Download Investigator Notification for Nivolumab and Ipilimumab

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
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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
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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
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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
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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
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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
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Fever (Pyrexia);
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26. Remarks continued
Center ID: 0093
25b. Name And Address of Reporters continued
SUSAR-Ipilimumab
UNITED STATES
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