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DATE: December 8, 2016 FROM: Howard Streicher, M.D., Investigational Drug Branch, CTEP, DCTD, NCI SUBJECT: Nivolumab (BMS-936558, MDX-1106) and Ipilimumab (BMS-734016, MDX-010) Investigator Notification: Autoimmune Inner Ear Disease Bristol-Myers Squibb Manufacturer Control # BMS-2016-085259 TO: Investigators Using Nivolumab (NSC 748726) and/or Ipilimumab (NSCs 732442, 720801) The U.S. Food and Drug Administration (FDA) regulations require sponsors of clinical studies conducted under a U.S. IND to notify the FDA and all participating investigators of any serious and unexpected adverse experiences that are possibly related to the investigational agent. The CIOMS Form, which describes autoimmune inner ear disease in a patient participating in a Bristol-Myers Squibb-sponsored trial utilizing the investigational agents nivolumab and ipilimumab, was recently distributed to investigators. The following must be completed by all investigators using nivolumab (NSC 748726) and/or ipilimumab (NSCs 732442, 720801): Send a copy of this letter to your Institutional Review Board (IRB) of record according to your policies and procedures. File a copy of this letter in your protocol file. Please note that for National Clinical Trials Network (NCTN) studies, the Operations Office will provide instructions for IRB submissions, any patient notifications, etc. Based on CTEP’s assessment of the current information in light of previous experience with nivolumab and/or ipilimumab, there does not appear to be a change in the risk-benefit ratio for nivolumab and/or ipilimumab studies; therefore, CTEP is not requiring a protocol amendment at this time. Please continue to report events according to the adverse event reporting guidelines in your protocol(s). The Dear Investigator Letter and CIOMS Form that describe the following adverse event are attached: A 75-year-old Caucasian female with malignant melanoma experienced grade 3 autoimmune inner ear disease while participating in a study utilizing the investigational agent nivolumab in combination with ipilimumab. There have been 5 cases of autoimmune disorder, and no cases of autoimmune inner ear disease reported to the NCI through CTEP-AERS under IND trials using nivolumab (NSC 748726). There have been 68 cases of autoimmune disorder, 2 cases of hearing impaired, 1 case of vestibular disorder, and no cases of autoimmune inner ear disease reported to the NCI through CTEP-AERS under IND trials using ipilimumab (NSCs 732442, 720801). A total of 2050 patients have been enrolled in NCI-sponsored IND clinical trials using nivolumab (NSC 748726) and 4148 patients have been enrolled in NCI-sponsored IND clinical trials using ipilimumab (NSCs 732442, 720801). Attachment: Dear Investigator Letter for Nivolumab Dear Investigator Letter for Ipilimumab CIOMS Report for Nivolumab and ipilimumab CONFIDENTIAL Page 1 of 1 P.O BOX 5400, Princeton, NJ-08543-5400 Tel 609-818-3000 www.bms.com 01-Dec-2016 SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION (SUSAR) REPORT Follow-up SUSAR Report for Nivolumab (BMS-936558) AWARE# BMS-2016-085259 Reference Document: Investigator Brochure Version 15 (24-Jun-2016) EVENT: Autoimmune inner ear disease PROTOCOL: CA209-401 SITE: 93 SUBJECT: 147 Dear Investigator: As the sponsor of clinical studies with the investigational medicinal product (IMP) specified above, Bristol-Myers Squibb Research & Development is issuing this safety report. The details of this adverse event/safety issue are being reported to you in compliance with regulations. For Suspected Unexpected Serious Adverse Reactions (SUSARs) occurring in blinded clinical trials, study treatments will remain blinded in reports sent to investigators. The attached report does not reflect a conclusion or constitute an admission by the sponsor that the IMP caused or contributed to this adverse event/safety issue. Your Institutional Review Board (IRB)/Ethics Committee (EC) must receive a copy of this SUSAR as per applicable regulation and local IRB/EC policy. Please consult the clinical trial personnel or documents/manuals regarding your responsibility for submitting SUSARs to your IRB/EC. Please also review your IRB/EC procedures relating to adverse events/safety issues that may necessitate changes to the Informed Consent Form. Please include this SUSAR with all copies of the Reference Document. We thank you in advance for your prompt attention to this information. Yuan Gao, M.D. Associate Medical Director Global Pharmacovigilance and Epidemiology Attachment: SUSAR Report Approved v 1.0 930108710 1.0 P.O BOX 5400, Princeton, NJ-08543-5400 Tel 609-818-3000 www.bms.com 01-Dec-2016 SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION (SUSAR) REPORT Follow-up SUSAR Report for Ipilimumab (BMS-734016) AWARE# BMS-2016-085259 Reference Document: Investigator Brochure Version 19 (02-Mar-2016) EVENT: Autoimmune inner ear disease PROTOCOL: CA209-401 SITE: 93 SUBJECT: 147 Dear Investigator: As the sponsor of clinical studies with the investigational medicinal product (IMP) specified above, Bristol-Myers Squibb Research & Development is issuing this safety report. The details of this adverse event/safety issue are being reported to you in compliance with regulations. For Suspected Unexpected Serious Adverse Reactions (SUSARs) occurring in blinded clinical trials, study treatments will remain blinded in reports sent to investigators. The attached report does not reflect a conclusion or constitute an admission by the sponsor that the IMP caused or contributed to this adverse event/safety issue. Your Institutional Review Board (IRB)/Ethics Committee (EC) must receive a copy of this SUSAR as per applicable regulation and local IRB/EC policy. Please consult the clinical trial personnel or documents/manuals regarding your responsibility for submitting SUSARs to your IRB/EC. Please also review your IRB/EC procedures relating to adverse events/safety issues that may necessitate changes to the Informed Consent Form. Please include this SUSAR with all copies of the Reference Document. We thank you in advance for your prompt attention to this information. Yuan Gao, M.D. Associate Medical Director Global Pharmacovigilance and Epidemiology Attachment: SUSAR Report Approved v 1.0 930108714 1.0 CIOMS FORM SUSPECT ADVERSE REACTION REPORT I. REACTION INFORMATION 1. PATIENT INITIALS (first, last) N/I 1a. COUNTRY SWEDEN 2. DATE OF BIRTH Day Month Year 2a. AGE 3. SEX 75 Years Female 3a. WEIGHT 61.50 kg 4-6 REACTION ONSET Day Month Year 03 OCT 2016 8-12 CHECK ALL APPROPRIATE TO ADVERSE REACTION PATIENT DIED 7 + 13 DESCRIBE REACTION(S) (including relevant tests/lab data) Event Verbatim [PREFERRED TERM] (Related symptoms if any separated by commas) INVOLVED OR PROLONGED INPATIENT HOSPITALISATION INVOLVED PERSISTENT OR SIGNIFICANT DISABILITY OR INCAPACITY Other Serious Criteria: Medically Significant Autoimmune inner ear disease bilateral [Autoimmune inner ear disease] Case Description: Protocol: (CA209-401) Clinical Trial of Nivolumab (BMS-936558) Combined with Ipilimumab Followed by Nivolumab Monotherapy as First-Line Therapy of Subjects with Histologically Confirmed Stage III (Unresectable) or Stage IV Melanoma LIFE THREATENING CONGENITAL ANOMALY PID: CA209-401-93-147 / AWARE # BMS-2016-085259 / Sweden OTHER (Continued on Additional Information Page) II. SUSPECT DRUG(S) INFORMATION 14. SUSPECT DRUG(S) (include generic name) 20. DID REACTION ABATE AFTER STOPPING DRUG? #1 ) NIVOLUMAB (NIVOLUMAB) SOLUTION FOR INJECTION #2 ) IPILIMUMAB (IPILIMUMAB) SOLUTION FOR INJECTION 15. DAILY DOSE(S) 16. ROUTE(S) OF ADMINISTRATION #1 ) 60 mg, UNK #2 ) 180 mg, UNK #1 ) IV #2 ) IV YES 17. INDICATION(S) FOR USE NO NA 21. DID REACTION REAPPEAR AFTER REINTRODUCTION? #1 ) Stage IV Melanoma (Malignant melanoma) #2 ) Stage IV Melanoma (Malignant melanoma) 18. THERAPY DATES(from/to) 19. THERAPY DURATION #1 ) 15-SEP-2016 / Unknown #2 ) 15-SEP-2016 / Unknown #1 ) Unknown #2 ) Unknown YES NO NA III. CONCOMITANT DRUG(S) AND HISTORY 22. CONCOMITANT DRUG(S) AND DATES OF ADMINISTRATION (exclude those used to treat reaction) #1 ) PREDNISOLONE (PREDNISOLONE) ; 02-SEP-2016 / Unknown #2 ) DALTEPARIN (DALTEPARIN) ; 09-SEP-2016 / Ongoing #3 ) PARACETAMOL (PARACETAMOL) ; 08-SEP-2016 / Ongoing #4 ) INSULIN ASPART (INSULIN ASPART) ; 08-SEP-2016 / Ongoing #5 ) DOXYCYCLINE (DOXYCYCLINE) ; 28-SEP-2016 / 06-OCT-2016 #6 ) CIPROFLOXACIN (CIPROFLOXACIN) ; 20-SEP-2016 / 26-SEP-2016 (Continued on Additional Information Page) 23. OTHER RELEVANT HISTORY. (e.g. diagnostics, allergies, pregnancy with last month of period, etc.) From/To Dates Type of History / Notes Description Unknown Unknown Historical Condition Vitamin B12 deficiency (Vitamin B12 deficiency) Historical Condition Diabetes (Diabetes mellitus) RELATED BY CORTISONE TREATMENT IV. MANUFACTURER INFORMATION 24a. NAME AND ADDRESS OF MANUFACTURER 26. REMARKS Bristol-Myers Squibb Company Eileen Leonard GPV HW19-1.01 P.O. Box 5400 Princeton, NJ 08543-5400 UNITED STATES Phone: 6098183513 World Wide #: SE-BRISTOL-MYERS SQUIBB COMPANY-BMS-2016-085259 Patient ID: 00147 Study ID: CA209-401(continued) 24b. MFR CONTROL NO. 25b. NAME AND ADDRESS OF REPORTER NAME AND ADDRESS WITHHELD. BMS-2016-085259 24c. DATE RECEIVED BY MANUFACTURER 21-NOV-2016 DATE OF THIS REPORT 01-DEC-2016 01-Dec-2016 17:42 24d. REPORT SOURCE STUDY HEALTH PROFESSIONAL NAME AND ADDRESS WITHHELD. LITERATURE SUSAR-CA209 OTHER: UNITED STATES 25a. REPORT TYPE INITIAL FOLLOWUP: 2 Approved v 1.0 (Continued on Additional Information Page) 930108710 1.0 Page 2 of 6 Mfr. Control Number: BMS-2016-085259 ADDITIONAL INFORMATION 7+13. DESCRIBE REACTION(S) continued Reportable SAE: Autoimmune inner ear disease (Verbatim: Autoimmune inner ear disease bilateral; Onset date: 03-Oct-2016) Study Medication: Nivolumab (BMS-936558) and Ipilimumab (BMS-734016) A clinical investigator reported that a 75 year-old White female patient was hospitalized due to Grade 3 autoimmune disorder (not specified), while enrolled in above study for the treatment of melanoma. Study therapy consisted of intravenous (IV) Nivolumab (60 mg) and IV Ipilimumab (180 mg) started on 15-Sep-2016. 03-Oct-2016: The patient was hospitalized due to autoimmune disorder. The patient reported bilateral sudden hearing loss. Laboratory test results (units and reference range were not available): absolute neutrophil count 3.9 (baseline results on13-Sep-2016: 8.8), hematocrit 0.34 (baseline: 0.38), hemoglobin 109 (baseline: 126), lymphocytes 1.4 (baseline: 0.48), platelets 400 (baseline: 233), white blood cells 5.8 (baseline: 9.8), glucose 8.9 (baseline: 14.0), alanine amino transferase 0.84 (baseline: 1.02), alkaline phosphatase 4.46 (baseline: 1.72), aspartate amino transferase 1.01 (baseline: 0.85), total bilirubin 6 (baseline: 7), albumin 24 (baseline: 32), free triiodothyronine 4.5 (baseline: 4.5), free thyroxine 20.0 (baseline: 20.3) and thyroid stimulating hormone 2.53 (baseline: 2.29). 06-Oct-2016: Treatment included prednisolone 60 mg/day for 5 days followed by a taper. The patient was scheduled for magnetic resonance tomography (MRT), audiogram and consultation with neurologist. Results pending. At the time of reporting, the event of autoimmune disorder was ongoing. Medical history included vitamin B12 deficiency, diabetes, colon cancer, gastritis, impaired hearing (since 2014), sigmoid thrombus of transverse sinus and Bell's palsy. Concomitant medications included prednisolone, dalteparin, paracetamol and insulin. Investigator causality assessment: Autoimmune disorder was related to nivolumab and ipilimumab study therapy. BMS causality assessment: Autoimmune disorder was not related to nivolumab and ipilimumab study therapy. Supplemental information received on 21-Nov-2016, 23-Nov-2016, 28-Nov-2016, 30-Nov-2016 and 01-Dec-2016 amended the event term of autoimmune disorder to autoimmune inner ear disease bilateral. Additional details were provided. Study therapy was discontinued in response to the event. The outcome of event is unknown. The investigator stated there were no other potential causes for sudden bilateral hearing loss (such as paraneoplastic syndrome, past medical history {Diabetes, Bell's palsy, B12 deficiency} or concomitant medications). A brain MRI (date unspecified) was negative for thrombus in sinus transversum and no signs of hypophysitis. A brain CT scan (unspecified date) showed no changes compared to baseline CT and was negative for vestibular neuritis. Consults with an audiogram consultant and neurologist were completed (results not provided). A diagnosis of autoimmune neuritis was ruled out. Investigator causality assessment: Autoimmune inner ear disease was related to nivolumab and ipilimumab study therapy. BMS causality assessment: Autoimmune inner ear disease was related to nivolumab and ipilimumab study therapy. BMS Medical Evaluation Comment: This 75 year-old White female patient developed sudden hearing loss and was hospitalized with a diagnosis of autoimmune inner ear disease 18 days after the first cycle of nivolumab and ipilimumab study therapy. She was treated with steroids. Based on the available information, and in the absence of an alternative etiology, a causal relationship between the reported event and the study therapy cannot be excluded. Contextual statement for nivolumab (Autoimmune inner ear disease): As of 03-Jul-2016, approximately 31,479 subjects have been exposed to nivolumab in BMS and ONO-sponsored clinical trials and expanded access program studies. A search of the preferred term (PT) "Autoimmune inner ear disease" revealed that there are zero (0) previously reported cases of Autoimmune inner ear disease within the corporate safety database (AWARE) associated with nivolumab. Contextual statement for ipilimumab (Autoimmune inner ear disease): As of 24-Mar-2016, approximately 16,038 patients have been exposed to ipilimumab in BMS clinical trials and extended access program studies. A search of the preferred term (PT) "Autoimmune inner ear disease" revealed that there are zero (0) previously reported cases of Autoimmune inner ear disease within the corporate safety database (AWARE) associated with ipilimumab. 13. Lab Data # 1 Date Test / Assessment / Notes 13-SEP-2016 Alanine aminotransferase increased 1.02 absent 01-Dec-2016 17:42 Approved v 1.0 Results 930108710 1.0 Normal High / Low Page 3 of 6 Mfr. Control Number: BMS-2016-085259 ADDITIONAL INFORMATION 13. Lab Data # Date Test / Assessment / Notes Results Normal High / Low Units & RR not available 2 03-OCT-2016 Alanine aminotransferase increased 0.84 absent Units & RR not available 3 13-SEP-2016 Aspartate aminotransferase 0.85 absent Units & RR not available 4 03-OCT-2016 Aspartate aminotransferase 1.01 absent Units & RR not available 5 13-SEP-2016 Blood albumin 32 absent Units & RR not available 6 03-OCT-2016 Blood albumin 24 absent Units & RR not available 7 13-SEP-2016 Blood alkaline phosphatase 1.72 absent Units & RR not available 8 03-OCT-2016 Blood alkaline phosphatase 4.46 absent Units & RR not available 9 13-SEP-2016 Blood bilirubin 7 absent Units & RR not available 10 03-OCT-2016 Blood bilirubin 6 absent Units & RR not available 11 13-SEP-2016 Blood glucose 14.0 absent Units & RR not available 12 03-OCT-2016 Blood glucose 8.9 absent Units & RR not available 13 13-SEP-2016 Blood thyroid stimulating hormone 2.29 absent Units & RR not available 14 03-OCT-2016 Blood thyroid stimulating hormone 2.53 absent Units & RR not available 15 01-Dec-2016 17:42 Computerised tomogram head normal absent normal showed no changes compared to baseline CT and was negative for vestibular neuritis Approved v 1.0 930108710 1.0 Page 4 of 6 Mfr. Control Number: BMS-2016-085259 ADDITIONAL INFORMATION 13. Lab Data # Date 16 13-SEP-2016 Test / Assessment / Notes Results Haematocrit 0.38 absent Units & RR not available 17 03-OCT-2016 Haematocrit 0.34 absent Units & RR not available 18 13-SEP-2016 Haemoglobin 126 absent Units & RR not available 19 03-OCT-2016 Haemoglobin 109 absent Units & RR not available 20 13-SEP-2016 Lymphocyte count 0.48 absent Units & RR not available 21 03-OCT-2016 Lymphocyte count 1.4 absent Units & RR not available 22 13-SEP-2016 Neutrophil count 8.8 absent Units & RR not available 23 03-OCT-2016 Neutrophil count 3.9 absent Units & RR not available 24 Nuclear magnetic resonance Negative for thrombus imaging brain absent Negative Negative for thrombus and no signs of hypophysitis 25 13-SEP-2016 Platelet count 233 absent Units & RR not available 26 03-OCT-2016 Platelet count 400 absent Units & RR not available 27 13-SEP-2016 Thyroxine free 20.3 absent Units & RR not available 28 03-OCT-2016 Thyroxine free 20.0 absent Units & RR not available 29 13-SEP-2016 Tri-iodothyronine 4.5 absent Units & RR not available 01-Dec-2016 17:42 Approved v 1.0 930108710 1.0 Normal High / Low Page 5 of 6 Mfr. Control Number: BMS-2016-085259 ADDITIONAL INFORMATION 13. Lab Data # Date 30 03-OCT-2016 Test / Assessment / Notes Results Tri-iodothyronine 4.5 absent Normal High / Low Units & RR not available 31 13-SEP-2016 White blood cell count 9.8 absent Units & RR not available 32 03-OCT-2016 White blood cell count 5.8 absent Units & RR not available 22. CONCOMITANT DRUG(S) AND DATES OF ADMINISTRATION continued #7 ) CYANOCOBALAMIN (CYANOCOBALAMIN) ; 2009 / Ongoing #8 ) ESTRADIOL (ESTRADIOL) ; 02-SEP-2016 / Ongoing #9 ) CARBOMER (CARBOMER) ; 02-SEP-2016 / Ongoing 23. OTHER RELEVANT HISTORY continued From/To Dates Type of History / Notes Description Unknown Procedure Appendectomy (Appendicectomy); Unknown Historical Condition Colon cancer (Colon cancer); Unknown Historical Condition Gastritis (Gastritis); Unknown Historical Condition Mucosal dryness (Mucosal dryness); Unknown Procedure Hysterectomy (Hysterectomy); Unknown Procedure Oophorectomy (Oophorectomy); 2014 to Unknown Historical Condition Hearing impaired (Hypoacusis); Unknown Historical Condition Pain (Pain); Unknown Historical Condition Bell's palsy (Facial paralysis); Unknown Historical Condition Transverse sinus thrombosis (Transverse sinus thrombosis); Thrombus right sinus transversus sigmoidei 12-MAY-2009 to Unknown Procedure Colon cancer 02-SEP-2016 to Unknown Disease History Melanoma malignant (Malignant melanoma); MIC WITHOUT BRAIN METASTASES Unknown Historical Condition 01-Dec-2016 17:42 Approved v 1.0 Surgery (Surgery); Fever (Pyrexia); 930108710 1.0 Page 6 of 6 Mfr. Control Number: BMS-2016-085259 ADDITIONAL INFORMATION 26. Remarks continued Center ID: 0093 25b. Name And Address of Reporters continued SUSAR-Ipilimumab UNITED STATES 01-Dec-2016 17:42 Approved v 1.0 930108710 1.0