Clinical trial NCT02341625
Conditions: Advanced Cancer
Sponsor: Bristol-Myers Squibb
Start date: 2015-06-19; Completion date: 2020-05-07
Enrollment: 126 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the safety, tolerability, pharmacokinetics, immunogenicity, antitumor activity and pharmacodynamics of BMS-986148 administered alone and in combination with nivolumab in patients with mesothelioma, non-small cell lung cancer, ovarian cancer, pancreatic cancer and gastric cancer.

Detailed description:

Arms: arm 1: BMS-986148 Intravenous injection at increasing doses on specific days until the maximum tolerated dose is reached. Five cancers will be studied in this part: mesothelioma, pancreatic, ovarian, gastric, and non-small cell lung cancer. Alternate dose and schedules may be explored. arm 2: BMS-986148 Intravenous injection of Maximum tolerated dose (MTD) on specific days. Five cancers will be studied in this part: mesothelioma, pancreatic, ovarian, gastric, and non-small cell lung cancer. arm 3: Set dose of nivolumab and BMS-986148 intravenous injection at increasing doses on specific days until the maximum tolerated dose is reached. Five cancers will be studied in this part: mesothelioma, pancreatic, ovarian, gastric, and non-small cell lung cancer. arm 4: Set dose of nivolumab and BMS-986148 intravenous injection at or below maximum tolerated dose on specific days. Five cancers will be studied in this part: mesothelioma, pancreatic, ovarian, gastric, and non-small cell lung cancer.
Interventions: intervention 1: BMS-986148 intervention 2: Nivolumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Official Title of Study: 
A Phase I/IIa Study of BMS-986148, a Mesothelin Directed Antibody Drug Conjugate, in Subjects With 
Select Advanced Solid Tumors 
 
NCT Number: NCT02341625 
Document Date (Date in which document was last revised): November 02, 2016 


Page:
1
Protocol Number:
CA008002
IND Number:
124,215
EUDRACT Number
2014-002485-70
Date:
25-Nov-2014
Revised Date:
02-Nov-2016
CLINICAL PROTOCOL CA008002
A Phase I/IIa Study of BMS 986148, a Mesothelin Directed Antibody Drug Conjugate, in 
Subjects with Select Advanced Solid Tumors
Revised Protocol Number 04
Incorporates Amendments 01, 02, 03, 04, 05 & 06
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International: 
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Lawrenceville, NJ 08543
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
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CA008002
BMS-986148
Mesothelin-ADC
Revised Protocol No.: 04
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Date: 02-Nov-2016
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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BMS-986148
Mesothelin-ADC
Revised Protocol No.: 04
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Date: 02-Nov-2016
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 04
02-Nov-16
Incorporates Amendment 06
Amendment 06
02-Nov-16
Added additional echocardiogram to cycle 2 for Part 3 (nivolumab 
combination treatment arm). Clarification of dosing administration 
(line flush between doses of BMS986148 and nivolumab) in Part 3.
Revised Protocol 03
21-Jul-2016
Incorporates Amendment 03
Amendment 05
21-Jul-2016
Removed flat dosing option. Added BMS-986148 and nivolumab 
combination therapy arm (Part 3).
Corrected typographical and consistency errors. 
Revised Protocol 
Number 02a - UK
19-May-2016
Incorporates Amendment 04
Amendment 04
19-May-2016
Incorporate changes 
 regarding use of contraceptives
Revised Protocol 
Number 02a - US
12-Apr-2016
Incorporates Amendment 03
Amendment 03
12-Apr-2016
Refined eligibility criteria 
Revised Protocol 02
02-Feb-2016
Incorporates Amendment 02
Amendment 02
02-Feb-2016
Added details for flat dosing, Added IHC scoring details for Part 2 of 
the study. Clarified eligibility criteria and corrected typographical 
errors.
Revised Protocol 01
31-Jul-2015
Incorporates Amendment 01
Amendment 01
31-Jul-2015
Incorporates 
 revisions regarding additional on-
treatment echocardiograms, DLT definitions, and dose selection for 
Part 2. Enhanced the survival period duration of follow-up and 
alignment of the survival period with other early development 
protocols. Added additional detail to DLT criteria. Added exclusion 
criteria for troponin. Added additional guidance on the collection of 
triplicate ECGs. Modified text for clarity. Added windows for the 
collection on eye exams and laboratory collections. Added C1D15 vital 
signs and targeted PE to Q weekly dosing. Added wording to footnote 
in PK collection tables. Addresses typographical errors
Original Protocol
28-Nov-2014
Not applicable
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CA008002
BMS-986148
Mesothelin-ADC
SYNOPSIS
Clinical Protocol CA008002
Protocol Title: A Phase 1/2a Study of BMS 986148, a Mesothelin-Directed Antibody Drug Conjugate, in Subjects 
with Select Advanced Solid Tumors
Investigational Product(s), Dose and Mode of Administration, with Investigational Product(s): Each subject will 
be administered intravenous doses of BMS-986148 or BMS-986148 and nivolumab per the cohort assignment as 
indicated in the study design below (See Figure 1 and Figure 2 in the synopsis).
Study Phase: 1/2a
Research Hypothesis:  There is no formal primary research hypothesis for this study to be statistically tested. The
purpose of this study is to evaluate the safety profile, tolerability, preliminary efficacy, pharmacokinetics (PK), and
pharmacodynamics (PD) of BMS-986148 administered alone and in combination with nivolumab in subjects with 
select advanced solid tumors.
Primary Objectives: To assess the safety and tolerability of BMS-986148 administered as monotherapy and in 
combination with nivolumab in subjects with select advanced solid tumors.
Secondary Objectives:
•
To assess the preliminary anti-tumor activity of BMS-986148 as monotherapy and in combination with 
nivolumab as measured by objective response rate (ORR), response duration, and progression-free survival 
(PFS)
•
To characterize the PK of the total antibody (unconjugated antibody + antibody conjugated to tubulysin or
antibody conjugated to any tubulysin metabolites), active anti-drug conjugate (ADC, antibody conjugated to 
tubulysin), and unconjugated tubulysin when BMS-986148 is administered as monotherapy and in 
combination with nivolumab
•
To characterize the PK of nivolumab when administered in combination with BMS-986148
•
To assess the effect of BMS-986148 monotherapy dosage regimen and exposure (active ADC and 
unconjugated tubulysin) on the QT interval
•
To characterize the immunogenicity of BMS-986148 as monotherapy and in combination with nivolumab
•
To characterize the immunogenicity of nivolumab in combination with BMS-986148
Revised Protocol No.: 04
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Mesothelin-ADC
Study Design: This is a Phase 1/2a, open-label study to characterize the safety and tolerability, as well as preliminary 
efficacy, PK, and PD of BMS-986148 administered alone and in combination with nivolumab in subjects with select 
advanced solid tumors (pancreatic, ovarian, non-small cell lung cancer [NSCLC], gastric, or mesothelioma). The study 
has 3 segments: Part 1 (Phase 1 study - dose escalation), Part 2 (Phase 2a - dose expansion), and Part 3 (BMS-986148 
in combination with nivolumab; Part 3A - dose escalation and Part 3B - dose expansion) (see Figure 1). All subjects 
will complete up to 4 study periods: Screening (up to 28 days), Treatment (21 days/cycle for Q3W dosing and 28 
days/cycle for QW dosing), Follow-up (60 days), and Survival Follow-up. After completing the Follow-up period, 
subjects will continue to be followed for 
 up to 2 years from first dose of study drug for subjects 
discontinuing study drug prior to 2 years. Subjects receiving study drug for more than 2 years, will be followed for 
6 months from their last treatment date in the Survival Follow up Period (see Figure 2). With Amendment 3, a dose 
escalation phase will be conducted with BMS-986148 and nivolumab combination therapy (Part 3A). In the BMS-
986148 and nivolumab combination therapy dose expansion phase (Part 3B), additional subjects with pancreatic, 
ovarian, NSCLC, gastric, or mesothelioma will be treated at or below the maximum tolerated dose (MTD) of the 
combination dose identified in Part 3A to confirm safety and evaluate anti-tumor activity. 
Figure 1:
Sequence of Study Phases 
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Figure 2:
Dosing (Q3W and QW) and Study Periods
Note: Subjects treated for > 2 years will be followed for 6 months after EOT in the Survival Follow-Up. In the Survival 
Follow-up, subjects discontinuing study drug prior to 2 years will be followed for up to 2 years from first dose of 
study drug. Additionally, specifically in Part 3, treatment duration is 24 weeks to a maximum of 48 weeks.
C1D1: Cycle 1 Day 1 (first dose); D: day; DLT: dose-limiting toxicity; EOT: end of treatment; QW: every week; 
Q3W: every 3 weeks.
Part 1A: BMS-986148 Administered Every 3 Weeks
Approximately 30 subjects will be enrolled in ascending dose cohorts starting with a dose of 0.1 mg/kg. BMS-986148 
will be administered Q3W in a 21-day cycle. The approach for selection of the next dose at each escalation step
(including Fibonacci and modified Fibonacci methods) and the rules for escalation decision based on dose limiting 
toxicity (DLT) criteria guided by the modified Toxicity Probability Interval (mTPI) design are described in Section 
3.1.1 of the protocol, with the dose escalation design described in Figure 3.1.1-1 of the protocol. 
At the end of dose escalation, the MTD will be selected as the dose with the smaller difference of estimated toxicity 
and the target DLT rate (27%), among the doses used, with isotonic regression modeling of the accumulated DLT data 
based on the mTPI design. 
Part 1B: BMS-986148 Administered Weekly for 3 Weeks and 1 Week Off 
Approximately 24 subjects will be enrolled in ascending dose cohorts. Part 1B may begin after determining the MTD 
or a tolerated dose below the MTD in Part 1A. The starting dose for Part 1B will be chosen by modeling active ADC 
concentration-time data from Part 1A and selecting a fractionated dose that provides similar exposure to that of the 
MTD or a tolerated dose below the MTD. In the event that concentration-time data are not available for modeling, the 
starting dose will be 1/3rd of the MTD or a tolerated dose below the MTD from Part 1A. In Part 1B, BMS-986148 is 
administered every week for 3 weeks and 1 week off in a 28 day cycle. Similar to Part 1A, the approach for selection 
of the next dose at each escalation step (including Fibonacci and modified Fibonacci) and the rules for escalation 
decision based on DLT criteria guided by the mTPI design are described in Section 3.1.1 of the protocol, with the dose 
escalation design described in Figure 3.1.1-1 of the protocol.
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Similar to the MTD determination in Part 1A, at the end of dose escalation, the MTD will be selected as the dose with 
the smaller difference of estimated toxicity and the target DLT rate (27%), among the doses used. 
Once the safety (during DLT evaluation) of a dose level has been established (Part 1A and/or Part1B), additional 
subjects may be added at that dose to better characterize the PK, safety, and PD profile.
Part 2: Monotherapy Dose Expansion
The purpose of the cohort expansion will be to assess preliminary antitumor efficacy, expanded safety experience and 
PD effects of BMS-986148. Additional subjects will be treated after the completion of Part 1A and/or Part 1B, at the 
MTD, or at an alternative dose below MTD as agreed upon by the BMS Medical Monitor and investigators. Part 2 
can begin before the completion of Part 1B as the Q3W dosing regimen is the intended regimen for Part 2. However, 
if the aggregate PK and safety data indicate similar safety but higher cumulative exposure with the weekly dose 
schedule, this schedule may also be evaluated in Part 2 in an additional cohort of 25 to 26 subjects, once the MTD or 
a tolerated dose below the MTD is identified in Part 1B. Treatment doses in the cohort expansion groups will not 
exceed the MTD. 
Five expansion cohorts will be restricted to these tumor types 1) mesothelioma 2) pancreatic 3) ovarian 4) NSCLC,
and 5) gastric cancer. Enrollment in cohort expansion will be determined by the mesothelin expression of an archived 
tumor sample (or fresh tumor sample if archived sample is not available). 
 
 
 
 
The enrollment in each expansion cohort will be guided by a Simon 2-Stage design framework exploring the efficacy 
in the following 2 populations: 
 
 
 
. 
Safety monitoring of subjects enrolled in the Part 2 (Phase 2a) portion of the study will be the same as that conducted 
during the dose escalation portion. During Part 2, if in a given arm the combined incidence of study drug-related AEs 
that require dose modification exceeds 29% (of treated subjects), then further enrollment to that arm will be interrupted 
and the findings will be discussed between the BMS Medical Monitor and investigators. An agreement will be reached 
as to whether a lower dose or an alternate dose schedule of BMS-986148 should be examined or whether any additional 
treatment guidelines should be implemented prior to enrollment of additional subjects on study.
Part 3: BMS-986012 in Combination with Nivolumab 
During the dose escalation phase with BMS-986148 and nivolumab combination therapy (Part 3A), approximately 12 
evaluable subjects are expected to be treated at 2 doses of BMS-986148 (0.8 mg/kg Q3W and 1.2 mg/kg Q3W) and 
nivolumab (360mg, Q3W) combination therapy (21 day cycle). In the BMS-986148 and nivolumab combination 
therapy dose expansion phase (Part 3B), approximately 25 to 26 evaluable subjects will be treated in each tumor 
cohort.
Subsequent escalation to 1.2 mg/kg Q3W of BMS-986148 (or MTD determined from Part 1A) in combination with 
nivolumab 360 mg Q3W will be guided by the mTPI design described in Section 3.1.3 of the protocol. In the event 
that the first dose level of BMS-986148 is determined to exceed the MTD in combination with 360 mg Q3W of 
nivolumab, a lower BMS-986148 dose may be explored based on available safety, PK
. 
Nivolumab will be administered as 360 mg IV Q3W in all the dose cohorts. Dose escalation decisions are similar to 
Part 1A and described in Figure 3.1.1-1 of the protocol. A DLT target rate of 29% (EI = 28% to 31%) will be utilized 
for combination treatment to guide escalation decisions. Dose escalation decisions will be based on the total number 
of subjects in a dose level who were DLT evaluable and the number of DLTs, guided by the mTPI Bayesian model 
and posterior inference.
Similar to the MTD determination in monotherapy parts, at the end of dose escalation, the cumulative number of 
subjects who experience a DLT at each dose level will be used to estimate the MTD using isotonic regression as the 
dose with the smaller difference of estimated toxicity rate and the target DLT rate (29%), among the doses used. 
Once the safety (during DLT evaluation) of a dose level has been determined, additional subjects may be added at that 
dose, to better characterize the PK, safety, and PD profile.
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Part 3B: Dose Expansion
The purpose of the cohort expansion will be to assess preliminary anti-tumor efficacy, expanded safety experience, 
and PD effects of BMS-986148 in combination with nivolumab. Additional subjects will be treated after the 
completion of Part 3A, at the MTD, or at an alternative dose below the MTD as agreed upon by the BMS Medical 
Monitor and investigators. Five expansion cohorts will be restricted to these tumor types: 1) mesothelioma, 
2) pancreatic, 3) ovarian, 4) NSCLC, and 5) gastric cancer. Enrollment in cohort expansion will be determined by the 
mesothelin expression of the archived tumor sample (or fresh tumor sample if archived sample is not available). 
 
 
 
The enrollment in each combination expansion cohort will also be guided by a Simon 2-Stage design framework (see 
Protocol Table 8.1-2), exploring efficacy in the 
.
Safety monitoring of subjects enrolled in the Part 3B portion of the study will be the same as that conducted during 
the dose escalation portion. During Part 3, if in a given arm the combined incidence of study drug-related AEs that 
require dose modification exceeds 31% (of treated subjects), then further enrollment to that arm will be interrupted, 
and the findings will be discussed between the BMS Medical Monitor and investigators. An agreement will be reached 
as to whether a lower dose or an alternate dose schedule of BMS-986148 in combination with nivolumab should be 
examined or whether any additional treatment guidelines should be implemented prior to enrollment of additional 
subjects on study.
Administration of Additional Treatment Cycles (Part 3): 
In Part 3 of the study, all subjects will be treated for 24 weeks (up to 8 cycles) of BMS-986148 in combination with 
nivolumab unless criteria for study drug discontinuation are met earlier (see Protocol Section 3.5). All subjects 
completing approximately 24 weeks of study therapy with ongoing disease control (complete response [CR], partial 
response [PR], or stable disease [SD]) may be eligible for an additional 24 weeks of study therapy (see Protocol 
Section 3.1.7) at the originally assigned dose regimen in both escalation and cohort expansion beyond the initial 24 
weeks, on a case-by-case basis, after careful evaluation and discussion with the BMS Medical Monitor to determine 
whether the benefit/risk ratio supports administration of further study therapy. Upon completion of 24 weeks of study 
therapy (or up to a maximum of 48 weeks if applicable), all subjects will enter the clinical/safety Follow-up period
Dose Limiting Toxicity: For the purpose of guiding dose escalation, DLTs are defined separately in Protocol Section 
4.5.1 and will be determined based on the incidence, intensity, and duration of AEs for which no clear alternative 
cause is identified. The DLT evaluation period for dose escalation in Part 1A is 21 days. The DLT evaluation period 
for dose escalation in Part 1B is 28 days and subjects must receive 3 doses during this period (unless DLT has occurred) 
to be considered evaluable for dose escalation decisions. The DLT evaluation period for dose escalation in Part 3A is 
21 days. Adverse events will be graded according to NCI CTCAE v4.03. For the purpose of subject management, any 
AE that meets DLT criteria, regardless of the cycle in which it occurs, will lead to dose interruption. Subjects who 
withdraw from the study during the DLT evaluation interval for reasons other than a DLT may be replaced at the same 
dose level. The incidence of DLT(s) during the first cycle of treatment (the DLT evaluation period) will be used in 
dose escalation decisions and to define the MTD. AEs occurring after the DLT period will be considered for the 
purposes of defining the MTD, upon agreement between the BMS Medical Monitor and investigators, if they are 
determined to have no clear alternative cause and are not related to disease progression. For Part 3A, every attempt 
must be made to assign relationship to BMS-986148, to nivolumab, or to both.
Once the safety (during DLT evaluation) of a dose level has been established (Parts 1A, 1B, and 3A), additional 
subjects may be added at that dose to better characterize the PK, safety, and PD profile.
Duration of Study: The total duration of the study is anticipated to be 5 years from the time of the first visit of the 
first subject to the required survival follow-up of the last subject enrolled. The end of the study will occur when the 
last subject has the last survival follow-up visit.
Number of Subjects: Approximately 179 to 204 subjects will be dosed in monotherapy (approximately 54 subjects 
in dose escalation [Part 1A and Part 1B] and approximately 125 to 150 subjects in dose expansion (Part 2]).
Approximately 137 to 162 subjects will be dosed in combination therapy (approximately 12 subjects in dose escalation 
[Part 3A] and approximately 125 to 150 subjects in dose expansion [Part 3B]).
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Study Population:  The study population will include men and women who are at least age 18 who meet the study 
eligibility criteria. Subjects must have histological confirmation of one of the following advanced or metastatic tumor 
types to be eligible: pancreatic, ovarian, NSCLC, gastric, or mesothelioma. At least 1 site of measurable disease as 
defined by RECIST version 1.1 or Modified RECIST for malignant pleural mesothelioma (See Protocol Appendix 4)
is mandatory. Additionally, in order to be eligible for enrollment to the study all subjects must have either archival 
tumor tissue (if slides are available, will require a minimum of 10 cut slides [for details of epitope stability, see lab 
manual]) identified and available, and consent to provide this archival tissue. Acquisition of adequate pre-treatment 
tumor tissue is mandatory for this study for all subjects. Subjects who do not have archival tissue available may consent 
to a pre-treatment fresh tumor biopsy to be eligible for this study if it can be performed at minimal acceptable clinical 
risk as judged by the investigator and if it is not in a target lesion or a lesion in an area treated with prior radiation 
therapy.  For the dose escalation phase, subjects with advanced or metastatic solid tumors must have received standard 
regimen and either experienced tumor progression or were intolerant to a minimum of ONE standard treatment 
regimen. For the dose expansion phase, subjects with advanced or metastatic solid tumors with tumor mesothelin 
expression must have received and either progressed or been intolerant to standard treatment regimens. 
Study Drug for CA008-002
Medication 
Potency 
IP/Non-IP 
BMS-986148
50 mg/vial
IP
Nivolumab
100 mg/ vial
(10 mg/mL)
IP
Study Assessments:  
• Safety Outcome Measures:  Adverse events will be assessed continuously during the study and for 60 days (or 100 
days for combination therapy) after the last treatment. Adverse events will be coded using the most current version 
of MedDRA and reviewed for potential significance and importance. Adverse events will be evaluated according 
to the NCI CTCAE v4.03. Subjects should be followed until all AEs for which no clear alternative cause is 
identified other than BMS-986148 have recovered to baseline or are deemed irreversible by the investigator. Safety 
assessments will be based on medical review of AE reports and the results of vital sign measurements, physical 
examinations, and clinical laboratory tests.
• Efficacy Assessments: Tumor measurements with computed tomography (CT) and/or magnetic resonance imaging 
(MRI), as appropriate, will be conducted at screening, at the start of Cycle 3, and then every 2 cycles ± 1 week
during the treatment phase. Tumor measurements should be conducted earlier, if clinically indicated. Subjects with 
SD, PR, or CR at the last clinical follow-up visit undergo tumor assessment via CT/MRI scans every 3 to 4 months 
during the survival follow-up phase until progression or death. Tumor measurements will be collected in all 
subjects until there is disease progression or until subjects discontinue from the study. Tumor response and 
progression will be evaluated in this study using RECIST version 1.1 or Modified RECIST for malignant pleural 
mesothelioma (See Protocol Appendix 4). Initial response assessment of PR or CR must be confirmed by a 
consecutive assessment no less than 4 weeks (28 days) later. 
• Pharmacokinetic Measures: Serum samples will be collected from all subjects at specified timepoints to evaluate 
concentrations of the total antibody, 
 active ADC, and nivolumab. Plasma samples will be collected 
from all subjects at specified timepoints to evaluate concentrations of
 unconjugated 
tubulysin. Pharmacokinetic parameters including Cmax, Tmax, AUC(0-t), AUC(TAU), Ctau, Ctrough, CLT, Vss, 
Vz, AI_AUC, AI_Cmax, AI_Ctau, Cavg, and T-HALF will be determined from serum and plasma concentration 
versus time data. 
• Immunogenicity Measures: Serum samples will be collected from all subjects at specified time points to evaluate 
the development of anti-drug antibody (ADA) responses to BMS-986148 (i.e. active ADC and specificity to 
antibody and/or tubulysin domains) or nivolumab. Serum samples designated for PK 
 assessments 
may also be used for immunogenicity analysis.
• Biomarker Measures: 
 
 
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In addition, mesothelin protein expression will be assessed using IHC on FFPE tumor samples from Parts
2, and 3 of the study. 
  IHC data will be generated 
prospectively during the screening period in Parts 2 and 3B to select only those subjects with tumor mesothelin 
expression for inclusion for treatment.
Endpoints:
Primary Endpoints: Incidence of AEs at worst grade, serious AEs (SAEs) at worst grade, AEs leading to 
discontinuations, deaths, and frequency of laboratory test toxicity grade shifting from baseline. Safety will be 
evaluated from the time that the subject signs the informed consent, and for up to 60 days (or 100 days for combination 
therapy) after the last dose of study drug.
Pharmacokinetic: Select PK parameters including Cmax, Tmax, AUC(0-t), AUC(TAU), Ctau, Ctrough, CLT, Vss, 
Vz, AI_AUC, AI_Cmax, AI_Ctau, Cavg, and T-HALF will be assessed from serum and plasma concentration-time 
data collected during Cycle 1 and Cycle 4.
Efficacy: BOR, ORR, duration of response, PFS rate at select times 
 
.
Immunogenicity: Frequency of subject immunogenicity status.
Electrocardiography (ECG): Changes in QTcF (ΔQTcF) from baseline at selected times.
Analyses:  
Efficacy Analyses: Efficacy results will be presented by tumor type, dose, and regimen for monotherapy and 
combination cohorts. Individual best overall response (BOR), duration of response and PFS will be listed using 
RECIST version 1.1 criteria or Modified RECIST for malignant pleural mesothelioma (Protocol Appendix 4). BOR 
outcomes will be tabulated by dose and dose regimen. The ORR and PFS rates (eg, at 24 weeks) and the confidence 
interval will be provided by dose and dose regimen for each tumor type if there is a large enough sample size. The 
duration of response and PFS will be estimated by Kaplan-Meier (K-M) methodology. PFS rates (eg, at 24 weeks) 
will be similarly estimated, based on K-M methodology. Individual changes in the tumor burden over time will be 
presented graphically by dose and dose regimen within a tumor type.
 
Sponsor can request scans for review at any time during or after the study.
Safety Analyses: All recorded AEs will be listed and tabulated by system organ class, preferred term and treatment. 
Clinical laboratory test results will be listed and summarized by treatment. Any significant physical examination 
findings and clinical laboratory results will be listed. Vital sign measurements will be listed. ECG readings (reviewed 
by a central laboratory) will be evaluated by the investigator and abnormalities, if present, will be listed.
For subjects with serial ECG measurements
, ΔQTcF, ECG 
intervals QRS and PR, and changes in heart rate (ΔHR) will be tabulated by dose and study day. Frequency
distributions of max QTcF values, max ΔQTcF, max QRS, max PR, and max HR in pre-specified categories will be 
tabulated by dose. Scatter plots of HR, ΔHR, QTc, and ΔQTcF versus time-matched active ADC and unconjugated 
tubulysin concentrations will be provided. A concentration-response effect of BMS-986148 on QTcF may be assessed 
by a linear mixed effects regression model for ΔQTcF on plasma and serum concentrations, stratified by study day, 
as well as pooled across days. Additional modeling of exposure-response may also be explored. 
Pharmacokinetic Analyses: PK parameters for the total antibody, 
 active ADC, 
 and 
unconjugated tubulysin will be calculated using noncompartmental analysis and tabulated following monotherapy and 
combination treatments. Summary statistics will be tabulated for the PK parameters by dose, dose regimen, and study 
day for each select analyte. To describe the dependency on dose, scatter plots of Cmax and AUC (TAU) versus dose 
will be provided on indicated study days for each dose regimen. 
 
 To 
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Mesothelin-ADC
assess the attainment of steady state geometric mean Cmin values will be plotted versus study day by dose and dose 
regimen. Summary statistics for nivolumab PK will also be tabulated.
Immunogenicity Analyses: All available immunogenicity data will be listed and flagged for subjects with at least 
1 positive ADA. The frequency of subjects with at least 1 positive ADA assessment at baseline and the frequency of 
subjects who develop ADA after initiation of treatment (ADA positive) will be provided. Details and potentially 
additional endpoints (eg, incidence of persistent positive ADA) and analysis will be provided in the SAP. Associations 
of immunogenicity measures with PK and/or selected AE may be explored. The above analysis will be provided for 
BMS-986148 after monotherapy and combination treatments and for nivolumab.
Exploratory Biomarker Analyses:
 
 
 
Association between efficacy measures 
 may be assessed by graphs and/or summary 
statistics for each select tumor type using data from Part 2. The same assessments will be made with respect to CA125 
levels in the ovarian cancer and mesothelioma cohorts only and with respect to CA19-9 levels in the pancreatic cancer 
cohort only. 
 
 
 
 
For the combination treatment cohorts, changes in inflammatory cytokines and in markers related to peripheral blood 
immune cell subsets will be described similarly. Associations of other tumor-based baseline markers,  and of mutations 
and other genetic anomalies with efficacy measures will be explored graphically and by summary statistics.
Interim Analysis: 
Because of the exploratory nature of the early phase study, data emerging from each dose level or each part of the 
study will be examined prior to the formal locking of the study database for timely decisions about, such as but not 
limited to, dose selection, regimen selection, and early termination of the study. There will be no formal hypothesis 
testing, nor will multiplicity be adjusted. 
Bayesian regression model may be utilized to inform dose selection starting for the third dose in Part 1A. A similar 
approach may be used in Part 1B.
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION 
 ..................................................... 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
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1.5 Overall Risk/Benefit Assessment ..................................................................... 
1.5.1 Risk/Benefit for BMS-986148 Monotherapy ............................................ 
1.5.2 Risk/Benefit for BMS-986148 and Nivolumab Combination Therapy ..... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Dose Escalation (Part 1) ......................................................................... 
3.1.2 Dose Expansion (Part 2) .......................................................................... 
3.1.3 BMS-986148 in Combination with Nivolumab (Part 3) .......................... 
3.1.3.1 Part 3A (Dose Escalation) .............................................................. 
3.1.3.2 Part 3B (Dose Expansion) .............................................................. 
3.1.4 Administration of Additional Treatment Cycles (Part 3) ......................... 
3.1.5 Treatment Beyond Progression ................................................................ 
3.1.6 Follow-Up ................................................................................................ 
3.1.7 Retreatment during Survival Follow-Up (Part 3) .................................... 
3.2 Post-Study Access to Therapy .......................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Guidelines for the Management of Infusion Reactions ............................ 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post-Study Drug Follow Up.............................................................................. 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Noninvestigational Product ............................................................................... 
4.3 Storage and Dispensing..................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Dose Limiting Toxicities .......................................................................... 
4.5.2 Guidelines for Dose Modifications .......................................................... 
4.5.3 Dose Delay Criteria (Applicable for Part 3) ........................................... 
4.5.4 Criteria to Resume Treatment for Part 3 ................................................. 
4.5.5 Study Drug Discontinuation (Part 3) ....................................................... 
4.6 Treatment beyond Disease Progression ............................................................ 
4.6.1 Discontinuation Due to Further Progression (Confirmed Progression) . 
4.7 Management Algorithms for Immuno-oncology Agents .................................. 
4.8 Blinding/Unblinding ......................................................................................... 
4.9 Treatment Compliance ...................................................................................... 
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4.10 Destruction of Study Drug .............................................................................. 
4.11 Return of Study Drug ...................................................................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening ..................................................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Laboratory Test Assessments ................................................................... 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Primary Efficacy Assessment ................................................................... 
5.4.3 Imaging Assessment for the Study............................................................ 
5.5 Pharmacokinetic and Immunogenicity Assessments ........................................ 
5.5.1 Pharmacokinetics and Immunogenicity: Collection and Processing ...... 
5.5.2 Pharmacokinetic Sample Analyses .......................................................... 
5.5.3 Antibody-Drug Antibody Sample Analyses .............................................. 
5.5.4 Labeling and Shipping of Biological Samples ......................................... 
5.8 Outcomes Research Assessments ..................................................................... 
5.10 Results of Central Assessments ...................................................................... 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug-Induced Liver Injury ................................................................ 
6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
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8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
8.3.2.1 Pharmacokinetics ............................................................................ 
8.3.2.2 Efficacy ........................................................................................... 
8.3.2.3 QTc .................................................................................................. 
8.3.2.4 Immunogenicity (Anti-Drug Antibodies) ......................................... 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.5 Immunogenicity Analysis ......................................................................... 
8.4.8 Outcomes Research Analyses .................................................................. 
8.4.9 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 DOSE ESCALATION DESIGN ALGORITHM BASED ON 
MODIFIED TOXICITY PROBABILITY INTERVAL (MTPI) METHOD FOR 
MONOTHERAPY .................................................................................................. 
APPENDIX 2 SIMULATIONS OF MTPI VS 3 + 3 DOSE ESCALATION DESIGNS
................................................................................................................................. 
APPENDIX 3 MANAGEMENT ALGORITHMS ....................................................... 
APPENDIX 4 RECIST V1.1 & MODIFIED RECIST CRITERIA FOR 
ASSESSMENT OF RESPONSE IN MALIGNANT PLEURAL 
MESOTHELIOMA ................................................................................................. 
APPENDIX 5 ECOG PERFORMANCE STATUS ..................................................... 
APPENDIX 6 NYHA CLASSIFICATION .................................................................. 
APPENDIX 7 DRUGS WITH RISK OF TORSADES DE POINTES ........................ 
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1
INTRODUCTION 
Patients with metastatic or refractory solid tumors have very poor prognosis.1 Despite advances 
in multimodal therapy, increases in overall survival (OS) in this patient population have been 
limited. The unmet need resides in the lack of effective treatments to deliver long-term survival,
hence the need to test compounds that have novel mechanisms of action in clinical studies to 
achieve better response rates.
Traditional cancer chemotherapy is often accompanied by systemic toxicity to the patient. 
Monoclonal antibodies against antigens on cancer cells offer an alternative tumor-selective 
treatment approach. However, most monoclonal antibodies are not sufficiently potent to be 
therapeutically active on their own. Antibody–drug conjugates (ADCs) use antibodies to deliver 
a potent cytotoxic compound selectively to tumor cells, thus improving the therapeutic index of 
chemotherapeutic agents. The recent approval of 2 ADCs, brentuximab vedotin2 (BV) and 
trastuzumab emtansine (T-DM1),3 for cancer treatment has spurred tremendous research interest 
in this field.
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1.2
Research Hypothesis 
There is no formal primary research hypothesis for this study to be statistically tested. The 
purpose of this study is to evaluate the safety profile, tolerability, preliminary efficacy, PK, and 
PD of BMS-986148 administered alone and in combination with nivolumab in subjects with 
select advanced solid tumors.
1.3
Objectives(s)
1.3.1
Primary Objectives
•
To assess the safety and tolerability of BMS-986148 administered as monotherapy and in 
combination with nivolumab in subjects with select advanced solid tumors
1.3.2
Secondary Objectives
•
To assess the preliminary anti-tumor activity of BMS-986148 as monotherapy and in 
combination with nivolumab as measured by objective response rate (ORR), response 
duration, and progression-free survival (PFS)
•
To characterize the PK of the total antibody (unconjugated antibody + antibody conjugated to 
tubulysin or antibody conjugated to any tubulysin metabolites), active ADC (antibody 
conjugated to tubulysin), and unconjugated tubulysin when BMS-986148 is administered as 
monotherapy and in combination with nivolumab
•
To characterize the PK of nivolumab when administered in combination with BMS-986148
•
To assess the effect of BMS-986148 monotherapy dosage regimen and exposure (active 
ADC and unconjugated tubulysin) on the QT interval
•
To characterize the immunogenicity of BMS-986148 as monotherapy and in combination 
with nivolumab
•
To characterize the immunogenicity of nivolumab in combination with BMS-986148
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1.5
Overall Risk/Benefit Assessment
1.5.1
Risk/Benefit for BMS-986148 Monotherapy 
There is no prior human experience with BMS-986148; therefore, clinical benefit has not been 
assessed in subjects with advanced cancer. Because of its high expression on multiple tumors, 
mesothelin has been suggested as an attractive target for antibody targeting. Several therapeutic 
agents that target cell surface mesothelin have been developed and some are being evaluated in 
preclinical and clinical studies. Three distinct molecules are in clinical development: an antibody 
fragment linked to an immunotoxin, a chimeric anti-mesothelin antibody, and an ADC linked to 
a cytotoxic payload DM-4.47 Recombinant immunotoxin SS1P is composed of a variable 
anti mesothelin fragment (Fv) that was obtained from a phage library of mice immunized with 
recombinant mesothelin, which was then fused to Pseudomonas exotoxin A (PE38).48,49
Two Phase 1 clinical trials of SS1P were completed at the National Cancer Institute (NCI).50,51
Based on Phase 1 clinical data of SS1P and its anti-tumor activity, a clinical trial of SS1P in 
combination with chemotherapy is currently ongoing. However, there are limitations with the 
immunotoxins, including high immunogenicity which limits repeat dosing.
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Additional clinical data comes from MORAb-009 (amatuximab), a chimeric antibody containing 
murine SS1 Fv and human IgGγ1 and κ constant region.52 A Phase 1 clinical trial of 
MORAb-009 for mesothelioma, pancreatic cancer, and ovarian cancer patients was completed.53
A total of 24 subjects were treated, including 13 mesothelioma, 7 pancreatic cancer, and 
4 ovarian cancer patients. Eleven subjects had stable disease (SD). Of interest, treatment of 
patients with MORAb-009 led to a marked increase in the CA125 levels, which returned to 
baseline when treatment was terminated. Thus far, the safety profile has been favorable, with an 
MTD of 200 mg/m2. Phase 2 studies of MORAb-009 in combination with pemetrexed and 
cisplatin in mesothelioma subjects54 reported that the combination was well tolerated. Median 
OS was 14.8 months.55
BAY 94-9343 is a fully human anti-human mesothelin IgG1 antibody linked to a cytotoxic 
tubulin-binding maytansinoid payload, DM-4, and is in Phase 1 clinical trials for the treatment of 
patients with advanced solid tumors.56 Based on poster and oral presentations at the 
2013-American Association for Cancer Research meeting, the half-life was reported to be 6 days 
for the antibody and 3.5 days for the DM-4 payload. The MTD was determined to be 6.5 mg/kg, 
based on significant AEs at 7.5 mg/kg notable for ocular/corneal toxicity, amylase and lipase 
elevation, peripheral neuropathy, hyponatremia, and AST elevations. The trial continues to 
accrue subjects in the expansion phase of the study.57
The nonclinical toxicology studies in rats and monkeys primarily demonstrated the expected 
toxicity profile that results from microtubule inhibition via tubulysin and mesothelin antigen 
targeting. The primary antigen-dependent targets were the serosal surfaces of various thoracic 
and abdominal organs and the conjunctiva and cornea of the eye. Nonantigen dependent 
toxicities involved the GI, liver, and bone marrow. These toxicities were dose dependent. 
 
The nonclinical toxicity profile was used to determine the starting dose and develop appropriate 
exclusion criteria and safety monitoring for this study. In addition, frequent complete blood 
counts (CBCs) and chemistry (including liver function) tests will be performed to assess the 
potential nonantigen dependent myelosuppression and liver function effects of BMS-986148. 
Subjects will be evaluated frequently by physical examination (PE), and they will be assessed for 
the development of ocular symptoms and peripheral neuropathy (although not seen in toxicology 
studies, peripheral neuropathy is a known side effect of some microtubule inhibitors). Subjects 
with Grade 2 or higher ocular symptoms or peripheral neuropathy will be excluded from the 
study. Ophthalmological examination by an ophthalmologist or locally qualified personnel will 
include an 8-point exam (visual acuity, pupils, extraocular motility and alignment, tonometry, 
visual field, external examination, slit lamp examination, and fundoscopy) at baseline and 
focused exams with visual acuity, slit lamp, and as indicated will be conducted during the study. 
Safety assessments are outlined in Section 5.3. The dose escalation plan uses Grade 2 ocular 
symptoms, as well as other Grade 3 and 4 DLTs, to trigger a transition from 100% dose 
escalation increments to a dose escalation increment sequence of 67%, 50%, 40%, and 
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continuing at 33%, to reduce the risk of drug related AEs.  No significant ocular toxicities have 
been observed in the 30 subjects dosed as of 01 July 2016.
In addition, subjects with a left ventricular ejection fraction (LVEF) below the lower limit of 
normal, New York Heart Association (NYHA) Class 2 or higher heart failure, and elevated
Troponin I or T will be excluded from the study. Cardiac monitoring with echocardiogram, 
EKG, and Troponin T or I will be conducted during the study. Safety assessments are outlined in 
Section 5.3. As of 01 July 2016, no troponin elevations were noted in the 30 subjects dosed in 
the monotherapy escalation of Part 1A. One SAE of Grade 3 pericardial effusion related to study 
drug was observed after the second cycle of BMS-986148 at the high dose of 1.6 mg/kg Q3W in 
Part 1A. This dose has been determined to be above the MTD, and no additional subjects will be 
treated at this dose level.
The frequent safety assessments will be utilized by the BMS Medical Monitor and investigators 
to determine whether dose modification, additional safety measures, or termination of the study 
is required at any time. Thorough evaluation of the above-described safety monitoring 
procedures and of AEs and SAEs will be reviewed on an ongoing basis by the BMS Medical 
Monitor and Global Pharmacovigilance and Epidemiology representatives to monitor for any 
safety signals or trends.
As BMS-986148 is an experimental agent, it is possible that unforeseen, unknown, or 
unanticipated reactions may occur. However, based on the clinical safety profile of BMS-986148
, and the 18.8-fold safety margin inherent in the planned starting dose of 
0.1 mg/kg given Q3W followed by a cautious dose escalation scheme, the potential safety risks 
are expected to be minimized. Predicted human exposure at the starting dose of 0.1 mg/kg is 
consistent with exposures that demonstrated anti-tumor activity in mouse xenograft tumor 
models and may be beneficial to subjects enrolled in this clinical study.
A need exists for new therapies for subjects with advanced cancer that has progressed or not 
responded to other treatments. Once a pharmacologically-active dose range is reached, there may 
be potential benefits to study subjects. Furthermore, the substantial preclinical efficacy profile 
 and the evidence for mesothelin expression in many human cancers 
, indicates that the balance of benefit to risk is likely to be favorable for study 
subjects treated with BMS-986148 monotherapy.
1.5.2
Risk/Benefit for BMS-986148 and Nivolumab Combination Therapy
Nivolumab has demonstrated clinical activity in subjects with advanced NSCLC, renal cell 
carcinoma, melanoma, and lymphomas, as well as other tumors, including ovarian, gastric, and 
mesothelioma. The clinical activity of nivolumab monotherapy observed to date in these 
malignancies suggests the potential for improved clinical outcomes relative to other approved 
therapies. 
Nivolumab has demonstrated a manageable safety profile. The overall safety experience, when 
used either as a monotherapy or in combination with another therapeutic, is based on experience 
in approximately 8,600 subjects treated to date. There is no pattern in the incidence, severity, or 
causality of AEs with respect to nivolumab dose level. The most common AEs (as of 01 July 
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2016) include fatigue, rash, pruritus, diarrhea, and nausea. Side effects of nivolumab therapy 
may include those associated with immune-mediated activation, such as pneumonitis, thyroiditis, 
and hepatitis. Most of these events resolved with immune-modulating medication. To mitigate 
risk from serious immune-mediated AEs, subject management algorithms for nivolumab-related 
AEs from prior collective nivolumab experience have been included (Appendix 3). 
There is potential for overlapping toxicity between clinical findings of BMS-986148 and 
nivolumab-related hepatoxicity, infusion-related reactions, and peripheral neuropathy.
Elevation of the liver transaminases were the DLTs noted in 4 of the 10 subjects treated with 
BMS-986148 at 1.6 mg/kg Q3W. This dose is above the MTD, and no additional subjects will be 
treated at this dose. At the selected starting dose of BMS-986148 of 0.8 mg/kg IV Q3W, no
DLTs were observed in the 4 evaluable subjects. However, the incidence of nivolumab-related 
hepatitis is quite low (approximately 1%). Subjects in this study receiving BMS-986148 
monotherapy or BMS-986148 and nivolumab combination therapy will be monitored closely for 
any LFT abnormalities via laboratory assessments and frequent assessment for the development 
of symptoms. Study drug will be discontinued for any significant LFT abnormalities. 
Peripheral neuropathy related to BMS-986148 is infrequent. No events related to study drug are 
noted to date as of 01 July 2016. Details of these events are summarized in Section 1.5.1. For 
nivolumab monotherapy, the incidence of neuropathies was < 1%, and management guidelines 
have been established as detailed in the nivolumab IB. To minimize potential risks, criteria 
excluding subjects with peripheral neuropathy and dose modifications have been developed. In 
addition, subjects in this study receiving BMS-986148 monotherapy or BMS-986148 and 
nivolumab combination therapy will be monitored closely for any peripheral neuropathy via 
neurologic assessments and frequent assessment for the development of neurologic symptoms. 
Study drug will be discontinued for any significant neurologic developments. 
Infusion reactions, including high-grade hypersensitivity reactions, following administration of 
nivolumab are uncommon. For BMS-986148, no infusion reactions have been reported to date 
(as of 01 July 2016 data cut-off date). Subjects will be monitored during the first cycle of the 
combination therapy and will continue to be monitored during subsequent cycles. Detailed 
management guidelines for infusion reactions are provided (see Section 4.5). 
Significant ocular toxicities as seen in the preclinical toxicology studies have not been noted in 
the study thus far. For nivolumab monotherapy, the incidence of uveitis was < 1%, and 
management guidelines have been established as detailed in the nivolumab IB. Subjects will
continue to be monitored by opthalmologic examination for ocular symptoms, throughout the 
study treatment. 
Subjects enrolling in Part 3 will have advanced solid tumor malignancies that has relapsed after 
standard of care chemotherapy or available therapies. The potential synergistic effects of 
nivolumab with BMS-986148 and the risk/benefit ratio support evaluation of this combination.
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to Bristol-Myers Squibb (BMS) immediately. A 
serious breach is a breach of the conditions and principles of GCP in connection with the study 
or the protocol, which is likely to affect, to a significant degree, the safety or physical or mental 
integrity of the subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The 
investigator or BMS should also provide the IRB/IEC with a copy of the IB or product labeling 
information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives 
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form(s) which will include all elements required by ICH, GCP, and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
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•
Provide a copy of the consent form(s) and written information about the study in the 
language in which the subject is most proficient prior to clinical study participation. The 
language must be nontechnical and easily understood. 
•
Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study.
•
Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form(s) and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
•
If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject.
•
Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed 
informed consent form and, in the US, the subjects’ signed Health Insurance Portability and 
Accountability Act Authorization.
The consent form(s) must also include a statement that BMS and regulatory authorities have 
direct access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a Phase 1/2a, open-label study to characterize the safety and tolerability, as well as 
preliminary efficacy, PK, and PD of BMS-986148 administered alone and in combination with 
nivolumab in subjects with select advanced solid tumors (pancreatic, ovarian, NSCLC, gastric, or 
mesothelioma). The study has 3 segments: Part 1 (Phase 1 study - dose escalation), Part 2 
(Phase 2a - dose expansion), and Part 3 (BMS-986148 in combination with nivolumab; Part 3A -
dose escalation and Part 3B - dose expansion) (see Figure 3.1-1). All subjects will complete up to 
4 study periods: Screening (up to 28 days), Treatment (21 days/cycle Q3W or 28 days/cycle 
QW), Follow-up (60 or 100 days), and Survival Follow-up (see Figure 3.1-2). After completing 
the Follow-up period, subjects will continue to be followed for 
up to 2 years from first dose 
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of study drug for subjects discontinuing study drug prior to 2 years. Subjects receiving study 
drug for more than 2 years will be followed in the Survival Follow-up period for 6 months from 
their last treatment date. With Amendment 3, a dose escalation phase will be conducted with 
BMS-986148 and nivolumab combination therapy (Part 3A). In the BMS-986148 and nivolumab 
combination therapy dose expansion phase (Part 3B), additional subjects with pancreatic, 
ovarian, NSCLC, gastric, or mesothelioma will be treated at or below the MTD of the 
combination dose identified in Part 3A to confirm safety and evaluate anti-tumor activity. 
The duration of the study is anticipated to be approximately 5 years from the time of the first 
visit of the first subject to the required Survival Follow-up of the last subject enrolled. The end of 
the study will occur when the last subject has the last Survival Follow-up visit.
Figure 3.1-1:
Sequence of Study Phases
QW: every week; Q3W: every 3 weeks.
Figure 3.1-2:
Dosing (Q3W and QW) and Study Periods
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Note: Subjects treated for > 2 years will be followed for 6 months after EOT in the Survival Follow-Up.
Additionally, specifically in Part 3, treatment duration is 24 weeks to a maximum of 48 weeks.
C1D1: Cycle 1 Day 1 (first dose); D: day; DLT: dose-limiting toxicity; EOT: end of treatment; QW: every week; 
Q3W: every 3 weeks.
3.1.1
Dose Escalation (Part 1)
Part 1 is divided into 2 sections. In Part 1A, BMS-986148 will be administered with Q3W dosing 
(21 days/cycle), and in Part 1B, BMS-986148 will be administered with QW dosing for 3 weeks 
followed by 1 week off (28 days/cycle). Part 1B may be initiated once the MTD or a tolerated 
dose below the MTD for Part 1A is established.
Part 1A: BMS-986148 Administered Every 3 Weeks
Approximately 30 subjects will be enrolled in ascending dose cohorts starting with a dose of 
0.1 mg/kg. BMS-986148 will be administered Q3W in a 21-day cycle. The approach for 
selection of the next dose at each escalation step and the rules for escalation decision based on 
DLT criteria guided by the mTPI design are described below, with more details in Section 4.5.1. 
Part 1A: Selection of Doses
A modified Fibonacci dose escalation will be used.
The first cohort of subjects will receive a starting dose of 0.1 mg/kg. Dose escalation for each 
subsequent cohort of subjects will be guided by the incidence of BMS-986148-related AEs as 
graded by NCI Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE 
v4.03) in the first 3 weeks of dosing (DLT evaluation period). Dose escalation will be in 
increments of 100% above the previous dose level until the first occurrence of any of the 
following: DLT, ≥Grade 3 decrease in neutrophil count lasting > 72 hours, ≥Grade 3 
thrombocytopenia lasting > 72 hours, ≥Grade 2 ocular toxicity, or 2 subjects with ≥Grade 2 
AEs in a single dose level cohort and considered related to BMS-986148 with the following 
exceptions: asymptomatic electrolyte abnormalities that can be managed with appropriate 
supplements and Grade 2 alopecia. In addition, Grade 2 fatigue that is less than 2 grades from 
baseline (ie, from Grade 1 to Grade 2) will not trigger a Fibonacci sequence. Once one or more 
of the above occur, a modified Fibonacci dose escalation will be employed for any subsequent 
dose escalations, with increments of 67%, 50%, 40%, and 33%. Any further dose escalations will 
be 33%. 
Intermediate doses may be evaluated if agreed upon by the BMS Medical Monitor and 
investigators. The next dose level will not exceed 100% or the dose increment per the modified 
Fibonacci dose escalation.
Part 1A: Dose Escalation Decision Rules
Enrollment in dose escalation and selection of the MTD will adhere to a mTPI design. The 
design provides a simple algorithm to guide decisions on escalation, expanding at the same dose, 
and de-escalation, depending on the number of observed toxicities after each dose cohort (see 
Figure 3.1.1-1). The mTPI method utilizes a target toxicity (DLT) rate and equivalence interval 
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(EI) to guide decisions on escalation after each cohort and to estimate the MTD. For this study 
the target DLT rate is 27%, and the EI is 25% to 29%. 
Dose escalation will begin at a dose of 0.1 mg/kg dose (Dose Level 1) and will be guided by the 
cumulative number of subjects who are DLT evaluable and who experience a DLT. An initial 
cohort of 2 subjects will be enrolled to Dose Level 1 and subsequently dose level 2 (if no DLTs 
in Dose Level 1 and criteria above for transitioning from 100% increment to Fibonacci is not 
met) in Part 1A; otherwise, 3 to 4 patients will be treated. In the first cohort, a 5-day interval is 
required between Cycle 1, Day 1 dosing for the first 2 subjects (ie, 5 days between Cycle 1, Day 
1 dosing for subjects 1 and 2). An initial cohort of 3 subjects will be enrolled to all other dose 
levels in Part 1A. A fourth subject may be enrolled in a dose escalation cohort following 
agreement between the investigator and the BMS Medical Monitor if able to start the first day of 
dosing within approximately 1 week of the third subject in the same dose escalation cohort. At 
any dose level, if the suggested decision by the mTPI design is to expand the same dose, 3 more 
subjects will be enrolled. If the suggested decision is to treat more subjects at a given dose level 
as specified by the mTPI algorithm when there are already at least 13 DLT evaluable subjects 
treated at the same dose level or a total of 30 DLT evaluable subjects treated, the dose escalation 
phase will be stopped.
Decisions to escalate, add more subjects to the current dose, de-escalate, or de-escalate and 
declare the current dose as unacceptable (exceeding the MTD), will be based on the rate of DLTs 
in evaluable subjects within the 21-day DLT evaluation period for Part 1A guided by the mTPI 
model and posterior inference (Figure 3.1.1-1 and Appendix 1). At least 2 DLT-evaluable 
subjects treated at each of the lowest 2 dose levels and at least 3 DLT-evaluated subjects treated 
at each of the other dose levels are required to enable decision making. Subjects with insufficient 
data to establish safety during the DLT evaluation period at the dose tested (eg, omitted or 
reduced doses for reasons other than a DLT) may be replaced upon agreement of the BMS 
Medical Monitor and investigators. 
In addition, if dose modifications for ocular toxicity occur in 2 or more subjects within the first 
5 subjects treated on study, or if with greater patient numbers > 20% of subjects require a dose 
modification due to ocular toxicity, enrollment will be suspended at all dose levels equal to or 
greater than the lowest dose level with a dose modification due to ocular toxicity, in order to 
assess the safety data. Enrollment may continue at lower dose levels where no dose 
modifications have occurred due to ocular toxicity while this safety assessment is being 
conducted.
There will be no intrasubject dose escalation of BMS-986148.
Figure 3.1.1-1 shows examples of scenarios guiding decision making that may be encountered 
during dose escalation with respect to the number of DLT evaluable subjects and the number of 
subjects with a DLT. All potential combinations of the number of DLTs and number of treated 
subjects evaluable for DLT are shown in Appendix 1. In addition to escalation or expansion 
decisions, dose re-escalation is permitted as per Figure 3.1.1-1 and Appendix 1 after a decision to 
de-escalate is made, except when a dose has been identified as exceeding the MTD. Therefore, a 
dose level could be revisited multiple times under the mTPI design.
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Figure 3.1.1-1:
Dose Escalation Algorithm
a
Treat 2 subjects initially if no DLTs in Dose Level 1 and criteria for transitioning from 100% increment to 
Fibonacci is not met; treat 3 to 4 subjects initially, otherwise.
b
At the same dose, decision making based on other combinations of k/n are shown in Appendix 1.
c
Treat the next cohort of subjects at the next higher dose.
d
Treat 3 more subjects at the current dose.
e
Treat 3 more subjects at the next lower dose.
f
Unacceptable current dose. Do not re-escalate to this dose.
DLT: dose-limiting toxicity; k: cumulative number of subjects who experienced DLT; MTD: maximum tolerated 
dose; n: cumulative number of DLT evaluable subjects; QW: every week; Q3W: every 3 weeks.
Part 1A: Maximum Tolerated Dose Determination
At the end of dose escalation, the MTD will be selected as the dose with the smaller difference of 
estimated toxicity and the target DLT rate (27%), among the doses used, with isotonic regression 
modeling of the accumulated DLT data based on the mTPI design. 
How many DLT evaluable subjects have been treated at this dose level?
Treat 3 more subjects
Decision making based on k/nb
T
dd
D
l
Expandd
1/2,   1/3
1/4,   1/5
2/5,   1/6
2/6,   2/7
3/7,   2/8
3/8,  2/9
...
De-escalatee
2/3,   2/4
3/6,   4/8
5/11,   6/13
Exceeds MTD, 
De-escalatef
2/2,   3/3
3/4,   3/5
4/6,   4/7
5/8,   5/9
5/10,   6/11
...
None
2 - 12
>=13
Stop Escalation
Part 1A 1st dose level: treat 2 subjects
Part 1A 2nd dose level: treat 2 or 3-4 subjectsa
Other dose level: treat 3-4 subjects
Escalatec
0/2,   0/3
0/4,   1/7
1/8,   1/9
2/13
If the number of all treated subjects reached 30 for Part 1A or 
24 for Part 1B, stop escalation; otherwise go back to top
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Part 1B: BMS-986148 Administered QW for 3 Weeks and 1 Week Off
Approximately 24 subjects will be enrolled in ascending dose cohorts. Part 1B may begin after 
determining the MTD or a tolerated dose below the MTD in Part 1A. The starting dose for Part 
1B will be chosen by modeling active ADC concentration-time data from Part 1A and selecting a 
fractionated dose that provides similar exposure to that of the MTD or a tolerated dose below the 
MTD. In the event that concentration-time data are not available for modeling, the starting dose 
will be 1/3rd of the MTD or a tolerated dose below the MTD from Part 1A. In Part 1B, 
BMS-986148 is administered every week for 3 weeks and 1 week off in a 28 day cycle. 
Part 1B: Selection of Doses
Similar to dose selection in Part 1A, a modified Fibonacci dose escalation will be used. Dose 
escalation for each subsequent cohort of subjects will be guided by the incidence of 
BMS-986148-related AEs as graded by NCI CTCAE v4.03 in the first 4 weeks of dosing (DLT 
evaluation period). Dose escalation will be in increments of 100% above the previous dose level  
until the first occurrence of any of the following: DLT, ≥Grade 3 decrease in neutrophil count 
lasting > 72 hours, ≥Grade 3 thrombocytopenia lasting for > 72 hours, ≥Grade 2 ocular toxicity, 
or 2 subjects with ≥Grade 2 AEs in a single dose level cohort and considered related to 
BMS-986148 with the following exceptions: asymptomatic electrolyte abnormalities that can be 
managed with appropriate supplements and Grade 2 alopecia. In addition, Grade 2 fatigue that is 
less than 2 grades from baseline (ie, from Grade1 to Grade 2) will not trigger a Fibonacci 
sequence. Once one or more of the above occur, a modified Fibonacci dose escalation will be 
employed for any subsequent dose escalations, with increments of 67%, 50%, 40%, and 33%. 
Any further dose escalations will be 33%. 
Intermediate doses may be evaluated if agreed upon by the BMS Medical Monitor and 
investigators. The next dose level will not exceed 100% or the dose increment per the modified 
Fibonacci dose escalation.
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Part 1B: Dose Escalation Decision Rules
The same mTPI design (Figure 3.1.1-1 and Appendix 1) as in Part 1A will be used to help guide 
escalation decisions except that all dose levels in Part 1B begin with an initial number of 3 to 
4 subjects. A fourth subject may be enrolled in a dose escalation cohort following agreement 
between the investigator and the BMS Medical Monitor if able to start the first day of dosing 
within approximately 1 week of the third subject in the same dose escalation cohort. The DLT 
evaluation period will be 28 days. At least 3 DLT-evaluable subjects treated at each of the dose 
levels in Part 1B will be required to enable a decision to escalate, add more subjects to the 
current dose level, or de-escalate. Subjects must receive 3 doses in Part 1B during the DLT 
evaluation period (unless DLT has occurred) to be considered evaluable for dose escalation 
decisions. Subjects with insufficient data to establish safety during the DLT evaluation period at 
the dose tested (eg, omitted or reduced doses for reasons other than a DLT) may be replaced 
upon agreement of the BMS Medical Monitor and investigators.
Part 1B: Maximum Tolerated Dose Determination 
Similar to the MTD determination in Part 1A, at the end of dose escalation, the MTD will be 
selected as the dose with the smallest difference of estimated toxicity and the target DLT rate 
(27%), among the doses used. See Section 4.5.1 for more information about DLTs.
Once the safety (during DLT evaluation) of a dose level has been established (Part 1A and/or 
Part 1B), additional subjects may be added at that dose to better characterize the PK, safety, and 
PD profile. 
3.1.2
Dose Expansion (Part 2)
The purpose of the cohort expansion will be to assess preliminary antitumor efficacy, expanded 
safety experience, and PD effects of BMS-986148. Additional subjects will be treated after the 
completion of Part 1A and/ or Part 1B, at the MTD, or at an alternative dose below MTD as 
agreed upon by the BMS Medical Monitor and investigators. Part 2 can begin before the 
completion of Part 1B as the Q3W dosing regimen is the intended regimen for Part 2. However, 
if the aggregate PK and safety data indicate similar safety but higher cumulative exposure with 
the QW dose schedule, this schedule may also be evaluated in Part 2 in an additional cohort of 
25 to 26 subjects, once the MTD or a tolerated dose below the MTD is identified in Part 1B. 
Treatment doses in the cohort expansion groups will not exceed the MTD. 
Five expansion cohorts will be restricted to these tumor types 1) mesothelioma 2) pancreatic 
3) ovarian 4) NSCLC, and 5) gastric cancer. Enrollment in cohort expansion will be determined 
by the mesothelin expression of the archived tumor sample (or fresh tumor sample if archived 
sample is not available). 
 
 
 
 
 
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The enrollment in each expansion cohort will be guided by a Simon 2-Stage design framework 
(see Table 8.1-1) exploring efficacy in the following 2 populations: 
 
 
 
.
Anti-tumor activity will be assessed initially in approximately 12 to 15 evaluable subjects per 
tumor type (Stage 1) treated in each monotherapy cohort, with the option to stop enrolling in a 
cohort without an initial anti-tumor activity signal. The number of subjects needed for the Stage 
1 review is guided by a Simon 2-Stage design as shown in Table 8.1-1 below for each tumor type 
with futility boundaries as follows: after Stage 1, if none of the first 15 evaluable subjects in the 
gastric or pancreatic cohorts, if ≤2 of the first 12 with mesothelioma, or ≤1 of the first 14 with 
NSCLC or ovarian cohort demonstrate clinical activity, enrollment in the cohort meeting criteria 
may be stopped for this population.
Evaluation of efficacy will occur independently in each tumor cohort. At the time of the Stage 1 
efficacy assessment, 
 
 to allow an initial efficacy assessment in both the
 
populations. If there is a lack of signal for preliminary efficacy (number of responders not 
exceeding the boundary), and after evaluation of all available data, enrollment may be stopped in 
that population. Otherwise, additional subjects will be treated in Stage 2 for the population in 
which there was an initial signal. 
 
Of note, fresh tumor biopsy at screening and on treatment will be mandatory for 10 ovarian 
cancer subjects and 10 gastric cancer subjects enrolled in Part 2. Fresh tumor biopsy at screening 
and on treatment will be optional for subjects with other indications. 
 
 
As the expected time of response relative to dose initiation and the actual recruitment rate are 
unknown, it is expected that during the efficacy evaluation of subjects in Stage 1, additional
subjects may have been enrolled and will be receiving treatment than the minimum needed for 
the Stage 1 assessment. Therefore, the above numbers are approximate, and enrollment may 
continue during the evaluation of the interim data.
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Safety monitoring of subjects enrolled in the Part 2 (Phase 2a) portion of the study will be the 
same as that conducted during the dose escalation portion. During Part 2, if in a given arm the 
combined incidence of study drug-related AEs that require dose modification exceeds 29% (of 
treated subjects), then further enrollment to that arm will be interrupted, and the findings will be 
discussed between the BMS Medical Monitor and investigators. An agreement will be reached as 
to whether a lower dose or an alternate dose schedule of BMS-986148 should be examined or 
whether any additional treatment guidelines should be implemented prior to enrollment of 
additional subjects on study. 
3.1.3
BMS-986148 in Combination with Nivolumab (Part 3)
During the dose escalation phase with BMS-986148 and nivolumab combination therapy 
(Part 3A), approximately 12 evaluable subjects are expected to be treated at 2 doses of 
BMS-986148 (0.8 mg/kg and 1.2 mg/kg Q3W) and nivolumab (360 mg Q3W) combination 
therapy. In the BMS-986148 and nivolumab combination therapy dose expansion phase (Part 
3B), approximately 25 to 26 evaluable subjects will be treated at each tumor cohort.
3.1.3.1
Part 3A (Dose Escalation)
Selection of Dose Levels to be Evaluated
The starting dose of BMS-986148 to be combined with nivolumab at 360 mg Q3W in Part 3A 
will be 0.8 mg/kg administered IV Q3W. 
Approximately 12 subjects will be enrolled in ascending dose cohorts starting with a dose of 
BMS-986148 (0.8 mg/kg IV Q3W, first dose level) with nivolumab 360 mg administered Q3W 
in a 21-day cycle. Subsequent escalation to 1.2 mg/kg Q3W of BMS-986148 (or MTD 
determined from Part 1A) in combination with nivolumab 360 mg Q3W will be guided by the 
mTPI design described below. In the event that the first dose level of BMS-986148 is determined 
to exceed the MTD in combination with 360 mg Q3W of nivolumab, a lower BMS-986148 dose 
tested in monotherapy escalation (such as 0.4 mg/kg and/or 0.2 mg/kg) may be explored based 
on available safety, PK
. Nivolumab will be administered as 360 mg 
IV Q3W in all dose cohorts.
Intermediate doses of BMS-986148 in combination with 360 mg Q3W of nivolumab may be 
evaluated if agreed upon by the BMS Medical Monitor and investigators. The next dose level 
will not exceed 100% of the dose increment. 
Dose Escalation Decision Rules
A similar mTPI design as in Part 1A will be used to guide dose escalation decisions and to select 
the MTD. A DLT target rate of 29% (EI = 28% to 31%) will be utilized for combination 
treatment to guide escalation decisions. Dose escalation decisions will be based on the total 
number of subjects in a dose level who were DLT evaluable and the number of DLTs, guided by 
the mTPI Bayesian model and posterior inference.
The number of subjects at the initial cohort of all dose levels in Part 3A will be 3 to 4. A fourth 
subject may be enrolled in a dose escalation cohort following agreement between the investigator 
and the BMS Medical Monitor if able to start the first day of dosing within approximately 
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1 week of the third subject in the same dose escalation cohort. The DLT evaluation period will 
be 21 days. Enrollment of additional cohorts at the same dose level will proceed in sample sizes 
of up to 3 or 4 subjects. Subsequent dose levels will follow similar cohort enrollment size and 
decision rules. At least 3 DLT-evaluable subjects treated at each of the dose levels in Part 3A 
will be required to enable a decision to escalate, add more subjects to the current dose level, or 
de-escalate and declare the current dose as unacceptable (exceeding the MTD). Subjects with 
insufficient data to establish safety during the DLT evaluation period at the dose tested (eg,
omitted or reduced doses for reasons other than a DLT) may be replaced upon agreement of the 
BMS Medical Monitor and investigators.
Table 3.1.3.1-1:
Dose Escalation Decision Guide in Combination with Nivolumab
Number of DLT Evaluable Subjects at a Dose Level
3
4
5
6
7
8
9
10
11
12
N of 
DLT 
at a 
dose 
level
0
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
2
D
S
S
E
S
S
S
S
E
E
3
DU
DU
D
E
S
S
S
S
S
S
4
DU
DU
DU
D
D
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
6
DU
DU
DU
DU
DU
DU
D
7
DU
DU
DU
DU
DU
DU
8
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
10
DU
DU
DU
11
DU
DU
12
DU
DLT: dose-limiting toxicity; E: escalate to next higher dose level; D: de-escalate to the next lower dose level; S: stay 
at the current dose level; DU: unacceptable dose level, not to be re-visited.
Part 3A: Maximum Tolerated Dose Determination 
Similar to the MTD determination in monotherapy parts, at the end of dose escalation, the 
cumulative number of subjects who experience a DLT at each dose level will be used to estimate 
the MTD using isotonic regression as the dose with the smaller difference of estimated toxicity 
rate and the target DLT rate (29%), among the doses used. For DLT, see Section 4.5.1.
Once the safety (during DLT evaluation) of a dose level has been determined, additional subjects 
may be added at that dose, to better characterize the PK, safety, and PD profile.
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3.1.3.2
Part 3B (Dose Expansion)
The purpose of the cohort expansion will be to assess preliminary anti-tumor efficacy, expanded 
safety experience, and PD effects of BMS-986148 in combination with nivolumab. Additional 
subjects will be treated after the completion of Part 3A, at the MTD or at an alternate dose below 
the MTD as agreed upon by the BMS Medical Monitor and investigators. Five expansion cohorts 
will be restricted to these tumor types: 1) mesothelioma, 2) pancreatic, 3) ovarian, 4) NSCLC,
and 5) gastric cancer. Enrollment in cohort expansion will be determined by the mesothelin 
expression of the archived tumor sample (or fresh tumor sample if archived sample is not 
available). 
 
 
 
 
The enrollment in each combination expansion cohort will also be guided by a Simon 2-Stage 
design framework (see Table 8.1-2), exploring efficacy in the 
 
.
Anti-tumor activity will be assessed initially in approximately 11 to 14 evaluable subjects per 
tumor type treated in a combination cohort, with the option to stop enrolling in a cohort without 
an initial anti-tumor activity signal. The number of subjects needed for the Stage 1 review is 
guided by a Simon 2-Stage design, assuming ORR as shown in Table 8.1-2 for each tumor type 
with futility boundaries as follows: after Stage 1, if 0 or 1 of the first 11 evaluable subjects in the 
gastric or pancreatic cohorts, 0 or 1 of the first 14 in the evaluable ovarian cohorts, ≤2 of the 
first 12 with mesothelioma cohort, or ≤1 in the first 10 in the NSCLC cohort show clinical 
activity, enrollment in the cohort meeting criteria may be stopped. 
Evaluation of efficacy will occur independently in each tumor cohort. At the time of the Stage 1 
efficacy assessment, subjects will be enrolled to include sufficient numbers in both the 
 
populations to allow an initial (Stage 1) efficacy assessment. If there is a lack of 
signal for preliminary efficacy (number of responders not exceeding the boundary), and after 
evaluation of all available data, enrollment may be stopped in that population. Otherwise, 
additional subjects will be treated in Stage 2 for the population in which there was an initial 
signal. 
 
As described for the monotherapy expansion, the above numbers are approximate, and 
enrollment may continue during the evaluation of the interim data.
Of note, fresh tumor biopsy at screening and on treatment will be mandatory for 10 ovarian 
cancer subjects and for 10 gastric cancer subjects enrolled in Part 3B. Fresh tumor biopsy at 
screening and on-treatment will be optional for subjects with other indications. 
 
 
  
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Safety monitoring of subjects enrolled in the Part 3B portion of the study will be the same as that 
conducted during the dose escalation portion. During Part 3, if in a given arm the combined 
incidence of study drug-related AEs that require dose modification exceeds 31% (of treated 
subjects), then further enrollment to that arm will be interrupted, and the findings will be 
discussed between the BMS Medical Monitor and investigators. An agreement will be reached as 
to whether a lower dose or an alternate dose schedule of BMS-986148 in combination with 
nivolumab should be examined or whether any additional treatment guidelines should be 
implemented prior to enrollment of additional subjects on study. 
3.1.4
Administration of Additional Treatment Cycles (Part 3) 
In Part 3 of this study, all subjects will be treated for 24 weeks (up to 8 cycles) of BMS-986148 
in combination with nivolumab unless criteria for study drug discontinuation are met earlier 
(Section 3.5). All subjects completing approximately 24 weeks of study therapy with ongoing 
disease control (CR, PR, or SD) may be eligible for an additional 24 weeks of study therapy at 
the originally assigned dose regimen in both escalation and cohort expansion beyond the initial 
24 weeks, on a case-by-case basis, after careful evaluation and discussion with the BMS Medical 
Monitor to determine whether the benefit/risk ratio supports administration of further study 
therapy. Upon completion of 24 weeks of study therapy (or up to a maximum of 48 weeks if 
applicable), all subjects will enter the clinical/safety Follow-up period.
Following every 2 treatment cycles (every 6 weeks [Q6W] for Part 3), the decision to treat a 
subject with additional cycles of study therapy will be based on radiological tumor assessments 
(initial evaluation performed at baseline and every 2 cycles or every 6 weeks). Treatment 
decisions related to subject management will be based exclusively on Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1 or Modified RECIST for malignant pleural 
mesothelioma (see Appendix 4).58 Assessments of PR and CR must be confirmed at least 4 
weeks following initial assessment. Subjects with an overall response of CR, PR, or SD will 
continue therapy until they develop CR confirmed, develop progressive disease, experience 
clinical deterioration, develop AEs requiring discontinuation of treatment, or withdraw consent. 
Individual subjects with confirmed CR will be given the option to continue BMS-986148 in 
combination with nivolumab on a case-by-case basis after specific consultation and agreement 
between the investigator and BMS Medical Monitor in settings where benefit/risk justify 
continuation of study therapy.
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3.1.5
Treatment Beyond Progression
Treatment beyond progression in Part 3 of this study may be allowed in select subjects with 
initial RECIST version 1.1 or Modified RECIST for malignant pleural mesothelioma-defined 
progressive disease after discussion and agreement with the BMS Medical Monitor that the 
benefit/risk assessment favors continued administration of study therapy (eg, subjects are 
continuing to experience clinical benefit as assessed by the investigator, tolerating treatment, and 
meeting other criteria specified in Section 4.6).
3.1.6
Follow-Up
Subjects who develop toxicity requiring discontinuation of treatment will enter the Follow-up
period. Subjects should be seen in follow up at least every 30 days, until the AE has resolved to 
baseline, stabilized, or been deemed irreversible. After completion of the Follow-up period, 
subjects will then enter the Survival Follow-up period. During this period, clinic visits or 
telephone contact every 3 months will be performed to assess survival status. The duration of this 
period is detailed in Section 3.1. Subjects in Survival Follow-up who have progression of disease 
will be eligible to receive anti-cancer therapy as appropriate. 
3.1.7
Retreatment during Survival Follow-Up (Part 3)
Retreatment may be allowed in Part 3 of this study with disease progression during follow-up. 
Subjects completing approximately 24 weeks of study therapy (or up to a maximum of 48 weeks 
if applicable), who enter Survival Follow-up with ongoing disease control (CR, PR, or SD) for 
reasons other than drug-related toxicity, may be eligible for retreatment, upon subsequent 
confirmed disease progression within 12 months of the last dose of study drug, on a case-by-case 
basis, after careful evaluation and discussion with the BMS Medical Monitor to determine 
whether the benefit/risk ratio supports administration of further study therapy. Subjects meeting 
criteria for retreatment will be treated up to an additional approximately 24 weeks with the 
originally assigned dose regimen (eg, same dose and dose schedule administered during the first 
24 weeks) or modified dose regimen, unless that dose and schedule were subsequently found to 
exceed the MTD, in which case the subject will be treated at the next lower or alternate dose and 
schedule (see Table 4.5.2-1). Subjects entering this phase will follow the schedule as outlined in
Table 5.5.1-4. Samples for PK will be collected less frequently (Table 5.5.1-4). 
 
 
3.2
Post-Study Access to Therapy
At the end of the study, BMS will not continue to provide BMS supplied study drug to 
subjects/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the subject receives appropriate standard of care to treat the condition under study.
3.3
Study Population
For entry into the study, the subject MUST fulfill the required eligibility criteria prior to dosing 
on Day 1. No exceptions will be granted.
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3.3.1
Inclusion Criteria
1) Signed Written Informed Consent
a) The subject must sign the informed consent form prior to the performance of any study 
related procedures that are not considered part of standard of care. 
2) Target Population
a) Subjects must have histological confirmation of one of the following solid tumors for 
participation in the study:
i)
Pancreatic cancer
ii) NSCLC (adenocarcinoma ONLY)
iii) Ovarian cancer (except mucinous carcinoma)
iv) Gastric cancer
v) Pleural or peritoneal mesothelioma (EXCLUDING sarcamatoid mesothelioma)
b) For dose escalation phase: Subjects with advanced or metastatic solid tumors must have 
received and either progressed or been intolerant to a minimum of ONE standard 
treatment regimen. 
c) For the dose expansion phase: Subjects with advanced or metastatic solid tumors must 
have received and either progressed or been intolerant to standard treatment regimens. 
 
 
 
i)
Pancreatic cancer
(a) Documented locally advanced, unresectable or metastatic pancreatic cancer 
who have failed (or are not candidates for) standard therapy.
ii) NSCLC
(a) Must have recurrent or progressive disease during or after platinum 
doublet-based chemotherapy for advanced or metastatic disease OR must have 
recurrent or progressive disease within 6 months after completing 
platinum-based chemotherapy for local disease.
(b) Subjects must have known epidermal growth factor receptor (EGFR),
anaplastic lymphoma kinase (ALK) status, ROS1, and receptor tyrosine 
kinase mutational status.
(c) Subjects with an activating EGFR mutation must have received an EGFR 
tyrosine kinase inhibitor.
(d) Subjects with an ALK translocation must have received an ALK inhibitor.
(e) Subjects must have received prior immunotherapy, if available (such as, but 
not limited to, PD-1/PD-L1 inhibitors, applicable for Parts 1 and 2 
monotherapy).
iii) Ovarian cancer
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(a) Histologically or cytologically documented epithelial ovarian cancer, primary 
peritoneal carcinoma, or fallopian tube cancer. 
(b) Completed at least 1 platinum-based therapy (PBT) regimen (carboplatin, 
cisplatin, or another organoplatinum compound).
(c) Evidence of platinum-resistant disease, relapse/progression within 6 months 
of the completion of PBT, or intolerant to PBT (inability to receive PBT due 
to hypersensitivity reactions to platinum).
(d) Documenetd germline BRCA mutation status, if known. If unknown, subjects 
must consent to allow submitted archived tumor tissue sample (block or 
unstained slides) to be tested.
iv) Gastric cancer
(a) Histologically confirmed, unresectable or metastatic gastric adenocarcinoma.
(b) Treatment with 1 to 2 prior chemotherapy regimens given in the metastatic 
setting for unresectable or metastatic gastric carcinoma.
(c) Documented HER2 mutation status, if known. If unkown, subjects must 
consent to allow submitted archived tumor tissue sample (block or unstained 
slides) to be tested.
v) Mesothelioma
(a) Subjects must have histologically confirmed pleural or peritoneal 
mesothelioma not amenable to potentially curative surgical resection.
(b) Subjects must have had at least 1 prior platinum-containing chemotherapy 
regimen. 
d) All subjects must have at least 1 measurable lesion at baseline by computed tomography 
(CT) or magnetic resonance imaging (MRI) as per RECIST version 1.1 or Modified 
RECIST criteria for malignant pleural mesothelioma (see Appendix 4).58
i)
Measurable lesions may be in an irradiated field as long as there is documented 
progression and the lesion(s) can be reproducibly measured. 
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e)
All subjects must have archival tumor tissue (if slides are provided, will require 
minimum of 10 cut slides [details of epitope stability are provided in the lab manual]) 
identified and available 
. All subjects must consent to 
provide tumor blocks or slides to the Sponsor, and the availability of the tissue must be 
confirmed prior to subjects receiving study medication. However, if an archived tumor 
specimen is unavailable or unsuitable 
, subjects may 
consent to a pre-treatment fresh tumor biopsy to be eligible for this study if it can be 
performed at minimal acceptable clinical risk as judged by the investigator and if it is not 
in a target lesion or a lesion in an area treated with prior radiation therapy.
 
 
f)
Fresh tumor biopsy at screening and on treatment will be mandatory for 10 ovarian 
cancer subjects and 10 gastric cancer subjects enrolled in Parts 2 and 3B of the study.
g) For indications other than ovarian and gastric cancer, subjects have the option to provide 
consent to obtain a fresh, pre-treatment biopsy in Parts 2 and 3B of the study. If consent 
is given to obtain this pre-treatment biopsy, then a fresh on-treatment biopsy will be 
mandatory.
h) Life expectancy of at least 3 months
i)
ECOG performance status score 0 to 1 (See Appendix 5)
3) Subject Re-enrollment:  This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been randomized/has not 
been treated). If re-enrolled, the subject must be re-consented.
4) Previous Treatment
a) Prior anti-cancer treatments are permitted (ie, chemotherapy, radiotherapy, hormonal, or 
immunotherapy).
b) Toxicity (except for alopecia) related to prior anti-cancer therapy and/or surgery must 
either have resolved, returned to baseline or Grade 1, or been deemed irreversible.
c) At least 4 weeks for cytotoxic agents must have elapsed from last dose of prior anti-
cancer therapy and the initiation of study therapy.
d) At least 4 weeks or 5 half-lives for noncytotoxic agents (whichever is shorter) must have 
elapsed from last dose of prior anti-cancer therapy and the initiation of study therapy. If 
5 half-lives is shorter than 4 weeks, agreement with BMS Medical Monitor is mandatory.
5) Age and Reproductive Status
a) Males and females, 18 years of age or greater or local age of majority.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotrophin) within 24 hours prior to the start of study drug.
c) Women must not be breastfeeding. WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with BMS-986148 monotherapy 
plus 5 half-lives of the total antibody (approximately 60 days) plus 30 days (duration of 
ovulatory cycle) for a total of 90 days post-treatment completion (Part 1 and Part 2).
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WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with BMS-986148 and nivolumab combination therapy for 23 weeks (30 
days plus the time required for nivolumab to undergo 5 half-lives) after the last dose of 
study drug (Part 3). 
d) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with BMS-986148 monotherapy
plus 5 half-lives of the total antibody (approximately 60 days) plus 90 days (duration of 
sperm turnover) for a total of 150 days post-treatment completion (Part 1 and Part 2). If 
treated with BMS-986148 and nivolumab combination, males who are sexually active 
with WOCBP must continue contraception for 31 weeks (90 days plus the time required 
for nivolumab to undergo 5 half-lives) after the last dose of study drug (Part 3).
e)
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However, the latter must still undergo 
pregnancy testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% when used consistently and correctly.
At a minimum, subjects must agree to use 1 highly effective method listed below:
Highly Effective Methods of Contraception
Highly effective methods of contraception have a failure rate of < 1% when used consistently 
and correctly. WOCBP and female partners of male subjects, who are WOCBP, are expected to 
use 1 of the highly effective methods of contraception listed below for at least 4 weeks before 
dosing. Male subjects must inform their female partners who are WOCBP of the contraceptive 
requirements of the protocol and are expected to adhere to using contraception with their partner. 
Contraception methods are as follows:
•
Progestogen only hormonal contraception associated with inhibition of ovulation
•
Hormonal methods of contraception, including oral contraceptive pills containing combined 
estrogen + progesterone, vaginal ring, injectables, implants, and intrauterine devices (IUDs) 
such as Mirena®
•
Nonhormonal IUDs, such as ParaGard®
•
Bilateral tubal occlusion
•
Vasectomized partner with documented azoospermia 90 days after procedure
−
Vasectomized partner is a highly effective birth control method provided that partner is 
the sole sexual partner of the WOCBP trial participant and that the vasectomized partner 
has received medical assessment of the surgical success.
•
Intrauterine hormone-releasing system 
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•
Complete abstinence
−
Complete abstinence is defined as the complete avoidance of heterosexual intercourse 
(refer to Glossary of Terms).
−
Complete abstinence is an acceptable form of contraception for all study drugs and must 
be used throughout the duration of the study treatment (plus 5 half-lives of the study drug 
plus 30 days for females, or plus 90 days for males).
−
It is not necessary to use any other method of contraception when complete abstinence is 
elected.
−
Female subjects who choose complete abstinence must continue to have pregnancy tests, 
as specified in Section 6.4.
−
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the subject chooses to forego complete abstinence.
−
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject.
Local laws and regulations may require use of alternative and/or additional contraception 
methods.
Unacceptable Methods of Contraception
•
Periodic abstinence (calendar, symptothermal, postovulation methods)
•
Withdrawal (coitus interruptus)
•
Spermicide only
•
Lactation amenorrhea method
3.3.2
Exclusion Criteria
1) Target Disease Exceptions
a) Subjects with known or suspected brain metastases or brain as the only site of disease
b) However, subjects with controlled brain metastases (no radiographic progression at least 
4 weeks following radiation and/or surgical treatment,
no new or progressive 
neurological signs or symptoms, and off glucocorticoids for at least 4 weeks) will be 
allowed
2) Medical History and Concurrent Diseases
a) A serious, uncontrolled medical disorder which would impair the ability of the subject to 
receive protocol therapy
b) Evidence of uncontrolled, active infection, requiring parenteral anti-bacterial, anti-viral,
or anti-fungal therapy ≤ 7 days prior to administration of study medication
c) Any major surgery within 4 weeks of study drug administration.
d) Subjects 
with 
concomitant 
second 
malignancies 
(except 
adequately 
treated 
nonmelanomatous skin cancers or in situ bladder, breast, or cervical cancers) are 
excluded unless a complete remission was achieved at least 3 years prior to study entry 
and no additional therapy is required or anticipated to be required during the study period
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e) Uncontrolled or significant cardiovascular disease including:
i)
Congestive heart failure NYHA Class 2 or greater within 3 months (Appendix 6)
ii) LVEF < the institutional lower limit of normal as determined by MUGA or 
echocardiogram
iii) Active coronary artery disease, unstable or newly diagnosed angina, or myocardial 
infarction in the past 6 months
iv) History of congenital long QT syndrome or clinically significant ventricular 
arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsade de 
Pointes). Controlled atrial fibrillation is not an exclusion criterion.
v) Troponin (T or I) > the institutional upper limit of normal (ULN)
vi) History of myocarditis of any etiology
f)
NCI CTCAE v4.03 Grade 2 or higher peripheral neuropathy (sensory or motor)
g)
Grade 2 of higher eye disorders (inclusive of all NCI CTCAE v4.03 criteria). Mild eye 
symptoms such as blurry vision, either age-related or due to ocular or systemic disorder 
(eg, diabetes, dry eyes, cataracts, uncorrected refraction abnormality) may be allowed at 
the discretion of the ophthalmologist if deemed as not constituting a predisposition to 
drug-induced corneal deposits and blurry vision.
h) Any other sound medical, psychiatric, and/or social reason as determined by the investigator
i)
For Part 3 only : Active, known, or suspected autoimmune disease 
−
Participants with well-controlled asthma and/or mild allergic rhinitis (seasonal 
allergies) are eligible
−
Participants with the following disease conditions are also eligible:
•
Vitiligo
•
Type 1 diabetes mellitus
•
Residual hypothyroidism due to autoimmune condition only requiring 
hormone replacement 
•
Euthyroid participants with a history of Grave’s disease (participants 
suspected autoimmune thyroid disorders must be negative for thyroglobulin 
and thyroid peroxidase antibodies and thyroid stimulating immunoglobulin 
prior to first dose of study drug)
j)
Psoriasis not requiring systemic treatment or conditions not expected to recur in the 
absence of an external trigger are permitted to enroll.
3) Physical and Laboratory Test Findings
a) Inadequate bone marrow function defined as:
i)
Absolute neutrophil count < 1,500 cells/mm3
ii) Platelet count < 100,000 cells/mm3
iii) Hemoglobin < 9.0 g/dL
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Mesothelin-ADC
b) Subjects with a stable chronic transfusion requirement (eg, due to cumulative toxicity 
from previous therapy) of no more than once per month will be allowed if the trough 
hemoglobin is ≥8.0 g/dL.
c) Inadequate hepatic function defined as:
i)
TB > 1.5 times the institutional ULN (except known Gilbert’s syndrome)
ii) ALT or AST > 3 times the institutional ULN
d) Inadequate renal function defined as: 
i)
Blood creatinine > 1.5 times the institutional ULN or creatinine clearance (CrCl) 
< 40 mL/min (measured using the Cockcroft-Gault formula below):
Female CrCl = (140 - age in years) × weight in kg × 0.85
72 × serum creatinine in mg/dL
Male CrCl = (140 - age in years) × weight in kg × 1.00
72 × serum creatinine in mg/dL
e) Any of the following on 12-lead ECG prior to study drug administration, confirmed by 
repeat:
i)
QRS ≥120 msec, except right bundle branch block
ii) QTcF ≥450 msec for males, ≥470 msec for females, except right bundle branch 
block
f)
Past or active hepatitis B or C infection (Does not include positive serologies resulting 
from passive transfer of antibodies, eg, intravenous immunoglobulin). Hepatitis B surface 
antigen and hepatitis C antibody (if hepatitis C antibody is positive reflex to hepatitis C 
ribonucleic acid [RNA]) or hepatitis C RNA will be done at screening for Part 3. Subjects 
with the following will be excluded:
1. Positive test for hepatitis B surface antigen
2. Positive test for qualitative hepatitis C viral load by polymerase chain reaction 
(PCR)
−
Participants with positive hepatitis C antibody and negative quantitative 
hepatitis C by PCR are eligible. History of resolved hepatitis A virus infection is 
not an exclusion criterion.
−
Additional testing or substitute testing per institutional guidelines to rule out 
infection is permitted.
g) Subjects with known or suspected human immunodeficiency virus (HIV). No HIV testing 
is required during screening unless required locally. 
4) Allergies and Adverse Drug Reaction
a) History of allergy to mesothelin-directed antibodies, tubulysin, monoclonal antibodies, or 
related compounds. 
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5) Prohibited Treatments or Therapies
a) Prior exposure to BMS-986148 or other mesothelin-directed monoclonal antibodies or 
ADCs
b) Exposure to any investigational drug within 4 weeks for cytotoxic agents 
c) For noncytotoxic agents, investigational drug exposure within 4 weeks or 5 half-lives 
(whichever is shorter) is prohibited. If 5 half-lives is shorter than 4 weeks, agreement 
with BMS Medical Monitor is mandatory. 
d) Subjects with prior exposure to therapy with any agent specifically targeting checkpoint 
pathway inhibition (such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-LAG-3, and anti-
CTLA-4 antibody) are permitted after a washout period of any time greater than 4 weeks 
from the last treatment.
e) Subjects with prior therapy with any agent specifically targeting T cell co-stimulation 
pathways, such as anti-glucocorticoid-induced TNFR family-related gene antibody, 
anti-CD137 antibody, or anti-OX40 antibody, are permitted after a washout period of any 
time greater than 4 weeks from the last treatment.
f)
History of life-threatening toxicity related to prior immune therapy (eg. anti-CTLA-4 or 
anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell 
co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur 
with standard countermeasures (eg, hormone replacement after adrenal crisis)
g) Exposure to any investigational drug concurrent with study drug administration.
h) Use of medications causing Torsades de Pointes within 1 week or 5 half-lives (whichever 
is longer) (see Appendix 7).
6) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) Inability to comply with restrictions and prohibited activities/treatments as listed in 
Section 3.4
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
WOCBP is defined as any female who has experienced menarche, has not undergone surgical 
sterilization (hysterectomy or bilateral oophorectomy), and is not postmenopausal. Menopause is 
defined as 12 months of amenorrhea in a woman over age 45 in the absence of other biological 
or physiological causes. In addition, females under the age of 55 years must have a documented 
serum follicle stimulating hormone (FSH) level > 40 mIU/mL to confirm menopause.
Females treated with HRT are likely to have artificially suppressed FSH levels and may require a 
washout period in order to obtain a physiologic FSH level. The duration of the washout period is 
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a function of the type of HRT used. The duration of the washout periods below are suggested 
guidelines and the investigators should use their judgement in checking serum FSH levels. If the 
serum FSH level is > 40 mlU/ml at any time during the washout period, the woman can be 
considered postmenopausal. 
•
1-week minimum for vaginal hormonal products (rings, creams, gels)
•
4-week minimum for transdermal products
•
8-week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
3.4
Concomitant Treatments
Glucocorticoids may be administered for treatment of infusion reaction and as premedication to 
prevent further infusion reaction.
Palliative radiation therapy to a limited field (eg, painful bone metastasis, painful lumps), if it is 
not the sole site of measurable and/or assessable disease, is allowed any time during study 
participation with prior approval of the BMS Medical Monitor.
3.4.1
Prohibited and/or Restricted Treatments
Prohibited and/or restricted medications taken prior to study drug administration in the study are 
described in Section 3.3.2. Medications taken within 4 weeks prior to study drug administration 
and until AEs and SAEs are collected in the Follow-up Period (until Day 60 post-treatment for 
Parts 1 and 2 and Day 100 for Part 3) must be recorded on the CRF; however, anti-cancer 
treatments will be collected during the Follow-up period. Medications for the treatment of SAEs 
will also be collected.
Concomitant medications are collected within 4 weeks prior to and during retreatment. 
Specific medications that may not be administered concomitantly with BMS-986148 include the 
following:
•
Concurrent chemotherapy, immunotherapy regimens, or radiation therapy, standard or 
investigational
•
Any investigational drug other than BMS-986148 or nivolumab
•
Medications causing Torsades de Pointes (See Appendix 7)
•
The following medications are prohibited during the study unless utilized to treat a 
drug-related AE (this criteria applies only to the BMS-986148 and nivolumab 
combination therapy in Part 3):
−
Immunosuppressive agents
−
Immunosuppressive doses of systemic corticosteroids (except as stated below)
♦Subjects with a condition requiring systemic treatment with either corticosteroids (> 
10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of the first dose of study drug are excluded. Inhaled or topical steroids and 
adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted 
in the absence of active autoimmune disease.
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BMS-986148
Mesothelin-ADC
♦Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption). Adrenal replacement 
steroid doses > 10 mg daily prednisone are permitted. A brief (less than 3 weeks) 
course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of 
nonautoimmune conditions (eg, delayed-type hypersensitivity reaction caused by a 
contact allergen) is permitted.
3.4.2
Guidelines for the Management of Infusion Reactions
In case of hypersensitivity reactions, the investigator should institute treatment measures deemed 
medically appropriate in accordance with current medical practice and treatment guidelines. 
Prophylactic premedication will not be routinely given before the first dose of Cycle 1.  
Prophylactic medication to prevent future infusion reactions may be considered after discussion 
and agreement between investigator(s) and the BMS Medical Monitor. Infusion reactions should 
be graded according to NCI CTCAE v4.03 guidelines and recorded in the CRF. Treatment 
recommendations are provided and may be modified based on local treatment standards and 
guidelines, as appropriate: In the case of infusion reactions during nivolumab administration, 
subsequent infusion times for individual subjects may be extended at the discretion of the 
investigator.
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not
indicated):
•
Remain at bedside and monitor subject until recovery from symptoms.
•
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 mg to 1000 
mg at least 30 minutes before additional study drug administrations.
For Grade 2 symptoms (moderate reaction; requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, nonsteroidal anti-inflammatory 
drugs, narcotics, corticosteroids, IV fluids]; prophylactic medications indicated for < 24 hours):
•
Stop the study drug infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg; remain at bedside and monitor subject until resolution of symptoms. Corticosteroid 
therapy and/or bronchodilator may also be administered as appropriate.
•
If infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor subject closely.
•
If symptoms recur, then no further study drug will be administered at that visit.
•
The amount of study drug infused must be recorded on the CRF.
•
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent), acetaminophen/paracetamol 325 to 1000 mg, and/or 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) should be administered at least 
30 minutes before additional study drug administrations. Remain at bedside and monitor 
subject until recovery from symptoms.
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For Grade 3 or Grade 4 symptoms (Grade 3: severe reaction; prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[eg, renal impairment, pulmonary infiltrates]. Grade 4: life threatening; pressor or ventilatory
support indicated):
•
Immediately discontinue infusion of study drugs.
•
Begin an IV infusion of normal saline and treat the subject as follows: recommend 
bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution for subcutaneous 
administration, 0.3 mg of a 1:1,000 solution for intramuscular administration, or 0.1 to 0.25 
mg of a 1:10,000 solution slowly for IV administration, and/or diphenhydramine 50 mg IV
(or equivalent) with methylprednisolone 100 mg IV (or equivalent), as needed.
•
Subject should be monitored until the investigator is comfortable that the symptoms will not 
recur. 
•
The amount of study drug infused must be recorded on the CRF.
•
For Grade 3 infusion reactions that resolve within 6 hours, the following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent), acetaminophen/paracetamol 325 to 1000 mg, and/or corticosteroids (up to 25 mg 
of hydrocortisone or equivalent) should be administered at least 30 minutes before additional 
BMS-986148 administrations. Remain at bedside and monitor subject until recovery from 
symptoms.
•
For a Grade 3 infusion reaction that does not resolve in 6 hours and Grade 4 infusion 
reactions, study drug will be permanently discontinued.
•
Investigators should follow their institutional guidelines for the treatment of anaphylaxis.
•
Remain at bedside and monitor subject until recovery from symptoms.
•
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given 
(eg, oral antihistamine or corticosteroids).
3.5
Discontinuation of Subjects following any Treatment with Study Drug
Subjects MUST discontinue investigational product (and noninvestigational product at the 
discretion of the investigator) for any of the following reasons:
•
Subject’s request to stop study treatment and/or participation in the study
•
Any clinical AE, laboratory abnormality, or intercurrent illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
subject
•
Termination of the study by BMS
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
•
Inability to comply with protocol
•
Discretion of the investigator
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•
Confirmed CR as defined by RECIST version 1.1 or Modified RECIST for malignant pleural 
mesothelioma (see Appendix 4)58 unless subject meets criteria to continue treatment with 
nivolumab 
•
Documented disease progression as defined by RECIST version 1.1 or Modified RECIST 
criteria for malignant pleural mesothelioma (see Appendix 4) unless subject meets criteria for 
treatment beyond progression (Section 4.5) (for subjects in Part 3) 
•
AE(s) requiring discontinuation as outlined in the Dose Modification section (See Section 
4.5.2)
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
All subjects who discontinue investigational product should comply with protocol specified 
follow-up procedures as outlined in Section 5. The only exception to this requirement is when a 
subject withdraws consent for all study procedures including post-treatment study follow-up or 
loses the ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment 
of either a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate CRF page.
3.6
Post-Study Drug Follow Up
Safety is a key endpoint of this study. Post-study follow-up is of critical importance and is 
essential to preserving subject safety and the integrity of the study. Subjects who discontinue 
study drug must continue to be followed for collection of outcome and/or Survival Follow-up
data as required and in line with Section 5 until death or the conclusion of the study.
BMS may request that survival data be collected on all treated subjects outside of the 
protocol-defined window (Table 5.1-2 through Table 5.1-8). At the time of this request, each 
subject will be contacted to determine their survival status unless the subject has withdrawn 
consent for all contacts or is lost to follow-up.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post-treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject is alive or dead) is being measured, publicly 
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available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of 3 documented phone 
calls, faxes, or emails as well as lack of response by subject to 1 registered mail letter. All 
attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of a third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. If after all 
attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.
4
STUDY DRUG
Study treatment includes both investigational medicinal product (IMP)/investigational product 
(IP) and noninvestigational medicinal product (NIMP)/non-IP and can consist of the following:
•
All products being tested in a clinical trial. 
•
Study required premedication, and other drugs administered as part of the study that are 
critical to claims of efficacy (eg, background therapy, rescue medications)
•
Diagnostic agents (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection.
Product description and storage information is described in Table 4-1.
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Table 4-1:
Study Drugs for CA008002
Product Description Class 
and Dosage Form
Potency
IP/NIMP
Blinded or 
Open Label
Packaging/Appearance
Storage Conditions
(per Label)
BMS-986148-01 for 
Injection
50 mg/vial
IP
Open
10 cc vial/White to off white, whole or 
fragmented cake in a vial
Lyophilized
Protect from light 
Store at 2°C to 8°C
Nivolumab
100 mg/ vial
(10 mg/mL)
IP
Open
Primary Packaging: 10 mL (10 cc) glass vial
Secondary Packaging: Outer carton
Appearance: Vial containing 10 mL Clear to 
opalescent, colorless to pale yellow liquid, 
light (few) particulates may be present.
2°C to 8°C (36°F - 46°F) 
Protect from light. 
Protect from freezing.
IP: investigational product; NIMP: non-investigational medicinal product.
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4.1
Investigational Product
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation. An investigational product, also known as an IMP in 
some regions, is defined a pharmaceutical form of an active substance or placebo being tested or 
used as a reference in a clinical study, including products already with a marketing authorization 
but used or assembled (formulated or packaged) differently than the authorized form, or used for 
an unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
4.2
Noninvestigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered noninvestigational products. Not applicable for this study.
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and BMS should be contacted immediately.
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration, and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
BMS-986148 Preparation
BMS-986148 is supplied as a sterile, nonpyrogenic, single use, preservative-free lyophilized 
cake with a strength of 50 mg/vial that must be reconstituted and diluted prior to dosing the 
subject as an IV injection formulation. A sufficient excess of BMS-986148 is incorporated into 
each vial to account for withdrawal losses.
Solutions for infusion are prepared by injecting a specific volume of BMS-986148 drug product 
and normal saline into an empty 50-cc IV infusion bag (supplied by the site) to yield appropriate 
solutions for infusion. 
BMS-986148-01 for injection is to be administered as an IV infusion, following reconstitution 
with sterile water for injection, and further dilution with normal saline (0.9% w/v sodium 
chloride) to concentrations appropriate for the dosing cohort. 
Instructions for the drug product preparation, administration, and storage are provided in the 
pharmacy manual.
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BMS-986148 Administration 
The administration of the entire bag contents (or the amount needed if the total dose is less than 
50 mg) should be infused within approximately 60 minutes through an IV infusion set (sterile, 
nonpyrogenic, low protein binding, polyethersulfone 0.2-μm in-line filter) (supplied by the site). 
Care must be taken to ensure the sterility of the prepared solution, as the drug product does not 
contain antimicrobial preservatives or bacteriostatic agents. Equilibration to room temperature is 
recommended for the drug product, infusion fluid, and their combination prior to administration.
Reconstituted (with sterile water for injection) and diluted solutions (in normal saline) of 
BMS-986148-01 for injection are stable for up to 24 hours, at either refrigerated conditions, 2°C
to 8°C (36°F to 46°F), and light protected or 4 hours at room temperature conditions, 15°C to 
25°C (59°F to 77°F), under ambient light. The constituted vial and diluted bag should not be 
shaken. Infusion of BMS-986148-01 injection must be completed within 24 hours of dilution. 
The start of drug infusion equals 0 hour.
For subjects receiving nivolumab in combination with BMS-986148, subjects should receive 
nivolumab at a dose of 360 mg as a 30-minute infusion on Day 1 of each 21-day treatment cycle 
until disease progression, unacceptable toxicity, withdrawal of consent, or the study ends, 
whichever occurs first. 
For combination treatment in Part 3, BMS-986148 will be administered as an infusion up to 60 
minutes. The infusion line containing BMS 986148 should be flushed with an appropriate 
amount of diluent to ensure that the entire dose is administered and that the infusion line is 
cleared of any remaining BMS-986148. The nivolumab dose would then be infused not less than 
30 minutes from the completion of the BMS-986148 infusion, which would then be infused over 
a period of 30 minutes.
The start and stop time of the all study therapy infusions and any interruptions or infusion rate 
reductions should be documented.
Refer to the IB for additional details about BMS-986148.
Nivolumab Preparation 
There will be no individual subject dose escalations or reductions of nivolumab allowed. 
Subjects should be carefully monitored for infusion reactions during nivolumab administration. 
If an acute infusion reaction is noted, subjects should be managed according to Section 4.5.
Subjects must be monitored in the clinic for at least 4 hours following the first 2 doses of 
nivolumab and at least 1 hour following subsequent doses.
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
subject tolerates the treatment. Dosing visits are not skipped, only delayed. 
Nivolumab is administered as an IV infusion over 30 minutes. At the end of infusion, the IV line 
should be flushed with an appropriate amount (15 to 20 mL) of diluent to ensure that the total 
dose is administered.
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Separate infusion bags and filters should be used when administering nivolumab and BMS-
986148 on the same day.
For details regarding drug storage, preparation, administration, and use time, refer to the 
nivolumab IB and/or Pharmacy Manual.
4.4
Method of Assigning Subject Identification
This is an open-label study. Enrolled subjects, including those not dosed, will be assigned 
sequential subject numbers starting with 00001 (eg, 00001, 00002, 00003.... 00010). Those 
enrolled subjects meeting eligibility criteria will be eligible to be dosed. Sequential subject 
numbering will be assigned by the IWRS/IVRS system for each participating site, as the distinct 
subject identification number will ultimately be comprised of the site number and subject 
number, eg, 0002 00001. 
Until an IWRS/IVRS system is implemented, once informed consent has been obtained, the 
investigator (or designee) will register the subject by transmitting a copy of the completed 
enrollment worksheet (registration form) to the Sponsor. The following information is required 
for registration:
•
Subject’s date of birth (month and year only are acceptable if required by local regulation)
•
Gender
•
Diagnosis
•
Statement that subject is eligible
•
Date of informed consent
•
Planned date of first dose
Treatment groups and/or dose levels will be provided to the site study team after the subject has 
registered and eligibility for the study confirmed. Site personnel/investigator will receive a 
receipt confirming treatment assignment. A copy of this documentation should remain in the 
subject’s chart.
In the dose escalation phase (Parts 1A, 1B, and 3A), if a subject discontinues treatment with 
BMS-986148 during the DLT period for reasons other than DLT, the subject may be replaced if 
necessary for safety assessments. Replacement subjects will receive the same treatment but will 
be assigned a new subject number.
Subjects may be permitted to rescreen for the study following agreement between the BMS 
Medical Monitor and investigators.
IWRS/IVRS instructions will be provided to the clinical site in a separate instruction manual.
4.5
Selection and Timing of Dose for Each Subject
Each subject will be assigned to a specific dose level as listed in sequential order during dose 
escalation (see Section 3.1.1). Subjects in the expansion cohorts will be enrolled at or below the 
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MTD as agreed upon by the BMS Medical Monitor and investigators (see Section 3.1.2). See 
Section 3.1.3 for combination therapy guidelines.
4.5.1
Dose Limiting Toxicities
For the purpose of guiding dose escalation, DLTs will be defined based on incidence, intensity, 
and duration of AEs for which no clear alternative cause is identified. The DLT evaluation 
period for dose escalation in Part 1A is 21 days. The DLT evaluation period for dose escalation 
in Part 1B is 28 days and subjects must receive 3 doses during this period (unless DLT has 
occurred) to be considered evaluable for dose escalation decisions. The DLT evaluation period 
for dose escalation in Part 3A is 21 days. AEs will be graded according to the NCI CTCAE 
v4.03. For the purpose of subject management, any AE that meets DLT criteria, regardless of the 
cycle in which it occurs, will lead to dose interruption. Subjects who withdraw from the study 
during the DLT evaluation interval for reasons other than a DLT may be replaced at the same 
dose level. The incidence of DLT(s) during the first cycle of treatment (the DLT evaluation 
period) will be used in dose escalation decisions and to define the MTD. AEs occurring after the 
DLT period will be considered for the purposes of defining the MTD, upon agreement between 
the BMS Medical Monitor and investigators, if they are determined to have no clear alternative 
cause and are not related to disease progression.
For Part 3A, every attempt must be made to assign relationship to BMS-986148, to nivolumab,
or to both.
DLT(s) will be defined as any of the following events unless a clear alternative cause is 
identified:
Nonhematologic DLT
Any of the following events will be considered a nonhematologic DLT:
•
≥Grade 2 uveitis or eye pain or reduction in visual acuity (defined as 20/40 or worse and at 
least 2-line reduction from baseline visual acuity and accompanied by symptoms limiting age 
appropriate instrumental activities of daily living [ADL] or diagnostic observations) that 
requires systemic treatment
•
≥Grade 2 uveitis or eye pain or reduction in visual acuity (defined as 20/40 or worse and at 
least 2-line reduction from baseline visual acuity and accompanied by symptoms limiting age 
appropriate instrumental ADL or diagnostic observations) that does not respond to topical 
therapy and that does not improve to Grade 1 within 2 weeks of initiation of topical therapy
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•
≥Grade 3 infusion-related reactions that recur despite appropriate medical management as in 
Section 3.4.1
•
≥Grade 3 nonhematologic toxicity, with the following exceptions.
The following Grade 3 or greater nonhematologic events will NOT be considered DLTs:
−
≥Grade 3 electrolyte abnormalities that are not complicated by associated clinical AEs, 
are not clinically significant, last less than 72 hours, and either resolve spontaneously or 
respond to conventional medical intervention.
−
Grade 3 elevations in serum transaminases (AST, ALT) or alkaline phosphatase that last 
≤5 days and are not associated with clinical symptoms, and bilirubin is not greater than 
2× the ULN in the absence of cholestasis.
−
Grade 3 nausea, vomiting, or diarrhea that lasts less than 48 hours and either resolves 
spontaneously or responds to conventional medical intervention.
−
≥Grade 3 elevations of amylase or lipase that are not associated with clinical or 
radiographic evidence of pancreatitis.
−
Isolated Grade 3 fever that is not associated with hemodynamic compromise 
(ie, hypotension, clinical or laboratory evidence of impaired end-organ perfusion).
−
Grade 3 endocrinopathy that is well controlled by hormone replacement.
−
Grade 3 tumor flare (defined as pain, irritation, or rash that localizes to sites of known or 
suspected tumor)
−
Grade 3 fatigue that lasts for less than 7 days.
−
Grade 3 infusion reaction that returns to Grade 1 in less than 6 hours.
Hematologic DLT
•
Grade 4 neutropenia > 5 days in duration
•
Grade 4 febrile neutropenia of any duration
•
Grade 3 febrile neutropenia 
•
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with clinically
significant bleeding
•
≥Grade 3 hemolysis
•
Grade 4 anemia
4.5.2
Guidelines for Dose Modifications
Subjects will be monitored continuously for AEs while on study therapy. Subjects will be 
instructed to notify their physician immediately for any and all AEs. For the purposes of subject 
management, drug-related AEs occurring at any time that meet the DLT definition will lead to 
dose interruption, dose modifications, and/or permanent discontinuation of study drug as defined 
in Table 4.5.2-1 and in this section. The criteria presented in this section and Table 4.5.2-1 for 
dose modifications and delays are meant as general guidelines.
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•
Subjects will continue to receive therapy as long as they have not had disease progression, 
meet discontinution criteria, or drug-related AE requiring dose modification as described 
below.
•
Dose modification, interruption, or delay may occur in the setting of lower grade AE and/or 
be more conservative than indicated in Table 4.5.2-1 based on the clinical judgment of the 
investigator and in consultation with the BMS Medical Monitor.
•
Dose reductions in this study are applicable to the administration of BMS-986148 and should 
be to the previous lower dose level. There are no dose reductions for nivolumab (applicable 
for Part 3). 
•
If several AEs of varying grade or severity occur simultaneously, the dose modification 
applied should be the greatest reduction of BMS-986148 applicable.
•
Assessment of causality (chronology, confounding factors such as disease, concomitant 
medications, diagnostic tests, and previous experience with the agent) must be determined 
and documented by the investigator prior to dose modification.
•
If the same ≥Grade 3 nonhematologic AE recurs despite a dose reduction, a second dose 
reduction versus discontinuation of the subject from further protocol therapy will be 
discussed and agreed upon by the BMS Medical Monitor and investigators.
•
No more than 2 dose reductions of BMS-986148 will be allowed per subject. If a third dose 
reduction is required, the subject must discontinue study drug. Dose re-escalation after a dose 
reduction may occur in limited circumstances (such as a change in attribution of an AE) after 
discussion and agreement of the BMS Medical Monitor and investigators.
•
Skipped BMS-986148 doses in Part 1B will not be administered within the same cycle.
•
For an AE requiring dose modification, study drugs should be interrupted to allow recovery 
from the AE. Re-initiation of study drug cannot occur until AE decreases to ≤Grade 1 or 
baseline assessment (See exception for Part 3 below in Section 4.5.4). In case of delayed 
recovery to ≤Grade 1 or baseline (except for alopecia) from treatment-related AEs that 
results in a delay of treatment for > 30 days, the subject will not receive additional protocol-
related therapy (applies to BMS-986148 monotherapy in Parts 1 and 2) and will still continue 
in follow-up periods unless discussed and agreed upon by the BMS Medical Monitor and 
investigators that it is in the best interest of the subject to receive additional therapy with 
BMS-986148 (for example, if the subject has demonstrated a response to therapy). For dose 
delay in Part 3, see below. 
•
For additional dose modifications pertinent to nivolumab (Part 3), see Sections 4.5.3 through 
4.5.5 below.
•
During the DLT evaluation period, if a subject is dose reduced and experiences a DLT at the 
lower dose, this DLT will be attributed to the highest dose level administered.
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Table 4.5.2-1:
Dose Modifications
Dose Modification Criteria for Drug-Related Adverse Events
BMS-986148 
(Parts 1, 2, and 3)
(Modification at Next Dose)
Grade 4 neutropenia lasting > 5 days
Decrease 1 level.
Grade 3 febrile neutropenia  lasting > 48 hours 
Decrease 1 level.
Grade 4 febrile neutropenia
Discontinue.
Grade 4 thrombocytopenia or ≥Grade 3 thrombocytopenia with clinically 
significant bleeding
Decrease 1 level.
QTcF > 500 msec confirmed by at least 1 repeat ECG and at least 60 msec 
above baseline
Interrupt if needed to optimize electrolyte management; if persists after 
electrolyte optimization (including dose modification of BMS-986148, if 
necessary), discontinue.
Grade 1 Troponin I or T confirmed when repeated in 72 hours 
Discontinue.
Grade 3 Troponin I or T 
Discontinue.
AST or ALT > 5 times the institutional ULN that last ≥5 days or is 
symptomatic 
Decrease 1 level.
≥Grade 3 infusion-related reaction
See Section 3.4.1.
≥Grade 3 peripheral neuropathy
Discontinue.
≥Grade 2 uveitis or eye pain or reduction in visual acuitya that improve to 
Grade 1 within 2 weeks of initiation of topical therapy
Interrupt dosing until improvement to Grade 1 or baseline and decrease 1 level.
≥Grade 2 uveitis or eye pain or reduction in visual acuitya that does not 
respond to topical therapy and that does not improve to Grade 1 within 2 weeks 
of initiation of topical therapy
Discontinue.
After improvement to Grade 1 or baseline, additional therapy with BMS-
986148 (decrease 1 level) may be considered after discussion and agreement 
by the BMS Medical Monitor and investigators that it is in the best interest of 
the subject (for example, if the subject has demonstrated a response to 
therapy).
≥Grade 3 eye symptoms
Discontinue.
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Table 4.5.2-1:
Dose Modifications
Dose Modification Criteria for Drug-Related Adverse Events
BMS-986148 
(Parts 1, 2, and 3)
(Modification at Next Dose)
Any other drug-related ≥Grade 3 nonhematologic AE (except in subjects not 
receiving maximum medical management or electrolyte abnormalities that may 
be managed with supplements ) that does not meet permanent discontinuation 
criteria (Section 3.5).
Decrease 1 level.
a Reduction in visual acuity is defined as 20/40 or worse and at least 2-line reduction from baseline visual acuity and accompanied by symptoms limiting age 
appropriate instrumental ADL or diagnostic observations.
ADL: activities of daily living; AE: adverse event; ALT: alanine transaminase; AST: aspartate transaminase; ECG: electrocardiogram; PI: principal investigator; 
QTcF: QT interval corrected by Fridericia’s formula; ULN: upper limit of normal.
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4.5.3
Dose Delay Criteria (Applicable for Part 3)
Subjects who experience a DLT must have both study drugs held. Every attempt must be made 
to assign relationship to BMS-986148, to nivolumab, or to both. If the toxicity is attributed to 
BMS-986148 (eg, early onset liver function tests [LFT] abnormalities or AEs similar to profile 
determined from monotherapy cohorts) will lead to dose modification of BMS-986148 according 
to Table 4.5.2-1 and nivolumab can be resumed. Similarly if the toxicitiy is attributed to 
nivolumab (eg, pneumonitis), dosing of nivolumab can be delayed or discontinued per the 
guidelines below and BMS-986148 can be resumed. Such modifications should be discussed and 
agreed upon by the BMS Medical Monitor and investigators. In addition, all Grade 2 hepatic, 
pulmonary, renal, gastrointestinal, and neurological AEs seen with nivolumab should be 
evaluated and managed per the toxicity management algorithms (Appendix 3). Subjects not 
meeting guidelines for permanent discontinuation will be permitted to resume therapy based on 
the criteria specified in Table 4.5.2-1. Subjects eligible to resume study therapy will resume 
study therapy at the treatment visit following their last received study drug dose.
The end-of-cycle tumor assessments (ie, CT/MRI, positron emission tomography, etc) will 
continue on an every-6-week schedule relative to the subject’s first dose regardless of any 
treatment delay incurred.
Study drug administration should be delayed for the following:
•
Any Grade ≥2 nonskin, drug-related AE, with the following exception:
−
Grade 2 drug-related fatigue does not require a treatment delay.
•
Grade 2 drug-related creatinine, AST, ALT, or TB abnormalities 
•
Any Grade 3 skin, drug-related AE
•
Any Grade 3 drug-related laboratory abnormality (excluding AST, ALT, or TB), with the 
following exceptions for lymphopenia and asymptomatic amylase or lipase:
−
Grade 3 lymphopenia does not require dose delay.
−
Any Grade ≥3 drug-related amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis does not require dose delay. 
•
Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of the 
investigator, warrants delaying the dose of study medication.
Subjects who require delay of study drugs should be re-evaluated QW or more frequently if 
clinically indicated and resume nivolumab dosing when retreatment criteria are met.
For data collection and analysis purposes, all subjects will continue to be classified by the 
original treatment arm.
4.5.4
Criteria to Resume Treatment for Part 3
Subjects may resume treatment with study drugs when the drug-related AE(s) resolves to 
Grade ≤1 or baseline value, with the following exceptions:
•
Subjects may resume treatment in the presence of Grade 2 fatigue.
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•
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity.
•
For subjects with Grade 2 creatinine, AST, ALT, or TB elevations, dosing may resume when 
laboratory values return to baseline, and management with corticosteroids, if needed, is 
complete.
•
Subjects with combined Grade 2 AST/ALT AND TB values meeting discontinuation 
parameters (Section 3.5) should have treatment permanently discontinued. 
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Subjects with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by BMS Medical Monitor.
•
Subjects with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical 
Monitor.
4.5.5
Study Drug Discontinuation (Part 3) 
In certain circumstances of nivolumab-related AE’s requiring discontinuation that do not overlap 
with known BMS-986148 toxicities, eg, pneumonitis, BMS-986148 can be resumed after 
discussion with the Sponsor/Medical Monitor if is in the best interest of the subject to receive 
additional therapy with BMS-986148 (for example, if the subject has demonstrated a response to 
therapy):
•
Any drug-related AE occurring at any time that meets DLT criteria as outlined in 
Section 4.5.1 will require discontinuation of nivolumab and/or dose modification of BMS-
986148 (Table 4.5.2-1), with the exception of the following:
−
Grade 3 diarrhea, nausea, vomiting, or abdominal pain that returns to Grade 1 or baseline 
within 3 days with medical intervention
−
Grade 3 pruritus or rash that returns to Grade 1 or baseline within 7 days, or baseline with 
medical intervention;
−
Isolated Grade 3 or 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset
−
Grade 4 neutropenia < 5 days in duration
−
Grade 4 lymphopenia or leukopenia
−
Grade 3 or 4 increase in amylase or lipase that is not associated with clinical or 
radiographic evidence of pancreatitis
−
Grade 3 or 4 drug-related endocrinopathy AEs, such as adrenal insufficiency, 
adrenocorticotropic hormone
deficiency, hyper-
or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor
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♦Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed. Prior to reinitiating treatment in a subject with a dosing delay lasting 
> 6 weeks from the previous dose, the BMS Medical Monitor must be consulted. 
Tumor assessments should continue as per protocol even if dosing is delayed. 
Periodic study visits to assess safety and laboratory studies should also continue Q6W 
for Parts 1A, 2, and 3 and every 8 weeks [Q8W] for Part 1B or more frequently if 
clinically indicated during such dosing delays.
♦Dosing delays lasting > 6 weeks from the previous dose that occur for nondrug-
related reasons may be allowed if approved by the BMS Medical Monitor. Prior to 
reinitiating treatment in a subject with a dosing delay lasting > 6 weeks, the BMS 
Medical Monitor must be consulted. Tumor assessments should continue as per 
protocol even if dosing is delayed. Periodic study visits to assess safety and 
laboratory studies should also continue Q6W or more frequently if clinically 
indicated during such dosing delays.
•
Any AE, laboratory abnormality, or intercurrent illness, which, in the judgment of the 
investigator, presents a substantial clinical risk to the subject with continued nivolumab 
dosing.
4.6
Treatment beyond Disease Progression
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of progressive disease. 
Subjects treated with study drugs will be permitted to continue treatment beyond initial RECIST 
version 1.1-defined progressive disease, assessed by the investigator, as long as they meet the 
following criteria:
•
Investigator-assessed clinical benefit
•
Tolerance of study drug
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, central nervous system metastases).
•
Subject provides written informed consent prior to receiving additional nivolumab treatment. 
All other elements of the main consent, including description of reasonably foreseeable risks 
or discomforts or other alternative treatment options, will still apply.
A radiographic assessment/scan should be performed within 6 weeks of initial 
investigator-assessed progression to determine whether there has been a decrease in the tumor 
size or continued progressive disease. The assessment of clinical benefit should be balanced by 
clinical judgment as to whether the subject is clinically deteriorating and unlikely to receive any 
benefit from continued treatment with nivolumab.
If the investigator feels that the subject continues to achieve clinical benefit by continuing 
treatment with the study drugs, the subject should remain on the trial and continue to receive 
monitoring according to the Time and Events Schedule (see Section 5.1).
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4.6.1
Discontinuation Due to Further Progression (Confirmed Progression)
For the subjects who continue study therapy beyond progression, further progression is defined 
as an additional 10% increase in tumor burden with a minimum 5 mm absolute increase from 
time of initial progressive disease. This includes an increase in the sum of diameters of all target 
lesions and/ or the diameters of new measurable lesions compared to the time of initial 
progressive disease. Study treatment should be discontinued permanently upon documentation of 
further progression.
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at 
least15 mm). Any new lesion considered nonmeasureable at the time of initial progression may 
become measureable and therefore included in the tumor burden if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). In situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions which become measurable, these new lesions must demonstrate an 
absolute increase of at least 5 mm.
For statistical analyses that include the investigator-assessed progression date, subjects who 
continue treatment beyond initial investigator-assessed, RECIST version 1.1-defined progressive 
disease will be considered to have investigator-assessed progressive disease at the time of the 
initial progression event.
4.7
Management Algorithms for Immuno-oncology Agents
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab is considered an I-O agent in this 
protocol. Early recognition and management of AEs associated with I-O agents may mitigate 
severe toxicity. Management algorithms have been developed to assist investigators in assessing
and managing the following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
The above algorithms are found in the nivolumab IB and Appendix 3 of this protocol.
4.8
Blinding/Unblinding
Not applicable.
4.9
Treatment Compliance
Study drug will be administered in the clinical facility by qualified medical personnel. The 
investigator and the study personnel will ensure that each subject receives the calculated dose of 
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the study drug. Treatment compliance will be monitored by drug accountability, as well as 
recording BMS-986148 administration in subjects’ medical records and CRF. Drug supplies will 
be inventoried and accounted for throughout the study. The Drug Accountability Log should be 
reviewed by the study monitor during site visits and at the completion of the study. Any 
discrepancy should be brought to the attention of the Sponsor.
4.10
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials, and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible BMS Study Monitor unless study drug containers must be immediately destroyed as 
required for safety or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s standard operating procedures and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period.
If conditions for destruction cannot be met, the responsible BMS Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.11
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
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Mesothelin-ADC
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule
Study assessments and procedures are presented in Table 5.1-2 through Table 5.1-8. The study 
assessments and procedures tables corresponding to each part of the study are outlined in Table 
5.1-1. In limited instances, scheduled events can occur outside of the indicated timeframes, but 
BMS should be notified.
Table 5.1-1:
List of Study Parts and Corresponding Study Assessments and 
Procedures Tables
Part of Study
Table
1A
Table 5.1-2, Screening and Cycle 1
Table 5.1-3, Cycle 2 to Off Study Visit
1B
Table 5.1-4, Screening and Cycle 1
Table 5.1-5, Cycle 2 to Off Study Visit
2
Table 5.1-2 and Table 5.1-4, Screening and Cycle 1 for Q3W and QW 
dosing, respectively 
Table 5.1-3 and Table 5.1-5, Cycle 2 to Off Study Visit for Q3W and QW 
dosing, respectively
3A
Table 5.1-6, Screening and Cycle 1 Combination Therapy
Table 5.1-7, Cycle 2 to Off Study Visit Combination Therapy
Table 5.1-8, Part 3 Retreatment (Part 3 subjects only)
3B
Table 5.1-6, Screening and Cycle 1 Combination Therapy
Table 5.1-7, Cycle 2 to Off Study Visit Combination Therapy
Table 5.1-8, Part 3 Retreatment (Part 3 subjects only)
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Table 5.1-2:
Screening and Cycle 1, Parts 1A and 2 (Q3W BMS-986148 Monotherapy Dosing / 21 Day Cycle) 
Procedural Outline (CA008002)
Procedurea
Pre-
Screening
Screening
Visit
D-28 to D-1
C1D1
C1D2
C1D4b
C1D8
C1D15
Notes
Eligibility Assessments
Informed Consent
X
A subject is considered enrolled only when a 
protocol specific informed consent is signed. In Part 
2, if allowed by institutional practices, sites are 
encouraged to use a pre-screening consent for the 
mesothelin-expressing tumor analysis. Other 
screening procedures should not be done before the 
mesothelin-expressing tumor analysis is available 
for the determination of subject eligibility.
Inclusion/Exclusion 
Criteria
X
ECOG
X
X
Medical History
X
Also include any toxicities or allergy related to 
previous treatments. Smoking history for all 
subjects.
Prior Treatments
X
Including prior cancer treatment regimens and 
medications administered within 4 weeks of dosing.
Safety Assessments
PE
X
X
If the screening PE is performed within 24 hours 
prior to dosing on Day 1, then a single exam may 
count as both the screening and pre-dose 
evaluation.
A neurological exam must be included at the 
screening or pre-dose at the C1D1 visit.
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Table 5.1-2:
Screening and Cycle 1, Parts 1A and 2 (Q3W BMS-986148 Monotherapy Dosing / 21 Day Cycle) 
Procedural Outline (CA008002)
Procedurea
Pre-
Screening
Screening
Visit
D-28 to D-1
C1D1
C1D2
C1D4b
C1D8
C1D15
Notes
Targeted PE
X
X
To include signs and symptoms of peripheral 
neuropathy and ocular toxicity. Any grade ocular 
toxicity requires ophthalmologist consultation and 
discussion with medical monitor as appropriate.
Ophthalmological 
Examinationc
X
Performed by ophthalmologist or locally qualified 
personnel. Any abnormality must be discussed with 
the medical monitor prior to dosing.
Physical Measurements
X
X
Height (screening only), weight.
Vital Signsd
X
X
X
X
Body temperature, blood pressure, and heart rate.
Blood pressure and heart rate should be measured 
after the subject has been resting quietly for at least 
5 minutes.
ECGs
X
X
X
X
ECGs should be recorded after the subject has been 
supine for at least 5 minutes. Triplicate ECGs 
should be taken within 5 minutes of the previous 
measurement.
For ALL subjects in Part 1 and up to 20 subjects in 
Part 2: time matched for PK; triplicate evaluations 
at C1D1 pre-dose and EOI, C1D2 (24 hours post 
dose), and C1D8 (168 hours post dose) AND at 
C4D1 pre-dose and EOI, C4D2 (24 hours post 
dose), and C4D8 (168 hours post dose).
QTcF assessment > 450 msec must be confirmed on 
repeat ECG.
MUGA/Echocardiogram
X
MUGA or echocardiogram done at screening to 
document LVEF. Echocardiogram done at the start 
of Cycle 3, then evey 3 cycles thereafter, and as 
clinically indicated for the evaluation of pericardial 
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Mesothelin-ADC 
Table 5.1-2:
Screening and Cycle 1, Parts 1A and 2 (Q3W BMS-986148 Monotherapy Dosing / 21 Day Cycle) 
Procedural Outline (CA008002)
Procedurea
Pre-
Screening
Screening
Visit
D-28 to D-1
C1D1
C1D2
C1D4b
C1D8
C1D15
Notes
effusion.
Laboratory Tests
X
X
X
X
X
X
If the screening laboratory tests are performed 
within 24 hours prior to dosing on Day 1, then a 
single exam may count as both the screening and 
pre-dose evaluation.
See Section 5.3.1 Urine - screening only, unless 
clinically indicated.
C1D4 and C4D4: CBC only.
Troponin T or I
X
X
X
X
During Part 1 only. The same evaluation must be 
collected throughout the study.
Pregnancy Test
X
X
PK and Immunogenicity Assessments (See Section 5.5)
Biomarker Assessments 
Tumor Sample (or 
Archival)
Part 2: Required for 
Eligibility
X
Part 2 only
X
(Part 1A and 
if not pre-
screened in 
Part 2)
In Part 2, subjects must have tumor mesothelin 
expression (refer to Section 5.6 for additional 
details on specific cut-off selection criteria). No 
other protocol-specific eligibility 
procedures/assessment should be conducted until 
the tumor mesothelin expression is confirmed.
Tumor material from archived samples will be used 
for the IHC analyses.  If archived tumor material is 
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Mesothelin-ADC 
Table 5.1-2:
Screening and Cycle 1, Parts 1A and 2 (Q3W BMS-986148 Monotherapy Dosing / 21 Day Cycle) 
Procedural Outline (CA008002)
Procedurea
Pre-
Screening
Screening
Visit
D-28 to D-1
C1D1
C1D2
C1D4b
C1D8
C1D15
Notes
unavailable or unsuitable for evaluation, then tumor 
material from a fresh biopsy must be provided for 
these analyses. If archived tumor material is to be 
used, then a tumor paraffin block or unstained 
slides from a tumor tissue block must be provided. 
 
 Every effort 
should be made to provide 20 slides (minimum of 
10 slides) for mesothelin IHC testing. Individual 
sample availability should be discussed with the 
Sponsor if at least 10 slides are not available for 
any subject.  
Mandatory Fresh Tumor 
Biopsy
Part 2 Only
X
For 10 ovarian cancer subjects and 10 gastric 
cancer subjects who consent to provide pre- and on-
treatment biopsies (C2D1 ±3 days).
Optional Fresh Tumor 
Biopsy
Part 2 Only
For subjects with indications other than ovarian 
cancer and gastric cancer who consent to provide 
pre- and on-treatment biopsies (C2D1 ±3 days).
Tumor Assessment
X
Baseline must be within approximately 30 days of 
C1D1.
Tumor Markers
(CA125 and CA19-9)
X
At the time of tumor assessments: serum CA125 for 
ovarian cancer and mesothelioma subjects only, 
serum CA19-9 for pancreatic cancer subjects only.
Baseline sample collection pre-dose on C1D1.
Concomitant Treatments
X
X
X
X
X
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Table 5.1-2:
Screening and Cycle 1, Parts 1A and 2 (Q3W BMS-986148 Monotherapy Dosing / 21 Day Cycle) 
Procedural Outline (CA008002)
Procedurea
Pre-
Screening
Screening
Visit
D-28 to D-1
C1D1
C1D2
C1D4b
C1D8
C1D15
Notes
Adverse Event Reporting
Clinical Complaints
X
Clinical complaints related to the disease under 
study must be collected within 14 days of the first 
dose of study drug.
Monitor for Non-SAEs
X
X
X
X
X
Non-SAEs will be collected starting with the first 
dose of study medication and through 60 days after 
discontinuation of dosing.
Monitor for SAEs
X
X
X
X
X
X
All SAEs must be collected from the date of 
subject’s written consent until 60 days from the last 
dose of study drug or subject’s participation in the 
study if the last scheduled visit occurs at a later 
time.
Clinical Drug Supplies
Dose Level Assignment
X
At the completion of screening procedures and 
eligibility determination.
BMS-986148
Administration
X
Those supplied by BMS.
a In the event multiple procedures are required at a single time point, the following is a list of procedures from highest priority to low: 1) ECG, 2) PK sampling, 
and 3) clinical labs.
b C1D4 visit: ± 1 day.
c Ophthalmological examination: 8-point exam (visual acuity, pupils, extraocular motility and alignment, tonometry, visual field, external examination, slit lamp 
examination and fundoscopy) conducted at baseline and focused exams with visual acuity, slit lamp, and as indicated will be conducted at the end of Cycle 1 
(pre-dose Cycle 2), every other cycle, EOT, and as clinically indicated during the study.
d During Cycle 1: vital signs will be obtained before the BMS-986148 infusion and then every 15 minutes (± 5 minutes) until 60 minutes after completion of the 
infusion. After Cycle 1, vital signs may be obtained pre-dose, every 30 minutes (± 10 minutes) until 30 minutes following completion of the infusion. If any 
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vital sign is abnormal at the final check, the subject must be observed further for a period of time, as clinically indicated. The start and stop time of the study 
drug infusion should be documented (start of drug infusion = 0 hour).
 C: cycle; CBC: complete blood cell (count); CRF: case report form; D: day; 
 
 ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EOI: end of infusion; EOT: end of treatment; IHC: immunohistochemistry; 
LVEF: left ventricular ejection fraction; MUGA: multigated acquisition; PE: physical examination; PK: pharmacokinetics; Q3W: every 3 weeks; QTcF: QT 
interval corrected by Fridericia’s formula; SAE: serious adverse event.
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Mesothelin-ADC 
Table 5.1-3:
Cycle 2 to Off Study Visit, Parts 1A and 2 (Q3W Dosing BMS-986148 Monotherapy Dosing / 21 Day 
Cycle) Procedural Outline (CA008002)
Procedurea
C2 and C3
C4
C5 and 
Beyond
EOT
Follow-up 
(30 and 
60 Days 
After Last 
Dose)
Survival 
Follow-upb
Notes
D1
D8
D15
D1
D2
D4c
D8
D15
D1
(±5 days)
(±2 weeks)
Safety Assessments
Targeted PE
X
X
X
X
X
X
X
To include signs and 
symptoms of peripheral 
neuropathy and ocular 
toxicity. Any ocular 
toxicity requires 
ophthalmologist 
consultation and 
discussion with medical 
monitor as appropriate.
Ophthalmological 
Examinationd
Start of Cycle 2, every 2 cycles thereafter and as clinically 
indicated
X
Performed by 
ophthalmologist or 
locally qualified 
personnel. Any 
abnormality must be 
discussed with the 
medical monitor prior to 
dosing. 
Ophthalmological 
exams can be done up to 
72 hours prior to dosing.
Physical Measurements 
X
X
X
X
X
Weight only.
Vital Signse
X
X
X
X
X
X
X
See note in screening 
procedures.
ECGs
X
X
X
X
X
X
X
See note in screening 
procedures. 
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Mesothelin-ADC 
Table 5.1-3:
Cycle 2 to Off Study Visit, Parts 1A and 2 (Q3W Dosing BMS-986148 Monotherapy Dosing / 21 Day 
Cycle) Procedural Outline (CA008002)
Procedurea
C2 and C3
C4
C5 and 
Beyond
EOT
Follow-up 
(30 and 
60 Days 
After Last 
Dose)
Survival 
Follow-upb
Notes
D1
D8
D15
D1
D2
D4c
D8
D15
D1
(±5 days)
(±2 weeks)
Echocardiogram
Start of Cycle 3, then every 3 cycles thereafter, and as 
clinically indicated.
X
On treatment 
echocardiogram exams 
may be done up to 
72 hours prior to dosing.
Laboratory Tests
X
X
X
X
X
X
X
X
See note in screening 
procedures and 
Section 5.3.1. Lab tests 
can be performed up to 
24 hours prior to dosing.
C4D4 (CBC only) 
collection to be time 
matched with PK 
collection pre-dose. 
Mandatory Fresh Tumor 
Biopsy 
Part 2 Only
X
C2D1 (±3 days). For 
10 ovarian cancer 
subjects and 10 gastric 
cancer subjects who 
provided pre-treatment 
biopsies.
Optional FreshTumor 
Biopsy 
Part 2 Only
X
C2D1 (±3 days).  For 
subjects with indications 
other than ovarian 
cancer and gastric 
cancer who provide pre-
treatment biopsies.
Pregnancy Test
X
X
X
X
X
Revised Protocol No.: 04
Date: 02-Nov-2016
90
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-3:
Cycle 2 to Off Study Visit, Parts 1A and 2 (Q3W Dosing BMS-986148 Monotherapy Dosing / 21 Day 
Cycle) Procedural Outline (CA008002)
Procedurea
C2 and C3
C4
C5 and 
Beyond
EOT
Follow-up 
(30 and 
60 Days 
After Last 
Dose)
Survival 
Follow-upb
Notes
D1
D8
D15
D1
D2
D4c
D8
D15
D1
(±5 days)
(±2 weeks)
Concomitant Treatments
X
X
X
X
X
X
X
X
X
X
Xf
Adverse Event Reporting
Monitor for Non-SAEs
X
X
X
X
X
X
X
X
X
X
X
See note in screening 
procedures.
Monitor for SAEs
X
X
X
X
X
X
X
X
X
X
X
See note in screening 
procedures.
PK and Immunogenicity Assessments (See Section 5.5)
Efficacy Assessments
Tumor Assessment
At the start of Cycle 3 and then every 2 cycles thereafter 
(±1 week).
X
Xg
Xh
See Section 5.4.1.
Tumor Markers 
(CA125 and CA19-9)
At the start of Cycle 3 and then every 2 cycles thereafter 
(±1 week).
X
X
X
See note in screening 
procedures. Baseline 
sample collection 
pre-dose on C1D1.
Clinical Drug Supplies
BMS-986148
Administration
X
X
X
Those supplied by 
BMS.
Other
Survival Follow-up
Xi
Revised Protocol No.: 04
Date: 02-Nov-2016
91
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
a In the event multiple procedures are required at a single time point, the following is a list of procedures from highest priority to low: 1) ECG, 2) PK sampling, 
and 3) clinical labs.
b In the Survival Follow-up, subjects discontinuing study drug prior to 2 years will be followed for up to 2 years from first dose of study drug. Subjects treated 
for > 2 years will be followed for 6 months after EOT.
c C4D4: ± 1 day.
d Ophthalmological examination: 8-point exam (visual acuity, pupils, extraocular motility and alignment, tonometry, visual field, external examination, slit lamp 
examination and fundoscopy) conducted at baseline and focused exams with visual acuity, slit lamp, and as indicated will be conducted at the end of Cycle 1 
(pre-dose Cycle 2), every other cycle, EOT and as clinically indicated during the study.
e Vital signs will be obtained before the BMS-986148 infusion and then every 30 minutes (± 10 minutes) until 30 minutes following completion of the last 
infusion. If any vital sign is abnormal at the final check, the subject must be observed further for a period of time, as clinically indicated. The start and stop 
time of the study drug infusion should be documented (start of drug infusion = 0 hour).
f Only anti-cancer treatments.
g Only at the 60-day follow-up visit, unless discontinued for disease progression.
h Subjects with SD, PR, or CR at the last clinical follow-up visit should undergo tumor assessment via CT/MRI scans at least every 3 to 4 months during the 
Survival Follow-up (Section 8.3.2.2) phase until progression.
i
Subject status will be assessed by either a clinic visit or telephone contact every 12 weeks (± 2 weeks) until the last treated subject has been followed for 2 
years from his/her first date of treatment. The nature and start dates of any new therapies during this period should be recorded. Only information related to 
subjects’ survival and the start date of any subsequent therapies will be collected at these telephone contacts. Subjects will be permitted to receive other anti-
cancer therapies, including investigational agents, during this follow-up period once the 60-day follow-up visit is completed.
C: cycle; CBC: complete blood cell (count); CR: complete response; CT: computed tomography; D: day; ECG: electrocardiogram; EOT: end of treatment; 
MRI: magnetic resonance imaging; PE: physical examination; PK: pharmacokinetics; PR: partial response; Q3W: every 3 weeks; SAE: serious adverse event; 
SD: stable disease.
Revised Protocol No.: 04
Date: 02-Nov-2016
92
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-4:
Screening and Cycle 1, Part 1B (Weekly Dosing BMS-986148 Monotherapy Dosing / 28 Day Cycle) 
Procedural Outline (CA008002)
Procedurea
Pre-
Screening
Screening
Visit
D-28 to D-1
C1D1
C1D2
C1D4b
C1D8
C1D15
C1D22
Notes
Eligibility Assessments
Informed Consent
X
A subject is considered enrolled only 
when a protocol specific informed 
consent is signed. In Part 2, if allowed 
by institutional practices, sites are 
encouraged to use a pre-screening 
consent for the mesothelin-expressing 
tumor analysis. Other screening 
procedures should not be done before 
the mesothelin-expressing tumor 
analysis is available for the 
determination of subject eligibility.
Inclusion/Exclusion 
Criteria
X
ECOG
X
X
Medical History
X
Also include any toxicities or allergy 
related to previous treatments. 
Smoking history for all subjects.
Prior Treatments
X
Including prior cancer treatment 
regimens and medications 
administered within 4 weeks of 
dosing.
Revised Protocol No.: 04
Date: 02-Nov-2016
93
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-4:
Screening and Cycle 1, Part 1B (Weekly Dosing BMS-986148 Monotherapy Dosing / 28 Day Cycle) 
Procedural Outline (CA008002)
Procedurea
Pre-
Screening
Screening
Visit
D-28 to D-1
C1D1
C1D2
C1D4b
C1D8
C1D15
C1D22
Notes
Safety Assessments
PE
X
X
If the screening PE is performed 
within 24 hours prior to dosing on Day 
1, then a single exam may count as 
both the screening and pre-dose 
evaluation.
A neurological exam must be included 
at screening or pre-dose at the C1D1 
visit.
Targeted PE
X
X
X
To include signs and symptoms of 
peripheral neuropathy and ocular 
toxicity. Any grade ocular toxicity 
requires ophthalmologist consultation 
and discussion with medical monitor 
as appropriate.
Ophthalmological 
Examinationc
X
Performed by ophthalmologist or 
locally qualified personnel. Any 
abnormality must be discussed with 
the medical monitor prior to dosing.
Physical Measurements
X
X
Height (screening only), weight.
Vital Signsd
X
X
X
X
X
Body temperature, blood pressure and 
heart rate. 
Blood pressure and heart rate should 
be measured after the subject has been 
resting quietly for at least 5 minutes.
Revised Protocol No.: 04
Date: 02-Nov-2016
94
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-4:
Screening and Cycle 1, Part 1B (Weekly Dosing BMS-986148 Monotherapy Dosing / 28 Day Cycle) 
Procedural Outline (CA008002)
Procedurea
Pre-
Screening
Screening
Visit
D-28 to D-1
C1D1
C1D2
C1D4b
C1D8
C1D15
C1D22
Notes
ECGs
X
X
X
X
X
ECGs should be recorded after the 
subject has been supine for at least 5 
minutes. Triplicate ECGs should be 
taken within 5 minutes of the previous 
measurement.
For ALL subjects in Part 1 and up to 
20 subjects in Part 2: time matched for 
PK; triplicate evaluations at C1D1 
pre-dose and EOI, C1D2 (24 hours 
post dose), and C1D8 (168 hours post 
dose) AND at C4D1 pre-dose and 
EOI, C4D2 (24 hours post dose), and 
C4D8 (168 hours post dose).
QTcF assessment > 450msec must be 
confirmed on repeat ECG.
MUGA/Echocardiogram
X
MUGA or echocardiogram done at 
screening to document LVEF. 
Echocardiogram done at the start of 
Cycle 3, then evey 3 cycles thereafter, 
and as clinically indicated for the 
evaluation of pericardial effusion.  
Laboratory Tests
X
X
X
X
X
X
X
If the screening laboratory is 
performed within 24 hours prior to 
dosing on Day 1, then a single exam 
may count as both the screening and 
pre-dose evaluation.
See Section 5.3.1, Urine - screening 
only, unless clinically indicated.
C1D4 and C4D4: CBC only.
Revised Protocol No.: 04
Date: 02-Nov-2016
95
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-4:
Screening and Cycle 1, Part 1B (Weekly Dosing BMS-986148 Monotherapy Dosing / 28 Day Cycle) 
Procedural Outline (CA008002)
Procedurea
Pre-
Screening
Screening
Visit
D-28 to D-1
C1D1
C1D2
C1D4b
C1D8
C1D15
C1D22
Notes
Troponin I or T
X
X
X
X
X
For Part 1 only. The same evaluation 
must be collected throughout the 
study.
Pregnancy Test
X
X
X
X
PK and Immunogenicity Assessments (See Section 5.5)
Biomarker Assessments 
Tumor Sample (or 
Archival)
Part 2: Required for 
Eligibility
X
For Part 2, subjects must have tumor 
mesothelin expression
 
 No 
other protocol-specific eligibility 
procedures/assessment should be 
conducted until the tumor mesothelin 
expression is confirmed. Tumor 
material from archived samples will 
be used for the IHC analyses.  If 
archived tumor material is unavailable 
or unsuitable for evaluation, then 
tumor material from a fresh biopsy 
must be provided for these analyses. If 
archived tumor material is to be used, 
then a tumor paraffin block or 
unstained slides from a tumor tissue 
Revised Protocol No.: 04
Date: 02-Nov-2016
96
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-4:
Screening and Cycle 1, Part 1B (Weekly Dosing BMS-986148 Monotherapy Dosing / 28 Day Cycle) 
Procedural Outline (CA008002)
Procedurea
Pre-
Screening
Screening
Visit
D-28 to D-1
C1D1
C1D2
C1D4b
C1D8
C1D15
C1D22
Notes
block must be provided. 
 
 
 
 Every effort should be made 
to provide 20 slides (minimum of 
10 slides) for mesothelin IHC testing.
Tumor Assessment
X
Baseline must be within 
approximately 30 days of C1D1.
Tumor Markers
(CA125 and CA19-9)
X
At the time of tumor assessments: 
serum CA125 for ovarian cancer and
mesothelioma subjects only, serum 
CA19-9 for pancreatic cancer subjects 
only.
Baseline sample collection pre-dose 
on C1D1.
Concomitant Treatments
X
X
X
X
X
X
Adverse Event Reporting
Clinical Complaints
X
Clinical complaints related to the 
disease under study must be collected 
within 14 days of the first dose of 
study drug.
Monitor for Non-SAEs
X
X
X
X
X
X
Non-SAEs will be collected starting 
with the first dose of study medication 
and through 60 days after 
discontinuation of dosing.
Monitor for SAEs
X
X
X
X
X
X
X
All SAEs must be collected from the 
date of subject’s written consent until 
Revised Protocol No.: 04
Date: 02-Nov-2016
97
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-4:
Screening and Cycle 1, Part 1B (Weekly Dosing BMS-986148 Monotherapy Dosing / 28 Day Cycle) 
Procedural Outline (CA008002)
Procedurea
Pre-
Screening
Screening
Visit
D-28 to D-1
C1D1
C1D2
C1D4b
C1D8
C1D15
C1D22
Notes
60 days from the last dose of study 
drug or subject’s participation in the 
study if the last scheduled visit occurs 
at a later time.
Clinical Drug Supplies
Dose Level Assignment
X
At the completion of screening 
procedures and eligibility 
determination.
BMS-986148 
Administration
X
X
X
Those supplied by BMS.
a In the event multiple procedures are required at a single time point, the following is a list of procedures from highest priority to low: 1) ECG, 2) PK sampling, 
and 3) clinical labs.
b C1D4: ± 1 day.
c Ophthalmological examination: 8-point exam (visual acuity, pupils, extraocular motility and alignment, tonometry, visual field, external examination, slit lamp 
examination and fundoscopy) conducted at baseline and focused exams with visual acuity, slit lamp, and as indicated will be conducted at the end of Cycle 1 
(pre-dose Cycle 2), every other cycle, EOT and as clinically indicated during the study.
d Cycle 1, Day 1: vital signs will be obtained before the BMS-986148 infusion and then every 15 minutes (± 5 minutes) until 60 minutes after completion of the 
infusion. During subsequent treatment visits, vital signs may be obtained every 30 minutes (± 10 minutes) until 30 minutes following completion of the last 
infusion. If any vital sign is abnormal at the final check, the subject must be observed further for a period of time, as clinically indicated. The start and stop 
time of the study drug infusion should be documented (start of drug infusion = 0 hour).
 C: cycle; CBC: complete blood cell (count); CRF: case report form; D: day; 
 
 ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EOI: end of infusion; EOT: end of treatment; IHC: immunohistochemistry; 
LVEF: left ventricular ejection fraction; MUGA: multigated acquisition; PE: physical examination; PK: pharmacokinetics; QTcF: QT interval corrected by 
Fridericia’s formula; SAE: serious adverse event.
Revised Protocol No.: 04
Date: 02-Nov-2016
98
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-5:
Cycle 2 to Off Study Visit, Part 1B (Weekly Dosing BMS-986148 Monotherapy Dosing / 28 Day Cycle)
Procedural Outline (CA008002)
Procedurea
C2 and C3
C4
C5 and Beyond
EOT
Follow-up 
(30 and 
60 Days
After Last 
Dose)
Survival 
Follow-
upb
Notes
D1
D8
D15
D22
D1
D2
D4c
D8
D15
D1
D8
D15
(±5 days)
(±2 weeks)
Safety Assessments
Targeted PE
X
X
X
X
X
X
X
X
To include signs and 
symptoms of 
peripheral neuropathy 
and ocular toxicity. 
Any grade ocular 
toxicity requires 
ophthalmologist 
consultation and 
discussion with 
medical monitor as 
appropriate.
Ophthalmological 
Examinationd
Start of Cycle 2, every 2 cycles thereafter, and as clinically indicated.
X
Performed by 
ophthalmologist or 
locally qualified 
personnel.
Any abnormality 
must be discussed 
with the medical 
monitor prior to 
dosing. 
Ophthalmological 
exams can be done up 
to 72 hours prior to 
dosing.
Physical 
X
X
X
X
X
Weight only.
Revised Protocol No.: 04
Date: 02-Nov-2016
99
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-5:
Cycle 2 to Off Study Visit, Part 1B (Weekly Dosing BMS-986148 Monotherapy Dosing / 28 Day Cycle)
Procedural Outline (CA008002)
Procedurea
C2 and C3
C4
C5 and Beyond
EOT
Follow-up 
(30 and 
60 Days
After Last 
Dose)
Survival 
Follow-
upb
Notes
D1
D8
D15
D22
D1
D2
D4c
D8
D15
D1
D8
D15
(±5 days)
(±2 weeks)
Measurements
Vital Signse
X
X
X
X
X
X
X
X
X
X
See note in screening 
procedures.
ECGs
X
X
X
X
X
X
X
X
See note in screening 
procedures. 
Echocardiogram
Start of Cycle 3, then every 3 cycles thereafter, and as clinically indicated.
X
On treatment 
echocardiogram 
exams may be done 
up to 72 hours prior 
to dosing.
Laboratory Tests
X
X
X
X
X
X
X
X
X
X
X
See note in screening 
procedures and 
Section 5.3.1. Lab 
tests can be 
performed up to 
24 hours prior to 
dosing.
C4D4 (CBC only) 
collection to be time 
matched with PK 
collection pre-dose.
Revised Protocol No.: 04
Date: 02-Nov-2016
100
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-5:
Cycle 2 to Off Study Visit, Part 1B (Weekly Dosing BMS-986148 Monotherapy Dosing / 28 Day Cycle)
Procedural Outline (CA008002)
Procedurea
C2 and C3
C4
C5 and Beyond
EOT
Follow-up 
(30 and 
60 Days
After Last 
Dose)
Survival 
Follow-
upb
Notes
D1
D8
D15
D22
D1
D2
D4c
D8
D15
D1
D8
D15
(±5 days)
(±2 weeks)
Tumor Biopsy 
(Fresh)
Part 2 Only
X
C2D1 (±3 days). For 
10 ovarian cancer 
subjects and 
10 gastric cancer 
subjects who 
provided 
pre-treatment 
biopsies.
Pregnancy Test
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Treatments
X
X
X
X
X
X
X
X
X
X
X
X
X
Xf
Adverse Event Reporting
Monitor for 
Non-SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See note in screening 
procedures.
Monitor for SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See note in screening 
procedures.
PK and Immunogenicity Assessments (See Section 5.5)
Efficacy Assessments
Tumor 
Assessment
At the start of Cycle 3 and then every 2 cycles thereafter (±1 week).
X
Xg
Xh
See Sections 5.3.1
and 5.4.1.
Tumor Markers
(CA125 and 
At the start of Cycle 3 and then every 2 cycles thereafter (±1 week).
X
X
X
See note in screening 
procedures. Baseline 
Revised Protocol No.: 04
Date: 02-Nov-2016
101
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-5:
Cycle 2 to Off Study Visit, Part 1B (Weekly Dosing BMS-986148 Monotherapy Dosing / 28 Day Cycle)
Procedural Outline (CA008002)
Procedurea
C2 and C3
C4
C5 and Beyond
EOT
Follow-up 
(30 and 
60 Days
After Last 
Dose)
Survival 
Follow-
upb
Notes
D1
D8
D15
D22
D1
D2
D4c
D8
D15
D1
D8
D15
(±5 days)
(±2 weeks)
CA19-9)
sample collection 
pre-dose on C1D1.
Clinical Drug Supplies
BMS-986148
Administration
X
X
X
X
X
X
X
X
X
Those supplied by 
BMS.
Other
Survival 
Follow-up
Xi
a In the event multiple procedures are required at a single time point, the following is a list of procedures from highest priority to low: 1) ECG, 2) PK sampling, 
and 3) clinical labs.
b In the Survival Follow-up, subjects discontinuing study drug prior to 2 years will be followed for up to 2 years from first dose of study drug. Subjects treated 
for > 2 years will be followed for 6 months after EOT.
c C4D4: ± 1 day.
d Ophthalmological examination: 8-point exam (visual acuity, pupils, extraocular motility and alignment, tonometry, visual field, external examination, slit lamp 
examination and fundoscopy) conducted at baseline and focused exams with visual acuity, slit lamp, and as indicated will be conducted at the end of Cycle 1 
(pre-dose Cycle 2), every other cycle, EOT and as clinically indicated during the study.
e Vital signs will be obtained before the BMS-986148 infusion and then every 30 minutes (± 10 minutes) until 30 minutes following completion of the last 
infusion. If any vital sign is abnormal at the final check, the subject must be observed further for a period of time, as clinically indicated. The start and stop 
time of the study drug infusion should be documented (start of drug infusion = 0 hour).
f Only anti-cancer treatments.
g Only at the 60-day follow-up visit, unless discontinued for disease progression.
Revised Protocol No.: 04
Date: 02-Nov-2016
102
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
h Subjects with SD, PR, or CR at the last clinical follow-up visit should undergo tumor assessment via CT/MRI scans every 3 to 4 months during the Survival 
Follow-up (Section 8.3.2.2) phase until progression.
i
Subject status will be assessed by either a clinic visit or telephone contact every 12 weeks (± 2 weeks) until the last treated subject has been followed for 2 
years from his/her first date of treatment.  The nature and start dates of any new therapies during this period should be recorded. Only information related to 
subjects’ survival and the start date of any subsequent therapies will be collected at these telephone contacts. Subjects will be permitted to receive other anti-
cancer therapies, including investigational agents, during this follow-up period once the 60-day follow-up visit is completed.
C: cycle; CBC: complete blood cell (count); CR: complete response; CT: computed tomography; D: day; ECG: electrocardiogram; EOT: end of treatment; 
MRI: magnetic resonance imaging; PE: physical examination; PK: pharmacokinetics; PR: partial response; SAE: serious adverse event; SD: stable disease.
Revised Protocol No.: 04
Date: 02-Nov-2016
103
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-6:
Screening and Cycle 1 (Part 3: Nivolumab Combination Arm / 21 Day Cycle) Procedural Outline 
(CA008002)
Procedurea
Pre-
Screening
Screening
Visit
D-28 to D-1
C1D1
C1D2
C1D4b
C1D8
C1D15
Notes
Eligibility Assessments
Informed Consent
X
A subject is considered enrolled only when a 
protocol specific informed consent is signed. 
In Part 3B, if allowed by institutional 
practices, sites are encouraged to use a pre-
screening consent for the 
mesothelin-expressing tumor analysis. Other 
screening procedures should not be done 
before the mesothelin-expressing tumor 
analysis is available for the determination of 
subject eligibility.
Inclusion/Exclusion 
Criteria
X
ECOG
X
X
Medical History
X
Also include any toxicities or allergy related 
to previous treatments. Smoking history for 
all subjects.
Prior Treatments
X
Including prior cancer treatment regimens and 
medications administered within 4 weeks of 
dosing.
Safety Assessments
PE
X
X
If the screening PE is performed within 24 
hours prior to dosing on Day 1 then a single 
exam may count as both the screening and 
pre-dose evaluation.
Revised Protocol No.: 04
Date: 02-Nov-2016
104
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-6:
Screening and Cycle 1 (Part 3: Nivolumab Combination Arm / 21 Day Cycle) Procedural Outline 
(CA008002)
Procedurea
Pre-
Screening
Screening
Visit
D-28 to D-1
C1D1
C1D2
C1D4b
C1D8
C1D15
Notes
A neurological exam must be included at the 
screening or pre-dose at the C1D1 visit.
Targeted PE
X
X
To include signs and symptoms of peripheral 
neuropathy and ocular toxicity. Any grade 
ocular toxicity requires ophthalmologist 
consultation and discussion with medical 
monitor as appropriate.
Ophthalmological 
Examinationc
X
Performed by ophthalmologist or locally 
qualified personnel. Any abnormality must be 
discussed with the medical monitor prior to 
dosing.
Physical Measurements
X
X
Height (screening only), weight.
Vital Signsd
X
X
X
X
Body temperature, blood pressure and heart 
rate. 
Blood pressure and heart rate should be 
measured after the subject has been resting 
quietly for at least 5 minutes.
Oxygen Saturation
X
Pulse oximetry collected at rest and as 
clinically indicated on study.
ECGs
X
X
X
X
ECGs should be recorded after the subject has 
been supine for at least 5 minutes.
MUGA/Echocardiogram
X
MUGA or echocardiogram done at screening 
to document LVEF. 
Laboratory Tests
X
X
X
X
X
X
If the screening laboratory tests are performed 
within 24 hours prior to dosing on Day 1 then 
a single exam may count as both the 
screening and pre-dose evaluation.
Revised Protocol No.: 04
Date: 02-Nov-2016
105
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-6:
Screening and Cycle 1 (Part 3: Nivolumab Combination Arm / 21 Day Cycle) Procedural Outline 
(CA008002)
Procedurea
Pre-
Screening
Screening
Visit
D-28 to D-1
C1D1
C1D2
C1D4b
C1D8
C1D15
Notes
Hep B surface antigen and Hep C antibody (if 
Hep C antibody is positive reflex to Hep C 
RNA) or Hep C RNA will be done at 
screening.
Note: Testing for HIV-1 and HIV-2 must be 
performed at sites where mandated by local 
requirements.
See Section 5.3.1 Urine - screening only, 
unless clinically indicated.
C1D4: CBC only.
Thyroid Function
X
TSH with reflexive fT3 and fT4.
Troponin T or I
X
X
X
X
During Part 3A only. The same evaluation 
must be collected throughout the study.
Pregnancy Test
X
X
PK and Immunogenicity Assessments (See Section 5.5)
Biomarker Assessments 
Tumor Sample (or 
Archival)
Part 3B: Required for 
Eligibility
X
Part 3B 
only
X
(Part 3A and 
if not pre-
screened in 
For Part 3B, subjects must have tumor 
mesothelin expression
 
. No other protocol-specific eligibility 
procedures/assessment should be conducted 
Revised Protocol No.: 04
Date: 02-Nov-2016
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Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-6:
Screening and Cycle 1 (Part 3: Nivolumab Combination Arm / 21 Day Cycle) Procedural Outline 
(CA008002)
Procedurea
Pre-
Screening
Screening
Visit
D-28 to D-1
C1D1
C1D2
C1D4b
C1D8
C1D15
Notes
Part 3B)
until the tumor mesothelin expression is 
confirmed. Tumor material from archived 
samples will be used for the IHC analyses. If 
archived tumor material is unavailable or 
unsuitable for evaluation, then tumor material 
from a fresh biopsy must be provided for 
these analyses. If archived tumor material is 
to be used, then a tumor paraffin block or 
unstained slides from a tumor tissue block 
must be provided.
 
 
 Every effort should be 
made to provide 20 slides (minimum of 10 
slides) for mesothelin IHC testing.
Mandatory Fresh Tumor 
Biopsy
Part 3B Only
X
For 10 ovarian cancer subjects and 10 gastric 
cancer subjects who consent to provide pre-
and on-treatment biopsies (C2D1 ±3 days).
Optional Fresh Tumor 
Biopsy
Part 3B Only
For subjects with indications other than 
ovarian and gastric cancer who consent to 
provide pre- and on-treatment biopsies 
(C2D1±3 days). 
Tumor Assessment
X
Baseline must be within approximately 30 
days of C1D1.
Revised Protocol No.: 04
Date: 02-Nov-2016
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Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-6:
Screening and Cycle 1 (Part 3: Nivolumab Combination Arm / 21 Day Cycle) Procedural Outline 
(CA008002)
Procedurea
Pre-
Screening
Screening
Visit
D-28 to D-1
C1D1
C1D2
C1D4b
C1D8
C1D15
Notes
Tumor Markers
(CA125 and CA19-9)
X
At the time of tumor assessments: serum 
CA125 for ovarian cancer and mesothelioma 
subjects only, serum CA19-9 for pancreatic 
cancer subjects only.
Baseline sample collection pre-dose on C1D1.
Concomitant Treatments
X
X
X
X
X
Adverse Event Reporting
Clinical Complaints
X
Clinical complaints related to the disease 
under study must be collected within 14 days 
of the first dose of study drug.
Monitor for Non-SAEs
X
X
X
X
X
Non-SAEs will be collected starting with the 
first dose of study medication and through 
100 days after discontinuation of dosing.
Monitor for SAEs
X
X
X
X
X
X
All SAEs must be collected from the date of 
subject’s written consent until 100 days from 
the last dose of study drug or subject’s 
participation in the study if the last scheduled 
visit occurs at a later time.
Clinical Drug Supplies
Dose Level Assignment
X
At the completion of screening procedures 
and eligibility determination.
BMS-986148 
Administration
X
Supplied by BMS.
Nivolumab Administration
X
Supplied by BMS. For Parts 3A and 3B only. 
See Section 4 for administration details. 
Observation in a clinical setting is required 
Revised Protocol No.: 04
Date: 02-Nov-2016
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Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-6:
Screening and Cycle 1 (Part 3: Nivolumab Combination Arm / 21 Day Cycle) Procedural Outline 
(CA008002)
Procedurea
Pre-
Screening
Screening
Visit
D-28 to D-1
C1D1
C1D2
C1D4b
C1D8
C1D15
Notes
for 4 hours after dose administration for 
Cycles 1 and 2 and 1 hour after dose 
administration in subsequent cycles.
a In the event multiple procedures are required at a single time point, the following is a list of procedures from highest priority to low: 1) ECG, 2) PK sampling, 
and 3) clinical labs.
b C1D4 visit: ± 1 day.
c Ophthalmological examination: 8-point exam (visual acuity, pupils, extraocular motility and alignment, tonometry, visual field, external examination, slit lamp 
examination and fundoscopy) conducted at baseline and focused exams with visual acuity, slit lamp, and as indicated will be conducted at the end of Cycle 1 
(pre-dose Cycle 2), every other cycle, EOT and as clinically indicated during the study.
d During Cycle 1: vital signs will be obtained before the BMS-986148 infusion and then every 15 minutes (± 5 minutes) until 60 minutes after completion of the 
infusion. After Cycle 1 vital signs may be obtained pre-dose, every 30 minutes (± 10 minutes) until 30 minutes following completion of the infusion. If any 
vital sign is abnormal at the final check, the subject must be observed further for a period of time, as clinically indicated. The start and stop time of the study 
drug infusion should be documented (start of drug infusion = 0 hour).
 C: cycle; CBC: complete blood cell (count); CRF: case report form; D: day; 
 
 ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EOT: end of treatment; fT3: free triiodothyronine; fT4: free thyroxine; Hep: 
hepatitis; HIV: human immunodeficiency virus; IHC: immunohistochemistry; LVEF: left ventricular ejection fraction; MUGA: multigated acquisition; PE: 
physical examination; PK: pharmacokinetics; RNA ribonucleic acid; SAE: serious adverse event; TSH: thyroid-stimulating hormone.
Revised Protocol No.: 04
Date: 02-Nov-2016
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Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-7:
Cycle 2 to Off Study Visit (Part 3: Nivolumab Combination Arm / 21 Day Cycle) Procedural Outline 
(CA008002)
Procedurea
C2 and C3
C4
C5 and 
Beyond
EOT
Follow-up 
(30, 60, and 
100 Days
after Last 
Dose)
Survival 
Follow-upb
Notes
D1
D
8
D1
5
D1
D2
D4c
D8
D15
D1
(±5 days)
(±2 weeks)
Safety Assessments
Targeted PE
X
X
X
X
X
X
X
To include signs and 
symptoms of peripheral 
neuropathy and ocular toxicity. 
Any ocular toxicity requires 
ophthalmologist consultation 
and discussion with medical 
monitor as appropriate.
If a subject shows pulmonary-
related signs (hypoxia, fever) 
or symptoms (eg, dyspnea, 
cough, and fever) consistent 
with possible pulmonary AEs, 
the subject should be 
immediately evaluated to rule 
out pulmonary toxicity, 
according to the suspected 
pulmonary toxicity 
management algorithm in the 
nivolumab IB.
Revised Protocol No.: 04
Date: 02-Nov-2016
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v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-7:
Cycle 2 to Off Study Visit (Part 3: Nivolumab Combination Arm / 21 Day Cycle) Procedural Outline 
(CA008002)
Procedurea
C2 and C3
C4
C5 and 
Beyond
EOT
Follow-up 
(30, 60, and 
100 Days
after Last 
Dose)
Survival 
Follow-upb
Notes
D1
D
8
D1
5
D1
D2
D4c
D8
D15
D1
(±5 days)
(±2 weeks)
Ophthalmological 
Examinationd
Start of Cycle 2, every 2 cycles thereafter and as clinically 
indicated
X
Performed by ophthalmologist 
or locally qualified personnel. 
Any abnormality must be 
discussed with the medical 
monitor prior to dosing. 
Ophthalmological exams can 
be done up to 72 hours prior to 
dosing.
Physical 
Measurements 
X
X
X
X
X
Weight only.
Vital Signse
X
X
X
X
X
X
X
See note in screening 
procedures.
ECGs
X
X
X
X
X
X
X
See note in screening 
procedures. 
Echocardiogram
X
See notes
X
Echocardiogram done at the 
start of Cycle 2 and Cycle 3, 
then every 3 cycles thereafter, 
and as clinically indicated for 
the evaluation of pericardial 
effusion. On treatment
echocardiogram exams may be 
done up to 72 hours prior to 
dosing.
Laboratory Tests
X
X
X
X
X
X
X
X
See note in screening 
procedures and Section 5.3.1.
Revised Protocol No.: 04
Date: 02-Nov-2016
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Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-7:
Cycle 2 to Off Study Visit (Part 3: Nivolumab Combination Arm / 21 Day Cycle) Procedural Outline 
(CA008002)
Procedurea
C2 and C3
C4
C5 and 
Beyond
EOT
Follow-up 
(30, 60, and 
100 Days
after Last 
Dose)
Survival 
Follow-upb
Notes
D1
D
8
D1
5
D1
D2
D4c
D8
D15
D1
(±5 days)
(±2 weeks)
Lab tests can be performed up 
to 24 hours prior to dosing.
C4D4 (CBC only) collection to 
be time matched with PK 
collection pre-dose. 
Tumor Biopsy 
(Fresh)
(Mandatory) -
Part 3B Only
X
C2D1 (±3 days). For 10 
ovarian cancer subjects and 
10 gastric cancer subjects who 
provided pre-treatment 
biopsies.
Tumor Biopsy 
(Fresh)
(Optional) -
Part 3B Only
X
C2D1 (±3 days).  For subjects 
with indications other than 
ovarian cancer and gastric 
cancer.
Thyroid Function
X
Odd 
cycles
TSH with reflexive fT3 and 
fT4 to be done every 6 weeks.
Pregnancy Test
X
X
X
X
X
Concomitant 
Treatments
X
X
X
X
X
X
X
X
X
X
X f
Adverse Event Reporting
Monitor for 
Non-SAEs
X
X
X
X
X
X
X
X
X
X
X
Collected continuously during 
the treatment period and for a 
minimum of 100 days 
following discontinuation of 
Revised Protocol No.: 04
Date: 02-Nov-2016
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Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-7:
Cycle 2 to Off Study Visit (Part 3: Nivolumab Combination Arm / 21 Day Cycle) Procedural Outline 
(CA008002)
Procedurea
C2 and C3
C4
C5 and 
Beyond
EOT
Follow-up 
(30, 60, and 
100 Days
after Last 
Dose)
Survival 
Follow-upb
Notes
D1
D
8
D1
5
D1
D2
D4c
D8
D15
D1
(±5 days)
(±2 weeks)
study treatment.
Every AE must be assessed by 
the investigator with regard to
whether it is considered 
immune-mediated. For events 
which are potentially immune-
mediated, additional 
information will be collected 
on the subject’s case report 
form.
Monitor for SAEs
X
X
X
X
X
X
X
X
X
X
X
See note in screening 
procedures.
PK and Immunogenicity Assessments (See Section 5.5)
Efficacy Assessments
Tumor Assessment 
At the start of Cycle 3 and then every 2 cycles 
thereafter (±1 week).
X
Xg
Xh
See Section 5.4.1.
Tumor Markers 
(CA125 and 
CA19-9)
At the start of Cycle 3 and then every 2 cycles 
thereafter (±1 week).
X
X
X
See note in screening 
procedures. Baseline sample 
collection pre-dose on C1D1.
Clinical Drug Supplies
BMS-986148 
Administration
X
X
X
Supplied by BMS.
Revised Protocol No.: 04
Date: 02-Nov-2016
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Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-7:
Cycle 2 to Off Study Visit (Part 3: Nivolumab Combination Arm / 21 Day Cycle) Procedural Outline 
(CA008002)
Procedurea
C2 and C3
C4
C5 and 
Beyond
EOT
Follow-up 
(30, 60, and 
100 Days
after Last 
Dose)
Survival 
Follow-upb
Notes
D1
D
8
D1
5
D1
D2
D4c
D8
D15
D1
(±5 days)
(±2 weeks)
Nivolumab 
Administration
X
X
X
Supplied by BMS. For Parts 
3A and 3B only. See Section 4
for administration details. 
Observation in a clinical 
setting is required for 4 hours 
after dose administration for 
Cycles 1 and 2 and 1 hour after 
dose administration in 
subsequent cycles.
Other
Survival Follow-up
Xi
a In the event multiple procedures are required at a single time point, the following is a list of procedures from highest priority to low: 1) ECG, 2) PK sampling, 
and 3) clinical labs.
b In the Survival Follow-up, subjects discontinuing study drug prior to 2 years will be followed for up to 2 years from first dose of study drug. Subjects treated 
for > 2 years will be followed for 6 months after EOT.
c C4D4: ± 1 day.
d Ophthalmological examination: 8-point exam (visual acuity, pupils, extraocular motility and alignment, tonometry, visual field, external examination, slit lamp 
examination and fundoscopy) conducted at baseline and focused exams with visual acuity, slit lamp, and as indicated will be conducted at the end of Cycle 1 
(pre-dose Cycle 2), every other cycle, EOT and as clinically indicated during the study.
e Vital signs will be obtained before the BMS-986148 infusion and then every 30 minutes (± 10 minutes) until 30 minutes following completion of the last 
infusion. If any vital sign is abnormal at the final check, the subject must be observed further for a period of time, as clinically indicated. The start and stop 
time of the study drug infusion should be documented (start of drug infusion = 0 hour).
f Only anti-cancer treatments.
Revised Protocol No.: 04
Date: 02-Nov-2016
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1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
g Only at the 60- and 100-day follow-up visits, unless discontinued for disease progression.
h Subjects with SD, PR, or CR at the last clinical follow-up visit should undergo tumor assessment via CT/MRI scans at least every 3 to 4 months during the 
Survival Follow-up (Section 8.3.2.2) phase until progression.
i
Subject status will be assessed by either a clinic visit or telephone contact every 12 weeks (± 2 weeks) until the last treated subject has been followed for 2 
years from his/her first date of treatment. The nature and start dates of any new therapies during this period should be recorded. Only information related to 
subjects’ survival and the start date of any subsequent therapies will be collected at these telephone contacts. Subjects will be permitted to receive other anti-
cancer therapies, including investigational agents, during this follow-up period once the 100-day follow-up visit is completed.
AE: adverse event; C: cycle; CBC: complete blood cell (count); CR: complete response; CT: computed tomography; D: day; ECG: electrocardiogram; 
EOT: end of treatment; fT3: free triiodothyronine; fT4: free thyroxine; IB: Investigator’s Brochure; MRI: magnetic resonance imaging; PE: physical 
examination; PK: pharmacokinetics; PR: partial response; SAE: serious adverse event; SD: stable disease; TSH: thyroid-stimulating hormone.
Revised Protocol No.: 04
Date: 02-Nov-2016
115
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-8:
Retreatment Day 0 and Cycle 1 Onwards (Part 3 Retreatment): Nivolumab Combination Arm / 21 Day 
Cycle) Procedural Outline (CA008002)
Procedurea
Day 0
C1 and 
Beyond
D1
EOT
Follow-up (30, 60, and 
100 Days
after Last Dose)
(±5 days)
Survival 
Follow-upb
(±2 weeks)
Notes
Eligibility Assessments
ECOG
X
X
Medical History
X
Interim history (medical, AE or SAE) that 
occurred during the Survival Follow-up period 
that was not previously reported.
Prior Treatments
X
Medications administered within 4 weeks of 
dosing.
Safety Assessments
PE
X
X
If the screening PE is performed within 
24 hours prior to dosing on Day 1 then a single 
exam may count as both the screening and pre-
dose evaluation.
A neurological exam must be included at the 
screening or pre-dose at the C1D1 visit.
Targeted PE
X
X
X
To include signs and symptoms of peripheral 
neuropathy and ocular toxicity. Any grade 
ocular toxicity requires ophthalmologist 
consultation and discussion with medical 
monitor as appropriate.
Ophthalmological 
Examinationc
X
X
Performed by ophthalmologist or locally 
qualified personnel. Any abnormality must be 
discussed with the medical monitor prior to 
dosing. 
Performed on Day 0, start of Cycle 2, every 2 
Revised Protocol No.: 04
Date: 02-Nov-2016
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1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-8:
Retreatment Day 0 and Cycle 1 Onwards (Part 3 Retreatment): Nivolumab Combination Arm / 21 Day 
Cycle) Procedural Outline (CA008002)
Procedurea
Day 0
C1 and 
Beyond
D1
EOT
Follow-up (30, 60, and 
100 Days
after Last Dose)
(±5 days)
Survival 
Follow-upb
(±2 weeks)
Notes
cycles thereafter and as clinically indicated.
Physical Measurements
X
X
X
X
Height (screening only), weight.
Vital Signsd
X
X
X
X
Body temperature, blood pressure, and heart 
rate. 
Blood pressure and heart rate should be 
measured after the subject has been resting 
quietly for at least 5 minutes.
Oxygen Saturation 
X
Pulse oximetry collected at rest at Day 0 and as 
clinically indicated on study. 
ECGs
X
X
X
X
ECGs should be recorded after the subject has 
been supine for at least 5 minutes.
MUGA/Echocardiogram
X
See notes
X
MUGA or echocardiogram done at Day 0 to 
document LVEF. Echocardiogram done at the 
start of Cycle 2 and Cycle 3, then every 3 
cycles thereafter, and as clinically indicated for 
the evaluation of pericardial effusion  
Laboratory Tests
X
X
X
X
If the Day 0 laboratory tests are performed 
within 24 hours prior to dosing on Day 1 then a 
single exam may count as both the screening 
and pre-dose evaluation.
Repeat the following if >6 months since last 
treatment: Hep B surface antigen and Hep C 
antibody (if Hep C antibody is positive reflex 
to Hep C RNA) or Hep C RNA will be done at 
screening.
Note: Testing for HIV-1 and HIV-2 must be 
performed at sites where mandated by local 
Revised Protocol No.: 04
Date: 02-Nov-2016
117
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-8:
Retreatment Day 0 and Cycle 1 Onwards (Part 3 Retreatment): Nivolumab Combination Arm / 21 Day 
Cycle) Procedural Outline (CA008002)
Procedurea
Day 0
C1 and 
Beyond
D1
EOT
Follow-up (30, 60, and 
100 Days
after Last Dose)
(±5 days)
Survival 
Follow-upb
(±2 weeks)
Notes
requirements
See Section 5.3.1 Urine - Day 0 only, unless 
clinically indicated.
Thyroid Function
X
X
TSH with reflexive fT3 and fT4 to be done 
every 6 weeks. 
Pregnancy Test
X
X
X
X
PK and Immunogenicity Assessments (See Table 5.5.1-4)
Tumor Assessment
X
X
Xe
Xf
Baseline must be within approximately 30 days 
of C1D1. Then at the start of Cycle 3 and then 
every 6 weeks thereafter (±1 week). See 
Section 5.4.1.
Tumor Markers
(CA125 and CA19-9)
X
X
X
X
At the time of tumor assessments: serum 
CA125 for ovarian cancer and mesothelioma 
subjects only, serum CA19-9 for pancreatic 
cancer subjects only.
Baseline sample collection pre-dose on C1D1.
Concomitant Treatments
X
X
X
Xg
Adverse Event Reporting
Clinical Complaints
X
Clinical complaints related to the disease under 
study must be collected within 14 days of the 
first dose of study drug.
Monitor for Non-SAEs
X
X
X
Non-SAEs will be collected starting with the 
Revised Protocol No.: 04
Date: 02-Nov-2016
118
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
Table 5.1-8:
Retreatment Day 0 and Cycle 1 Onwards (Part 3 Retreatment): Nivolumab Combination Arm / 21 Day 
Cycle) Procedural Outline (CA008002)
Procedurea
Day 0
C1 and 
Beyond
D1
EOT
Follow-up (30, 60, and 
100 Days
after Last Dose)
(±5 days)
Survival 
Follow-upb
(±2 weeks)
Notes
first dose of study medication and through 
100 days after discontinuation of dosing.
Monitor for SAEs
X
X
X
X
All SAEs must be collected from the date of 
subject’s written consent until 100 days from 
the last dose of study drug 
Clinical Drug Supplies
Dose Level Assignment
X
At the completion of Day 0 procedures and 
eligibility assessements (see above) cofirmed.
BMS-986148 
Administration
X
Supplied by BMS.
Nivolumab Administration
X
Supplied by BMS. See Section 4 for 
administration details. Observation in a clinical 
setting is required for 4 hours after dose 
administration for Cycles 1 and 2 and 1 hour 
after dose administration in subsequent cycles.
Other
Survival Follow-up
Xh
a In the event multiple procedures are required at a single time point, the following is a list of procedures from highest priority to low: 1) ECG, 2) PK sampling, 
and 3) clinical labs.
b In the Survival Follow-up, subjects discontinuing study drug prior to 2 years will be followed for up to 2 years from first dose of study drug. Subjects treated 
for > 2 years will be followed for 6 months after EOT.
c Ophthalmological examination: 8-point exam (visual acuity, pupils, extraocular motility and alignment, tonometry, visual field, external examination, slit lamp 
examination, and fundoscopy) conducted at baseline and focused exams with visual acuity, slit lamp, and as indicated will be conducted at the end of Cycle 1 
(pre-dose Cycle 2), every other cycle, EOT, and as clinically indicated during the study.
Revised Protocol No.: 04
Date: 02-Nov-2016
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v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC 
d Vital signs will be obtained before the BMS-986148 infusion and then every 30 minutes (± 10 minutes) until 30 minutes following completion of the last 
infusion. If any vital sign is abnormal at the final check, the subject must be observed further for a period of time, as clinically indicated. The start and stop 
time of the study drug infusion should be documented (start of drug infusion = 0 hour).
e Only at the 60- and 100-day follow-up visits, unless discontinued for disease progression.
f Subjects with SD, PR, or CR at the last clinical follow-up visit should undergo tumor assessment via CT/MRI scans at least every 3 to 4 months during the 
Survival Follow-up (Section 8.3.2.2) phase until progression.
g Only anti-cancer treatments.
h Subject status will be assessed by either a clinic visit or telephone contact every 12 weeks (± 2 weeks) until the last treated subject has been followed for 2 
years from his/her first date of treatment. The nature and start dates of any new therapies during this period should be recorded. Only information related to 
subjects’ survival and the start date of any subsequent therapies will be collected at these telephone contacts. Subjects will be permitted to receive other anti-
cancer therapies, including investigational agents, during this follow-up period once the 100-day follow-up visit is completed.
AE: adverse event; C: cycle; CR: complete response; CRF: case report form; CT: computed tomography; D: day; ECG: electrocardiogram; ECOG: Eastern 
Cooperative Oncology Group; EOT: end of treatment; fT3: free triiodothyronine; fT4: free thyroxine; Hep: hepatitis; HIV: human immunodeficiency virus; 
LVEF: left ventricular ejection fraction; MRI: magnetic resonance imaging; MUGA: multigated acquisition; PE: physical examination; PK: pharmacokinetics; 
PR: partial response; RNA ribonucleic acid; SAE: serious adverse event; SD: stable disease; TSH: thyroid-stimulating hormone.
Revised Protocol No.: 04
Date: 02-Nov-2016
120
Approved
7.0
v
Approved
1.0
v


Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC
5.1.1
Retesting During Screening
Retesting of laboratory parameters and/or other assessments within any single Screening period 
will be permitted (in addition to any parameters that require a confirmatory value).
Any new result will override the previous result (ie, the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current clinical state.
5.2
Study Materials
The site will provide all required materials for the tests performed locally (ie, relevant clinical 
laboratory tests). The site will have available a well-calibrated scale for recording body weight, a 
12-lead ECG machine (the central laboratory will provide the machine for protocol required 
collections), and a calibrated sphygmomanometer and thermometer for vital signs assessments. 
A current and fully-stocked advanced cardiac life support or basic cardiac life support cart will 
be immediately available on the premises and all medications to manage acute infusion reactions 
should be available. The site will have a refrigerated centrifuge, a monitored and alarmed 
refrigerator, and freezer (-20°C or below), as well as containers and dry ice for shipment and 
storage of blood. The site will provide all materials required for accurate source documentation 
of study activities and for housing the subjects during the study. 
ECG (12-lead) machine should be provided by the central vendor. 
BMS will provide a BMS-approved protocol, any amendments or administrative letters (if 
required), and IB. CRFs (electronic or hard copy) will be provided by BMS. BMS/the central 
laboratory will provide labels and tubes for the collection of blood samples for PK, 
 analysis.
5.3
Safety Assessments
All subjects who receive at least 1 dose of study drug will be evaluated for safety parameters. 
Additionally, any occurrence of an SAE from the time of consent until 60 days (or 100 days for 
combination therapy) post discontinuation of study drug dosing will be documented. Any 
occurrence of nonserious AEs will be collected from first dose of study drug until 60 days (or 
100 days for combination therapy) post discontinuation of dosing. 
AEs will be coded using the most current version of Medical Dictionary for Regulatory 
Activities and reviewed for potential significance and importance. Adverse events will be 
evaluated according to the NCI CTCAE v4.03. Subjects should be followed until all AEs for 
which no clear alternative cause is identified other than BMS-986148 have recovered to baseline 
or are deemed irreversible by the investigator. Safety assessments will be based on medical 
review of AE reports and the results of vital sign measurements, PEs, and clinical laboratory 
tests. The incidence of AEs will be tabulated and reviewed for potential significance and clinical 
importance. The schedule of required visits, tests, procedures, and assessments are described in 
Table 5.1-2 through Table 5.1-8. In limited instances, scheduled events (including events other 
than safety assessments) can occur outside of the indicated timeframes but the Sponsor should be 
notified.
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Only data for the procedures and assessments specified in this protocol (see Table 5.1-2 through 
Table 5.1-8) should be submitted to BMS. Additional procedures and assessments may be 
performed as part of standard of care; however, data for these assessments should remain in the 
subject’s medical record and should not be provided to BMS unless specifically requested by the 
Sponsor.
If a subject has a delay in study drug administration for any reason, then assessments and 
laboratory tests (with the exception of any tests needed to ensure subject safety) should be 
correspondingly delayed with the exception of tumor assessments (ie, continue scans Q6W for 
Parts 1A, 2, and 3 and Q8W for Part 1B ± 1 week regardless of dosing delays).
At baseline, a medical history will be obtained to capture relevant underlying conditions. 
Baseline signs and symptoms are those that are assessed within 2 weeks prior to subject 
enrollment. Any new or worsening clinically significant changes must be reported on the 
appropriate nonserious or serious AE page.
Additional measures, including nonstudy required laboratory tests, should be performed as 
clinically indicated.
Sites should collect these screening samples between -28 to -1 days from enrollment to ensure 
that results required for eligibility purposes are verified prior to registration (tumor scans are 
allowed approximately 30 days prior to dosing). Pregnancy testing must be performed within 24 
hours prior to the initial administration of investigational product at baseline and then prior to 
administration of either study medication during study therapy and at the follow-up visit. CBC 
plus differential and serum chemistry panel should be drawn within 24 hours prior to each 
subsequent scheduled cycle. On-study laboratory tests will be performed on site/locally. 
Laboratory tests may be obtained more frequently if indicated. Grade 3 decreases in neutrophil 
and thrombocytopenia must be repeated within 72 hours. Additional laboratory tests should be 
performed as per standard of care.
Laboratory toxicities (eg, suspected drug induced liver enzyme elevations) will be monitored 
during the Follow-up period via on site/local labs until all study drug toxicities for which no 
clear alternative cause is identified other than BMS-986148 or nivolumab resolve to baseline, 
stabilize, or are deemed irreversible.
Ophthalmological examination by an ophthalmologist or locally qualified personnel will include 
an 8-point exam (visual acuity, pupils, extraocular motility and alignment, tonometry, visual 
field, external examination, slit lamp examination, and fundoscopy) at baseline and focused 
exams with visual acuity, slit lamp, and as indicated will be conducted at the end of cycle 1 (pre-
dose cycle 2), at EOT, and as clinically indicated during the study. Any abnormality must be 
discussed with the medical monitor prior to dosing. For symptoms of ocular toxicity that occur at 
any time during the treatment with study drug, dose interruption of study drug is recommended 
and prompt consultation and management with an ophthalmologist is recommended until the 
symptoms resolves. After recovery, dose reduction or discontinuation should be considered, 
depending on the severity of the eye symptoms and at the discretion of the consulting 
ophthalmologist and discussion with the medical monitor (see Section 3.1.1).
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BMS-986148
Mesothelin-ADC
Cardiac monitoring with echocardiogram at baseline, start of Cycle 3, then every 3 cycles, and 
EOT will be conducted during the Part 1 and 2 (Monotherapy treatrment) . For subject in Part 3 
combination treatment, an additional echocardiogram at the start of cycle 2 will be done. MUGA 
scan can be used for the assessment of LVEF at baseline. Echocardiograms done during 
treatment for the monitoring of pericardial effusion may be obtained more frequently if 
indicated. Troponin T or I will be monitored QW during the first cycle. Grade 1 elevation 
requires dose interruption of study drug and repeat assessment within 72 hours; BMS-986148 
should be discontinued if Grade 1 Troponin T or I is confirmed when repeated assessment 
occurs. If persistent elevation, dose discontinuation should be considered at the discretion of the 
consulting cardiologist and discussion with the medical monitor. Grade 3 elevation of Troponin I 
or T requires discontinuation of study drug and prompt consultation and management with a 
cardiologist is recommended until it resolves.  
5.3.1
Laboratory Test Assessments
A central and/or local laboratory will perform the analyses and will provide reference ranges for 
these tests.
Results of clinical laboratory tests performed on Day 1 must be available prior to dosing.
The following clinical laboratory tests will be performed:
Hematology
Hemoglobin 
Total leukocyte count, including differential 
Hematocrit 
Platelet count
Serum Chemistry
AST
ALT
TB
Direct bilirubin (only if TB is elevated)
Alkaline phosphatase
Lactate dehydrogenase
Creatinine
Blood urea nitrogen or Urea
Uric acid
Glucose
Part 3 only: 
Thyroid panel (including thyroid-stimulating 
hormone, free T3, and free T4)
Amylase and Lipase (at screening only and as 
clinically indicated)
Serology
Serum for hepatitis C antibody (if hepatitis C 
antibody is positive reflex to hepatitis C RNA) or 
Total Protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Magnesium
Creatine kinase with reflex
measurement of isoenzymes if elevated
Troponin I or T at screening and Part 1
and Part 3A cycle 1 only.
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BMS-986148
Mesothelin-ADC
hepatitis C RNA, Hepatitis B surface antigen, HIV-
1, HIV-2 antibody (testing for HIV-1 and HIV-2 
must be performed at sites where mandated by local 
requirements).
Screening only:
FSH (Section 3.3.3)
Urinalysis
Protein 
Glucose 
Blood 
Leukocyte esterase 
Specific gravity 
pH
Microscopic examination of the sediment if blood, protein or leukocytes esterase are positive 
on the dipstick
Other Analyses
At the time of tumor assessments:
• CA125 for subjects with ovarian carcinoma and mesothelioma
• CA19-9 for subjects with pancreatic carcinoma
Pregnancy test (WOCBP only: screening, pre-dose [each dose of BMS-986148], EOT, and 
follow-up).
Results of all laboratory tests required by this protocol must be provided to BMS, either recorded 
on the laboratory pages of the CRF or by another mechanism as agreed upon between the 
investigator and BMS (eg, provided electronically). If the units of a test result differ from those 
printed on the CRF, the recorded laboratory values must specify the correct units. Any abnormal 
laboratory test result considered clinically significant by the investigator must be recorded on the 
appropriate AE page of the CRF (see Section 6.3).
5.4
Efficacy Assessments
Data for the tumor assessments specified in this protocol (see Table 5.1-2 through Table 5.1-8) 
should be submitted to BMS. Additional assessments may be performed as part of standard of 
care; however, data for these assessments should remain in the subject’s medical record and 
should not be provided to BMS unless specifically requested by the Sponsor. Sponsor can 
request scans for review at any time during or after the study.
5.4.1
Primary Efficacy Assessment
Tumor measurements with CT and/ or MRI, as appropriate, will be conducted at screening, at the 
start of Cycle 3, and then every 2 cycles (± 1 week) during the treatment phase. Tumor 
measurements should be conducted earlier, if clinically indicated. Subjects with SD, PR, or CR
at the last clinical follow-up visit undergo tumor assessment via CT/MRI scans every 3 to 4 
months during the Survival Follow-up (Sections 8.3.2.2 and 8.5) phase until progression or 
death. Tumor measurements will be collected in all subjects until progression or the subject’s 
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BMS-986148
Mesothelin-ADC
discontinuation from the study as per Table 5.1-2 to Table 5.1-8. Tumor response and 
progression will be evaluated in this study using RECIST version 1.1 criteria or Modified 
RECIST for malignant pleural mesothelioma (Appendix 4).58 Initial response assessment of PR 
or CR must be confirmed by a consecutive assessment no less than 4 weeks (28 days) later.
At the Sponsor’s discretion, de-identified scans and measurements may be collected and 
reviewed by independent radiologists using RECIST version 1.1 criteria or Modified RECIST 
for malignant pleural mesothelioma at a later date or at any time during the study.
5.4.3
Imaging Assessment for the Study
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the study investigator as per 
standard medical/clinical judgment.
Computed Tomography/Magnetic Resonance Imaging
Contrast-enhanced CT scans acquired on dedicated CT equipment is preferred for this study. CT 
with contrast of the chest, abdomen, and pelvis are to be performed for tumor assessments as 
indicated in Table 5.1-2 through Table 5.1-8. CT scans should be acquired with 5 mm slices with 
no intervening gap (contiguous). 
Should a subject have a contraindication for CT IV contrast, a noncontrast CT of the chest and a 
contrast enhanced MRI of the abdomen and pelvis may be obtained. MRIs should be acquired 
with slice thickness of ≤5 mm with no gap (contiguous). 
Every attempt should be made to image each subject using an identical acquisition protocol on 
the same scanner for all imaging time points.
It is the local imaging facility’s responsibility to determine, based on subject attributes (eg, 
allergy history, diabetic history, and renal status), the appropriate imaging modality and contrast 
regimen for each subject. Imaging contraindications and contrast risks should be considered in 
this assessment. Subjects with renal insufficiency should be assessed as to whether or not they 
should receive contrast and if so, what type and dose of contrast is appropriate. Specific to MRI, 
subjects with severe renal insufficiency (ie, estimated glomerular filtration rate < 
30 mL/min/1.73m2) are at increased risk of nephrogenic systemic fibrosis. MRI contrast should 
not be given to this subject population. In addition, subjects are excluded from MRI if they have 
tattoos, metallic implants, pacemakers, etc.   
The ultimate decision to perform MRI in an individual subject in this study rests with the site 
radiologist, the investigator, and the standard set by the local Ethics Committee.
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BMS-986148
Mesothelin-ADC
5.5
Pharmacokinetic and Immunogenicity Assessments
Serum samples for total antibody, active ADC, 
 and nivolumab PK assessments as 
well as plasma samples for 
 unconjugated tubulysin PK assessments 
will be collected in all subjects. Serum samples for antibody-drug antibody (ADA) assessments 
will also be collected in all subjects. The PK parameters to be assessed include:
Cmax
Maximum observed serum or plasma concentration
Tmax
Time of maximum observed serum or plasma concentration
AUC(0-t)
Area under the concentration-time curve from time 0 to the time of the last 
quantifiable concentration
AUC(TAU)
Area under the concentration-time curve in 1 dosing interval
Ctau
Concentration in a dosing interval
Ctrough
Trough observed serum or plasma concentration (this includes pre-dose 
concentrations and Ctau concentrations)
CLT
Total body clearance calculated as Dose divided by AUC(TAU)
Vss
Volume of distribution at steady state
Vz
Apparent volume of distribution at steady state
AI_AUC
AUC accumulation index; ratio of AUC(TAU) at steady-state to AUC(TAU) after 
the first dose
AI_Cmax
Cmax accumulation index; ratio of Cmax at steady-state to Cmax after the first 
dose
AI_Ctau
Ctau accumulation index; ratio of Ctau at steady-state to Ctau after the first dose
Cavg
Average concentration over a dosing interval calculated by dividing AUC(TAU) 
by tau
T-HALF
Terminal serum or plasma half-life
Individual subject PK parameter values will be derived by noncompartmental methods using a 
validated PK analysis program. Actual times will be used for the analyses.
5.5.1
Pharmacokinetics and Immunogenicity: Collection and Processing
Table 5.5.1-1 and Table 5.5.1-2 list the sampling schedules to be followed for the assessment of 
PK and ADA for the every 3 week (Q3W) and the QW for 3 weeks followed by 1 week off 
dosing regimens, respectively. Table 5.5.1-3 lists the sampling schedules to be followed for the 
assessment of PK and ADA for the Q3W dosing regimen in combination with nivolumab. Table 
5.5.1-4 lists the sampling schedules to be followed for the assessment of PK and ADA for the 
Q3W dosing regimen during retreatment with BMS-986148 in combination with nivolumab. All 
time points are relative to the start of study drug administration. Pre-dose samples should be 
taken within 30 minutes before the start of dose administration. If the end of the infusion is 
delayed to beyond the nominal infusion duration, the collection of this sample should also be 
delayed accordingly. On-treatment PK samples are intended to be drawn relative to actual dosing 
days, if a dose occurs on a different day within the cycle due to delays or minor schedule 
adjustments, PK samples should be adjusted accordingly. Samples for ADA are to be collected 
prior to the administration of study drug. Further details of sample collection, processing, and 
shipment will be provided in the laboratory procedures manual. Serum samples designated for 
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BMS-986148
Mesothelin-ADC
PK 
 assessments may also be used for immunogenicity analysis, if required 
(eg, insufficient volume for complete immunogenicity assessment or to follow up on a suspected 
immunogenicity-related AE).
Table 5.5.1-1:
PK and ADA Sampling Schedule for BMS-986148 Monotherapy Q3W 
Dosing Regimen
Study Day of 
Sample 
Collection
Event
Time 
(Relative To Start of Infusion)
Hour: Min
PK Sample
(Serum and Plasma)
ADA Sample
(Serum)
Cycle 1
1
Predose
00:00
X
X
1
EOIa
01:00
X
1
04:00
X
2
24:00
X
4
72:00
X
8
168:00
X
15
336:00
X
X
Cycle 2
1
Predose
00:00
X
1
EOI
01:00
X
Cycle 3
1
Predose
00:00
X
X
1
EOI
01:00
X
Cycle 4
1
Predose
00:00
X
X
1
EOI
01:00
X
1
04:00
X
2
24:00
X
4
72:00
X
8
168:00
X
15
336:00
X
Every 2 Cycles Starting at Cycle 5 (PK Only)
1
Predose
00:00
X
Every 5 Cycles Starting at Cycle 9 (PK and ADA)
1
Predose
00:00
X
X
EOT
X
X
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BMS-986148
Mesothelin-ADC
Table 5.5.1-1:
PK and ADA Sampling Schedule for BMS-986148 Monotherapy Q3W 
Dosing Regimen
Study Day of 
Sample 
Collection
Event
Time 
(Relative To Start of Infusion)
Hour: Min
PK Sample
(Serum and Plasma)
ADA Sample
(Serum)
30-Day 
Follow-Up
X
60-Day 
Follow-Up
X
X
Event Drivenc
X
X
a EOI = Sample must be collected immediately following the end of the infusion. End of Infusion Serum will be 
collected for measuring total antibody, 
 and active ADC concentrations. Plasma will be collected for 
measuring 
 unconjugated tubulysin concentrations.
c In the event that labs are drawn and the subject is not dosed.
ADA: anti-drug antibody; ADC: antibody-drug conjugate; EOI: end of infusion; EOT: end of treatment; 
min: minimum; PK: pharmacokinetics; Q3W: every 3 weeks.
Table 5.5.1-2:
PK and ADA Sampling Schedule for BMS-986148 Monotherapy QW 
Dosing Regimen
Study Day of 
Sample 
Collection
Event
Time 
(Relative To Start of Infusion)
Hour: Min
PK Sample
(Serum and Plasma)
ADA Sample
(Serum)
Cycle 1
1
Predose
00:00
X
X
1
EOIa
01:00
X
1
04:00
X
2
24:00
X
4
72:00
X
8
Predose
00:00
X
8
EOI
01:00
X
15
Predose
00:00
X
X
15
EOI
01:00
X
22
168:00
X
Cycle 3
1
Predose
00:00
X
X
Cycle 4
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BMS-986148
Mesothelin-ADC
Table 5.5.1-2:
PK and ADA Sampling Schedule for BMS-986148 Monotherapy QW 
Dosing Regimen
Study Day of 
Sample 
Collection
Event
Time 
(Relative To Start of Infusion)
Hour: Min
PK Sample
(Serum and Plasma)
ADA Sample
(Serum)
1
Predose
00:00
X
X
1
EOI
01:00
X
1
04:00
X
2
24:00
X
4
72:00
X
8
Predose
00:00
X
8
EOI
01:00
X
15
Predose
00:00
X
15
EOI
01:00
X
22
168:00
X
Every 2 Cycles Starting at Cycle 5 (PK Only)
1
Predose
00:00
X
Every 4 Cycles Starting at Cycle 8 (PK and ADA)
1
Predose
00:00
X
X
EOT
X
X
30-Day Follow-
Up
X
60-Day Follow-
Up
X
X
Event Drivenc
X
X
a EOI = Sample must be collected immediately following the end of the infusion. End of Infusion Serum will be 
collected for measuring total antibody, 
 and active ADC concentrations. Plasma will be collected for 
measuring 
 unconjugated tubulysin concentrations.
 
c In the event that labs are drawn and the subject is not dosed.
ADA: anti-drug antibody; ADC: antibody-drug conjugate; EOI: end of infusion; EOT: end of treatment; 
min: minimum; PK: pharmacokinetics; QW: every week.
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BMS-986148
Mesothelin-ADC
Table 5.5.1-3:
PK and Anti-Drug Antibody Sampling Schedule for BMS-986148 
Q3W Dosing Regimen in Combination with Nivolumab
Study Day of 
Sample 
Collection
Event
Time
(Relative to Start of 
Infusion)
Hour:Min
BMS-986148 
PK Sample
(Serum and 
Plasma)
Nivolumab PK 
Sample
(Serum)
BMS-986148 
and Nivolumab 
ADA Samples
(Serum)
Cycle 1
1
Predose
00:00
X
X
X
1
EOIa
00:30
X
1
EOIa
01:00
X
1
04:00
X
2b
24:00
X
X
4
72:00
X
X
8
168:00
X
X
15
336:00
X
X
X
Cycle 2
1
Predose
00:00
X
X
1
EOI
00:30
X
1
EOI
01:00
X
Cycle 3
1
Predose
00:00
X
X
X
1
EOI
00:30
X
1
EOI
01:00
X
Cycle 4
1
Predose
00:00
X
X
X
1
EOI
00:30
X
1
EOI
01:00
X
1
04:00
X
2b
24:00
X
X
4
72:00
X
X
8
168:00
X
X
15
336:00
X
X
Every 2 Cycles Starting at Cycle 5 (PK Only)
1
Predose
00:00
X
X
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CA008002
BMS-986148
Mesothelin-ADC
Table 5.5.1-3:
PK and Anti-Drug Antibody Sampling Schedule for BMS-986148 
Q3W Dosing Regimen in Combination with Nivolumab
Study Day of 
Sample 
Collection
Event
Time
(Relative to Start of 
Infusion)
Hour:Min
BMS-986148 
PK Sample
(Serum and 
Plasma)
Nivolumab PK 
Sample
(Serum)
BMS-986148 
and Nivolumab 
ADA Samples
(Serum)
Every 5 Cycles Starting at Cycle 9 (PK and ADA)
1
Predose
00:00
X
X
X
EOT
X
X
X
30-Day
Follow-Up
X
X
X
60-Day 
Follow-Up
X
X
X
100-Day 
Follow-Up
X
X
X
Event Drivend
X
X
X
a EOI = Sample must be collected immediately following the end of the infusion. End of Infusion Serum will be 
collected for measuring total antibody, 
 and active ADC concentrations. Plasma will be collected for 
measuring 
 unconjugated tubulysin concentrations.
b ± 2 hours.
d In the event that labs are drawn and the subject is not dosed.
ADA: anti-drug antibody; ADC: antibody-drug conjugate; EOI: end of infusion; EOT: end of treatment; min: 
minimum; PK: pharmacokinetics; Q3W: every 3 weeks.
Table 5.5.1-4:
PK and Anti-Drug Antibody Sampling Schedule for BMS-986148 
Q3W Dosing Regimen in Combination with Nivolumab During 
Retreatment
Study Day of 
Sample 
Collection
Event
Time
(Relative to Start of 
Infusion)
Hour:Min
BMS-986148 PK 
Sample
(Serum and 
Plasma)
Nivolumab PK 
Sample
(Serum)
BMS-986148 
and Nivolumab 
ADA Samples
(Serum)
Cycle 1
1
Predose
00:00
X
X
X
Cycle 3
1
Predose
00:00
X
X
X
Cycle 4
1
Predose
00:00
X
X
X
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CA008002
BMS-986148
Mesothelin-ADC
Table 5.5.1-4:
PK and Anti-Drug Antibody Sampling Schedule for BMS-986148 
Q3W Dosing Regimen in Combination with Nivolumab During 
Retreatment
Study Day of 
Sample 
Collection
Event
Time
(Relative to Start of 
Infusion)
Hour:Min
BMS-986148 PK 
Sample
(Serum and 
Plasma)
Nivolumab PK 
Sample
(Serum)
BMS-986148 
and Nivolumab 
ADA Samples
(Serum)
Every 5 Cycles Starting at Cycle 9
1
Predose
00:00
X
X
X
EOT
X
X
X
30-Day 
Follow-Up
X
X
X
60-Day 
Follow-Up
X
X
X
100-Day 
Follow-Up
X
X
X
Event 
Drivena
X
X
X
a In the event that labs are drawn and the subject is not dosed.
ADA: anti-drug antibody; ADC: antibody-drug conjugate; EOI: end of infusion; EOT: end of treatment; min: 
minimum; PK: pharmacokinetics; Q3W: every 3 weeks.
5.5.2
Pharmacokinetic Sample Analyses
Serum samples for total antibody, 
 active ADC, and nivolumab concentrations and 
plasma samples for unconjugated tubulysin concentrations will be analyzed using a series of 
validated assays. 
 
 
5.5.3
Antibody-Drug Antibody Sample Analyses
ADA assessment utilizes a tiered approach to testing for ADA through detection, confirmation, 
and titer and domain specificity characterization as is applicable. All assay tiers are fully 
validated ligand binding assays.
5.5.4
Labeling and Shipping of Biological Samples
Detailed instructions for the PK blood collection, labeling, processing, storage, and shipping will 
be provided to the site in the procedure manual.
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Mesothelin-ADC
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CA008002
BMS-986148
Mesothelin-ADC
Revised Protocol No.: 04
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Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC
Revised Protocol No.: 04
Date: 02-Nov-2016
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Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC
Revised Protocol No.: 04
Date: 02-Nov-2016
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Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC
Revised Protocol No.: 04
Date: 02-Nov-2016
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Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC
Revised Protocol No.: 04
Date: 02-Nov-2016
138
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Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC
Revised Protocol No.: 04
Date: 02-Nov-2016
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Clinical Protocol
CA008002
BMS-986148
Mesothelin-ADC
Revised Protocol No.: 04
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5.8
Outcomes Research Assessments
Not applicable.
5.10
Results of Central Assessments
Not applicable
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6
ADVERSE EVENTS
An AE is defined as any new untoward medical occurrence or worsening of a preexisting 
medical condition in a clinical investigation subject administered study drug and that does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess 
all AEs. The causal relationship can be 1 of the following:
•
Related: There is a reasonable causal relationship between study drug administration and the 
AE.
•
Not related: There is not a reasonable causal relationship between study drug administration 
and the AE. 
The term “reasonable causal relationship” means there is evidence to suggest a causal 
relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of 1 or more AEs.)
6.1
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose: 
•
Results in death
•
Is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)
•
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below)
•
Results in persistent or significant disability/incapacity
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•
Is a congenital anomaly/birth defect 
•
Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent 1 of the other serious outcomes listed in the definition above). Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias, or convulsions that do not result in 
hospitalization. p-DILI is also considered an important medical event. (See Section 6.6 for 
the definition of p-DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE.
Although pregnancy, overdose, cancer, and p-DILI are not always serious by regulatory 
definition, these events must be handled as SAEs (see Section 6.1.1 for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
−
A visit to the emergency room or other hospital department < 24 hours that does not 
result in admission (unless considered an important medical or life-threatening event)
−
Elective surgery, planned prior to signing consent
−
Admissions as per protocol for a planned medical/surgical procedure
−
Routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy)
−
Medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases.
−
Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason).
−
Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the IB represent the Reference Safety Information to determine 
expectedness of serious AEs for expedited reporting. Following the subject’s written consent to 
participate in the study, all SAEs, whether related or not related to study drug, must be collected, 
including those thought to be associated with protocol-specified procedures. All SAEs must be 
collected that occur during the screening period and within 60 days (or 100 days for combination 
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therapy) of discontinuation of dosing. If applicable, SAEs must be collected that relate to any 
later protocol-specified procedure (eg, a follow-up skin biopsy). 
The investigator should report any SAE that occurs after these time periods and that is believed 
to be related to study drug or protocol-specified procedure. 
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or 
designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on a 
Pregnancy Surveillance Form (electronic or paper forms). The preferred method for SAE data 
reporting collection is through the electronic case report form (eCRF). The paper SAE/pregnancy 
surveillance forms are only intended as a back-up option when the eCRF system is not 
functioning. In this case, the paper forms are to be transmitted via email or confirmed facsimile 
(fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, 
the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A non-SAE is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of non-SAE information should begin at initiation of study drug. Non-SAE 
information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. 
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Non-SAEs should be followed to resolution or stabilization, or reported as SAEs if they become 
serious (see Section 6.1.1). Follow-up is also required for non-SAEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as appropriate. 
All identified non-SAEs must be recorded and described on the non-SAE page of the CRF (paper 
or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the non-SAE CRF page 
or SAE Report Form (paper or electronic) as appropriate:
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted
•
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of study exposure, including during at 
least 5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours and in accordance with SAE reporting procedures 
described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough 
discussion of benefits and risk with the subject.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
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Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
All occurrences of overdose must be reported as SAEs (see Section 6.1.1 for reporting details).
6.6
Potential Drug-Induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a p-DILI event. All occurrences of p-DILIs, meeting the defined 
criteria, must be reported as SAEs (see Section 6.1.1 for reporting details). The criteria for 
identifying p-DILI events depend on whether the subject’s baseline liver biochemistry is normal 
or abnormal (see Figure 6.6-1).
Figure 6.6-1:
Algorithm for p-DILI Identification and Mandatory SAE Reporting 
in Subjects with (i) Normal Baseline Liver Biochemistry and (ii) 
Abnormal Baseline Liver Biochemistry
ALT: alanine transaminase; AST: aspartate transaminase; SAE: serious adverse event; p-DILI: potential drug-
induced liver injury; TB: total bilirubin; ULN: upper limit of normal.
The key responsibilities for investigators during p-DILI assessment include: (i) Early detection, 
medical evaluation (including the exclusion of other potential causes), and rapid laboratory 
confirmation of liver-related abnormalities, and (ii) BMS notification of p-DILI cases via SAE 
forms. Following the gathering and assessment of relevant clinical information BMS is 
responsible for: (iii) Timely evaluation and triaging of p-DILI cases, (iv) Expedited reporting of 
p-DILI cases, and (v) Expanded review of p-DILI cases including a detailed assessment of all 
available clinical information, investigations, and biochemical data.
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Investigators are expected to monitor ongoing routine and ad hoc hepatic laboratory test results 
to rapidly determine whether a subject meets p-DILI criteria. They are expected to promptly 
notify BMS of all p-DILI cases. p-DILI cases may be identified by abnormal liver biochemistry 
values, whether or not they are accompanied by liver-related signs and/or symptoms. In both 
cases, expedited confirmation with repeat laboratory testing should occur within 3 business days 
using a Hepatic Laboratory Panel (ALT, AST, TB, and alkaline phosphatase). Any subject with 
an abnormal Hepatic Laboratory Panel that meets p-DILI criteria (see Figure 6.6-1) is a 
candidate for study drug discontinuation. Any confirmed p-DILI events must be reported (along 
with a description of the clinical findings) to BMS as an SAE within 24 hours of confirmation. 
An extensive clinical history, examination, and appropriate investigations should be obtained to 
exclude cholestatic and other apparent causes that may explain the observed abnormalities in 
liver function and/or hepatic signs and symptoms. Other apparent causes include, 
nonexhaustively and by way of example only: infectious diseases (such as active hepatitis A, B,
and C), congenital diseases (such as Gilbert’s syndrome), neoplastic diseases (such as 
hepatocellular carcinoma), automimmune diseases (such as primary biliary cirrhosis), and the 
use of concomitant hepatotoxic medications (such as antibiotics, the oral contraceptive pill, and 
herbal medicines). All investigations to exclude potential causes of liver function abnormalities 
or hepatic signs and/or symptoms should be guided by relevant factors such as the subject’s age, 
gender, clinical history, and signs and symptoms.
6.7
Other Safety Considerations
Any significant worsening noted during interim or final PEs, ECG, x-ray filming, or any other 
potential safety assessment required or not required by protocol should also be recorded as a 
non-SAE or SAE, as appropriate, and reported accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Not applicable
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
Dose Escalation: In the monotherapy dose escalation part of the study, ie, both Parts 1A and 1B, 
a total of approximately 30 and 24 evaluable subjects are expected to be treated, respectively. 
The exact sample size per dose level cannot be precisely determined but depends on the observed 
DLT and will be guided by the mTPI design, with a target DLT rate of 27% (25% to 29%), based 
on Bayesian modeling and posterior inference. Between 2 and up to 13 DLT evaluable subjects 
may be enrolled to a given monotherapy cohort in Part 1A. Treating additional subjects beyond 
the 13 would be unlikely to alter the decision specified by the mTPI algorithm. In the 
combination dose escalation part (Part 3A), a total of approximately 12 evaluable subjects are 
expected to be treated across 2 dose levels, with the sample size per dose level guided by a mTPI 
design with target DLT rate of 29% (28% to 31%).
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Cohort Expansion: During this part of the study, approximately up to 25 to 26 subjects in the
population of interest
are expected to be treated in 
each tumor cohort at the MTD or alternate dose below the MTD (as determined from dose 
escalation), or other agreed dose level. This number per cohort is based on achieving a 
reasonable precision of the ORR and adequate control on the false negative rate (FNR) and false 
positive rate (FPR) (assuming a historic and target response rate as shown for monotherapy 
cohorts below):
In a cohort of 25 marker positive subjects, if 5 or 6 responses are observed (eg, for gastric or 
pancreatic cohorts), then the ORR 90% confidence intervals (CIs) are (8.2%, 37.5%) and (11%, 
42%), respectively. If 7 responses are observed (eg, NSCLC and ovarian cohorts), then the 90% 
CI is (14%, 46.2%), and if 8 or 9 responses are observed (eg, mesothelioma cohort), then the 
90% CIs for ORR are: (17%, 50.4%) and (20%, 54.4%), respectively. These calculations are 
based on the Clopper-Pearson method for exact CIs. 
In addition, 25 subjects per cohort provide the following FNR and FPR under assumptions of 
expected true ORR. If the true ORR is 40% (eg, mesothelioma), then with 25 subjects in a cohort 
there is 97% and 93% chance of observing at least 6 or 7 responses, respectively, and there is 7% 
chance of observing 6 or fewer responses (FNR). If the true ORR for this tumor is only 20% 
(rather than 40%), then there is 22% and 11% chance respectively of observing at least 7 and at 
least 8 responses among 25 subjects (FPR). 
Similarly if the true ORR is 20% (eg, gastric and pancreatic cohorts), then there is 97% and 90% 
probability of observing at least 2 or 3 responses respectively, among 25 subjects and 10% of 
observing 2 or fewer responses (FNR). If the true ORR for these tumors is 10% (rather than 
20%) then there is 24% and 10% chance, respectively, of observing at least 4 and at least 5 
responses (FPR).  
If the true ORR is 30% (eg, NSCLC and ovarian cohorts), then there is 91% and 81% probability 
of observing at least 5 or 6 responses, respectively, in 25 subjects and 9% of observing 5 or 
fewer responses (FNR). If the true ORR for these tumors is 15% (rather than 30%) then there is 
16% and 7% chance, respectively, of observing at least 6 and at least 7 responses (FPR).  
The Simon 2-Stage design will be used in the monotherapy and nivolumab combination 
expansion cohorts, with a minimum of subjects treated initially as per the Stage 1 n of Table 8.1-
1 and Table 8.1-2 below. Efficacy will be explored in both the 
 
populations; there will be no adjustment for multiple comparisons. In each of monotherapy or 
combination cohorts after a minimum number of subjects (n for Stage 1) are treated, there will be 
an initial evaluation of efficacy independently in each cohort. If there is a lack of signal in either
population, then treatment in that cohort may be stopped in that population; if there is an initial 
efficacy signal, subjects will continue to be treated in Stage 2 for the population in which there 
was a signal.
 
The above results will inform potential early decisions and guide planning/operations or early 
termination after taking into consideration additional data, for example, duration of response 
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and/or SD and safety. The operational characteristics of these Simon 2-Stage designs are 
provided in the following tables.
Table 8.1-1:
Monotherapy Operating Characteristics for 2-Stage Simon Design
Tumor Type
Historic 
ORR (%)
Target ORR
(%)
Stage 1/ 
Total n
Stage 1a
Futility 
Boundary
Alpha / 
Power
Early 
Stopping 
Probability
Gastric
10
20
15 / 25
0
0.24 / 0.76
0.21
Mesothelioma
20
40
12 / 25
2
0.10 / 0.80
0.45
NSCLC Adeno
15
30
14 / 26
1
0.18 / 0.82
0.36
Ovarian
15
30
14 / 26
1
0.18 / 0.82
0.36
Pancreatic
10
20
15 / 25
0
0.24 / 0.76
0.21
a Number of responses indicating the cut-off for lack of efficacy signal.
n: number of subjects; NSCLC: non-small cell lung carcinoma; ORR: objective response rate.
Similarly the operating characteristics of the 2-stage Design in the expansion cohort are shown in 
Table 8.1-2 below:
Table 8.1-2:
Nivolumab Combination Operating Characteristics for 2-Stage Simon 
Design
Tumor Type
Historic 
ORR (%)
Target ORR
(%)
Stage 1/ 
Total n
Stage 1a
Futility 
Boundary
Alpha / 
Power
Early 
Stopping 
Probability
Gastric
10
30
11 / 25
1
0.10 / 0.84
0.70
Mesothelioma
20
40
12 / 25
2
0.10 / 0.80
0.45
NSCLC Adeno
15
40
10 / 22
1
0.10 / 0.90
0.54
Ovarian
15
30
14 / 26
1
0.18 / 0.82
0.36
Pancreatic
10
30
11 / 25
1
0.10 / 0.84
0.70
a Number of responses indicating the cut-off for lack of efficacy signal.
n: number of subjects; NSCLC: non-small cell lung carcinoma; ORR: objective response rate.
8.2
Populations for Analyses
•
All Enrolled Subjects: All subjects who sign an informed consent form.
•
All Treated Subjects: All subjects who receive at least 1 dose of study medication.
•
PK Subjects: All subjects who receive at least 1 dose of BMS-986148 and have available 
serum and plasma concentration data.
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•
Immunogenicity (ADA) Population: all treated subjects who had baseline and at least 
1 post-treatment immunogenicity assessment
•
ECG Evaluable Population: all treated subjects who had a baseline ECG and at least 1 on-
study ECG.
•
Response Evaluable Population: all treated subjects who had baseline tumor measurement 
and at least 1 other tumor measurement after treatment, clinical progression, or death prior to 
the first on-treatment tumor assessment.
8.3
Endpoints
8.3.1
Primary Endpoint(s)
Incidence of AEs at worst grade, SAEs at worst grade, AEs leading to discontinuations, deaths, 
and frequency of laboratory test toxicity grade shifting from baseline. Safety will be evaluated 
from the time that the subject signs the informed consent, and for up to 60 days (or 100 days for 
combination therapy) after the last dose of study drug.
8.3.2
Secondary Endpoint(s)
8.3.2.1
Pharmacokinetics
The PK of total antibody, active ADC, unconjugated tubulysin, and nivolumab will be 
characterized using the following endpoints (previously defined in Section 5.5):
•
Cmax
•
Tmax
•
Ctau
•
Ctrough
•
AUC(0-t)
•
AUC(TAU)
•
T-HALF
•
CLT
•
Vss
•
Vz
•
AI_AUC
•
AI_Cmax
•
AI_Ctau
•
Cavg
 
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8.3.2.2
Efficacy
Efficacy based on RECIST version 1.1 or Modified RECIST for malignant pleural mesothelioma
(Appendix 4)58 will be assessed using the following secondary endpoints:
•
Best overall response (BOR): defined as the best response designation over the study as a 
whole, recorded between the dates of first dose until the last tumor assessment prior to 
subsequent therapy. CR or PR determinations included in the BOR assessment must be 
confirmed by a second scan performed no less than 4 weeks after the criteria for response are 
first met. For those subjects who have surgical resection, only pre-surgical tumor assessments 
will be considered in the determination of BOR. 
•
ORR: defined as the total number of subjects whose BOR is either a CR or PR divided by the 
total number of subjects in the population of interest. 
•
Duration of response: defined as the time between the date of first response and the 
subsequent date of objectively documented disease progression or death, whichever occurs 
first. For those subjects who remain alive and have not progressed or received subsequent 
therapy, duration of response will be censored on the date of last tumor assessment
•
PFS: defined as the time from the first dose of study medication to the date of the first 
objective documentation of tumor progression or death due to any cause. Subjects who did 
not progress nor died will be censored on the date of their last tumor assessment. Subjects 
who did not have any on-study tumor assessments will be censored on the date of the first 
dose of study medication.
•
PFS rate at week ‘t’: defined as the proportion of subjects who remain progression free and 
surviving at ‘t’ weeks (eg, t=12, 24, and 36 weeks, and following the corresponding planned 
tumor scan visit). The proportion will be calculated by the product-limit method (Kaplan-
Meier estimate) which takes into account censored data.
8.3.2.3
QTc
Changes in QTcF (ΔQTcF) from baseline, at selected times.
8.3.2.4
Immunogenicity (Anti-Drug Antibodies)
The endpoints of immunogenicity of BMS-986148 (after monotherapy and after combination 
with nivolumab) include frequency of different subject immunogenicity status, for example, 
subject positive ADA, persistent positive ADA, and others. The above endpoints will also be 
generated for nivolumab. Definitions of all the immunogenicity endpoints will be provided in the 
Statistical Analysis Plan.
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8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Frequency distributions of gender and race will be tabulated. Summary statistics for age, body 
weight, height, and body mass index will be tabulated. Prior therapy will be tabulated.
8.4.2
Efficacy Analyses
Efficacy results will be presented by tumor type, dose and regimen for monotherapy and 
combination cohorts. Individual BOR, duration of response and PFS will be listed using RECIST 
version 1.1 criteria or Modified RECIST for malignant pleural mesothelioma (Appendix 4). BOR 
outcomes will be tabulated by dose and dose regimen. The ORR and PFS rates (eg, at 24 weeks) 
and the CI will be provided by dose and dose regimen for each tumor type if there is a large 
enough sample size. The duration of response and PFS will be estimated by Kaplan-Meier (K-M) 
methodology, PFS rates (eg, at 24 weeks) will be similarly estimated, based on K-M 
methodology. Individual changes in the tumor burden over time will be presented graphically by 
dose and dose regimen within a tumor type. 
 
 
Sponsor can request scans for review at any time during or after the study. Sponsor 
can request scans for review at any time during or after the study.
8.4.3
Safety Analyses
All recorded AEs will be listed and tabulated by system organ class, preferred term, and 
treatment. Clinical laboratory test results will be listed and summarized by treatment. Any 
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significant PE findings and clinical laboratory results will be listed. Vital sign measurements will 
be listed. ECG readings (reviewed by a central laboratory) will be evaluated by the investigator 
and abnormalities, if present, will be listed.
For subjects with serial ECG measurements and time-matched PK related to 
 
 changes in the QTcF (ΔQTcF), ECG intervals QRS and PR, and in heart rate (ΔHR) 
will be tabulated by dose and study day. Frequency distributions of max QTcF values, max 
ΔQTcF, max QRS, max PR, and max HR in pre-specified categories will be tabulated by dose. 
Scatter plots of HR, ΔHR, QTc, and ΔQTcF versus time-matched active ADC and unconjugated 
tubulysin concentrations will be provided. A concentration-response effect of BMS-986148 on 
QTcF may be assessed by a linear mixed effects regression model for ΔQTcF on plasma and 
serum concentrations, stratified by study day, as well as pooled across days. Additional modeling 
of exposure-response may also be explored.
8.4.4
Pharmacokinetic Analyses
PK parameters for the total antibody, 
 active ADC, 
 and 
unconjugated tubulysin will be calculated using noncompartmental analysis and tabulated 
following monotherapy and combination treatments. 
 
 
To describe the dependency on dose, scatter plots of Cmax and AUC (TAU) versus dose will be 
provided on indicated study days for each dose regimen. 
 
 
 To assess the attainment of steady state geometric mean minimum serum 
concentration values will be plotted versus study day by dose and dose regimen.
Summary statistics for nivolumab PK will also be tabulated.
Associations between PK and select safety measures may be explored.
Population PK and exposure-response analyses may be conducted, which would be presented in 
a separate report.
8.4.5
Immunogenicity Analysis
All available immunogenicity data will be listed and flagged for subjects with at least 1 positive 
ADA. The frequency of subjects with at least 1 positive ADA assessment at baseline and the 
frequency of subjects who develop ADA after initiation of treatment (ADA positive) will be 
provided. Details and potentially additional endpoints (eg, incidence of persistent positive ADA) 
and analysis will be provided in the SAP. Associations of immunogenicity measures with PK 
and/or selected AE may be explored. The above analysis will be provided for BMS-986148 after 
monotherapy and combination treatments and for nivolumab. 
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8.4.8
Outcomes Research Analyses
Not applicable.
8.4.9
Other Analyses
The effect of treatment on changes in CA125 levels in the ovarian cancer and mesothelioma 
cohorts only and changes in CA19-9 levels in the pancreatic cancer cohort only will also be 
explored by summary statistics and plots over time. 
 
 
 
 
8.5
Interim Analyses
Because the exploratory nature of the early phase study, data emerging from each dose level or 
each part of the study will be examined prior to the formal locking of the study database for 
timely decisions about, such as but not limited to, dose selection, regimen selection and early 
termination of the study. There will be no formal hypothesis testing, nor will multiplicity be 
adjusted. 
Bayesian regression model may be utilized to inform dose selection starting for the third dose in 
Part 1A. A similar approach may be used in Part 1B.
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9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:
•
IRB/IEC for review and approval/favorable opinion
•
BMS
•
Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable. 
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.2.1
Source Documentation
The investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, and original and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any other kind of 
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electronic devices) as part of regulated clinical trial activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health records, 
AE tracking/reporting, protocol required assessments, and/or drug accountability records).
When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
BMS will provide quality investigational staff training prior to study initiation. Training topics 
will include but are not limited to: AE reporting, study details and procedure, electronic CRFs, 
study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product. 
Records or logs must comply with applicable regulations and guidelines and should include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number 
•
amount dispensed to and returned by each subject, including unique subject identifiers
•
amount transferred to another area/site for dispensing or storage
•
nonstudy disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for bioavailability/bioequivalence, if applicable 
•
dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
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BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS EDC tool, electronic CRFs will be prepared for all data collection fields 
except for fields specific to SAEs and pregnancy, which will be reported on the paper or 
electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator 
and who is delegated this task on the Delegation of Authority Form .For electronic CRFs, review 
and approval/signature is completed electronically through the BMS EDC tool. The investigator 
must retain a copy of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS EDC tool using the unique user account provided by BMS. User 
accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A signatory investigator must be selected to sign the clinical study report. 
For this protocol, the signatory investigator will be selected as appropriate based on the 
following criteria:
•
Subject recruitment (eg, among the top quartile of enrollers)
•
Involvement in trial design
•
Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study require approval by BMS prior to publication or presentation 
and must adhere to BMS’s publication requirements as set forth in the approved clinical trial 
agreement (CTA). All draft publications, including abstracts or detailed summaries of any 
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proposed presentations, must be submitted to BMS at the earliest practicable time for review, but 
at any event not less than 30 days before submission or presentation unless otherwise set forth in 
the CTA. BMS shall have the right to delete any confidential or proprietary information 
contained in any proposed presentation or abstract and may delay publication for up to 60 days 
for purposes of filing a patent application.
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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If 1 form of contraception is required, complete abstinence is 
defined as complete avoidance of heterosexual intercourse and 
is an acceptable form of contraception for all study drugs. 
Female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective contraception 
must be discussed in the event that the subject chooses to 
forego complete abstinence.
If 2 forms of contraception is required, complete abstinence is 
defined as complete avoidance of heterosexual intercourse and 
is an acceptable form of contraception for all study drugs. 
Subjects who choose complete abstinence are not required to 
use a second method of contraception, but female subjects 
must continue to have pregnancy tests. Acceptable alternate 
methods of highly effective contraception must be discussed in 
the event that the subject chooses to forego complete 
abstinence.
Expanded definition Complete abstinence as defined as 
complete avoidance of heterosexual intercourse is an 
acceptable form of contraception for all study drugs. This also 
means that abstinence is the preferred and usual lifestyle of the 
patient. This does not mean periodic abstinence (eg, calendar, 
ovulation, symptothermal, profession of abstinence for entry 
into a clinical trial, postovulation methods) and withdrawal, 
which are not acceptable methods of contraception. Subjects 
who choose complete abstinence are not required to use a 
second method of contraception, but female subjects must 
continue to have pregnancy tests. Acceptable alternate 
methods of highly effective contraception must be discussed in 
the event that the subject chooses to forego complete 
abstinence.
Additional Research
Those scientific activities which cannot be reasonably 
anticipated at the time of trial design, for which we would like 
to collect and/or retain samples from study participants. 
Examples of Medical Research include, but are not limited to, 
new assay development and validation, companion diagnostic 
development, new hypotheses in the interaction of drug and 
the human body, and exploration of emerging science in the 
understanding of disease.
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11
LIST OF ABBREVIATIONS
Term
Definition
ADA
antibody-drug antibody
ADC
antibody-drug conjugate 
ADL
activities of daily living
AE
adverse event
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after the 
first dose
AI_Ctau
Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the 
first dose
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
AUC(0-t)
area under the concentration-time curve from time 0 to the time of the last 
quantifiable concentration
AUC(TAU)
area under the concentration-time curve in 1 dosing interval
BMS
Bristol-Myers Squibb
BOR
best overall response
BV
brentuximab vedotin
Cavg
average concentration
CBC
complete blood count
CI
confidence interval
CL
clearance
CLT
total body clearance
Cmax
maximum observed plasma concentration
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Term
Definition
CR
complete response
CRCl
creatinine clearance
CRF
case report form, paper or electronic
CT
computed tomography
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte associated antigen 4
Ctrough
trough observed plasma concentration
CV
cardiovascular
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EI
equivalence interval
EGFR
epidermal growth factor receptor
EOT
end of treatment
FFPE
formalin-fixed, paraffin-embedded
FNR
false negative rate
FPR
false positive rate
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal tract
HER2
human epidermal growth factor receptor 2
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Term
Definition
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
I-O
immuno-oncology
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IHC
immunohistochemistry
IMP
investigational medicinal product
IP
investigational product
IRB
Institutional Review Board
IUD
intrauterine device
IV
intravenous
IVIG
intravenous immunoglobulin
IVRS
interactive voice response system
k
cumulative number of subjects who experienced DLT
Kd
dissociation constant
LVEF
left ventricular ejection fraction
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
mTPI
modified toxicity probability interval
MUGA
multigated acquisition 
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Term
Definition
n
cumulative number of DLT evaluable subjects
NCI
National Cancer Institute
NIMP
noninvestigational medicinal product
NSCLC
non-small cell lung cancer
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
PBT
platinum-based therapy
p-DILI
potential drug-induced liver injury
PD
pharmacodynamics
PD-1
programmed cell death protein 1
PD-L1
programmed death protein ligand 1
PE
physical examination
PI
prediction interval
PFS
progression-free survival
PK
pharmacokinetics
PR
partial response
QW
once a week/weekly
Q2W
every 2 weeks
Q3W
every 3 weeks
Q6W
every 6 weeks
Q8W
every 8 weeks
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
SAE
serious adverse event
SD
stable disease
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Term
Definition
TB
total bilirubin
T-DM1
trastuzumab emtansine
T-HALF
terminal half-life
Tmax
time of maximum observed concentration
ULN
upper limit of normal
USP
U.S. Pharmacopeia
Vss/F (or Vss)
apparent volume of distribution at steady state
Vz
volume of distribution of terminal phase (if IV and if multi-exponential 
decline)
WOCBP
women of childbearing potential
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12
REFERENCES
1
Rosenberg SA, editors. Cancer: principles & practice of oncology. Philadelphia PA: 
Lippincott Williams & Wilkins; 2011. pp. 332–44.
2
de Claro RA, McGinn K, Kwitkowski V, et al. U.S. Food and Drug Administration approval 
summary: brentuximab vedotin for the treatment of relapsed Hodgkin lymphoma or relapsed 
systemic anaplastic large-cell lymphoma. Clin Cancer Res 2012;18(21):5845–9.
3
Amiri-Kordestani L, Blumenthal GM, Xu QC, et al. FDA approval: ado-trastuzumab 
emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin 
Cancer Res 2014;20(17):4436–41.   
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47 Kelly RJ, Sharon E, Pastan I, et al. Mesothelin-targeted agents in clinical trials and in 
preclinical development. Mol Cancer Ther 2012;11(3):517–25.
48 Chowdhury PS, Viner JL, Beers R, et al. Isolation of a high-affinity stable single-chain Fv 
specific for mesothelin from DNA immunized mice by phage display and construction of a 
recombinant immunotoxin with anti-tumor activity. Proc Natl Acad Sci U S A 1998;95:669–
74.
49 Chowdhury PS, Pastan I. Improving antibody affinity by mimicking somatic hypermutation 
in vitro. Nat Biotechnol 1999;17:568–72.
50 Hassan R, Bullock S, Premkumar A, et al. Phase I study of SS1P, a recombinant anti-
mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-
expressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res 2007;13:5144–9.
51 Kreitman RJ, Hassan R, Fitzgerald DJ, et al. Phase I trial of continuous infusion 
antimesothelin recombinant immunotoxin SS1P. Clin Cancer Res 2009;15:5274–9.
52 Hassan R, Ebel W, Routhier EL, et al. Preclinical evaluation of MORAb-009, a chimeric 
antibody targeting tumor associated mesothelin. Cancer Immunol 2007;7:20.
53 Hassan R, Cohen SJ, Phillips M, et al. Phase I clinical trial of the chimeric anti-mesothelin 
monoclonal antibody MORAb 009 in patients with mesothelin-expressing cancers. Clin 
Cancer Res 2010;16:6132–8.
54 Clinical Trials.gov NCT00570713.
55 Hassan R, Kindler HL, Jahan T, et al. Phase II clinical trial of amatuximab, a chimeric anti-
mesothelin antibody with pemetrexed and cisplatin in advanced unresectable pleural 
mesothelioma. Clin Cancer Res 2014;20(23):5927–36.
56 ClinicalTrials.gov NCT01439152.
57 Bendell J, Blumenschein G, Zinner R, et al. First-in-human phase I dose escalation study of a 
novel anti-mesothelin antibody drug conjugate (ADC), BAY 94-9343, in patients with 
advanced solid tumors. Cancer Res 2013;73(8 Suppl): Abstract LB-291.
58 Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant 
pleural mesothelioma. Ann Oncol 2004;15(2):257–60.
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APPENDIX 1 
DOSE ESCALATION DESIGN ALGORITHM BASED ON 
MODIFIED TOXICITY PROBABILITY INTERVAL (MTPI) 
METHOD FOR MONOTHERAPY
Table 1:a
mTPI Designb Decision Rule with up to 15 Subjects at a Dose
Number of patients treated at current dose
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Number of subjects with DLT
0
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
D
S
S
S
S
S
E
E
E
E
E
E
E
E
E
2
DU
D
D
S
S
S
S
S
S
S
S
E
E
E
3
DU
DU
DU
D
S
S
S
S
S
S
S
S
S
4
DU
DU
DU
DU
D
S
S
S
S
S
S
S
5
DU
DU
DU
DU
DU
DU
D
S
S
S
S
6
DU
DU
DU
DU
DU
DU
DU
D
S
S
7
DU
DU
DU
DU
DU
DU
DU
DU
DU
8
DU
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
DU
12
DU
DU
DU
DU
13
DU
DU
DU
14
DU
DU
15
DU
b Target DLT at MTD = 27% (+/-2%), flexible cohort size
a E = Escalate to next higher dose, S = Stay at the current dose, D = De-escalate to the next lower dose, U = The 
current dose is unacceptably toxic
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APPENDIX 2
SIMULATIONS OF MTPI VS 3 + 3 DOSE ESCALATION
DESIGNS
1
SIMULATIONS FOR MONOTHERAPY DOSE ESCALATION, WITH 6
DOSE LEVELS
Simulations of mTPI and 3+3 designs, as shown below, demonstrate that the mTPI design has a 
greater chance of selecting the correct MTD than the 3+3 design, and treating fewer subjects at 
sub-optimal doses.
The mTPI uses a set of decision rules guided by simple Bayesian models and requires a clinically 
relevant pre-determined target DLT rate and an equivalence interval (EI), within which any dose 
is considered close to the true maximum tolerated dose (MTD). For this study, the selected target 
toxicity (DLT) rate is 27% and EI [25%, 29%]. 
The mTPI design makes decisions using the same two observed numbers as the traditional 3+3 
design, the number of DLT evaluable subjects and the number of subjects with DLT. Based on 
these two numbers, unit probability mass is calculated within each of three regions as stated 
above, and decision is based on which region has the largest unit probability mass:
•
E: escalating to the higher dose if interval (0, 25%) has the largest unit probability mass,
•
S: staying at the same dose if interval [25, 29%] has the largest unit probability mass,
•
D: de-escalating to the lower dose if interval (29, 100%) has the largest unit probability mass.
At the end of the trial, MTD will be picked, by isotonic regression estimation method, to be the 
dose whose estimated toxicity rate is closest to the target toxicity rate among all the tried doses.
Simulations were performed to examine the performances of mTPI and 3 + 3 design for this 
study. Escalation decisions based on the mTPI are shown in the protocol. Decisions based on the 
3+3 design are shown below:
•
E: no subject with DLT out of 3 DLT evaluable subjects initially, or at most 1 subject with 
DLT out of 6 DLT evaluable subjects after adding 3 more subjects.
•
S: 1 subject with DLT out of 3 DLT evaluable subjects initially.
•
D: at least 2 subjects with DLT out of 3 DLT evaluable subjects initially, or at least 2 
subjects with DLT out of 6 DLT evaluable subjects after adding 3 more subjects
Settings of simulation:
•
6 dose-toxicity scenarios, each of which with a number of 6 (expected) dose levels
•
1000 trials per scenario
•
Target toxicity (Pt) for mTPI design: 27% with Equivalence Interval (EI) = [25, 29%]
•
mTPI: an initial cohort size of 2 followed by (multiple) cohort size of 3 for the lowest 2 dose 
levels, and an initial cohort size of 3 followed by (multiple) cohort size of 3 for the rest of the 
4 dose levels. 
•
Stopping rule for mTPI: When there are already 13 DLT evaluable subjects treated at a dose 
level, and mTPI still make decision to treat more subjects at the same dose level, dose 
escalation can be stopped.
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•
Maximum number of DLT evaluable subjects for the study is 30.
•
A nominal dose level of -1 is added to account for the case when de-escalation decision is 
made for dose level 1. However, no subjects will be assigned to dose level -1, and simulation 
will stop.
Dose-Toxicity Curve Scenarios
Six (6) scenarios of dose-toxicity (DLT) curves are selected to cover various possibilities and 
presented in the following figure with scenario ID shown at the end of line. The target toxicity 
rate of 0.27 is also superposed in the figure as a horizontal dashed line. The exact numeric values 
of DLT probability are available in each of the simulation results.
Figure 1-1:
Dose-Toxicity Probability Scenarios for Monotherapy
Simulation Results
Simulation results are summarized from all the simulated trials per scenario, and include the 
following statistics:
•
MTD Selected: Frequency of each dose level being selected as MTD.
•
Subjects Allocated: Number of subjected being allocated to each dose level.
•
DLT rate: The average number of subjects who have DLT across all dose levels.
•
Average Sample Size: The average number of subjects across all dose levels.
•
Early Stop Prob: For mTPI only. It is frequency that mTPI stopping rule was triggered during 
the trials.
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Scenario 1
Dose Level
Average 
DLT 
Rate
Average 
Sample Size
-1
1
2
3
4
5
6
True DLT rate
0.05
0.09
0.14
0.18
0.22
0.27
MTD 
Selected 
(%)
3+3
3.6
7.8
15.8
19.3
18.2
14.1
21.3
15.5
mTPI
0.1
2.4
5.0
19.7
24.4
23.7
24.7
16.2
Subjects 
Allocated
(n)
3+3
3.6
4.0
4.0
3.4
2.7
1.5
19.1
mTPI
2.9
3.8
6.6
5.8
4.2
3.0
26.2
Note:
The true MTD is dose level 6, the highest dose level. This represents the case that all the tested 
doses can be considered to be tolerated. In this case, mTPI has a better chance of picking the 
highest dose level.
Scenario 2
Dose Level
Average 
DLT 
Rate
Average 
Sample Size
-1
1
2
3
4
5
6
True DLT rate
0.05
0.10
0.15
0.20
0.27
0.40
MTD 
Selected 
(%)
3+3
2.8
9.6
16.8
19.7
23.9
18.4
8.8
16.8
mTPI
0.2
2.0
8.2
20.6
30.3
28.0
10.8
18.4
Subjects 
Allocated
(n)
3+3
3.7
4.1
4.0
3.6
2.7
1.2
19.2
mTPI
2.9
4.1
6.6
6.3
4.3
1.6
25.8
Note:
The true MTD is dose level 5, the second highest dose level. This presents the case when there is 
an over-toxic dose in the selected doses. mTPI picks the correct MTD by nearly 10 points (0.10) 
more than 3+3 does. Selection of dose level 6, the over toxicity dose, is slightly higher for mTPI.
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Scenario 3
Dose Level
Average
DLT 
Rate
Average 
Sample Size
-1
1
2
3
4
5
6
True DLT rate
0.05
0.10
0.15
0.27
0.40
0.50
MTD 
Selected 
(%)
3+3
3.4
10.0
17.3
33.9
25.4
7.5
2.5
18.6
mTPI
0.4
3.5
6.6
29.9
42.0
15.2
2.4
20.6
Subjects 
Allocated
(n)
3+3
3.7
4.1
4.3
3.7
1.9
0.5
18.2
mTPI
3.0
4.0
7.5
7.3
2.7
0.5
25.1
Note:
The true MTD is dose level 4, and as such, there are three sub-optimal dose levels and two over 
toxicity dose levels. mTPI chooses the correct MTD with 42% rate, more than 16 points over 
3+3. Selection of over toxicity dose levels is more frequently by mTPI, however, at 17.6% 
chance versus 10.0% of 3 + 3.
Scenario 4
Dose Level
Average 
DLT 
Rate
Average 
Sample Size
-1
1
2
3
4
5
6
True DLT rate
0.10
0.15
0.27
0.40
0.50
0.55
MTD 
Selected 
(%)
3+3
8.3
19.3
35.5
26.7
8.4
1.7
0.1
22.8
mTPI
1.8
7.3
22.4
48.3
17.0
2.7
0.5
24.6
Subjects 
Allocated
(n)
3+3
4.1
4.5
3.9
2.0
0.6
0.1
15.1
mTPI
3.7.1
5.9
8.9
3.8
0.7
0.1
23.1
Note:
The true MTD is dose level 3. Under this case, there are two sub-optimal doses and three over 
toxicity dose levels.  mTPI picks the correct MTD by nearly 22 points (0.22) more than 3+3 
does. Selection of over toxicity dose levels by mTPI is more frequently relative to 3+3 by 10 
points (0.10).
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Scenario 5
Dose Level
Average 
DLT 
Rate
Average 
Sample Size
-1
1
2
3
4
5
6
True DLT rate
0.15
0.27
0.40
0.50
0.55
0.60
MTD 
Selected 
(%)
3+3
19.3
39.8
30.3
8.6
1.8
0.2
0.0
28.9
mTPI
3.6
26.8
44.2
21.7
3.3
0.4
0.0
28.7
Subjects 
Allocated
(n)
3+3
4.9
4.2
2.2
0.6
0.1
0.0
12.1
mTPI
6.2
7.9
5.3
0.9
0.1
0.0
20.4
Note:
The true MTD is dose level 2, the second lowest dose level. This presents the case when there is 
one sub-optimal dose level and four over-toxic dose levels. mTPI picks the correct MTD about 
44% while 3+3 picks about 30% of times. For selection of over toxicity dose levels, mTPI picks 
more often, about 15 points (0.15) more than 3+3. 
Scenario 6
Dose Level
Average 
DLT 
Rate
Average 
Sample Size
-1
1
2
3
4
5
6
True DLT rate
0.27
0.40
0.50
0.55
0.60
0.65
MTD 
Selected 
(%)
3+3
48.1
37.9
11.9
1.9
0.2
0.0
0.0
38.8
mTPI
24.8
46.8
24.0
4.2
0.2
0.0
0.0
40.9
Subjects 
Allocated
(n)
3+3
5.2
2.8
0.8
0.1
0.0
0.0
9.0
mTPI
8.8
5.2
1.7
0.1
0.0
0.0
15.8
Note:
The true MTD is dose level 1, the lowest dose, which represents an unlikely case when only the 
lowest dose level is considered to be tolerated. mTPI selects the correct MTD 46.8% while 3+3 
does similarly, 37.9%. mTPI picks dose level -1 at a much lower rate, but chooses high dose 
levels more frequently. 
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2
SIMULATIONS FOR NIVOLUMAB COMBINATION DOSE ESCALATION, 
WITH 2 DOSE LEVELS
Similarly to the monotherapy setting simulations for the BMS-986148 and nivolumab 
combination therapy show that the mTPI design has a greater chance of selecting the correct 
MTD than the 3 + 3 design, and treats fewer subjects at suboptimal doses than the 3 + 3 design.
The mTPI design described above was set up with a target toxicity (DLT) rate of 29% (EI [28%, 
31%]) because somewhat higher toxicity is expected and acceptable in the combination setting. 
The mTPI design makes decisions using the number of DLT evaluable subjects and the number 
of subjects with DLT. Based on these 2 numbers, the unit probability mass calculated in each 
region is defined by the EI for the combination setting, with the decision based on the region that 
has the largest unit probability mass, similarly as described above for the monotherapy.
In the simulation with mTPI, 1 out of 4 subjects may drop out with a probability of 0.5. Dropout 
is not simulated in the 3 + 3 design, since replacement subject is always needed to reach a 
decision.
Settings of Simulation:
•
5 dose-toxicity scenarios, each of which with a number of 2 (expected) dose levels
•
1,000 trials per scenario
•
Target toxicity (Pt) for mTPI design: 29% (EI [28, 31%])
•
mTPI: an initial cohort size of 4 followed by (multiple) cohort size of 4 
•
Stopping rule for mTPI: When there are already 9 DLT evaluable subjects treated at a dose 
level and mTPI still makes the decision to treat more subjects at the same dose level, dose 
escalation can be stopped.
•
Maximum number of DLT evaluable subjects for the study is 12.
•
A nominal dose level of -1 is added to account for the case when de-escalation decision is 
made for dose level 1. However, no subjects will be assigned to dose level -1, and simulation 
will stop.
Dose-Toxicity Curve Scenarios
Five scenarios of dose-toxicity (DLT) curves are selected to cover various possibilities and 
presented in Figure 2-1 with scenario identification shown at the end of the line. The target 
toxicity rate of 0.29 is also superposed in the figure as a horizontal dashed line. The exact 
numeric values of DLT probability are available in each of the simulation results.
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Figure 2-1:
Dose-Toxicity Probability Scenarios for Combination Therapy
Simulation Results
Simulation results are summarized from all the simulated trials per scenario and include the same 
statistics as for the monotherapy simulations: MTD selected, subjects allocated, average DLT 
rate, and average sample size, as defined previously.
Scenario 1
Dose Level
Average DLT 
Rate
Average Sample 
Size
-1
1
2
True DLT rate
0.15
0.25
MTD Selected (%)
3 + 3
19.7
31.3
49.0
19.8
mTPI
3.7
30.3
66.0
22.0
Sample size (n)
3 + 3
4.7
3.4
8.1
mTPI
5.0
4.5
9.5
Note:
The true MTD is higher than dose level 2. This represents a case when both doses are well tolerated (DLT rate 
< 29%). In this case, mTPI has a 17% better chance of picking the correct MTD than 3 + 3 and is 16% less likely to 
pick a lower than tested dose. Both have similar average DLT rate.
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Scenario 2
Dose Level
Average DLT 
Rate
Average Sample 
Size
-1
1
2
True DLT rate
0.20
0.27
MTD Selected (%)
3 + 3
33.3
26.7
40.0
25.4
mTPI
9.1
38.0
52.9
26.5
Subjects Allocated (n)
3 + 3
4.7
2.9
7.6
mTPI
5.3
3.7
9.0
Note: 
The true MTD is dose level 2. The performance is similar as in scenario 1; mTPI picks the correct MTD 12.9% 
more often than 3 + 3 does and picks the lower than tested dose 24.2% less often than the 3 + 3.
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Scenario 3
Dose Level
Average DLT 
Rate
Average Sample 
Size
-1
1
2
True DLT rate
0.25
0.40
MTD Selected (%)
3 + 3
45.5
37.4
17.1
35.1
mTPI
14.6
51.7
33.7
34.0
Subjects Allocated (n)
3 + 3
5.1
2.5
7.6
mTPI
5.7
2.7
8.4
Note: 
The true MTD is dose level 1. This represents the case when 1 dose is over-toxic; mTPI picks the correct MTD 
14.3% more frequently than 3 + 3 and picks lower than tested dose 30.9% time less often than 3 + 3; mTPI also 
picks the highest (more toxic) dose 16.6% more often than the 3 + 3.
Scenario 4
Dose Level
Average DLT 
Rate
Average Sample 
Size
-1
1
2
True DLT rate
0.15
0.35
MTD Selected (%)
3 + 3
21.2
47.3
31.5
23.9
mTPI
4.3
40.4
55.3
25.7
Subjects Allocated (n)
3 + 3
5.1
3.5
8.6
mTPI
5.3
4.2
9.5
Note: 
The true MTD is dose level 1, and Dose Level 2 exceeds MTD. mTPI has a slightly lower chance (6.9%) of 
picking the correct MTD than 3 + 3, a higher chance (23.8%) of picking a higher dose, and a lower chance (16.9%) 
of picking the dose below the lowest tested. 
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Scenario 5
Dose Level
Average DLT 
Rate
Average Sample 
Size
-1
1
2
True DLT rate
0.27
0.45
MTD Selected (%)
3 + 3
49.7
37.3
13.0
37.4
mTPI
15.8
54.4
29.8
35.4
Subjects Allocated (n)
3 + 3
5.1
2.4
7.5
mTPI
5.7
2.6
8.3
Note:
The true MTD is dose level 1. mTPI picks the correct MTD about 17.1% more frequently than 3 + 3; it also picks 
the highest dose 16.8% more frequently than 3 + 3 and picks a dose below the lower tested dose 33.9% less often 
than 3 + 3.
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APPENDIX 3
MANAGEMENT ALGORITHMS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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Mesothelin-ADC
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GI ADVERSE EVENT MANAGEMENT ALGORITHM
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and continue I-O therapy. 
Opiates/narcotics may mask symptoms of perforation. Infliximab should not be used in cases of perforation or sepsis.
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids.
Grade of Diarrhea/
Colitis
4)
NCI CTCAE v
(
Management
Follow-up
Grade 1
< 4 stools/day over baseline;
Diarrhea:
asymptomatic
Colitis:
Grade 3-4
Diarrhea (G3): ≥7 stools per day over 
baseline; incontinence; IV fluids ≥24
hrs; interfering with ADL
Colitis (G3): severe abdominal pain, 
medical intervention indicated, 
peritoneal signs
G4: life-threatening, perforation
• Continue  I-O therapy per 
protocol
• Symptomatic treatment
• Discontinue I-O therapy per 
protocol 
• 1.0 to 2.0 mg/kg/day 
methylprednisolone  IV or  IV 
equivalent
• Add prophylactic antibiotics for 
opportunistic infections
• Consider lower endoscopy
• Close monitoring for worsening symptoms. 
• Educate patient to report worsening immediately
: 
If worsens
• Treat as Grade 2 or 3/4
If improves: 
• Continue steroids until grade 1, then taper over at 
least 1 month
If persists > 3-5 days, or recurs after improvement:
• Add infliximab 5 mg/kg (if no contraindication).      
Note: Infliximab should not be used in cases of 
perforation or sepsis
Grade 2
Diarrhea: 4-6 stools per day over 
baseline; IV fluids indicated <24 hrs; 
not interfering with ADL
Colitis:abdominal pain; blood in stool
• Delay I-O therapy per protocol
• Symptomatic treatment
: 
If improves to grade 1
• Resume I-O therapy per protocol
If persists > 5-7 days or recur:
•
mg/kg/day methylpredni
0.5-1.0
solone or oral equivalent 
• When symptoms improve to grade 1, taper steroids over 
at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per 
protocol.
: 
If worsens or persists > 3-5 days with oral steroids
• Treat as grade 3/4
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RENAL ADVERSE EVENT MANAGEMENT ALGORITHM
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy.
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids.
Grade of Creatinine  
Elevation           
4)
NCI CTCAE v
(
Management
Follow-up
Grade 1
Creatinine > ULN and  > 
than baseline but  ≤1.5x 
baseline
Grade 4
Creatinine > 6x ULN
• Continue I-O therapy per protocol
• Monitor creatinine weekly
• Discontinue I-O therapy per 
protocol
• Monitor creatinine daily
• 1.0-2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent
• Consult nephrologist
• Consider renal biopsy
If returns to baseline: 
•Resume routine creatinine monitoring per protocol 
If worsens:
•Treat as Grade 2 or 3/4
:  Taper steroids over at least 1 month and
If returns to Grade 1 
add prophylactic antibiotics for opportunistic infections
Grade 2-3
Creatinine > 1.5x baseline 
to ≤6x ULN
• Delay I-O therapy per protocol
• Monitor creatinine every 2-3 days
•
to 1.0 mg/kg/day 
0.5
methylprednisolone  IV or oral 
equivalent
• Consider renal biopsy with 
nephrology consult 
If returns to Grade 1:
•Taper steroids over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and resume I-O therapy 
and routine creatinine monitoring per protocol
If elevations persist > 7 days or worsen:
•Treat as Grade 4
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BMS-986148
Mesothelin-ADC
Updated 05-Jul-2016
PULMONARY ADVERSE EVENT MANAGEMENT ALGORITHM
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Evaluate with imaging and 
pulmonary consultation.
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids.
Grade of 
Pneumonitis
(NCI CTCAE v4)
Management
Follow-up
Grade 1
Radiographic changes only 
Grade 3-4
Severe new symptoms;
New/worsening hypoxia;
Life-threatening
• Consider delay of I-O therapy
• Monitor for symptoms every 2-3 
days
• ConsiderPulmonary and ID 
consults
• Discontinue  I-O therapy per 
protocol
• Hospitalize
• Pulmonary and ID consults
•
  mg/kg/day 
2-4
methylprednisolone IV or IV 
equivalent
• Add prophylactic antibiotics for 
opportunistic infections
• Consider bronchoscopy, lung 
biopsy
• Re-image at least every 3 weeks
If worsens:
• Treat as Grade 2 or 3-4
If improves to baseline:
• Taper steroids over at least 6 weeks
If not improving after 48 hours or worsening:
• Add additional immunosuppression
Grade 2
Mild to moderate  new
symptoms
• Delay I-O therapy per protocol
• Pulmonary and ID consults
• Monitor symptoms daily, consider 
hospitalization
•
-
1.0 mg/kg/day methyl
prednisoloneIV or oral equivalent
• Consider  bronchoscopy, lung 
biopsy
• Re-imageevery 1-3 days
If improves:  
• When symptoms return to nearbaseline, taper steroids over 
at least 1 month and then resume I-O therapy per protocol 
and consider prophylactic antibiotics
If not improving after 2 weeks  or worsening:
• Treat as Grade 3-4
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BMS-986148
Mesothelin-ADC
Updated 05-Jul-2016
HEPATIC ADVERSE EVENT MANAGEMENT ALGORITHM
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider imaging for 
obstruction. 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. *I-O therapy may be delayed rather than discontinued if AST/ALT ≤ 8 x ULN or T.bili ≤ 5 x ULN. 
**The recommended starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV.
Grade of Liver 
Test  Elevation                               
4)
NCI CTCAE v
(
Management
Follow-up
Grade 1
AST or ALT > ULN to 3.0 x 
ULN and/or T. bili > ULN  
to 1.5 x ULN
Grade 3-4
AST or ALT > 5 x ULN  or
T.bili >3 x ULN
• Continue I-O therapy per protocol
• Discontinue  I-O therapy*
• Increase frequency of monitoring 
to every 1-2 days
•
to 2.0 mg/kg/day 
1.0
methylprednisolone IV or IV 
equivalent**
• Add prophylactic antibiotics for 
opportunistic infections
• Consult gastroenterologist
• Continue LFT monitoring per protocol
If worsens:
• Treat as Grade 2 or 3-4
If returns to grade 2:
• Taper steroids over at least 1 month
If does not improve in >3-5 days, worsens or rebounds:
• Add  mycophenolatemofetil1 g BID
• If no response within an additional 3-5 days, consider other 
immunosuppressants per local guidelines
Grade 2
AST or ALT > 3.0 to ≤5 x 
and/or T. bili > 1.5 
ULN 
to ≤3 x ULN
• Delay I-O therapy per protocol
• Increase frequency of monitoring 
to every 3 days
If returns to baseline: 
•Resume routinemonitoring, resume I-O therapy per protocol
If elevations persist > 5-7days or worsen :
•
mg/kg/day methylprednisolone or oral equivalent and 
0.5-1
when LFT returns to grade 1 or baseline, taper steroids over at 
least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per protocol
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CA008002
BMS-986148
Mesothelin-ADC
Updated 05-Jul-2016
ENDOCRINOPATHY MANAGEMENT ALGORITHM
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider visual field 
testing, endocrinology consultation, and imaging.
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids.
Asymptomatic 
TSH elevation
Suspicion of adrenal 
crisis (e.g. severe 
dehydration, 
hypotension, shock 
out of proportion to 
current illness
• Continue I-O therapy per protocol
• If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently ou t of range in 2 subsequent measurements: include fT4 at 
subsequent cycles as clinically indicated; consider endocrinology consult
• Delay or discontinue I-O therapy per protocol
• Rule out sepsis
• Stress dose of IV steroids with mineralocorticoid activity
• IV fluids
• Consult endocrinologist
• If adrenal crisis ruled out,  then treat as above for symptomatic 
endocrinopathy
Symptomatic 
endocrinopathy
• Evaluate endocrine function
• Consider pituitary scan
Symptomatic with abnormal lab/pituitary scan:
• Delay I-O therapy per protocol
• 1-2 mg/kg/day methylprednisolone IV or  PO equivalent
• Initiate appropriate hormone therapy
No abnormal lab/pituitary MRI scan but symptoms persist:
• Repeat labs in 1-3 weeks / MRI in 1 month
If improves  (with or without
hormone replacement):
• Taper steroids over at least 1 
month and consider prophylactic 
antibiotics for opportunistic 
infections
• Resume I-O therapy per protocol
• Patients with adrenal 
insufficiency may need to 
continue steroids with 
mineralocorticoidcomponent
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BMS-986148
Mesothelin-ADC
Updated 05-Jul-2016
SKIN ADVERSE EVENT MANAGEMENT ALGORITHM
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids.
*Refer to NCI CTCAE v4 for term-specific grading criteria.
^If SJS/TEN is suspected, withhold I-O therapy and refer patient for specialized care for assessment and treatment. If SJS or TEN is diagnosed, permanently 
discontinue I-O therapy.
Grade of 
Rash 
4)
NCI CTCAE v
(
Management
Follow-up
Grade 1-2
Covering  ≤30% 
BSA*
Grade 3-4
Covering >30% BSA; 
Life threatening 
consequences*^
• Symptomatic therapy (e.g. antihistamines, 
topical steroids)
• Continue I-O therapy per protocol
• Delay or discontinue I-O therapy per 
protocol
• Consider skin biopsy
• Dermatology consult
• 1.0-2.0 mg/kg/day IV methylprednisolone 
IV or IV equivalent
If persists > 1-2 weeks or recurs:
• Consider skin biopsy
• Delay I-O therapy per protocol
• Consider 0.5-1.0 mg/kg/day methylprednisolone IV or 
oral  equivalent. Once improving , taper steroids over 
at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per 
protocol
If worsens:
• Treat as Grade 3-4
If improves to Grade 1:
• Taper steroids over at least 1 month and add 
prophylactic antibiotics for opportunistic infections
• Resume I-O therapy per protocol
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CA008002
BMS-986148
Mesothelin-ADC
Updated 05-Jul-2016
NEUROLOGICAL ADVERSE EVENT MANAGEMENT ALGORITHM
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy.
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids.
Grade of 
Neurological 
Toxicity 
(
4)
NCI CTCAE v
Management
Follow-up
Grade 1
Asymptomatic or 
mild symptoms; 
Intervention not 
indicated
Grade 3-4
Severe symptoms; 
Limiting self-care  
ADL;                         
Life-threatening
• Continue I-O therapy per protocol
• Discontinue I-O therapy per protocol
• Obtain neurology consult
• Treat symptoms per local guidelines
• 1.0-2.0 mg/kg/day IV 
methylprednisolone  IV or IV equivalent
• Add prophylactic antibiotics for 
opportunistic infections
Continue to monitor the patient. 
If worsens:
• Treat as Grade 2 or 3-4
: 
If improves to Grade 2
• Taper steroids over at least 1 month
If worsens or atypical presentation:
• Consider IVIG or other immunosuppressive therapies per 
local guidelines
Grade 2
Moderate symptoms; 
Limiting instrumental 
ADL
• Delay I-O therapy per protocol
• Treat symptoms per local guidelines
• Consider  0.5 to 1.0 mg/kg/day 
methylprednisolone  IV or  PO 
equivalent
: 
If improves to baseline
•Resume I-O therapy per protocol when improved to baseline
:
If worsens
• Treat as Grade 3-4
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APPENDIX 4
RECIST V1.1 & MODIFIED RECIST CRITERIA FOR 
ASSESSMENT OF RESPONSE IN MALIGNANT PLEURAL 
MESOTHELIOMA
1
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
Subjects must have measureable disease to be eligible for this study.
To assess objective response or future progression, it is necessary to estimate the overall tumor
burden at baseline and use this as a comparator for subsequent measurements. Measurable disease 
is defined by the presence of at least one measurable tumor lesion. When CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
1.1
Measurable lesions
Measurable lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of the measurement to be recorded) with a minimum size of:
•
10 mm by CT/MRI scan - (CT/MRI scan slice thickness no greater than 5 mm)
•
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable)
•
20 mm by chest x-ray
•
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, 
only the short axis will be measured and followed.
1.2
Non-measurable lesions
•
All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥10 to < 15 mm short axis), as well as truly non-measurable lesions.  
•
Lesions considered truly non-measurable include:  leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement 
of skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that in not measurable by reproducible imaging techniques.  
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1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions
•
Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence 
or disappearance of bone lesions. 
•
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue
components, that can be evaluated by cross sectional imaging techniques such as CT or 
MRI can be considered as measurable lesions if the soft tissue component meets the 
definition of measurability described above.
•
Blastic bone lesions are non-measurable.
1.3.2
Cystic lesions
•
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
•
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same subject, these are preferred for selection as target 
lesions.
1.3.3
Lesions with prior local treatment
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional 
therapy, are usually not considered measurable unless there has been demonstrated progression in 
the lesion.  Measurable lesions may be in an irradiated field as long as there is documented 
progression and the lesion(s) can be reproducibly measured.
1.4
Specifications by methods of measurements
1.4.1
Measurement of lesions
All measurements should be recorded in metric notation (mm). All baseline evaluations should be 
performed as close as possible to the treatment start and never more than 30 days before the 
beginning of the treatment.
1.4.2
Method of assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
1.4.2.1
CT/MRI scan
CT/MRI is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT/MRI scan is based on the assumption that 
CT/MRI slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness.
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1.4.2.2
Chest X-ray
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions 
on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated
lung.
1.4.2.3
Clinical lesions 
Clinical lesions will only be considered measurable when they are superficial and ≥10 mm 
diameter as assessed using calipers. For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested. As previously noted, 
when lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the study.
1.4.2.4
Ultrasound
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. 
1.4.2.5
Endoscopy, laparoscopy
The utilization of these techniques for objective tumor evaluation is not advised.
1.4.2.6
Tumor markers 
Tumor markers alone cannot be used to assess objective tumor response.
2
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
2.1
Target lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated
measurements.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted below, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
2.1.1
Lymph nodes
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of ≥15 
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mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. Nodes 
that have a short axis < 10 mm are considered non-pathological and should not be recorded or 
followed.
2.2
Non-target lesions
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’. In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).
3
TUMOR RESPONSE EVALUATION 
3.1
Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR):  At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progression).
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
3.1.1
Special notes on the assessment of target lesions
3.1.1.1
Lymph nodes
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of ≥15 
mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. Nodes 
that have a short axis <10 mm are considered non-pathological and should not be recorded or 
followed.
3.1.1.2
Target lesions that become ‘too small to measure’
All lesions (nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g. 2 mm). If the radiologist is 
able to provide an actual measurement, that should be recorded, even if it is below 5 mm.
However, when such a lesion becomes difficult to assign an exact measure to then:
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•
if it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
•
if the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned (note: in case of a lymph node believed to be 
present and faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well). This default value is derived from the 5 mm CT 
slice thickness (but should not be changed with varying CT slice thickness).
3.1.1.3
Target lesions that split or coalesce on treatment
•
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions 
should be added together to calculate the target lesion sum.
•
As lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have 
truly coalesced such that they are no longer separable, the vector of the longest diameter 
in this instance should be the maximal longest diameter for the ‘coalesced lesion’
3.2
Evaluation of non-target lesions
While some non-target lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively at the time points specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be non-
pathological in size (< 10 mm short axis).
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s).
Progressive Disease (PD):  Unequivocal progression of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered progression).
3.2.1
Special notes on assessment of non-target lesions
The concept of progression of non-target disease requires additional explanation as follows:
3.2.1.1
When the subject also has measurable disease
•
To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must 
be an overall level of substantial worsening in non-target disease such that, even in 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.
•
A modest ‘increase’ in the size of one or more non-target lesions is usually not 
sufficient to quality for unequivocal progression status.
3.2.1.2
When the subject has only non-measurable disease
•
To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must 
be an overall level of substantial worsening such that the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy.
•
A modest ‘increase’ in the size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status.
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•
Because worsening in non-target disease cannot be easily quantified (by definition: if 
all lesions are non-measurable) a useful test that can be applied when assessing subjects 
for unequivocal progression is to consider if the increase in overall disease burden 
based on the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease: i.e. an increase 
in tumor burden representing an additional 73% increase in ‘volume’ (which is 
equivalent to a 20% increase diameter in a measurable lesion). Examples include an 
increase in a pleural effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease 
from localized to widespread, or may be described in protocols as ‘sufficient to require 
a change in therapy’.
•
If ‘unequivocal progression’ is seen, the subject should be considered to have had 
overall PD at that point. 
3.2.1.3
Tumor markers
Tumor markers will not be used to assess objective tumor responses.
3.3
New lesions
The appearance of new malignant lesions denotes disease progression. The finding of a new lesion 
should be unequivocal: i.e. not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly important 
when the subject’s baseline lesions show partial or complete response. For example, necrosis of a 
liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the subject
who has visceral disease at baseline and while on study has a CT or MRI brain scan ordered which 
reveals metastases. The subject’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan.
4
RESPONSE CRITERIA
4.1
Time point response
A response assessment should occur at each time point specified in the protocol.
For subjects who have measurable disease at baseline Table 1 provides a summary of the overall 
response status calculation at each time point.
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Table 1.
Time point response: subjects with target (+/– non-target) 
disease.
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any 
PD
Yes or No
PD
Any
Any 
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE =not evaluable.
4.1.1
Missing assessments and not evaluable designation
When no imaging/measurement is done at all at a particular time point, the subject is not evaluable 
(NE) at that time point. If only a subset of lesion measurements are made at an assessment, the 
case is also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not have changed the assigned time point 
response.
4.1.2
Confirmation Scans
•
Verification of Response: Confirmation of PR and CR is required within 4 weeks to 
ensure responses identified are not the result of measurement error.
4.2
Best Overall Response: all time points
The best overall response is determined once all the data for the subject is known. It is the best 
response recorded from the start of the study treatment until the end of treatment taking into 
account any requirement for confirmation. The subject’s best overall response assignment will 
depend on the findings of both target and non-target disease and will also take into consideration 
the appearance of new lesions.
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Best response is defined as the best response across all time points with subsequent confirmation. 
Complete or partial responses may be claimed only if the criteria for each are met at a subsequent 
time point as specified in the protocol (generally 4 weeks later).
In this circumstance, the best overall response can be interpreted as specified in Table 2. When SD 
is believed to be best response, it must meet the protocol specified minimum time from baseline.
Measurements must have met the SD criteria at least once after study entry at a minimum interval 
(in general not less than 6–8 weeks) that is defined in the study protocol.
Table 2.
Best overall response when confirmation of CR and PR IS required.
Overall 
response
Overall response
BEST overall response
First time 
point
Subsequent time 
point
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteria for SD duration met, 
otherwise, PD
CR
PD
SD provided minimum criteria for SD duration met, 
otherwise, PD
CR
NE
SD provided minimum criteria for SD duration met, 
otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met,
otherwise, PD
PR
NE
SD provided minimum criteria for SD duration met, 
otherwise NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not evaluable.
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
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when subsequent scans suggest small lesions were likely still present and in fact the subject had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
4.3
Duration of response
4.3.1
Duration of overall response
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study).
The duration of overall complete response is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented.
4.3.2
Duration of stable disease  
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD).
Eisenhauer et al.  New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). European Journal of Cancer.  2009.  Vol 45, p 228-247.
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Modified RECIST criteria for assessment of response in malignant pleural mesothelioma
The current standard for medical image-based tumor response assessment for patients with 
malignant pleural mesothelioma is the modified Response Evaluation Criteria In Solid Tumors 
(RECIST) measurement technique with changes classified according to the standard RECIST 
response classification criteria. While the modified RECIST measurement technique was 
developed specifically for the unique morphology and growth patterns of mesothelioma and is as 
follows.1 Uni-dimensional measurements of tumor thickness perpendicular to the chest wall or 
mediastinum should be performed, measured in 2 sites at 3 different levels on CT scan. 
Transverse cuts used for measurement must be at least 1 cm apart, and related to anatomical 
landmarks in the thorax, preferably above the level of division of the main bronchi. At 
reassessment, pleural thickness must be measured at the same position and level. Nodal, 
subcutaneous, and other bi-dimensionally measurable lesions are measured uni-dimensionally as 
per the RECIST criteria. Uni-dimensional measurements are added to produce the total tumor 
measurement. The sum of 6 pleural thickness measurements = one univariate diameter2
CR was defined as the disappearance of all target lesions with no evidence of tumor elsewhere, 
and PR was defined as at least a 30% reduction in the total tumor measurement. A confirmed 
response required a repeat observation on two occasions 4 weeks apart. Progressive disease (PD) 
was defined as an increase of at least 20% in the total tumor measurement over the nadir 
measurement, or the appearance of one or more new lesions. Patients with stable disease (SD) 
were those who fulfilled the criteria for neither PR nor PD.
                                                       
1 Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in
malignant pleural mesothelioma. Ann Oncol. 2004 Feb;15(2):257-60. PubMed PMID:
14760119.
2Tsao AS, Garland L, Redman M, Kernstine K, Gandara D, Marom EM. A practical
guide of the Southwest Oncology Group to measure malignant pleural mesothelioma tumors by RECIST and 
modified RECIST criteria. J Thorac Oncol. 2011 Mar;6(3):598-601. doi: 10.1097/JTO.0b013e318208c83d. PubMed 
PMID: 21270668; PubMed Central PMCID: PMC3643692.
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APPENDIX 5
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUS1
Grade
ECOG
0
Fully active, able to carry on all predisease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours.
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours.
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.
5
Dead
                                                       
1 Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity and Response 
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655.
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APPENDIX 6
NYHA CLASSIFICATION
NYHA Classification
Class I
Subjects with no limitation of physical activity; ordinary physical 
activity does not cause undue fatigue, palpitation, or dyspnea (shortness 
of breath).
Class II
Subjects with slight limitation of physical activity; they are comfortable 
at rest, but ordinary physical activity results in fatigue, palpitation, or 
dyspnea.
Class III
Subjects with marked limitation of physical activity; they are 
comfortable at rest, but less than ordinary activity causes fatigue, 
palpitation, or dyspnea. 
Class IV
Subjects who are unable to carry out any physical activity without 
discomfort; they have symptoms of cardiac insufficiency at rest; if any 
physical activity is undertaken, discomfort is increased.
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APPENDIX 7
DRUGS WITH RISK OF TORSADES DE POINTES
Refer to:
http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm
https://crediblemeds.org/index.php/drugsearch
https://crediblemeds.org/oncosupport/  
Subjects are prohibited from taking medications listed in Category 1: Drugs with Risk of Torsades 
de Pointes. Caution is warranted when administering BMS-986148 to subjects taking drugs 
associated with prolongation of QTc listed in Category 2: Drugs with Possible Risk of Torsades 
de Pointes.
Although ondansetron is listed in Category 1, because the effect on QTc has been shown to occur 
at the highest drug concentrations, IV doses of ondansetron not greater than 16 mg are permitted, 
as are any oral doses.
Additional information on ondansetron is available at:
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProduct
s/ucm310219.htm
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SAP_001.pdf: 
Official Title of Study: 
A Phase I/IIa Study of BMS-986148, a Mesothelin Directed Antibody Drug Conjugate, in Subjects With 
Select Advanced Solid Tumors 
 
 
NCT Number: NCT02341625 
Document Date (Date in which document was last revised): Jun 26, 2015 


STATISTICAL ANALYSIS PLAN
FOR EARLY-PHASE ONCOLOGY STUDIES
ONCOLOGY PROTOTYPE
PROTOCOL(S) CA008002
VERSION # 1.0
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TABLE OF CONTENTS
PROTOCOL(S) CA008002.............................................................................................................1
TABLE OF CONTENTS.................................................................................................................2
1
BACKGROUND AND RATIONALE.........................................................................5
2
STUDY DESCRIPTION..............................................................................................5
2.1
Study Design.................................................................................................................5
2.2
Treatment Assignment..................................................................................................6
2.3
Blinding and Unblinding ..............................................................................................6
2.4
Protocol Amendments ..................................................................................................6
3
OBJECTIVES...............................................................................................................6
3.1
Primary .........................................................................................................................6
3.2
Secondary .....................................................................................................................6
4
ENDPOINTS ................................................................................................................7
4.1
Primary Endpoints ........................................................................................................7
4.2
Secondary Endpoints ....................................................................................................7
4.2.1
Pharmacokinetics .........................................................................................................7
4.2.2
Efficacy .........................................................................................................................8
4.2.3
QTc ...............................................................................................................................9
4.2.4
Immunogenicity (Anti-Drug Antibodies) ......................................................................9
4.2.5
Biomarker .....................................................................................................................9
5
SAMPLE SIZE AND POWER ..................................................................................10
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES.......................................................................................................10
6.1
Study Periods..............................................................................................................10
6.2
Treatment Regimens...................................................................................................10
6.3
Populations for Analyses ............................................................................................11
7
STATISTICAL ANALYSES.....................................................................................11
7.1
General Methods.........................................................................................................11
7.2
Grouping Scheme .......................................................................................................11
7.2.1
Study Information .......................................................................................................12
7.2.2
Accrual........................................................................................................................12
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7.2.3
Relevant Protocol Deviations.....................................................................................13
7.3
Study Population.........................................................................................................14
7.3.1
Subject Disposition.....................................................................................................14
7.3.2
Demographics and Other Baseline Characteristics...................................................14
7.4
Extent of Exposure .....................................................................................................15
7.4.1
Study Therapy.............................................................................................................15
7.4.2
Modification of Study Therapy ...................................................................................15
7.4.3
Prior and Concomitant Medications ..........................................................................15
7.5
Efficacy.......................................................................................................................16
7.6
Safety..........................................................................................................................16
7.6.1
Overall Adverse Events...............................................................................................17
7.6.2
Deaths.........................................................................................................................17
7.6.3
Other Serious Adverse Events ....................................................................................18
7.6.4
Adverse Events Leading to Discontinuation of Study Therapy ..................................18
7.6.5
Multiple Events...........................................................................................................18
7.6.6
Adverse Events of Special Interest..............................................................................19
7.6.7
Clinical Laboratory Evaluations................................................................................19
7.6.7.1
Abnormal Hepatic Test...............................................................................................19
7.6.7.2
Other Labs of Interest.................................................................................................19
7.6.8
ECG ............................................................................................................................20
7.6.9
Vital Signs and Other Safety Evaluation ....................................................................20
7.6.10
Immunogenicity...........................................................................................................20
7.7
Pharmacokinetics........................................................................................................21
7.8
Biomarker Analyses....................................................................................................22
8
CONVENTIONS........................................................................................................23
8.1
Decimal Places............................................................................................................23
8.2
Pharmacokinetic Summaries ......................................................................................23
8.2.1
In-text Tables ..............................................................................................................23
8.2.2
Handling of Non-Quantifiable Concentrations4.........................................................23
8.2.3
Treatment of Outliers..................................................................................................24
8.2.4
PK Exclusions.............................................................................................................24
9
CONTENT OF REPORTS.........................................................................................24
10
DOCUMENT HISTORY ...........................................................................................24
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11
REFERENCES ...........................................................................................................24
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1
BACKGROUND AND RATIONALE
Research Hypothesis:  
There is no formal primary research hypothesis for this study to be statistically tested. The 
purpose of this study is to evaluate the safety profile, tolerability, preliminary efficacy, 
pharmacokinetics and pharmacodynamics of BMS-986148 in subjects with select advanced solid 
tumors.
Schedule of Analyses:
Data emerging from each dose level or each part of the study will be examined prior to the 
formal locking of the study database for timely decisions about, but not limited to, dose 
selection, regimen selection and early termination of the study. No formal inferences requiring 
any adjustment to statistical significance level will be performed. 
The final analysis will be performed following the database lock after all subjects have 
completed the study. 
2
STUDY DESCRIPTION
2.1
Study Design
This is a phase I/IIa, open label study to characterize the safety and tolerability of BMS-986148 
in subjects with select advanced solid tumors (pancreatic, ovarian, NSCLC, gastric, or 
mesothelioma). The study has two segments Part 1 (Phase I study - dose escalation) and Part 2 
(Phase IIa - dose expansion) (see Figure 2.1.1-1). All subjects will complete up to four study 
periods (see Figure 2.1.1-2): Screening (up to 28 days), Treatment (21 days/cycle for Q3 weekly 
dosing and 28 days/cycle for Q weekly dosing), Follow-up (60 days), and Survival Follow-up 
(up to 1 year following the last dose of study drug). Part 1 is divided into two sections, i.e., Part 
1A and Part 1B. BMS-986148 will be administrated every 3 weeks (Q3 week dosing, 21 
day/cycle) in Part 1A, and weekly for 3 weeks with one week off in Part 1B. Part 2 includes five 
expansion cohorts restricted to these tumor types 1) mesothelioma 2) pancreatic 3) ovarian 4) 
NSCLC and 5) gastric cancer.
The duration of the study is anticipated to be approximately 5 years. The end of the study will 
occur when the last subject has the last survival follow-up visit.
Figure 2.1.1-1:
Sequence of Study Phases
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Figure 2.1.1-2:
Dosing (Q3W and QW) and Study Periods
DLT: Dose limiting toxicity; EOT: End of Treatment; D: Day; C1D1: Cycle 1 Day 1 (first dose)
2.2
Treatment Assignment
All enrolled subjects who have signed informed consent, registered, and have eligibility for the 
study confirmed will be administered intravenous doses of BMS-986148 per the cohort 
assignment and the duration of treatment as indicated in the study design.
2.3
Blinding and Unblinding
Not applicable.
2.4
Protocol Amendments
This SAP incorporates the following protocol amendments.
Table 1:
Protocol Amendments
Amendments
Date of Issue
Summary of Major Changes
3
OBJECTIVES
3.1
Primary
To assess the safety and tolerability of BMS-986148 in subjects with select advanced solid 
tumors.
3.2
Secondary
•
To assess the preliminary anti-tumor activity of BMS-986148 as measured by overall 
response rate (ORR), response duration, and progression free survival (PFS)
•
To characterize the pharmacokinetics (PK) of the total antibody (unconjugated antibody + 
antibody conjugated to tubulysin or antibody conjugated to any tubulysin metabolites), active 
ADC (antibody conjugated to tubulysin), and unconjugated tubulysin
•
To assess the effect of dosage regimen and exposure (active ADC and unconjugated 
tubulysin) on the QT interval
•
To characterize the immunogenicity of BMS-986148
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4
ENDPOINTS
4.1
Primary Endpoints
Incidence of adverse events (AEs) at its worst grade, serious adverse events (SAEs) at its worst 
grade, adverse events leading to discontinuations, deaths, frequency of laboratory test toxicity 
grade shifting from baseline. Safety will be evaluated from the time that the subject signs the 
informed consent, and for up to 60 days after the last dose of study drug.
AEs and Laboratory values will be graded according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
4.2
Secondary Endpoints
4.2.1
Pharmacokinetics
The pharmacokinetics of total antibody, 
 active ADC, 
 and 
unconjugated tubulysin will be characterized using the following endpoints:
•
Cmax: Maximum observed serum or plasma concentration
•
Tmax: Time of maximum observed serum or plasma concentration
•
AUC(0-t): Area under the concentration-time curve from time zero to time t
•
AUC(TAU): Area under the concentration-time curve in one dosing interval
•
Ctau: Concentration at the end of a dosing interval
•
Ctrough: Trough observed serum or plasma concentration (includes pre-dose and Ctau 
concentrations)
•
CLT: Total body clearance
•
Vss: Apparent volume of distribution at steady state
•
Vz: Volume of distribution of terminal phase 
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•
AI_AUC: AUC Accumulation Index; ratio of AUC(TAU) at steady state to AUC(TAU) after 
the first dose
•
AI_Cmax: Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after the first 
dose
•
AI_Ctau: Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the first dose
•
Cavg: average concentration over the dosing interval; AUC(TAU)/tau
•
T-HALF: Terminal serum or plasma half life
4.2.2
Efficacy
Efficacy based on RECIST v1.1 or Modified RECIST for malignant pleural mesothelioma will 
be assessed using the following secondary endpoints:
•
Best overall response (BOR): defined as the best response designation over the study as a 
whole, recorded between the dates of first dose until the last tumor assessment prior to 
subsequent therapy. CR or PR determinations included in the BOR assessment must be 
confirmed by a second scan performed no less than 4 weeks after the criteria for response are 
first met. For those subjects who have surgical resection, only pre-surgical tumor assessments 
will be considered in the determination of BOR.
•
Objective Response Rate (ORR): defined as the total number of subjects whose best overall 
response (BOR) is either a CR or PR divided by the total number of subjects in the 
population of interest.
•
Duration of Response (DOR): defined as the time between the date of first response and the 
subsequent date of objectively documented disease progression or death, whichever occurs 
first. For those subjects who remain alive and have not progressed or received subsequent 
therapy, duration of response will be censored on the date of last tumor assessment.
•
Progression Free Survival (PFS): defined as the time from the first dose of study 
medication to the date of the first objective documentation of tumor progression or death due 
to any cause. Subjects who did not progress nor died will be censored on the date of their last 
tumor assessment. Subjects who did not have any on-study tumor assessments will be 
censored on the date of the first dose of study medication.
•
Progression Free Survival Rate (PFSR) at week ‘t’: defined as the proportion of subjects 
who remain progression free and surviving at ‘t’ weeks (t=12, 24, 36, etc). The proportion 
will be calculated by the product-limit method (Kaplan-Meier estimate) which takes into 
account censored data.
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4.2.3
QTc
Change in QTcF, (ΔQTcF) from baseline, at selected times.
4.2.4
Immunogenicity (Anti-Drug Antibodies)
The endpoints of immunogenicity of BMS-986148 include frequency of different subject 
immunogenicity status, e.g., subject positive ADA, persistent positive ADA and others. 
Definitions of all the immunogenicity endpoints are given below:
Sample ADA Status: 
•
Baseline ADA-positive sample: ADA is detected in the last sample before initiation of 
treatment 
•
Baseline ADA-negative sample: ADA is not detected in the last sample before initiation of 
treatment 
•
ADA-positive sample: After initiation of treatment, (1) an ADA detected (positive 
seroconversion) sample in a subject for whom ADA is not detected at baseline, or (2) an 
ADA detected sample with ADA titer to be at least 4-fold or greater (≥) than baseline 
positive titer 
•
ADA-negative sample: After initiation of treatment, ADA not positive sample relative to 
baseline 
Subject ADA Status:
•
Baseline ADA-positive subject: A subject with baseline ADA-positive sample 
•
ADA-positive subject: A subject with at least one ADA positive-sample relative to baseline 
at any time after initiation of treatment
−
Persistent Positive (PP): ADA-positive sample at 2 or more consecutive time points, 
where the first and last ADA-positive samples are at least 16 weeks apart 
−
Not PP-Last Sample Positive: Not persistent positive with ADA-positive sample at the 
last sampling timepoint 
−
Other Positive: Not persistent positive but some ADA-positive samples with the last 
sample being negative 
•
ADA-negative subject: A subject with no ADA-positive sample after the initiation of 
treatment 
4.2.5
Biomarker
The biomarker endpoints are exploratory summaries for 
 
 CA125, and CA19-9. 
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5
SAMPLE SIZE AND POWER
Dose Escalation: In the dose escalation part of the study, i.e., both Part 1A and 1B, the sample 
size per dose level cannot be precisely determined but depends on the observed DLTs and the 
decision rules of mTPI. Between 2 and up to 13 DLT evaluable subjects may be enrolled to a 
given cohort. Treating additional subjects beyond the 13 would be unlikely to alter the decision 
specified by the mTPI algorithm. 
Cohort Expansion: During this part of the study approximately 25 subjects with high expression 
of mesothelin are expected to be treated in each tumor cohort at the maximally administered dose 
or at a dose near the MTD (as determined from dose escalation). This number is based on 
achieving a reasonable precision of the objective response rate (ORR) and adequate control on
the false negative rate (FNR) and false positive rate (FPR) (assuming a historic and target 
response rate). In a cohort of 25 marker positive subjects if 5 or 6 responses are observed (e.g. 
for gastric or pancreatic cohorts) then the ORR 90% CI are (8.2%, 37.5%) and (11%, 42%), 
respectively. If 7 responses are observed (e.g. NSCLC cohort), then the 90% CI is (14%, 46.2%), 
and if 8 or 9 responses are observed (e.g. mesothelioma or ovarian cohorts), then the 90% CI for 
ORR are: (17%, 50.4%) and (20%, 54.4%), respectively. These calculations are based on the 
Clopper- Pearson method for exact confidence intervals. 
In addition, 25 subjects per cohort provide the following FNR and FPR under assumptions of 
expected true ORR. If the true objective response rate (ORR) is 40% (e.g. mesothelioma and 
ovarian cohorts), then with 25 subjects in a cohort there is 97% and 93% chance of observing at 
least 6 or 7 responses, respectively, and there is 7% chance of observing 6 or fewer responses 
(false negative rate). If the true ORR for these tumors is only 20% (rather than 40%), then there 
is 22% and 11% chance respectively of observing at least 7 and at least 8 responses among 25
subjects (false positive rate). 
Similarly if the true ORR is 20% (e.g. gastric and pancreatic cohorts), then there is 97% and 90% 
probability of observing at least 2 or 3 responses respectively, among 25 subjects and 10% of 
observing 2 or fewer responses (false negative rate). If the true ORR for these tumors is 10% 
(rather than 20%) then there is 24% and 10% chance respectively, of observing at least 4 and at 
least 5 responses (FPR).
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
This study consists of four periods: Screening (up to 28 days), Treatment (21 days/cycle for Q3 
weekly dosing and 28 days/cycle for Q weekly dosing), Follow-up (60 days), and Survival 
Follow-up (up to 1 year following the first dose of study drug).
6.2
Treatment Regimens
In escalation phase, the selection of doses for the two cohorts Part 1A and Part 1B will be based 
on a modified Fibonacci dose escalation and an mTPI design. BMS-986148 will be administrated 
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every 3 weeks in Part 1A and weekly for 3 weeks with one week off in Part 1B. In the expansion 
phase, the optimal regimen from Part 1A or 1B selected upon agreement between the 
Sponsor/Medical Monitor and Investigators will be adopted in the five cohorts corresponding to 
these tumor types: mesothelioma, pancreatic, ovarian, NSCLC, and gastric cancer.  
The analysis and reporting of safety data will be performed on an as assigned basis at time of 
study therapy initiation unless otherwise specified. If a subject received the incorrect study 
medication for the entire period of treatment, the subject will be analyzed in the treatment group 
associated with the incorrect study medication.
6.3
Populations for Analyses
•
All Enrolled Subjects: All subjects who signed an informed consent form
•
All Treated Subjects: All subjects who received at least one dose of study medication 
•
Pharmacokinetic Subjects: All subjects who received at least one dose of BMS-986148 and 
have evaluable serum and plasma concentration data 
 
•
Immunogenicity (ADA) Subjects: All treated subjects who have baseline and at least one 
post baseline immunogenicity assessment
•
ECG Evaluable Population: all treated subjects who had a baseline ECG and at least one on-
study ECG.
•
Response Evaluable Population: all treated subjects who had baseline tumor measurement 
and at least one other tumor measurement after treatment, clinical progression, or death prior 
to the first on-treatment tumor assessment.
7
STATISTICAL ANALYSES
All analyses will be performed in SAS using version 9.2 or higher. Some figures may be 
generated using S-Plus.
7.1
General Methods
Continuous variables will be summarized using descriptive statistics, ie, medians, minimums, 
maximums, and means with standard deviations/standard errors of the mean. Categorical 
variables will be summarized by frequencies and percentages. Percentages will be rounded and 
may not always add up to 100.
7.2
Grouping Scheme
Individual subject’s data will be listed in the order of subject ID and collection time.
Throughout this analysis plan, a cohort is defined a unique group of subjects identified by study 
phase (escalation, expansion), dose, dose regimen (Q3W or QW for 3 weeks followed by one 
week off), and tumor type (if in expansion phase). Summary analyses in this study will be 
performed with various grouping schemes: cohort, dose+dose regimen, expansion cohorts only, 
and overall, as shown in Table 2. The scheme of dose + dose regimen consists of groups decided 
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by the unique combination of dose and dose regimen, regardless of tumor type and study phase. 
The scheme of expansion cohorts only has the five groups of subjects with different tumor types 
enrolled into the expansion cohorts.
Grouping for efficacy analyses are further divided by different endpoints as in Table 2, where 
analyses of BOR and ORR will be done by cohort, and other endpoints will be summarized for 
expansion cohorts only by tumor type. 
Safety analyses will be conducted using data from all cohorts by dose, dose regimen and overall. 
If appropriate, certain safety endpoints may be summarized with further grouping of tumor type. 
Table 2:
Grouping Scheme for Analyses
Analyses
Dose+Dose 
Regimen
Cohort
Expansion 
Cohorts Only
Overall
Subject 
Disposition
X
X
Demographics 
and Baseline 
Characteristics
X
X
Extent of 
Exposure
X
X
BOR, ORR
X
X
PFSR, 
 
PFS, DOR
X
Safety
X
X
Immunogenicity
X
X
PK
X
7.2.1
Study Information
Listing:
•
Batch number of study drug
7.2.2
Accrual
The following will be presented on the All Enrolled Subjects.
Summary:
•
Number (%) of subjects accrued by country and investigational site: Include country, site 
number, Principal Investigator’s name, number of subjects enrolled, and number of subjects 
treated
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•
Subjects accrued by country and investigational site
7.2.3
Relevant Protocol Deviations
Relevant Protocol Deviation is a deviation that could potentially affect the interpretability of the 
study results. Any change to the SAP that involves analysis/reporting of Relevant Protocol 
Deviations should be made prior to breaking the blind (or prior to the database lock for open-
label study.
Non-programmable relevant eligibility and on-treatment protocol deviations, as well as 
significant (both programmable and non-programmable) will be reported through 
 
listings. The following programmable deviations from inclusion and exclusion criteria will be 
considered as relevant protocol deviations and a listing will be provided, subject to data 
availability and applicability. 
Inclusion Criteria
1) Only subjects with high expression of mesothelin in the tumor tissue will be enrolled in the 
expansion phase 
2) All subjects must have at least one measurable lesion at baseline by CT or MRI as per 
RECIST v1.1 or Modified RECIST criteria for malignant pleural mesothelioma
3) ECOG performance status score 0-1
Exclusion Criteria
4) Grade 2 or higher eye disorders (inclusive of all NCI CTCAE v4.03 criteria). Mild eye 
symptoms such as blurry vision, either age-related or due to ocular or systemic disorder (e.g. 
diabetes, dry eyes, cataracts, uncorrected refraction abnormality) may be allowed at the 
discretion of the ophthalmologist if deemed as not constituting a predisposition to 
drug-induced corneal deposits and blurry vision.
5) Physical and Laboratory Test Findings
a) Inadequate bone marrow function defined as:
i)
Absolute neutrophil count (ANC) < 1,500 cells/mm3 ;
ii) Platelet count < 100,000 cells/mm3; 
iii) Hemoglobin < 9.0 g/dL
b) Subjects with a stable chronic transfusion requirement (e.g. due to cumulative toxicity 
from previous therapy) of no more than once per month will be allowed if the trough 
hemoglobin is > 8.0 g/dL.
c) Inadequate hepatic function defined as:
i)
Total bilirubin > 1.5 times the institutional ULN (except known Gilbert’s syndrome);
ii) Alanine transaminase (ALT) or aspartate transaminase (AST) > 3 times the 
institutional ULN.
d) Inadequate renal function defined as:
i)
Blood creatinine > 1.5 times the institutional ULN
e) Any of the following on 12-lead electrocardiogram (ECG) prior to study drug 
administration, confirmed by repeat.
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i)
QRS ≥ 120 msec, except right bundle branch block
ii) QTcF ≥ 450 msec for males, ≥ 470 msec for females, except right bundle branch 
block
7.3
Study Population
7.3.1
Subject Disposition
Summary:
•
Pre-treatment period: The number (%) of subjects of the following will be summarized on the 
All Enrolled Subjects.
−
All enrolled into the study
−
Entering the treatment period
−
Enrolled but not entering the treatment period together with the reasons
•
End of treatment period and of study: The number (%) of subjects of the following will be 
summarized by cohort and overall, based on the All Treated Subjects.
−
All treated subjects
−
Subject completing the treatment period
−
Reasons for not completing the treatment period
−
Subjects continuing in the study
−
Subjects not continuing in the study
−
Reasons for not continuing in the study
•
All related data will be listed
7.3.2
Demographics and Other Baseline Characteristics
Summary:
Descriptive statistics will be summarized for the following baseline characteristics for all treated 
subjects by cohort and overall.
•
Age (in years) ; age category (<65, ≥65)
•
Gender
•
Race
•
Ethnicity (if applicable)
•
Height
•
Weight
•
BMI
•
ECOG performance status
•
Baseline mesothelin expression
•
Disease characteristics such as stage and factors that might affect response to therapy and 
possibly relevant variables (eg, smoking)
•
Prior cancer therapy
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Listing:
•
All relevant data, generally variables listed above by cohort.
7.4
Extent of Exposure
The extent of exposure will be characterized according to the number of subjects exposed, the 
duration of exposure, and the dose to which they were exposed. Analyses in this section will be 
performed on the All Treated Subjects.
7.4.1
Study Therapy
Summary:
Descriptive statistics will be provided by cohort for the following.
•
Number of doses, if appropriate
•
Duration of therapy (weeks) = (last dose date - first dose date + 7)/7 for Q weekly dosing 
cohort(s) and (last dose date - first dose date + 21)/7 for Q3 weekly dosing cohort(s)
•
Cumulative dose = the sum of all actual doses that a subject received
•
Dose intensity = Cumulative dose/Duration of therapy.
•
Relative dose intensity (%) = (dose intensity / planned dose intensity)*100
−
Categories: <50%; 50 - < 70%; 70 - < 90%; 90 - < 110%;  ≥ 110%
Listing:
•
Drug administration of BMS-986148
•
Duration of therapy, cumulative dose, dose intensity and relative dose intensity
7.4.2
Modification of Study Therapy
Summary:
The following will be provided by cohort.
•
Number (%) of subjects with dose delay, omission and discontinuation along with the reason
•
Number (%) of subjects with dose reduction along with the reason 
•
Infusion interruptions
−
Number (%) of subjects with at least one infusion interruption along with the reason
−
Number of infusion interruptions per subject
−
Number (%) of subjects with at least one IV infusion rate reduction along with the reason
Listing:
•
All relevant information on dose modification listed above
7.4.3
Prior and Concomitant Medications
Prior and concomitant medications will be coded using the WHO Drug Dictionary. Concomitant 
medications are defined as medications other than study medications which are taken at any time 
on-treatment.
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Listing:
•
All prior and concomitant medications
7.5
Efficacy
In general, efficacy analyses will be performed for All Treated Subjects unless otherwise 
specified. Limited efficacy analyses may be performed on the Response-evaluable Subjects (e.g.,
ORR summary).
Time to event distribution (e.g. progression free survival, overall survival, and duration of 
response) will be estimated using Kaplan-Meier (K-M) method. When appropriate, the median 
along with 95% CI will be provided using Brookmeyer and Crowley methodology1. Available 
medians and confidence intervals will also be presented in K-M plots. Rates at fixed time points 
(e.g. PFSR at 12, 24, 36 weeks) will be derived from the K-M estimates and corresponding 
confidence intervals will be derived based on Greenwood formula.
Summary:
•
BOR and ORR outcomes (confidence interval will be calculated by the Clopper-Pearson 
method) will be tabulated by cohort
•
The duration of response (with median [95% CI] and range [min, max]), PFS will be 
estimated by Kaplan-Meier (K-M) methodology by tumor type for the expansion cohorts
only. PFSR (e.g., at 12, 24, 36 weeks) will be similarly estimated based on the Kaplan-Meier 
methodology
Figure:
•
Percent change from baseline in target lesions (aka spider plot) by tumor type
•
Maximum reduction in baseline target lesions (aka waterfall plot) by tumor type
•
Swimmer plot of time to response, duration of response by tumor type
Listing:
•
Sum of target lesions at each visit, along with corresponding percent change from baseline, 
percent increase from nadir, and other lesion information will be provided in the order of 
cohort, subject ID, and assessment study day
•
Subject level BOR, duration of response, and PFS will be provided using RECIST v1.1 
criteria or Modified RECIST for malignant pleural mesothelioma
7.6
Safety
Analysis of safety will be based on All Treated Subjects and presented by dose, dose regimen, 
and overall (if appropriate). 
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Adverse events (AEs) will be coded according to the most current version of MedDRA and be 
graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
Drug-related AEs are those events with relationship to study drug “Related” as recorded on the 
CRF. If the relationship to study drug is missing, the AE will be considered as drug-related. 
Listing of adverse events will include all enrolled subjects as SAEs and deaths are collected 
pretreatment. Summaries of adverse events will include (1) events occurring from the first dose 
date to 60 days (inclusive) after the last dose of BMS-986148 for subjects who are off study 
treatment and (2) all events occurring from first dose date for subjects who are still on study 
medication. 
When reporting adverse events by CTC grade, summary tables will be provided based on the 
event with worst CTC grade (independent of relationship to study medication). Subjects will 
only be counted (1) once at the preferred term (PT) level, (2) once at the system organ class 
(SOC) level, and (3) once in the ‘Total subject’ row at their worst CTC grade, regardless of SOC 
or PT.
The analysis of laboratory results will be based on All Treated Subjects. Laboratory results will 
be categorized according to NCI CTCAE (version 4.03) grade. Baseline is defined as the last 
non-missing measurement prior to the first dosing date and time. Summaries of laboratory results 
include baseline and (1) post-baseline results up to 60 days (inclusive) after the last dose of 
BMS-986148 for subjects who are off study treatment and (2) all available post-baseline results 
for subjects who are still on study medication. 
7.6.1
Overall Adverse Events
Summary:
AEs and drug-related AEs will be tabulated by descending frequency of SOC and descending 
frequency of PT within each SOC, unless specified otherwise.
•
Overall summary of any AEs by worst CTC grade (grade 1, 2, 3, 4, 5, unknown) presented 
by SOC/PT
•
Overall summary of drug-related AEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by SOC/PT. 
•
Overall summary of any non-serious AEs presented by PT. This table will be restricted to 
events with an incidence greater or equal to 5% in any dose+dose regimen group for all 
treated subjects (total).
Listing:
All recorded Adverse Events occurring in the pre-treatment, on-treatment, and post treatment 
period will be listed.
7.6.2
Deaths
Summary:
All deaths during the study within 60 days after the last dose of BMS-986148 will be 
summarized for cause of deaths by treatment.
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Listing:
All recorded deaths for All Enrolled subjects will be listed.
7.6.3
Other Serious Adverse Events
Summary:
•
Summary of SAEs by worst CTC grade (grade 1, 2, 3, 4, 5, unknown) presented by SOC/PT.
•
Summary of drug-related SAEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by SOC/PT.
Listing:
By-subject SAE listing will be provided for the All Enrolled Subjects.
7.6.4
Adverse Events Leading to Discontinuation of Study Therapy
Adverse events leading to study drug discontinuation are AEs with action taken = “Drug was 
discontinued”.
Summary:
•
Overall summary of AEs leading to discontinuation by worst CTC grade (grade 1, 2, 3, 4, 5, 
unknown) presented by SOC/PT. 
•
Overall summary of drug-related AEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5)  presented by SOC/PT.
Listing:
By-subject AEs leading to discontinuation listing will be provided.
7.6.5
Multiple Events
Analyses that take into account the multiple occurrences of a given adverse event will be 
conducted. In order to prepare these analyses, the CRF data will be processed according to 
standard BMS algorithms2 in order to collapse adverse event records into unique records based 
on the preferred term. This data will be presented as the rate per 100 patient-years of exposure. 
This analysis will take into account all on-treatment events (allowing more than 1 event per 
subject) and the total duration of exposure. The patient-years exposure will be computed as the 
sum over the subjects’ exposure expressed in years where the duration of exposure is defined as 
•
Date of last dose of study treatment - date of first dose of study treatment + 7 (for QW dosing 
regimen) or + 21 (for Q3W dosing regimen) days, for subject who are off study treatment
and were followed at least 60 days after last dose of study medication.
•
Last known date alive- date of first dose of study medication +1, for subjects who are still on-
treatment or who are off study treatment and were followed less than 60 days after last dose 
of study medication.
Summary:
The following summary tables will be provided:
•
Total number and rate (exposure adjusted) of occurrences for all AEs occurring in at least 5% 
of the subjects treated in any dose + dose regimen group.
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Listing:
•
Unique instances of all AEs, ie, after duplicates have been eliminated and overlapping and 
contiguous occurrences of the same event (ie, same PT) have been collapsed.
7.6.6
Adverse Events of Special Interest
Not applicable at the time of the development of this statistical analysis plan.
7.6.7
Clinical Laboratory Evaluations
Clinical laboratory data will be first analyzed using International System of Units (SI). Analyses 
will be repeated using US conventional units.
Summary:
The number (%) of subjects with the following will be summarized by treatment and overall, if 
appropriate, using the worst CTC grade on-treatment per subject.
•
Post-baseline grade
•
Grade change from baseline
•
Descriptive statistics of laboratory test result and their changes from baseline by treatment 
and study day
Listing:
A by-subject listing of these laboratory parameters will be provided. Laboratory abnormality 
criteria and laboratory results outside of normal range will be listed.
7.6.7.1
Abnormal Hepatic Test
Summary:
The number of subjects with the following laboratory abnormalities from on-treatment 
evaluations will be summarized by dose and dose regimen:
•
ALT or AST > 3 x ULN, > 5 x ULN, > 10 x ULN and > 20 x ULN
•
Total bilirubin > 2 x ULN
•
Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
Figure:
•
Scatter plot of Total bilirubin peak vs AST peak
•
Scatter plot of Total bilirubin peak vs ALT peak
On-treatment peak total bilirubin and on-treatment peak AST/ALT needs to happen on the same 
day of liver testing. 
Listing:
A by-subject listing of these specific abnormalities will be provided.
7.6.7.2
Other Labs of Interest
A by-subject listing of these specific labs of interest, e.g. related to neotropenia (neutrophil 
count) and thrombocytopenia (platelet count) will be provided with flags for abnormal value. 
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Additional plots may be provided to explore potential effects of changes over time in these lab 
parameters.
7.6.8
ECG 
Summary
•
ECG measures
−
The frequency distribution of subjects’ maximum recorded post-dose QTcF, PR, QRS 
and ΔQTcF will be tabulated by treatment and summarized for the following ranges:
♦For QTcF:  QTcF ≤ 450 msec, 450 msec < QTcF ≤ 480 msec, 480 msec < QTcF ≤ 
500 msec, QTcF > 500 msec
♦For PR: PR ≤ 200 msec, PR > 200 msec
♦For QRS: QRS ≤ 120 msec, QRS > 120 msec
♦For ΔQTcF: ΔQTcF ≤ 30 msec, 30 msec < ΔQTcF ≤ 60 msec, ΔQTcF > 60 msec
Figure:
•
ECG measures
−
Scatterplot and regression of ΔQTcF on active ADC, 
 and 
unconjugated tubulysins concentrations, respectively. 
Listing:
•
ECG measures
−
Individual QTcF, PR, QRS or ΔQTcF values will be listed.
•
ECG abnormalities
7.6.9
Vital Signs and Other Safety Evaluation
Summary:
•
Vital signs 
Listing:
•
Vital signs
•
Diagnostic procedures
•
Medical treatment procedures
7.6.10
Immunogenicity
Summary:
The number (%) of subjects with the following anti-drug responses will be reported by dose, if 
applicable, and overall.
•
Baseline ADA Positive
•
ADA Positive
−
Persistent Positive
−
Only the Last Sample Positive
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−
Other Positive
•
ADA Negative
Listing:
•
All collected immunogenicity will be listed with flags indicating baseline positive sample, 
ADA positive sample or ADA negative sample, and information regarding specificity to the 
antibody or unconjugated tubulysin if such data are available.
7.7
Pharmacokinetics
PK parameters for the total antibody, 
 active ADC, 
 and 
unconjugated tubulysin will be calculated using noncompartmental analysis. All available 
plasma/serum concentration-time data from subjects who receive BMS-986148 will be reported. 
All available derived PK parameter values will be included in the PK dataset and reported, but 
only subjects with adequate PK profiles will be included in summary statistics and statistical 
analysis.
PK analysis will be provided separately for each of the above analytes. In general, summary 
statistics will be tabulated for the pharmacokinetics parameters by dose, dose regimen, and study 
day for each select analyte. To assess the attainment of steady state geometric mean Ctrough 
values will be plotted versus study day by dose and dose regimen.
Exploratory assessment of dose proportionality for total antibody, 
 and unconjugated 
tubulysin will be performed based on the power model described by Gough et al. 3
PK Parameter ൌA כ Doseఉ,
which be estimated by the simple linear regression of the natural log of the PK Parameter (Cmax,
AUC(TAU)) on the natural log of Dose:
EሾlogሺPK Parameterሻ|Doseሿൌߙ൅ߚכ logሺDoseሻ.
A slope (ߚ) equal to 1 would indicate perfect dose proportionality. For each PK parameters
(Cmax, AUC(TAU)), the point estimates and 90% CI of the slopes will be provided. Note that 
dose proportionality analysis may not be performed if there are two few different doses under 
some dose regimen, e.g., for the QW dosing for three weeks with one week off.
 
 
A population pharmacokinetic analysis may be conducted, which would be presented in a 
separate report.
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Summary statistics will be provided for the following all listed parameters in Section 4.2.1 by 
dose, dose regimen, study day and time.
Geometric means and coefficients of variation will be presented for all parameters after the first 
dose except Tmax and T_HALF. Median, minimum, and maximum will be presented for Tmax, 
T_HALF.
Figure:
•
Plot of individual Ctrough and their geometric mean at each cycle for each dose + dose 
regimen group. 
•
Scatter plot of AUC(TAU) vs dose in log-log scale by regimen and superposed with the 
regression line from the power model. Regression line’s mathematical equation is also shown 
in the figure.
•
Scatter plot of Cmax vs dose in log-log scale by regimen and superposed with the regression 
line from the power model. Regression line’s mathematical equation shown in the figure.
Listing:
•
All individual PK parameters will be listed including any exclusions and reasons for 
exclusion from summaries
7.8
Biomarker Analyses
Due to the exploratory nature of this study, analyses listed below may or may not be performed 
depending on data availability (some exploratory measurements in the study may be subject to 
change as technologies and assay methods evolve). Additional types of analyses may be 
conducted on a post-hoc basis pending review of data. Not all exploratory analyses will be 
included in the Clinical Study Report (CSR) unless they represent meaningful findings or are 
relevant to subject management.
Summary:
•
Summary statistics (e.g., mean, median, minimum value, maximum value, standard 
deviation) will be provided for: (1)
 
 CA125 and CA19-9; (2) change and percent change from baseline in 
 CA125 and CA19-9. Those analyses will primarily 
grouped by dose and dose regimen. When applicable, similar analyses will be conducted by 
cohort.
Figure:
•
Subject level longitudinal trend plot by cohort for 
 CA
125 and CA19-9.
 
•
Individual subject percent change from baseline over time for 
 
 CA125 and C19-9 respectively.
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8
CONVENTIONS
In general, EmBARC standard time windowing, imputation rules, and counting rules will be 
applied.
8.1
Decimal Places
The number of decimal places displayed in all listings will be determined by the number of 
decimal places in the raw data. 
Unless otherwise specified, minimum and maximum will be reported to the precision as the data 
collected, one more decimal place for the mean and median, and two more decimal places for the 
standard deviation. The adjusted geometric mean, geometric mean ratio and the lower and upper 
limits of confidence interval will be displayed to three decimal places.
8.2
Pharmacokinetic Summaries
8.2.1
In-text Tables
For in-text pharmacokinetic tables, coefficient of variation (%CV) will be reported as integers. 
For other statistics except for standard deviations, values of 100 or higher will be presented as 
integers, values of 10 - <100 will be displayed to one decimal place, and values of 1 - < 10 will 
be displayed to two decimal places. Values less than 1 will be displayed to three decimal places. 
Ratios will also be displayed to three decimal places. Standard deviations will be reported to a 
precision of 1 decimal place more than the mean.
8.2.2
Handling of Non-Quantifiable Concentrations4
For the summaries of serum concentration-time data, concentrations that are less than the lower 
limit of quantification (LLOQ) should be displayed as “< LLOQ” in the listings and be treated as 
missing in summary tables and plots. For the purpose of calculating PK parameters, other than 
Ctrough, pre-dose concentrations that are less than LLOQ and concentrations prior to the first 
quantifiable concentration that are less than LLOQ will be set to zero, and all other 
concentrations less than LLOQ will be set to missing. 
Summary statistics for Ctrough concentrations, analyses of PD-concentrations and ECG-
concentration relationships will be calculated by imputing values less than LLOQ as ½ * LLOQ. 
This imputation is done for Ctrough concentrations because it is treated like a PK parameter; the 
imputation is not done for Day 1 pre-dose concentrations. Individual Ctrough listings will 
display these concentrations as “< LLOQ.”
All available serum concentration-time data and derived pharmacokinetic parameter values will 
be included in the PK data set and listed accordingly.
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8.2.3
Treatment of Outliers
Individual serum concentrations, if deemed to be anomalous, may be excluded from the analysis 
following a review of available documentation (e.g., bioanalytical report, clinical data). Any 
such exclusion will be clearly listed in the study report along with justification for exclusion. 
Entire serum concentration-time profiles for a subject may be excluded following review of 
available documentation (e.g., bioanalytical report, clinical data). However, results of analysis 
with and without the excluded profiles may be presented in the study report. Any such exclusion 
will be clearly listed in the study report along with justification for exclusion.
8.2.4
PK Exclusions4
PK Analysis, Reporting, and Exclusion criteria should following the BMS PK Harmonization 
document Version 2.0. Specific guideline for exclusionary criteria for half-life and how other PK 
parameters are affected for exclusion is under section 9.2 of the BMS PK Harmonization 
document. 
Exclusion of one or more parameters or the entire dataset may be considered due to incomplete 
profile such as AUC(TAU) or when T-HALF cannot be reliably calculated, or there is no sample 
around the suspected Cmax. In addition, subjects may be excluded from the analysis if they 
missed doses, had diarrhea, or vomited at or before a time equal to twice the median Tmax for 
immediate-release products, or vomited at any time during sampling after the administration of 
modified-release formulations.
9
CONTENT OF REPORTS
The complete list of analyses contributing to the clinical study report is given in the Data 
Presentation Plan.
10
DOCUMENT HISTORY
Version Number
Author(s)
Description
1.0
Initial version
11
REFERENCES
1
Brookmeyer R. and Crowley J. A confidence interval for the median survival time. 
Biometrics 38:29-41, 1982.
2
Global Biometric Sciences, SAS Analysis Dataset Specification, Adverse event. Version 1.0, 
January 10, 2011.
3
Gough, K., Hutchison, M., Keene, O., Byrom, B., Ellis, S., Lacey, L., & McKellar, J. (1995). 
Assessment of dose proportionality: report from the statisticians in the pharmaceutical 
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industry/pharmacokinetics UK joint working party. Drug Information Journal, 29(3), 1039-
1048.
4
PK Harmonization Document, Clinical Pharmacology and Pharmacometrics, Version 2.0, 
Bristol-Myers Squibb Research and Development, 2013.
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