 1 to > Baseline -2.5 xuln, grade 2 >2.5xULN The need for grade 4 (life-threatening) AST, ALT given these should be reported as hepatic failure

19 Resources Where to find CTCAE efault.htm How to contact us? 18