Clinical trial NCT02819804
Conditions: B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); BCR-ABL1 Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Childhood Acute Lymphoblastic Leukemia Refractory Adult Acute Lymphoblastic Leukemia Refractory Childhood Acute Lymphoblastic Leukemia
Sponsor: Northwestern University
Start date: 2017-08-17; Completion date: 2018-08-30
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this research study is to determine the acceptable upper limit dose of nivolumab in combination with dasatinib that may be given to patients with relapsed/refractory philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Nivolumab is currently Food and Drug Administration (FDA) approved for other cancers, but has not yet been investigated in Ph+ ALL. Dasatinib is currently FDA approved for the treatment of Ph+ ALL, but has not yet been investigated in combination with nivolumab for this disease. There is evidence that dasatinib not only blocks the Philadelphia chromosome or breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) mutation, but also increases the activity of cells in your immune system. Nivolumab increases T cells in your immune system, which allows your immune system to attack the cancer. We think the combination of these drugs will be more effective against your leukemia than either drug used alone.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of nivolumab when given in combination with dasatinib in patients with relapsed/refractory Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL).

SECONDARY OBJECTIVES:

I. To evaluate the toxicities and safety profile of nivolumab and dasatinib in patients with relapsed/refractory Ph+ ALL.

II. To determine the rate of complete hematologic remission (CR) after three cycles of nivolumab and dasatinib.

III. To determine the rate of molecular remission after three cycles of nivolumab and dasatinib.

IV. To study the pharmacokinetics of nivolumab and dasatinib. V. To evaluate programmed cell death 1 (PD1) expression levels and saturation in the peripheral blood and bone marrow.

VI. To measure peripheral T-cell levels and activation in response to treatment.

TERTIARY OBJECTIVES:

I. To evaluate the 30 day mortality rate, overall survival (OS), progression free survival (PFS), and duration of remission (DOR) one year after treatment with nivolumab when given in combination with dasatinib in patients with relapsed/refractory Ph+ ALL.

II. To compare the OS between patients who receive a hematopoietic stem cell transplant and those who receive no further therapy following remission.

III. To evaluate for resistance mutations at the time of disease progression.

OUTLINE:

Patients receive dasatinib orally (PO) once daily (QD ) on days 1-28 and nivolumab intravenously (IV) over 30 minutes on days 8 and 22 of course 1 and on days 1 and 15 of subsequent courses. Courses repeat every 28 days in the absence of disease progression, unacceptable toxicity, or withdrawal from the study for other reasons.

After completion of study treatment, patients are followed up at 30 days and then monthly for up to 1 year.

Arms: arm 1: Patients receive dasatinib PO QD on days 1-28 and nivolumab IV over 30 minutes on days 8 and 22 of course 1 and on days 1 and 15 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Dasatinib intervention 2: Laboratory Biomarker Analysis intervention 3: Nivolumab intervention 4: Pharmacological Study
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Given IV intervention 4: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
CONFIDENTIAL 
This material is the property of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.  
Do not disclose or use except as authorized in writing by the study sponsor. 
1 
 
 
Phase Ib Study of Nivolumab and Dasatinib in Patients with 
Relapsed/Refractory Philadelphia Chromosome Positive Acute 
Lymphoblastic Leukemia (Ph+ ALL) 
 
Principal Investigator:  
Shira Dinner, MD 
 
 
 
 
Northwestern University  
 
 
 
 
676 N. St Clair, Suite 850 
 
 
 
 
Chicago, IL 60611 
 
 
 
 
Phone: 312-695-6180 
 
 
 
 
Email: sdinner@nm.org 
 
Sub-Investigator(s): 
 
Jessica K. Altman, MD 
 
 
 
 
Olga Frankfurt, MD 
 
 
 
 
Erin Pettijohn, MD 
 
 
 
 
Department of Internal Medicine, Division of Hematology/Oncology 
 
 
 
 
Northwestern University 
 
Biostatistician: 
 
Alfred Rademaker, PhD  
 
 
 
 
 
 
 
Biostatistics Shared Resource 
 
 
 
 
Robert H. Lurie Comprehensive Cancer Center 
 
 
 
 
rademaker@northwestern.edu 
 
 
 
 
 
 
 
 
 
 
Study Intervention(s):  
Nivolumab (Opdivo), Dasatinib (Sprycel) 
 
IND Number: 
 
 
n/a 
 
IND Holder: 
 
 
n/a 
 
Funding Source:  
Bristol Myers Squibb 
 
 
Version Date: 
 
 
6/29/2/2016 (Amendment 2) 
 
Coordinating Center:  
Clinical Research Office 
 
 
 
 
Robert H. Lurie Comprehensive Cancer Center  
Northwestern University 
676 N. St. Clair, Suite 1200 
Chicago, IL  60611 
 
 
 
 
 
http://cancer.northwestern.edu/CRO/index.cfm 
 
 
 
 
 
 
 
 
 
 
 
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NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
2 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS............................................................................................................. 5 
STUDY SCHEMA ............................................................................................................................ 6 
STUDY SUMMARY ......................................................................................................................... 6 
1.0 Introduction – BACKGROUND & RATIONALE ...................................................................... 9 
1.1 
Disease Background........................................................................................................ 9 
1.2 
Intervention Background & Overview .............................................................................. 9 
1.3 
Rationale for the Current Study ..................................................................................... 10 
1.4 
Exploratory Studies........................................................................................................ 11 
2.0 OBJECTIVES & endpoints ..................................................................................................... 11 
2.1 
Primary Objective & Endpoint ........................................................................................ 11 
2.2 
Secondary Objectives & Endpoints ............................................................................... 11 
2.3 
Exploratory Objectives & Endpoints .............................................................................. 11 
3.0 PATIENT ELIGIBILITY ............................................................................................................ 12 
3.1 
Inclusion Criteria ............................................................................................................ 12 
3.2 
Exclusion Criteria ........................................................................................................... 13 
4.0 TREATMENT PLAN ................................................................................................................ 15 
4.1 
Overview ........................................................................................................................ 15 
4.2 
Treatment Administration .............................................................................................. 15 
4.3 
Phase I Dose De-Escalation Scheme ........................................................................... 16 
4.4 
Toxicity Management & Dose Delays/Modifications ..................................................... 17 
4.5 
Concomitant Medications/Treatments ........................................................................... 21 
4.6 
Other Modalities or Procedures ..................................................................................... 23 
4.7 
Duration of Therapy ....................................................................................................... 23 
4.8 
Duration of Follow Up .................................................................................................... 23 
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NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
3 
4.9 
Removal of Subjects from Study Treatment and/or Study as a Whole ......................... 24 
4.10 
Patient Replacement ..................................................................................................... 24 
5.0 STUDY PROCEDURES ........................................................................................................... 25 
6.0 Endpoint assessment ............................................................................................................ 27 
6.1 
Primary Endpoint ........................................................................................................... 27 
6.2 
Secondary and Exploratory Endpoints .......................................................................... 27 
6.2.2 
Central Nervous System (CNS) Disease....................................................................... 28 
7 ADVERSE EVENTS.................................................................................................................... 29 
7.1 
Adverse Event Monitoring ............................................................................................. 29 
7.2 
Definitions & Descriptions .............................................................................................. 29 
7.3 
Adverse Event Reporting ............................................................................................... 31 
8 DRUG INFORMATION ............................................................................................................... 32 
8.1 
Dasatinib ........................................................................................................................ 32 
8.2 
Nivolumab ...................................................................................................................... 33 
9 CORRELATIVES/SPECIAL STUDIES ....................................................................................... 35 
9.1 
Sample Collection Guidelines ........................................................................................ 35 
9.2 
Assay Methodology ....................................................................................................... 35 
10 STATISTICAL CONSIDERATIONS ......................................................................................... 35 
10.1 
Study Design/Study Endpoints ...................................................................................... 35 
10.2 
Sample Size and Accrual .............................................................................................. 36 
10.3 
Data Analyses Plans...................................................................................................... 36 
11 STUDY MANAGEMENT ........................................................................................................... 36 
11.1 
Institutional Review Board (IRB) Approval and Consent ............................................... 36 
11.2 
Amendments .................................................................................................................. 37 
11.3 
Registration Procedures ................................................................................................ 37 
11.5 
Data Management and Monitoring/Auditing .................................................................. 37 
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NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
4 
11.6 
Adherence to the Protocol ............................................................................................. 38 
11.7 
Investigator Obligations ................................................................................................. 38 
11.8 
Publication Policy ........................................................................................................... 38 
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NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
5 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALL 
ALT 
Acute Lymphoblastic Leukemia 
Alanine Aminotransferase 
ANC 
Absolute Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
DMC 
Dose Limiting Toxicity 
Data Monitoring Committee 
DSMB 
Data and Safety Monitoring Board 
ECOG 
FOCBP 
Eastern Cooperative Oncology Group 
Females of Child-Bearing Potential 
H&PE 
History & Physical Exam 
IV (or iv) 
Intravenously 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate or Objective Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Ph+ 
PI 
Progressive Disease 
Philadelphia positive 
Principal Investigator 
                  
PFS 
Progression Free Survival 
PO (or p.o.) 
Per os/by mouth/orally 
PR 
Partial Response 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
QTc 
QT interval corrected 
WBC 
White Blood Cells 
 
 
 
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NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
6 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relapsed/Refractory 
Ph+ ALL 
Dasatinib 140mg PO daily until disease 
progression + Nivolumab 80mg or 240mg Q2 
wks 
 
 
Response assessment ** 
beginning on cycle 2 day 1 and 
day 1 of all subsequent cycles 
 
 
*Cycle length = 28 days 
 
Patients may continue treatment until disease progression, unacceptable toxicity, or 
withdrawal from the study for other reasons  
 
**Response assessment will consist of peripheral blood draw and bone marrow biopsy. If 
patient has documented molecular remission, subsequent bone marrow biopsies will be 
deferred to the treating physician and patient will be monitored by peripheral blood PCR 
for BCR-ABL 
Screening and 
registration 
Follow up once monthly for 1 
year after completing treatment 
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NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
7 
STUDY SUMMARY 
Title 
Phase 1b Study of Nivolumab and Dasatinib in Patients with 
Relapsed/Refractory Philadelphia Chromosome Positive Acute 
Lymphoblastic Leukemia (Ph+ ALL) 
Short Title 
Nivolumab and dasatinib in relapsed/refractory Ph+ ALL 
Version 
 June 2September 2, 2016 (Amendment 2) 
Study Design 
Phase 1b, open label, modified 3+3 dose de-escalation design  
Study Center(s) 
Robert H. Lurie Comprehensive Cancer Center of Northwestern 
University 
Objectives 
Primary objective: To determine the maximally tolerated dose (MTD) of 
nivolumab when given in combination with dasatinib in patients with 
relapsed/refractory Ph+ ALL. 
 
Secondary objectives: 
 
To evaluate the toxicities and tolerability of nivolumab and 
dasatinib in patients with relapse/refractory Ph+ ALL  
 
Rate of complete hematologic remission 
 
Rate of MRD negativity or molecular remission 
 
To study the pharmacokinetics of nivolumab and dasatinib 
 
To evaluate PD1 expression levels and saturation in the 
peripheral blood and bone marrow  
 
To measure peripheral T-cell levels and activation in 
response to treatment  
 
Sample Size 
6-12 patients will be enrolled across all the dose de-escalation cohorts, 
and an additional 10 evaluable patients will be enrolled in the dose 
expansion cohort. Up to a total of 25 patients will be enrolled to allow for 
22 evaluable patients. 
Diagnosis & Key 
Eligibility Criteria 
Adults with Ph+ ALL who have primary refractory ALL based on failure to 
achieve a hematologic or molecular remission after induction therapy 
with dasatinib and steroids or dasatanib and chemotherapy, or have 
relapsed after treatment with a tyrosine kinase inhibitor with or without 
chemotherapy. Patients who have previously been treated with drugs 
targeting checkpoint pathways or T-cell co-stimulation, or who have a 
severe intolerance to prior tyrosine kinase inhibitors will be excluded.  
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NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
8 
Treatment Plan 
The safety lead-in phase will begin in a standard 3+3 design with 
enrollment of 3 patients to cohort 1 to receive dasatinib 140mg PO daily 
and nivolumab 240mg IV once every 2 weeks, beginning on day 8 and 
day 22 of the first cycle.  This will allow for a lead in phase during cycle 
one with single agent dasatinib to assess T-cell subsets prior to the 
addition of nivolumab.  Starting with cycle 2, nivolumab will be given on 
day 1 and day 15 of each cycle.  If ≤1 patients experiences a dose-
limiting toxicity (DLT), an additional 3 patients will be enrolled to cohort 1.  
If 0 or 1 DLTs occur in 6 patients, 10 additional patients will be enrolled 
onto the dose expansion cohort with nivolumab 240mg IV every 2 weeks 
and dasatinib 140mg PO daily.  If 2 or more patients of the initial 6 
patients from cohort 1 experience a DLT, 3 additional patients will be 
enrolled at a de-escalated dose of nivolumab 80mg IV every 2 weeks with 
dasatinib 140mg PO daily.  If ≤ 1 patient experiences a DLT, an additional 
3 patients will be enrolled to cohort 2. If 0 or 1 DLTs occur in 6 patients, 
10 additional patients will be enrolled to the dose expansion phase at the 
de-escalated dose of nivolumab 80mg every 2 weeks. Enrolled patients 
will be treated in repeating 28-day cycles until disease progression, 
unacceptable toxicity, or withdrawal from the study for other reasons. 
Statistical Methodology 
This is a phase Ib design where up to 6 patients will be treated at each 
dose level. For each dose, three patients will be initially treated. If 2 or 3 
patients at dose level 1 experience a DLT, then the dose will be de-
escalated. If 0 or 1 of 3 patients has a DLT, then an additional 3 patients 
will be added to this dose. If 1 of 6 have a DLT, then the dose will be 
chosen as the dose for the expansion cohort.  If 2 or 3 of 6 have a DLT, 
then the de-escalation dose is the MTD, provided 6 patients have been 
treated at that dose and have had 1 or fewer DLTs. This 3+3 component 
of the design has a 95% chance (64%, 30%) of declaring acceptable 
toxicity when the true toxicity rate for that dose is 10% (30%, 50%).  With 
two doses, the expected sample size in the dose finding portion of the 
study will be between 6 and 12. Up to 10 additional patients will be 
enrolled at any dose  found to be acceptable in the 3+3 component.  
While it is theoretically possible to expand each dose with 10 patients so 
that the possible maximum sample size is 32, it is expected that the dose 
expansion will occur only at the MTD so that the total expected sample 
size is 16-22 patients Toxicity profile will be presented by rate of overall 
toxicity and rates of > grade 3 toxicities analyzed separately and 
combined. AEs will be summarized and accompanied by 95% 
confidence intervals using binomial distribution. Patients’ characteristics 
will be summarized using mean, median, and standard deviation for 
continuous variables, and tables for discrete variables. We will 
descriptively report observed secondary and exploratory endpoints, 
including rates of complete hematologic and molecular remission after 3 
cycles of nivolumab and  dasatinib, duration of remission, progression 
free survival, overall survival, 30-day mortality rate, and the outcomes for 
patients that go on to HSCT vs those that do not receive further therapy. 
Rates will be estimated using exact binomial probabilities and 95% 
confidence intervals. Molecular remission will be estimated using an 
exact binomial confidence interval. PFS and OS will be estimated using 
Kaplan-Meier curves. T cell levels after treatment will be assessed using 
the paired t-test or the signed rank test. Levels of PD1 expression will be 
compared with responders versus non-responders using a Wilcoxon 
rank sum test. Basic pharmacokinetic parameters will be calculated and 
summarized using means, medians and ranges. 
 
 
 
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NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
9 
1.0 
INTRODUCTION – BACKGROUND & RATIONALE 
 
1.1 
Disease Background 
Acute lymphoblastic leukemia (ALL) is a rare disease, representing only approximately 
20% of all leukemia diagnosed in adults. The Philadelphia chromosome 
[t(9;22)(q34;q11)] resulting in the BCR-ABL oncogene fusion is the most common 
cytogenetic abnormality in adult ALL.  The incidence of Philadelphia chromosome 
positive ALL (Ph+ ALL) increases with age and is associated with lower remission rates 
and a poor prognosis. Among patients over 60 years old, approximately 50% have the 
Philadelphia chromosome at diagnosis.1 The introduction of tyrosine kinase inhibitor (TKI) 
therapy targeted against the BCR-ABL kinase, such as imatinib and dasatinib, has 
resulted in improved hematologic remission rates of 80-90% both in combination with 
chemotherapy and when used with steroids.2,3,4,5,6,7 However, it has been reported that 
only 20-50% achieve molecular remissions when treated with TKI and steroids. Further, 
patients that do not achieve molecular remission are at higher risk for relapse.7,8 For both 
elderly patients that cannot tolerate intensive multi-agent chemotherapy and younger 
patients that would like to mitigate the use of these agents and their associated toxicities, 
it would be attractive to optimize the efficacy of TKIs. Because immunotherapies such as 
the graft-versus-leukemia effect of hematopoietic stem cell transplant (HSCT) and 
antibodies have demonstrated efficacy in ALL as monotherapies, adding an 
immunotherapy to TKI therapy may provide further benefit. 
 
1.2 
Intervention Background & Overview 
Dasatinib is an FDA-approved second-generation TKI that inhibits the BCR-ABL kinase 
as well as the SRC family kinase. The SRC kinase is thought to drive an alternate 
signaling pathway in imatinib-resistant ALL. Dasatinib demonstrated a 325-fold greater 
potency for inhibiting growth of ALL cells compared to imatinib in vitro,9 and is active 
against Ph+ ALL cells with imatinib-resistant ABL kinase domain mutations.10 Dasatinib 
has shown activity in patients with relapsed or refractory Ph+ ALL who could not tolerate 
or were resistant to imatinib.11 Additionally, dasatinib is known to cross the blood brain 
barrier and is effective in central nervous system leukemia in preclinical xenograft models 
and in a small group of patients with Ph+ ALL with CNS involvement.12 Thus, dasatinib 
may be more beneficial than imatinib in Ph+ ALL. 
The Italian GIMEMA LAL1205 study investigated dasatinib 70 mg PO twice daily with 
steroids as frontline treatment for 53 adult Ph+ ALL patients with a median age of 54 
years. All patients achieved a complete hematologic response (CHR), with no induction 
deaths. BCR-ABL transcript levels decreased rapidly during induction therapy, and the 
percentage of patients achieving a molecular remission (BCR-ABL levels < 0.001%) 
increased from 23% at day 22 to 52% at day 85. At 20 months, the overall survival (OS) 
was 69% and disease free survival (DFS) was 51%. Notably, BCR-ABL levels < 0.001% 
at day 85 correlated with improved DFS.7 These results with dasatinib without any 
cytotoxic chemotherapy are encouraging, but demonstrated that single-agent dasatinib is 
not sufficient to cure this disease.  In the subsequent trial, GIMEMA LAL1509, if patients 
did not achieve complete molecular response after a prolonged 84 day induction with 
dasatinib 140 mg daily and steroids, they received more intensive multi-agent 
chemotherapy and/or an allogeneic hematopoietic stem cell transplantation. At day 85, 
58/60 (97%) patients achieved a complete hematologic remission, however only 11 
(18.6%) patients achieved a complete molecular remission (CMR) with TKI plus steroid 
induction, once again demonstrating the need for additional post-remission therapy.8 No 
deaths occurred during induction in either trial, confirming dasatinib is well tolerated in 
Ph+ ALL and can likely be safely combined with immunotherapies. 
Programmed death (PD)-1 is a T-cell surface receptor that leads to T-cell inactivation and 
down regulation of cellular immune response upon binding the PD-1 or PD-2 ligand (PD-
L1, PD-L2) in order to serve as a checkpoint in the immune system. PD-L1 is expressed 
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NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
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Amendment 2: September 2, 2016 
 
10 
on malignant cells and also at low levels on most normal hematopoietic cells in patients 
with a variety of hematologic malignancies including lymphoma, multiple myeloma, and 
chronic and acute leukemia.13,14,15,16 The co-expression of PD-L1 by malignant cells and 
normal cells in the tumor microenvironment has been shown to prevent the host immune 
response from exerting a beneficial impact on the tumor. Therefore, blockade of PD-1 
may significantly enhance anti-tumor immunity resulting in durable responses. 
Nivolumab is a fully human antibody against the PD-1 receptor that selectively blocks the 
interaction between PD-1 and its ligands PD-L1 and PD-L2. By inhibiting this interaction, 
nivolumab can enhance T-cell function, which may result in anti-tumor activity. In a phase 
1 study in solid tumors, nivolumab demonstrated a tolerable safety profile and objective 
responses.17 The subsequent trial in advanced melanoma, non–small-cell lung cancer, 
castration- resistant prostate cancer, renal-cell and colorectal cancer treated patients at a 
dose of 0.1 to 10.0 mg/kg every 2 weeks. No maximum tolerated dose (MTD) was 
reached and the drug was well-tolerated. Common treatment-related adverse events 
(AE) included fatigue, rash, diarrhea, pruritus, decreased appetite, and nausea, however 
only 5% of patients discontinued therapy related to an AE. All dose levels demonstrated 
anti-tumor activity.18 In an ongoing trial of nivolumab in relapsed/refractory lymphoid 
malignancies, the safety profile has been similar to that observed in solid tumors. While 
single agent nivolumab is highly active in Hodgkin lymphoma with an overall response 
rate of 87%, in non-Hodgkin lymphomas response rates were only 17-28% and multiple 
myeloma patients did not respond.19,20 This suggests that anti-PD1 therapies may be best 
used in combination with other targeted therapies in lymphoid malignancies. 
 
1.3 
Rationale for the Current Study 
Dasatinib has immunomodulatory properties that may make it the ideal TKI to combine 
with immunotherapy. Data from patients with chronic myeloid leukemia (CML) treated 
with dasatinib demonstrated that approximately 30-50% developed a marked and 
persistent lymphocytosis due to expansion of large granular lymphocytes (LGL) with 
clonal T-cell receptor (TCR) delta or gamma gene rearrangements.21,22,23 
Rapid 
mobilization and expansion of cytotoxic T lymphocytes has also been observed with 
dasatinib.24 
Further, clonal LGL lymphocytosis may be associated with response to 
dasatinib.21Similarly, natural killer cell and LGL expansion has been observed in Ph+ ALL 
patients treated with dasatinib and is associated with optimal molecular response.25 The 
mechanism of action for this T-cell expansion with dasatinib is not completely 
understood, but suggests that it may play an important role in its anti-leukemia activity 
that should be exploited further to improve efficacy. We therefore propose a phase 1b 
clinical trial of nivolumab given in combination with dasatinib in patients with Ph+ ALL that 
have not achieved a complete hematologic remission or molecular remission after 
induction therapy with dasatinib and steroids or have relapsed after treatment with a TKI 
with or without chemotherapy.  The study design will be a phase 1b, open-label 3+3 
design with the starting dose of nivolumab at 240mg given IV every 2 weeks.  The safety 
and efficacy of 240mg as a flat dose is expected to be similar to the 3mg/kg dosing 
currently FDA approved for use in lung cancer and melanoma given that across tumor 
types, nivolumab has been shown to be safe and well-tolerated up to a dose level of 
10mg/kg with relatively similar efficacy.  A flat dose of 240mg is therefore being 
investigated.   This will be given with dasatinib at a dose of 140mg PO daily, which is also 
the dose currently approved for treatment of Ph+ALL and CML.  In the event of 
unexpected toxicity, patients will be enrolled to a dose level -1 with a nivolumab dose of 
80mg every 2 weeks with the same dasatinib dose.  The primary endpoint will be the 
incidence of dose-limiting toxicity when nivolumab is used in combination with dasatinib 
in relapsed/refractory Ph+ ALL.   
 
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NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
11 
1.4 
Exploratory Studies 
As described above, both dasatinib and nivolumab have demonstrated the ability to 
modulate the immune system and expand T cells as single agents. We therefore 
hypothesize that nivolumab and dasatinib will act synergistically to increase T cell levels 
and activation, and induce lysis of ALL blast cells.  
  
 
2.0 
OBJECTIVES & ENDPOINTS 
 
2.1 
Primary Objective & Endpoint 
1.1.12.1.1 
Primary Objective: 
 To determine the maximum tolerated dose (MTD) of nivolumab when given in 
combination with dasatinib in patients with relapsed/refractory Ph+ ALL. The 
MTD will be defined as the highest dose level at which ≤ 1 DLT occurs in 6 
patients. 
 
1.1.22.1.2 
Primary Endpoint: 
 The incidence of dose-limiting toxicity (DLT), as defined in section 4.3.1, 
assessed by the Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03.   
 
2.2 
Secondary Objectives & Endpoints 
1.1.32.2.1 
Secondary Objectives: 
 To evaluate the toxicities and safety profile of nivolumab and dasatinib in 
patients with relapsed/refractory Ph+ ALL  
 To determine the rate of complete hematologic remission (CR) after three 
cycles of nivolumab and dasatinib. 
 To determine the rate of molecular remission after three cycles of nivolumab 
and dasatinib. 
 To study the pharmacokinetics of nivolumab and dasatinib. 
 To evaluate PD1 expression levels and saturation in the peripheral blood and 
bone marrow. 
 To measure peripheral T-cell levels and activation in response to treatment. 
 
1.1.42.2.2 
Secondary Endpoints: 
 The number, frequency, and severity of adverse events (as defined by 
the NCI Common Terminology Criteria for Adverse Events or CTCAE 
version 4.03) will be recorded from consent until 30 days after treatment (100 
days for SAE’s). 
 Clinical response defined as complete remission (CR) rate and/or molecular 
remission after three cycles of nivolumab and dasatinib. 
 PD1 expression levels and saturation in the peripheral blood and bone marrow 
before and after treatment. T cell levels and activation will be measured in the 
peripheral blood after treatment. 
 
2.3 
Exploratory Objectives & Endpoints 
1.1.52.3.1 
Exploratory Objectives:  
 To evaluate the 30 day mortality rate, overall survival (OS), progression free 
survival (PFS), and duraton of remission (DOR) one year after treatment with 
nivolumab when given in combination with dasatinib in patients with 
relapsed/refractory Ph+ ALL. 
 To compare the OS between patients who receive a hematopoietic stem cell 
transplant and those who receive no further therapy following remission. 
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NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
12 
 To evaluate for resistance mutations at the time of disease progression. 
Endpoint: Presence of resistance mutations based on molecular analysis of the 
bone marrow aspirate at the time of disease progression. 
 
3.0 
PATIENT ELIGIBILITY 
The target population for this study is patients with relapsed or refractory Ph+ ALL.  This will be a 
multi-center trial conducted at The Robert H. Lurie Comprehensive Cancer Center of 
Northwestern University. Northwestern University will serve as the lead site and coordinating 
center for this study.  
 
A total of up to 25 patients will be needed for this trial for 16-22 evaluable patients. Approximately 
6 potentially eligible patients are seen per month, and it is anticipated that at least 2 per month 
will be accrued. Potential patients may be referred to the Principal Investigator (PI) at 
Northwestern University, Dr. Shira Dinner at 312-695-6180. 
 
Eligibility will be evaluated by the study team according to the following criteria. Eligibility waivers 
are not permitted. Subjects must meet all of the inclusion and none of the exclusion criteria to be 
registered to the study. Study treatment may not begin until a subject is registered. Please refer 
to Section 11 for complete instructions regarding registration procedures. 
 
3.1 
Inclusion Criteria 
3.1.1 
Patients must have a histologically confirmed diagnosis of Ph+ ALL. 
 
3.1.2 
Detection of one of the following must be present: 
 
t(9;22)(q34;q11) or 3-way variant by metaphase cytogenetics 
 
BCR-ABL positive status by molecular analysis with qualitative PCR or 
FISH    
 
3.1.3 
Patients must have primary refractory ALL based on failure to achieve a 
hematologic or molecular remission after induction therapy with dasatinib and 
steroids or dasatanib and chemotherapy, or have relapsed after treatment with a 
tyrosine kinase inhibitor with or without chemotherapy. 
 
Note: Prior course of dasatinib and steroid induction therapy should have 
included dasatinib 140mg PO daily on days 1-84 and prednisone 
60mg/m2 (capped at 120mg, or equivalent steroid dose) on days 1-28. If 
patients were unable to tolerate full steroid dose during induction therapy 
they will still be eligible.   
 
Note: Patients with refractory or relapsed disease in the central nervous 
system will be eligible. 
 
3.1.4 
Prior chemotherapy or TKI treatment, aside from dasatinib, must be ≥ 7 days 
before first investigational agent dose. 
 
3.1.5 
Patients must be age ≥ 18 years. 
 
3.1.6 
Patients must exhibit an ECOG performance status of 0-2 
 
3.1.7 
Patients must have adequate organ function prior to registration, as defined 
below:  
 
ALT and AST < 2 x institutional upper limit of normal (IULN).  Total bilirubin < 
2.0 x IULN (unless Gilbert syndrome has been diagnosed). If leukemia 
infiltration of the liver is suspected to be causing liver function abnormalities 
the patient will still be eligible with PI approval  
 
Creatinine < 2 x IULN, Creatinine clearance >40 mL/min (measured by 
Cockroft-Gault) 
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NU Study Number: NU 15H13 
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Amendment 2: September 2, 2016 
 
13 
3.1.8 
Females of child-bearing potential (FOCBP)   must have a negative pregnancy 
test within 7 days of registration. 
 
Note: A FOCBP is any woman (regardless of sexual orientation, having 
undergone a tubal ligation, or remaining celibate by choice) who meets the  
following criteria: 
 
Has not undergone a hysterectomy or bilateral oophorectomy 
 
Has had menses at any time in the preceding 12 consecutive months (and 
therefore has not been naturally postmenopausal for > 12 months) 
 
3.1.9 
Women must not be breastfeeding at the time of study registration. 
 
3.1.10 Women and men of reproductive potential should agree to use two effective 
means of birth control as dictated in Appendix 3.  
 
For women, contraception should continue for 23 weeks after the last dose of 
nivolumab and 12 weeks after the last dose of dasatinib to allow complete 
clearance of drug and its principal metabolites from the body.  
 
For men, contraception should continue for 31 weeks after nivolumab and 12 
weeks after dasatinib.  
 
3.1.11 Patients must have the ability to understand and the willingness to sign a written 
informed consent prior to registration on study. 
 
3.2 
Exclusion Criteria 
3.2.1 
Patients may not be receiving any other investigational agents within 5 half-lives 
of the drug (if known). If the half-life is not known, investigational agents should 
not be taken within two weeks.  
 
3.2.2 
Patients are not eligible if they have an intolerance to most recent prior TKI (other 
than dasatinib) at the lowest possible effective dose, defined as a Grade ≥ 3 
toxicity considered at least possibly related to that TKI.  Patients are also 
excluded if they are intolerant or allergic to dasatinib and discontinued prior 
therapy due to a ≥ Grade 2 treatment related adverse event.  
 
3.2.3 
Patients must not have a history of a grade 4 anaphylactic reaction to 
monoclonal antibody therapy or known hypersensitivity reactions to drugs 
formulated with polysorbate 90. 
 
3.2.4 
Patients must not have had any prior therapy with an anti-PD-1, anti-PD-L1, anti-
PD-L2, anti-CD137 or anti-CTLA-4 antibody (or any antibody or drug specifically 
targeting T-cell costimulation or checkpoint pathways.  For questions or 
uncertainties, please contact the PI or QAM. 
 
3.2.5 
Patients who have had allogeneic hematopoietic stem cell transplant (HSCT) are 
not eligible if they meet any of the following:  
 
transplant is within 2 months from C1D1   
 
Has clinically significant graft-versus-host disease requiring treatment 
 
Has ≥ Grade 3 persistent non-hematological toxicity related to the transplant  
3.2.6 
Concomitant use of strong inhibitors of the CYP3A4 isoenzyme is not permitted.  
Must have wash-out period of 5 times the half-life of the compound before first 
dasatinib dose. Please see Appendix 2 for examples. 
 
3.2.7 
Concomitant use of QT prolonging agents strongly associated with Torsades de 
Pointes (See Section 4.5.2) is not permitted.   
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NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
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Amendment 2: September 2, 2016 
 
14 
 
 
3.2.8 
Patients who have a known dasatinib-resistant ABL-kinase mutation such as 
T315I are not eligible.  For confirmation, please contact PI. 
 
3.2.9 
Patients who have any serious or uncontrolled medical disorder that would impair 
the ability of the subject to receive protocol therapy are not eligible. These 
include, but are not limited to:  
 
Active infection that is not well controlled 
 
Known pleural or pericardial effusion at baseline  
 
Clinically significant gastrointestinal disease or digestive dysfunction 
compromising absorption of dasatinib 
 
Pulmonary arterial hypertension  
 
Uncontrolled or significant cardiovascular disease, including: 
o 
Myocardial infarction within 6 months of enrollment date 
o 
Uncontrolled angina or congestive heart failure within 3 months of 
enrollment date 
o 
Left ventricular ejection fraction (LVEF) <40% 
o 
Significant cardiac conduction abnormality, including:  
 
History of clinically significant ventricular arrhythmia (such as 
ventricular tachycardia, ventricular fibrillation, or Torsades de 
Pointes) 
 
History of second or third degree heart block (except for 
second degree type 1) 
 
QTc interval >500 msec, unless a cardiac pacemaker is 
present 
 
Prior malignancy active within the previous 3 years, except for locally curable 
cancers that have been apparently cured, such as basal or squamous cell 
skin cancers, superficial bladder cancer, or carcinoma in situ of the prostate, 
cervix or breast.  
 
Subjects with active, known or suspected autoimmune disease.  (Note: 
Subjects with vitiligo, type I diabetes mellitus, hypothyroidism due to 
autoimmune condition only requiring hormone replacement, psoriasis not 
requiring systemic treatment, or conditions not expected to recur in the 
absence of an external trigger are permitted to enroll).  
 
Psychiatric illness/social situations that would limit compliance with study 
requirements 
 
Any other illness or condition that the treating investigator feels would 
interfere with study compliance or would compromise the patient’s safety or 
study endpoints 
 
3.2.10 Female patients who are pregnant or nursing are not eligible. 
 
3.2.11 Patients are not eligible if they have a known positive test for hepatitis B virus 
surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) 
indicating acute infection.  
 
Note: Patients with evidence of chronic hepatitis B infection will be allowed to 
enroll if on appropriate suppressive medications under the direction of a 
hepatologist and with PI approval. 
 
3.2.12 Patients who are known to be positive for human immunodeficiency virus (HIV) 
or known acquired immunodeficiency syndrome (AIDS) are not eligible. 
 
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NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
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Amendment 2: September 2, 2016 
 
15 
3.2.13 Patients must not have live vaccine therapies for prevention of infectious 
diseases within 28 days of first nivolumab dose.  
 
3.2.14 Patients who are unable to swallow oral medication are not eligible. 
 
3.2.15 Patients with active autoimmune disease or history of autoimmune disease that 
might recur, which may affect vital organ function or require immune suppressive 
treatment including chronic prolonged systemic corticosteroids (defined as 
corticosteroid use of duration one month or greater), should be excluded. These 
include but are not limited to patients with a history of: 
 
immune related neurologic disease 
 
multiple sclerosis 
 
autoimmune (demyelinating) neuropathy 
 
Guillain-Barre syndrome 
 
myasthenia gravis 
 
systemic autoimmune disease such as SLE 
 
connective tissue diseases 
 
scleroderma 
 
inflammatory bowel disease (IBD) 
 
Crohn’s 
 
ulcerative colitis 
 
patients with a history of toxic epidermal necrolysis (TEN) 
 
Stevens-Johnson syndrome 
 
anti-phospholipid syndrome  
NOTE: Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism 
due to autoimmune condition only requiring hormone replacement, psoriasis not 
requiring systemic treatment, or conditions not expected to recur in the absence 
of an external trigger are permitted to enroll. 
 
4.0 
TREATMENT PLAN 
4.1 
Overview 
This will be a phase 1b dose de-escalation study of nivolumab and dasatinib in 
relapsed/refractory Ph+ ALL. Please refer to section 4.3 for the dose de-escalation 
details. Enrolled patients will be treated in repeating 28-day cycles until disease 
progression, unacceptable toxicity, or withdrawal from the study for other reasons.   
Response will be assessed via peripheral blood and bone marrow biopsies on day 1 of 
each cycle beginning with cycle 2. If a patient has a documented complete hematologic 
response and molecular remission based on PCR for BCR-ABL or cytogenetics, 
subsequent bone marrow biopsies may be done based on physician’s discretion. These 
patients will be monitored by peripheral blood PCR for BCR-ABL on day 1 of each cycle 
after documentation of complete hematologic response and molecular remission. 
 
4.2 
Treatment Administration 
Treatment Administration Summary 
Agent 
Premedications 
Dose 
Route 
Schedule 
Cycle 
Length 
Supportive 
Therapies 
Dasatinib 
None 
140mg 
PO before 
nivolumab 
Daily 
 28 
days 
 
None 
Nivolumab 
None 
240mg 
or 
80mg 
IV over 30 
min after 
dasatinib 
Every 2 
weeks* 
None 
*Nivolumab will be administered on C1D8, C1D22, D1 and D15 of all subsequent cycles. 
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Amendment 2: September 2, 2016 
 
16 
 
4.2.1 
Dasatinib  
Dasatinib is dosed at 140mg PO daily on a continuous 28-day cycle. Treatment 
with dasatinib will begin 7 days prior to starting nivolumab. This 7 day period will 
be referred to as “Cycle 0”.On days where both dasatinib and nivolumab are 
administered, dasatinib administration should be immediately before nivolumab 
infusion is begun.  Dasatinib should be taken the same time each day, with or 
without food. If the dose administration time is missed, the dose can be made up 
within the same day as long as the time between subsequent doses is at least 12 
hours. If a day’s dose is missed it should not be made up the next day (i.e. do not 
take more than one dose in any treatment day). If a dose is vomited it should not 
be made up.  Any time the patient has a planned study visit, dasatinib should be 
taken in clinic after labs have been drawn (specifically for PK trough 
determinations) and immediately before nivolumab administration, when 
applicable.  Patients will record dosing details in a diary provided each cycle. 
Dasatinib is commercially available for the treatment of Ph+ ALL and will not be 
supplied by the sponsor. 
 
4.2.2 
Nivolumab  
The starting dose of nivolumab will be 240mg IV over 30 minutes with a dose de-
escalation to 80mg in the event of increased toxicity as described in section 4.3.  
Nivolumab should be administered as an IV infusion on day 8 (± 3 days) and day 
22 (± 3 days) of the first cycle, and day 1 (± 3 days) and day 15 (± 3 days) of all 
subsequent cycles starting with cycle 2. Nivolumab infusion should begin 
immediately after administration of dasatinib whenever possible.  Please refer to 
section 4.4.3 for use of premedications. Missed doses of nivolumab will not be 
made up. Nivolumab will be provided by the clinical trial sponsor. 
 
4.3 
Phase I Dose De-Escalation Scheme 
Following signed informed consent, the dose de-escalation phase will begin in a  3+3 
design with enrollment of 3 patients to cohort 1 to receive dasatinib 140mg PO daily 
continuously in a 28-day cycle. Initially, 3 patients will be enrolled at the starting dose 
(level 1), and monitored until all 3 patients complete the DLT evaluation period (defined 
as cycle 1 or the first 28 days of treatment). Once all 3 patients complete the DLT period 
and toxicity data has been submitted, the Data Monitoring Committee (DMC) will review 
the data and confirm the presence or absence of any DLTs (defined below).  The starting 
dose of nivolumab will be 240mg IV every 2 weeks, which is tolerable as a single agent 
and is within the range that has shown anti-tumor activity in solid tumors, and is the same 
dose and schedule used in global Phase 3 studies that are currently ongoing. If the first 3 
patients do not experience a dose limiting toxicity (DLT), an additional 3 patients will be 
evaluated for DLT. If ≤ 1 of these 6 patients experience a DLT, nivolumab 240mg will be 
determined to be the recommended dose for the expansion cohort, in which case, 10 
additional patients will be enrolled to the dose expansion phase at the dose level 1 dose 
of nivolumab 240mg every 2 weeks. If 2 or more of the initial 6 patients or 5 or more of 
the total of 16 at that dose  experience a DLT the nivolumab dose will be reduced to 
80mg. Three patients will then be entered at the 80mg dose (i.e. the dose level -1 
cohort). If 0 or 1 patient has a DLT at the dose -1 cohort, the cohort will be expanded to 6 
patients. If ≤1 of these 6 patients experience a DLT, nivolumab 80mg will be determined 
to be the recommended dose for the expansion cohort, and 10 additional patients will be 
enrolled to the dose expansion phase at the de-escalated dose of nivolumab, 80mg every 
2 weeks. If 2 or more of the initial 6 patients or 5 or more of the total of 16 patients at this 
dose experience a DLT the protocol will be suspended and reviewed by the primary 
investigator and sponsor to determine if it should be terminated or amended with further 
dose cohorts. Nivolumab will be administered once every 2 weeks, on day 1 and day 15 
of each cycle.   
 
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NU Study Number: NU 15H13 
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Amendment 2: September 2, 2016 
 
17 
Dose De-Escalation Scheme 
Dose Level 
Nivolumab 
Dasatinib 
# of Patients^ 
Level -1 
80mg 
140mg 
3-6 
Level 1* 
240mg 
140 mg 
3-6 
*Starting dose level 
^A minimum of 3 patients will be treated per cohort; a total of 6 patients should be 
treated at whichever dose level is determined to be the MTD. 
 
4.3.1 
Definitions 
 
 
o 
Patients will be evaluated for DLTs during the first 28 days at each dose level 
(DLT period).  
o 
DLT observed during cycle 1 wil be defined as any treatment-related grade 3 
or greater nonhematologic toxicity defined by version 4.03 of the National 
Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) that lasts for > 7 days, with the exception of transaminitis and 
elevated amylase or lipase that resolves to ≤ grade 2 by the next cycle. 
o 
Patients missing 7 or more doses of dasatinib due to toxicity during cycle 1 
will be considered to have experienced a dose limiting toxicity 
o 
The MTD will be defined as the highest dose level at which ≤ 1 DLT occurs in 
6 patients. 
o 
The recommended phase II dose (RP2D) will be determined after careful 
review of all clinical data at the end of the dose de-escalation and expansion 
phase 
 
4.4 
Toxicity Management & Dose Delays/Modifications 
Any patient who receives at least one dose of study therapy will be evaluable for toxicity 
endpoints. Each patient will be assessed for the development of toxicity according to the 
timeframe referenced in the Schedule of Events table. Toxicity will be assessed 
according to version 4.03 of the National Cancer Institute’s Common Terminology Criteria 
for Adverse Events (CTCAE).   
 
General Principles:  
 
Investigators should, whenever possible, determine which medication is causing the 
toxicity and interrupt or dose reduce the offending drug as applicable. If the offending 
medication cannot be established, reduction of dasatinib is recommended.  
 
No dose modifications are permitted for nivolumab. 
 
Dose modifications for dasatinib should be made when dasatinib related toxicity is 
suspected.   
 
Following dose reduction for dasatinib, the dose should not be re-escalated unless 
there is a clear clinical benefit after discussion and agreement by the PI. 
 
When treatment is interrupted due to toxicity, the subject should be re-evaluated in 
approximately 1 week intervals until resolution of the toxicity. 
 
Withdrawal from the study is required for any delay in therapy >28 days during the 
DLT period.  After the DLT period, subjects may be allowed to remain on study 
despite delays in treatment >28 days if approved by the PI and DMC.  
 
4.4.1 
Dasatinib Toxicity Management:  
 
 
Table 4.4.1-1 
 
 
 
 
 
 
Dose Modification Levels for Dasatinib Toxicities 
Starting Dose 
140mg QD 
Level -1 
100mg QD 
Level -2 
80mg QD 
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18 
 
Table 4.4.1-2 
 
Toxicity 
Grade/ 
Description 
Dasatinib 
Hematologic Toxicities 
Thrombocytopeni
a or Neutropenia 
(after achieving 
complete 
hematologic 
remission or 
molecular 
remission) 
Grade 1 or 2 
Maintain dose level. 
 
Grade 3 
 
 
 
 
 
 
Grade 4 
**For both Grade 3 & 4, perform bone marrow biopsy to 
assess for relapsed disease** 
 
Interrupt until ANC ≥ 1.0 x 109/L and platelets ≥ 50 x 109/L. 
Resume dasatinib at original dose if recovery occurs in ≤ 7 
days.  If >7 days, resume dasatinib at dose level -1. For 2nd 
episode, resume at dose level -2 (see Table 4.4.1-1)  
 
Interrupt until ANC ≥ 1.0 x 109/L and platelets ≥ 50 x 109/L. 
Resume dasatinib at dose level -1 if recovery occurs in ≤ 7 
days.  For 2nd episode, reduce to dose level -2.  If >7 days, 
discontinue dasatinib. 
Non-hematologic Toxicities 
Pleural Effusion 
Grade 1 
For patients that are asymptomatic with incidental finding of 
pleural effusion on imaging treatment may be continued 
without dose reduction. 
≥ Grade 2 
Hold both dasatinib and nivolumab until resolved to  ≤ 
grade 1. Dasatinib should then be resumed at dose level -1 
if no prior reduction. If dasatinib has been previously 
reduced may resume at dose level -2. If event has not 
improved within 14 days thoracentesis, should be 
performed for therapeutic and diagnostic purposes. For 2nd 
episode, resume at dose level -2 if dose has not already 
been reduced to this level. If patients are already receiving 
dose level -2 and 2nd episode occurs treatment will be 
discontinued. 
LFTs 
≥ Grade 3 
Interrupt until ≤ Grade 1 or baseline and resume dasatinib 
at same dose level.   
QTcb >500 msec, 
confirmed by 
repeat ECG 
n/a 
Interrupt until ≤ Grade 1.  Eliminate drugs that prolong QTc, 
supplement K, Mg.  Consider monitored re-challenge of 
dasatinib.  NOTE: subject should be discontinued in the 
event of QTcb >530 msec. 
LVEF 
Grade 2 (or decrease 
by >10% from 
baseline), confirmed 
by repeat Echo 
Interrupt until ≤ Grade 1 or baseline and resume dasatinib 
at same dose.  For 2nd episode, reduce one dose level.  If ≥ 
Grade 3, reduce by one dose level. 
Other  
Grade 1 or 2 
Maintain dose level. 
Other 
Grade ≥ 3 
Hold dose until resolved to ≤ Grade 1 or baseline.  Once 
resolved, resume at one dose level reduction. 
 
Unresolved (persisting > 2 weeks) or recurrent event: 
permanently discontinue. 
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19 
4.4.2 
Nivolumab Toxicity Management 
Immunotherapy agents such as nivolumab are associated with AEs that can 
differ in severity and duration compared to other therapeutic classes of 
medications.  Early recognition and management of AEs associated with 
nivolumab can mitigate severe toxicity.  Corticosteroids are the primary therapy 
for drug-related AEs.  Management algorithms have been developed to assist 
investigators in assessing and managing nivolumab associated AEs, which can 
be found in Appendix 1 of this protocol.  The guidance provided in these 
algorithms should not replace the Investigator’s medical judgment. 
Should a female patient become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician immediately. 
 
4.4.3 
Nivolumab Related Infusion Reaction 
Infusion reactions should be graded according to CTCAE v 4.03 allergic 
reaction/hypersensitivity. Treatment of infusion reactions should follow 
institutional standards with recommendations provided below. Reactions may 
manifest as fever, chills, headache, rash, pruritus, arthralgias, hypo-or 
hypertension, bronchospasm or other symptoms. Severe infusion reactions 
require immediate interruption of nivolumab and permanent discontinuation from 
further treatment. Appropriate supportive care including epinephrine, 
corticosteroids, antihistamines, bronchodilators and oxygen should be available 
in the event of an infusion reaction.  Subjects should be premedicated with 
acetaminophen and diphenhydramine for future treatments following an infusion 
reaction.   
 
 
Grade 1 Infusion Reaction: 
o 
Infusion interruption not indicated 
o 
For future infusions, premedication with 50mg diphendydramine and 
325mg-1000mg acetaminophen at least 30 minutes prior to 
nivolumab is recommended  
 
 
Grade 2 Infusion Reaction: 
o 
Stop nivolumab infusion and begin infusion of normal saline 
o 
Treat with diphenhydramine 50mg IV and 325mg-1000mg 
acetaminophen or equivalents 
o 
Corticosteroids may be administered if indicated 
o 
When symptoms resolve, restart the infusion at 50% of the original 
infusion rate. If symptoms reoccur, discontinue remainder of infusion.  
Subsequent infusions should be administered over 2 hours with 
premedication of 50mg diphendydramine and 325mg-1000mg 
acetaminophen at least 30 minutes prior to nivolumab. Up to 25mg of 
SoluCortef or equivalent may also be used.  
 
 
Grade 3 or 4 Infusion Reaction: 
o 
Immediately discontinue nivolumab infusion and begin infusion of 
normal saline 
o 
The following, or equivalents, should be used to manage such 
reactions, per institutional standards: 
o 
 bronchodilators, epinephrine 0.2 to 1mg of a 1:1,000 
solution SQ or 0.1 to 0.25mg of a 1:10,000 solution injected 
IV, diphenhydramine 50mg IV, and methylprednisolone 
125mg IV as needed.  
o 
Nivolumab should be permanently discontinued  
 
 
 
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20 
4.4.4 
Nivolumab Discontinuation 
Nivolumab treatment should be permanently discontinued for the following: 
 
 
Any Grade 2 drug-related uveitis, eye pain, or blurred vision that does not 
respond to topical therapy and does not improve to Grade 1 severity within 
the re-treatment period OR requires systemic treatment 
 
 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the 
following exceptions for laboratory abnormalities, drug-related uveitis, 
pneumonitis, bronchospasm, hypersensitivity reactions, infusion reactions, 
and endocrinopathies: 
- 
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, 
hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation 
- 
Grade  3  drug-related  endocrinopathies  adequately  controlled  with  
only  physiologic hormone replacement do not require discontinuation 
- 
Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except: 
 Grade 3 drug-related thrombocytopenia > 7 days or associated with 
bleeding requires discontinuation 
 
 
Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation: 
- 
AST or ALT > 5-10 x ULN for > 2 weeks 
- 
AST or ALT > 10 xULN 
- 
Total bilirubin > 5 x ULN 
- 
Concurrent AST or ALT > 3 xULN and total bilirubin > 2 x ULN 
 
 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for 
the following events which do not require discontinuation: 
- 
Grade 4 neutropenia  
- 
Grade 4 lymphopenia or leukopenia 
- 
Isolated Grade 4 amylase or lipase abnormalities that are not associated 
with symptoms or clinical manifestations of pancreatitis. The Medical 
Monitor should be consulted for Grade 4 amylase or lipase 
abnormalities. 
- 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not 
associated with clinical sequelae   and   are   corrected   with   
supplementation/appropriate   management   within72 hours of their 
onset 
- 
Grade  4  drug-related  endocrinopathy  adverse  events,  such  as  
adrenal  insufficiency, ACTH 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. 
 
Any event that leads to interruption in dosing lasting > 6 weeks from the previous 
dose requires discontinuation, with the following exceptions: 
 
- 
Dosing interruptions to allow for prolonged steroid tapers to manage drug-
related adverse events are allowed. Prior to re-initiating treatment in a 
subject with a dosing interruptions lasting > 6 weeks from the previous dose, 
the medical monitor must be consulted. Tumor assessments should continue 
as per protocol even if dosing is interrupted. Periodic study visits to assess 
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21 
safety and laboratory studies should also continue every 6 weeks or more 
frequently if clinically indicated during such dosing interruptions. 
 
- 
Dosing interruptions lasting > 6 weeks from the previous dose that occur for 
non-drug- related reasons may be allowed if approved by the medical 
monitor. Prior to re-initiating treatment in a subject with a dosing interruption 
lasting > 6 weeks, the Medical Monitor must be consulted. Tumor 
assessments should continue as per protocol even if dosing is interrupted. 
Periodic study visits to assess safety and laboratory studies should also 
continue every 6 weeks or more frequently if clinically indicated during such 
dosing interrupted. 
- 
Any adverse event, laboratory abnormality, or intercurrent illness which, in 
the judgment of the Investigator, presents a substantial clinical risk to the 
subject with continued nivolumab dosing. 
 
4.5 
Concomitant Medications/Treatments 
4.5.1 
Prohibited Treatments 
4.5.1.1 Medications Associated with Immune Suppression  
Medications associated with suppression of the immune system are 
prohibited while subjects are on active therapy with nivolumab during this 
study. See Appendix 1 for specific management of AE’s requiring such 
medications.  Prohibited medications include:  
 
Chronic systemic corticosteroids >10mg daily prednisone equivalent, 
with the following exceptions: 
o 
Patients may receive steroids for control of leukocyte count 
until cycle 1, day 5. Steroid should then be discontinued to 
avoid mitigating nivolumab efficacy. 
o 
Subjects are permitted the use of topical, ocular, intranasal, 
intra-articular, and inhalational corticosteroids.  
o 
Immunosuppressive doses (prednisone >10mg/day or 
equivalent) and/or physiologic replacement doses are 
permitted in the context of treating adverse events.   
o 
A brief course of corticosteroids for prophylaxis (eg, contrast 
dye allergy) or for treatment of non-autoimmune conditions 
(eg, delayed-type hypersensitivity reaction caused by a 
contact allergen) is permitted.  
 
Concurrent immunosuppressive agents or any immunotherapy 
 
Influenza vaccines containing live virus or other clinically indicated 
vaccinations for infectious diseases (eg, pneumovax, varicella, etc) 
may be permitted but must be discussed with the Principal 
Investigator and QAM  and may require a study drug washout period 
prior to and after administration of the vaccine.   
o 
The inactivated seasonal influenza vaccine is permitted 
without restriction 
o 
 
4.5.1.2 Medications that Prolong the QT Interval 
Medications associated with QT interval prolongation that are prohibited 
while subjects are on active therapy with dasatinib alone or dasatinib 
with nivolumab during this study include:  
o 
quinidine, procainamide, disopyramide 
o 
amiodarone, sotalol, ibutilide, dofetilide 
o 
erythromycins, clarithromycin 
o 
chlorpromazine, haloperidol, mesoridazine, thioridazine, 
pimozide 
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22 
o 
cisapride, bepridil, droperidol, methadone, arsenic, 
chloroquine, domperidone, halofantrine, levomethadyl, 
pentamidine, sparfloxacin, lidoflazine 
 
Ideally, subjects enrolled in this study should not begin taking other 
medications known to prolong the QT interval.  Further information on 
medications known to prolong the QT interval can be found at the 
following website: 
https://www.crediblemeds.org/pdftemp/pdf/CompositeList.pdf.  If in the 
opinion of the investigator, a potential QT interval prolonging medication 
(other than those listed above which are explicitly prohibited) is vital to a 
subject’s care, then additional ECGs should be completed at the 
investigator’s discretion. 
 
4.5.2 
Medications to Use with Caution 
 
4.5.2.1 Use of Growth Factors  
Growth factors such as G-CSF are not permitted during the first cycle (28 
days), as these may mask potential DLTs.  G-CSF may be used outside 
of this period (including pre-treatment) at the treating physician’s 
discretion if there is concern for active infection or the patient has 
experienced infectious complications during prior cycles.  
 
 
4.5.2.2 H2-Agonists, PPIs and Antacids 
Histamine (H2) antagonists (eg, famotidine), proton pump inhibitors (eg, 
omeprazole), and aluminum hydroxide/magnesium hydroxide (eg, 
Maalox) may reduce the exposure to dasatinib.  H2 antagonists and 
proton pump inhibitors are not recommended (but not prohibited) and 
aluminum hydroxide/magnesium hydroxide products should be 
administered at least 2 hours before or after dasatinib.  
 
 
4.5.2.3 Antiplatelet Agents and Anticoagulants  
Dasatinib may increase the likelihood of bleeding.  Subjects undergoing 
surgical procedures, including dental procedures, should hold dasatinib 
24 hours prior and 24 hours after the procedure.  Caution should be used 
with concomitant medications that inhibit platelet function.  
Anticoagulants should also be avoided in the setting of Grade 3 or 4 
thrombocytopenia while subjects are on active dasatinib treatment.  
 
 
4.5.2.4 Agents Affecting CYP3A4 
. 
Strong and moderately potent inhibitors of CYP3A4 should be 
avoided while subjects are on active dasatinib treatment as they 
may increase dasatinib concentrations.  CYP3A4 inducers may 
decrease the concentration of dasatinib and should be used with 
caution as well.  Alternative agents with less enzyme-inducing or 
inhibiting potential should be considered as indicated.  See 
Appendix 2 for a list of agents affecting the CYP enzyme system. If 
use of an azole antifungal is necessary, it is recommended that an 
agent with the least inhibitory effect on CYP3A4 be selected if 
possible. The following azoles appear in order of strength of 
inhibition of CYP3A4 (high to low): voriconazole, itraconazole, 
posaconazole, and fluconazole. Fluconazole at doses of 200 mg or 
less is not thought to be a significant inhibitor of CYP3A4.    
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23 
 
4.5.3 
Permitted Concomitant Medications/Treatments 
 
4.5.3.1 Supportive Care Management 
 The use of hydroxyurea is permitted to keep the total WBC 
<50,000/mm3 with no maximal allowed dosage.   
 Allopurinol may also be used in subjects with an elevated WBC in 
order to prevent or treat elevated uric acid.   
 The use of growth factor support is prohibited during the first cycle (28 
days), but acceptable outside this time period.  
 
 
4.5.3.2  Supplementation and Prophylaxis 
 Due to expected osteoclast inhibition with dasatinib, calcium 
supplementation is recommended to maintain serum calcium within 
the institutional normal range during dasatinib treatment.  Vitamin D 
supplementation may also be appropriate for persistent 
hypocalcemia.   
 Infectious complications are a known risk with dasatinib.  
Consideration should be given to the use of appropriate prophylactic 
therapy for subjects at high risk of infection.  
 
4.6 
Other Modalities or Procedures 
Response will be assessed via peripheral blood and bone marrow biopsies on day 1 of 
each cycle beginning with cycle 2. If a patient has a documented complete hematologic 
response and is MRD negative (molecular remission) by PCR for BCR-ABL, subsequent 
bone marrow biopsies may be done based on physician’s discretion. These patients will 
be monitored by peripheral blood PCR for BCR-ABL on day 1 of each cycle after 
documentation of complete hematologic response and MRD negativity. Subjects who 
achieve complete hematologic remission and/or molecular remission will be considered 
for eligibility for allogeneic hematopoietic stem cell transplant (HSCT), as per current 
standard of care for all patients with Ph + ALL.  Timing of HSCT will depend on donor 
availability and medical stability of the subject, but will be pursued as soon as able upon 
confirmation of remission. Patients may continue to receive treatment on study until they 
proceed to HSCT. 
 
4.7 
Duration of Therapy 
Patients may continue to receive treatment until any of the following occur:  
 
Disease progression  
 
Development of an inter-current illness that prevents further administration of 
treatment 
 
Unacceptable adverse event(s) 
 
Patient decides to withdraw from either study treatment or the whole study 
 
The treating investigator determines that the patient should be taken off treatment for 
any reason (i.e. changes in condition, inability to comply with study treatment or 
procedures) 
 
4.8 
Duration of Follow Up 
Once patients finish treatment, they should return for monthly follow-up visits for up to 
one year.  All patients should have the first end of treatment visit 30 days +/- 7 days after 
the last dose of nivolumab, or prior to starting another therapy, whichever comes first. 
Patients removed from treatment for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event.  Date of disease progression or death 
should be documented. 
 
 
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4.9 
Removal of Subjects from Study Treatment and/or Study as a Whole 
Patients can be taken off the study treatment and/or study as a whole at any time at their 
own request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation must be clearly 
documented on the appropriate eCRF and may include: 
 
Patient voluntarily withdraws from treatment (follow-up permitted) 
 
Patient withdraws consent (no follow-up permitted) 
 
Patient is unable to comply with protocol requirements 
 
Patient demonstrates disease progression  
 
Patient experiences unacceptable toxicity  
 
QTc value becomes >530 msec  
 
Treating physician determines that continuation on the study would not be in the 
patient’s best interest 
 
Patient becomes pregnant  
 
Patient develops a second malignancy that requires treatment which would interfere 
with this study 
 
Patient becomes lost to follow-up (LTF)  
Once off treatment, patients will be followed monthly according to table 5.0 for one year 
or until death, whichever occurs first. Patients who progress or start new treatment will 
continue follow-up survival. 
4.10 
Patient Replacement 
Three patients within a dose level must be observed for one cycle (28 days) before 
accrual to the next dose level or expansion cohort may begin. If a patient is withdrawn 
from the study prior to completing 22 days of dasatinib and 2 doses of nivolumab therapy 
without experiencing a DLT prior to withdrawal, an additional patient may be added to 
that dose level with approval from the DMC, however these patients will still count 
towards overall accrual. Any patient who has received at least one dose of either study 
drug may not be replaced for overall accrual. 
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25 
5.0 
STUDY PROCEDURES 
 
Table 5.0  
  
Screening 
Cycle 1 (±3 days) 
Cycle 2+  
(±3 days)  
End of  
Treatment3 
Follow up16 
Procedure 
Day -21 to 
-11 
D1 
2 
8 
15 
22 
D12 
D15 
Signed ICF 
X 
  
  
  
  
  
  
 
  
  
Medical history 
X 
  
  
  
  
  
  
 
  
  
Physical exam4 
X 
X 
  
X 
X  
X  
X 
 
X 
 X 
ECOG PS 
X 
X 
  
X 
 X 
X  
X 
 
X 
  
12-lead ECG5 
X 
  
X  
  
  
 
X 
  
Chest x-ray (or 
chest CT) 
X 
 
  
  
  
  
  
 
  
  
CBC with 
differential6 
X1 
X 
  
X 
X  
X  
X 
X 
X 
X  
Chemistry7 
X1 
X 
  
X 
X  
X  
X 
X 
X 
Bone marrow 
assessment 
X8 
  
  
  
  
  
X9 
 
X9 
  
TSH 
X 
X  
  
  
  
  
X  
 
  
  
Correlative & PK 
blood samples10 
  
X 
X  
X 
X  
 X 
  
 
  
  
Adverse 
events11 
 X 
X 
  
X 
X  
 X 
X 
 
X 
X11  
Concomitant 
medications 
X 
X 
  
X 
X  
X 
X 
 
X 
  
Pregnancy 
Serum or Urine 
test 
X1 
 X1 
  
  
  
  
  
 
  
  
LVEF 12 
X 
  
  
  
  
  
 
 
 
  
Dasatinib 
administration13 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Nivolumab 
infusion14 
 
X 
 
X 
X 
X 
X 
X 
 
 
Molecular 
analysis15 
X 
  
  
  
  
  
X 
 
  
  
Mutation 
analysis for 
T315I17 
 X 
  
  
  
  
  
  
 
X 
  
Survival Status 
 
 
 
 
 
 
 
 
 
X 
 
Table 5.0 Footnotes: 
1. Protocol-specified screening procedures that are performed as part of standard of care and within 21 
days of Day 1 of Cycle 1 may be used for screening purposes.  Clinical laboratory studies and 
pregnancy test must be performed within the 7-day period before registration. A pregnancy test 
should also be confirmed as negative within 24 hours of starting treatment. 
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26 
2. If the study treatment is well tolerated and the patient experiences no leukemic progression, clinic 
visits will be scheduled every 28 days (+/- 3 days) at beginning of each cycle until disease 
progression or unacceptable toxicity. 
3. The end-of-study visit should be scheduled 30 days (±7 days) within the 28-day period after the last 
dose of study drug and before starting any new anti-neoplastic therapy. 
4. Includes vitals, weight, and height (baseline only). A complete physical examination will be performed 
at screening.  All subsequent physical examinations will be disease-specific. 
5. ECG is performed after the patient has been in a supine position for at least 5 minutes.  It is 
performed at screening, C1D15 (pre-dose), and at the end-of-study visit. Additional ECGs may be 
performed as clinically indicated.  
6. A CBC with a differential count will be performed every 7 days until remission, than at every cycle, 
and at the end of the study. 
7. Serum chemistry studies will be performed at each visit. Chemistries will include, complete metabolic 
panel with transaminases and total bilirubin. The CMP should include: Glucose, BUN, Calcium, Total 
Protein, Albumin, ALT, AST, GFR, Sodium, Potassium, Chloride, Carbon Dioxide, Alk Phos, 
Creatinine, Magnesium, and total bilirubin. 
8. Bone marrow aspiration and biopsy with evaluation of morphology, blast percentage, cytogenetics, 
and flow cytometry is required for all patients at screening. A T315I Mutation analysis is required at 
screening and the End of Treatment visit. An aspirate sample must be preserved at every time 
point for correlative studies (see section 9.0 for details).  
9. Bone marrow aspiration and biopsy should be performed within 7 days of the beginning of every 
cycle, starting with Cycle 2.  
After a molecular remission has been documented, a follow-up bone marrow assessment may be 
performed as clinically indicated.  Bone marrow assessment must include morphologic assessment 
and flow cytometry, PCR for BCR-ABL, and cytogenetics per institutional standard to evaluate for 
MRD.  
When obtaining bone marrow aspirates, samples must be preserved for correlative studies (see 
section 9.0 for details).  
10. Blood samples for PK analysis will be collected on Cycle 1, day 2 (24 hours after Day 1 dasatinib 
dosing ± 2 hours) to assess dasatinib single agent levels. Both dasatinib and nivolumab levels will be 
assessed pre-dose on Cycle 1 Day 8, 15, & 22. Blood will be collected for analysis of T cell subsets 
before dosing on Cycle 1 days 1, 2, 8, 15, & 22. See section 9.0 for details. 
11. AEs will be monitored from the time of consent until 30 days after completing study treatment (100 
days for SAE’s) throughout the study via safety-related assessments, observation, and patient 
reports. 
12. Either ECHO or MUGA can be performed at investigator’s discretion.  However, the same imaging 
platform should be used throughout the study if repeat assessment is clinically indicated (i.e 
evaluation for pericardial effusion). 
13. Dasatinib will follow continuous dosing at 140mg PO QD starting at Cycle 1 Day 1 until disease 
progression or unacceptable toxicity. Any time a patient has a scheduled study visit, he or she should 
take their dose of dasatinib in clinic, after labs and immediately before the nivolumab infusion, if 
applicable. 
14. Nivolumab will be given IV over 30 minutes on C1D8, C1D22, and Days 1 & 15 of all subsequent 
cycles (+/- 3 days) until disease progression or unacceptable toxicity. The starting dose will be 
240mg, with possible de-escalation to 80mg. 
15. If patient achieves complete hematologic remission they will be assessed for molecular remission on 
bone marrow. After achieving a molecular remission on bone marrow aspirate, patients should then 
be followed with peripheral blood BCR-ABL PCR on day 1 of each cycle. 
16. Patients will be followed monthly for up to one year after treatment discontinuation. 
17.  T315I Mutation testing will be performed as part of the bone marrow procedure.  
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6.0 
ENDPOINT ASSESSMENT 
 
6.1 
Primary Endpoint 
The primary endpoint is the incidence of dose-limiting toxicity (DLT), as defined in 
protocol section 4.3.1, as assessed by the Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03. Toxicity will be assessed weekly during cycle 1 of 
treatment. All patients that receive at least one dose of nivolumab will be considered 
evaluable for this endpoint. 
 
6.2 
Secondary and Exploratory Endpoints 
The secondary endpoints are the safety profile of the combination treatment, the 
pharmacokinetics of nivolumab and dasatinib, PD1 expression levels and saturation in 
the peripheral blood and bone marrow before and after treatment, as well as T cell levels 
and activation in the peripheral blood after treatment as defined in section 9.0 of the 
protocol.  
The number, frequency, and severity of adverse events (as defined by the NCI CTCAE 
v4.03) will be recorded from the time of consent until 30 days after treatment (100 days 
for SAE’s). 
The pharmacokinetic profile of dasatinib and nivolumab will be studied by measuring the 
serum level of dasatinib 24 hours after the start of cycle 1, and both dasatinib and 
nivolumab serum levels on treatment days 8, 15, and 22 prior to treatment during cycle 1.    
In order to address the effects of nivolumab on dasatinib’s ability to induce T-cell 
expansion and activation, lymphocyte subpopulations, specifically T-cells, will be 
quantitatively measured on cycle 1 day 1, 8, 15, and 22.  Bone marrow samples that are 
required for response assessment will also be used to characterize T-cell receptor clonal 
expansion/diversity.  
Patients that receive at least one cycle of treatment will be evaluable for these endpoints. 
 
Exploratory endpoints: 
 
The rate of complete hematologic remission and molecular remission after 3 
cycles of nivolumab and dasatinib as defined in section 6.2.1 
 
Duration of remission as defined in section 6.2.4 
 
Progression free survival as defined in section 6.2.4 
 
Overall survival as defined in section 6.2.4 
 
30-day mortality rate as defined in section 6.2.4 
 
The PFS and OS for patients that go on to HSCT vs those that do not receive 
further therapy after completing nivolumab and dasatinib. 
 
Monitoring for the presence of resistance mutations at the time of disease 
progression. Bone marrow samples at the end of treatment visit will be sent for 
molecular analysis to evaluate for mutations that increase resistance to tyrosine 
kinase therapies. 
6.2.1 Response Definitions   
Response to treatment will be defined per NCCN guidelines version 2.2015 as 
outlined below: 
 
Complete Response (CR) 
o 
No circulating blasts or extramedullary disease 
o 
No lymphadenopathy, splenomegaly, skin/gum infiltration / testicular 
mass / CNS involvement 
o 
Trilineage hematopoiesis (TLH) and <5% blasts 
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28 
o 
Absolute neutrophil count (ANC) > 1,000/uL 
o 
Platelets > 100,000/uL 
o 
No recurrence for 4 weeks 
 
CR with incomplete blood count recovery (CRi)  
o 
Recovery of platelets but <100,000 or ANC is <1,000uL 
 
Molecular remission:  
 
Real time quantitative polymerase chain reaction (RQ-PCR) negative for the 
BCR-ABL1 fusion gene 
 
Overall response rate (ORR) = CR + CRi 
 
Refractory Disease:  
Failure to achieve CR at the end of induction 
 
Progressive Disease (PD):  
Increase of at least 25% in the absolute number or circulating or bone 
marrow blasts or development of extramedullary disease 
 
Relapsed Disease: Reappearance of blasts in the blood or bone marrow 
(>5%) or in any extramedullary site after a CR 
 
6.2.2 
Central Nervous System (CNS) Disease 
6.2.2.1  Classification of CNS status 
 CNS-1: No lymphoblasts in CSF regardless of WBC count. 
 CNS-2: WBC <5/mcL in CSF with presence of lymphoblasts. 
 CNS-3: WBC ≥5/mcL in CSF with presence of lymphoblasts. 
 
If the patient has leukemic cells in the peripheral blood and the LP is 
traumatic and WBC ≥5/mcL in CSF with blasts, then compare the CSF 
WBC/RBC ratio to the blood WBC/RBC ratio. If the CSF ratio is at least 
two-fold greater than the blood ratio, then the classification is CNS-3; if 
not, then it is CNS-2 
 
6.2.2.2  Response Criteria for CNS Disease 
 CNS remission: Achievement of CNS-1 status in a patient with CNS-2 
or CNS-3 status at diagnosis. 
 CNS relapse: New development of CNS-3 status or clinical signs of 
CNS leukemia such as facial nerve palsy, brain/eye involvement, or 
hypothalamic syndrome. 
 
6.2.3 Response Criteria for Mediastinal Disease 
 CR: Complete resolution of mediastinal enlargement by CT. 
 CR Unconfirmed (CRu): Residual mediastinal enlargement that has regressed 
by >75% in the sum of the product of the greatest perpendicular diameters 
(SPD). 
 PR: >50% decrease in the SPD of the mediastinal enlargement. 
 PD: >25% increase in the SPD of the mediastinal enlargement. 
 No Response (NR): Failure to qualify for PR or PD. 
 Relapse: Recurrence of mediastinal enlargement after achieving CR or CRu. 
 
 
6.2.4 Survival outcomes definitions: 
 
Duration of remission (DOR) 
Duration of remission is defined as the time from achieving CR until the time 
of disease relapse as defined in section 6.2.1 
 
Overall Survival (OS) 
OS is defined as the time from the initiation of study treatment until death 
from any cause. 
 
Progression-Free Survival (PFS) 
PFS is defined as the time from the initiation of study treatment until the 
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time of disease progression or relapse as defined in section 6.2.1. 
 
30 day mortality rate:  
 
Number and percentage of patients that die within the first 30 days of 
initiating treatment. 
 
7.0 
ADVERSE EVENTS 
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of the 
Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please refer to 
Appendices for additional information). The level of risk attributed to this study requires High 
Intensity Monitoring, as outlined in the DSMP. In addition, the study will abide by all safety 
reporting regulations, as set forth in the Code of Federal Regulations.   
 
7.1 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial (see Section 5 for timepoints). In 
addition, certain adverse events must be reported in an expedited manner to allow for 
optimal monitoring and patient safety and care.  
 
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be followed until:  
 
the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
 
any abnormal laboratory values have returned to baseline;  
 
there is a satisfactory explanation other than the study drug for the changes 
observed; or 
 
death 
 
7.2 
Definitions & Descriptions 
7.2.1 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention.  
 
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms. In general, AEs are not procedures or measurements, 
but should reflect the reason for the procedure or the diagnosis based on the 
abnormal measurement. Preexisting conditions that worsen in severity or 
frequency during the study should also be recorded (a preexisting condition that 
does not worsen is not an AE). Further, a procedure or surgery is not an AE; 
rather, the event leading to the procedure or surgery is considered an AE. 
 
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the AE whenever possible.  However, a complete 
description of the signs, symptoms and investigations which led to the diagnosis 
should be provided. For example, if clinically significant elevations of liver 
function tests are known to be secondary to hepatitis, “hepatitis” and not 
“elevated liver function tests” should be recorded. If the cause is not known, the 
abnormal test or finding should be recorded as an AE, using appropriate medical 
terminology (e/g/ thrombocytopenia, peripheral edema, QT prolongation). 
 
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7.2.2 
Severity of AEs 
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The 
CTCAE v4 is available at http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
 
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities. 
 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
 
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
 
Life-threatening (grade 4): the patient was at risk of death at the time of the 
event. 
 
Fatal (grade 5): the event caused death. 
 
7.2.3 
Serious Adverse Events (SAEs) 
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 30 100 days after the last administration of study drug, must be 
reported upon discovery or occurrence. 
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that: 
 
Results in death. 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
 
Is life-threatening. 
The patient was at risk of death at the time of the event; it does not refer to 
an event that hypothetically might have caused death if it were more severe. 
 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
 
Results in persistent or significant disability or incapacity. 
 
Is a congenital anomaly/birth defect. 
 
Is an important medical event. 
Any event that does not meet the above criteria, but that in the judgment of 
the investigator jeopardizes the patient, may be considered for reporting as a 
serious adverse event. The event may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition of “Serious 
Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency. 
 
7.2.4 
Unanticipated Problems Involving Risks to Subject or Others 
A UPIRSO is a type of SAE that includes events that meet ALL of the following 
criteria: 
 
Is unanticipated in terms of nature, severity, or frequency 
 
Places the research subject or others at a different or greater risk of harm 
 
Is deemed to be at least possibly related to participation in the study.    
 
 
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7.3 
Adverse Event Reporting 
7.3.1 
Routine Reporting 
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF according to the time intervals noted in the appendices. Routine AEs will 
be reviewed by the Data Monitoring Committee (DMC) according to the study’s 
phase and risk level, as outlined in the DSMP.  
 
7.3.2 
Determining if Expedited Reporting is Required 
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must 
also be reported accordingly. 
 
 
1) 
Identify the type of adverse event using the NCI CTCAE v 4.0. 
 
 
2) 
Grade the adverse event using the NCI CTCAE v 4.0. 
 
 
3) 
Determine whether the adverse event is related to the protocol therapy.   
 
 
 
Attribution categories are as follows: 
 
Definite: AE is clearly related to the study treatment. 
 
Probable: AE is likely related to the study treatment. 
 
Possible: AE may be related to the study treatment. 
 
Unlikely: AE not likely to be related to the study treatment. 
 
Unrelated: AE is clearly NOT related to the study treatment. 
 
 
4) 
Determine the prior experience of the adverse event. 
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in: 
 
the current protocol 
 
the drug package insert 
 
the current Investigator’s Brochure 
 
7.3.3 
Expedited Reporting of SAEs/Other Events 
7.3.3.1 Reporting to the Northwestern University QAM/DMC 
All SAEs must be reported to the assigned QAM within 24 hours of 
becoming aware of the event. Completion of the NU CRO SAE Form is 
required.  NU CRO SAE forms should be sent to 
croqualityassurance@northwestern.edu.  If drug company reporting is 
required, Both reports can be emailed simultaneously (see section 
7.3.3.4 for details on BMS reporting). 
 
The completed form should assess whether or not the event qualifies as 
a UPIRSO. The report should also include: 
 
Protocol description and number(s) 
 
The patient’s identification number 
 
A description of the event, severity, treatment, and outcome (if 
known) 
 
Supportive laboratory results and diagnostics 
 
The hospital discharge summary (if available/applicable) 
 
All SAEs will be reported to, and reviewed by, the DMC at their next 
meeting. 
 
 
 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
32 
 
 
7.3.3.2 Reporting to the Northwestern University IRB 
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow 
their local IRB guidelines for reporting to their local IRBs. 
 
Any death of an NU subject that is unanticipated in nature and at 
least possibly related to study participation will be promptly reported 
to the NU IRB within 24 hours of notification.  
 
Any death of an NU subject that is actively on study treatment 
(regardless of whether or not the event is possibly related to study 
treatment) 
 
Any death of a non-NU subject that is unanticipated and at least 
possibly related and any other UPIRSOs will be reported to the NU 
IRB within 10 working days of notification. 
 
All other deaths of NU subjects not previously reported, other non-
NU subject deaths that were unanticipated and unrelated, and any 
other SAEs that were not previously reported as UPIRSOs will be 
reported to the NU IRB at the time of annual continuing review. 
 
 
7.3.3.3 Reporting to the FDA  
The FDA will be notified within 7 calendar days of any SAE that is 
associated with study treatment, is unexpected, and is fatal or life-
threatening. 
 
The FDA will be notified within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not 
fatal or life-threatening. This includes any previous SAEs that were not 
initially deemed reportable, but are later determined to meet the criteria 
for reporting (i.e. by the DMC). 
 
All other SAEs will be reported on an annual basis as part of the annual 
FDA report. 
 
 
 
7.3.3.4 Reporting to Bristol Meyers SquibbBMS (completed by study 
coordinator) 
All SAE reports (including death by any cause), regardless of attribution 
and any other relevant safety information will be reported within 24 hours 
to BMS Global Safety (using the NU CRO SAE Form and referencing the 
BMS study number, CA 209-613). The assigned study coordinator will 
facilitate all reporting to BMS.Global Safety and email QA a copy of the 
report upon completion. BMS Global Safety can be notified at: 
 
 
 
 
Email Address:  Worldwide.Safety@BMS.com 
 
 
 
 
Facsimile Number:  609-818-3804 
 
8.0 
DRUG INFORMATION 
8.1 
Dasatinib  
 
8.1.1 
Other Name 
 
 
Sprycel   
 
8.1.2 
Classification and Mode of Action 
Dasatinib is a multi-kinase inhibitor which is known to inhibit BCR-ABL, SRC 
family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFR-beta kinases.  In 
vitro, desatinib has been active in leukemic cell lines, including variants of 
imatinib sensitive and resistant disease.  Dasatinib has been shown to inhibit the 
growth of chronic myeloid leukemia and acute lymphoblastic leukemia cells 
which over-express BCR-ABL.  
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
33 
 
 
8.1.3 
Storage and stability 
Dasatinib will be dispensed in white to off-white, biconvex, round, film-coated 
tablets with “BMS” debossed on one side and “524” on the other side.  Dasatinib 
should be stored at 20° to 25°C (68° to 77°F).  Excursions permitted between 
15°-30°C (59°-86°F).       
 
8.1.4 
Protocol dose specifics 
Dasatinib will be given at the standard dose of 140mg PO daily. 
 
8.1.5 
Preparation 
No preparation is required given oral administration. 
 
8.1.6 
Route of administration for this study 
Dasatinib should be given orally once daily, at approximately the same time each 
day, with or without food.  
 
8.1.7 
Incompatibilities 
Use of concomitant strong CYP3A4 inducers may decrease dasatinib plasma 
concentrations and should be avoided.  CYP3A4 inhibitors may increase 
dasatinib plasma concentrations.  Selection of an alternate concomitant 
medication, if possible, is recommended. If dasatinib must be administered with a 
strong CYP3A4 inhibitor, a dose decrease should be considered. 
 
8.1.8 
Availability & Supply  
Dasatinib is commercially available and will not be supplied by the study.  
 
8.1.9 
Side effects 
Most Frequent Adverse Events (>10%): Myelosuppression, fluid retention events 
(pleural effusion, superficial localized edema, generalized edema), diarrhea, 
headache, musculoskeletal pain and rash. 
 
 
 
Serious Adverse Events: pleural effusion (2%), hemorrhage (2%), congestive 
heart failure (1%), and pyrexia (1%).   
 
8.1.10 Return and Retention of Study Drug 
 
 
Not applicable 
 
8.2 
Nivolumab 
 
8.2.1 
Other Name 
 
 
Opdivo  
 
 
8.2.2 
Classification and Mode of Action 
Nivolumab is a human monoclonal antibody that blocks the interaction of PD-1 
with its ligands, PD-L1 and PD-L2.  By inhibiting the binding of PD-1 with its 
ligands, nivolumab blocks the inhibition of T-cell proliferation and cytokine 
production, therefore allowing for active T-cell immune surveillance of tumors. 
 
8.2.3 
Storage and stability 
Nivolumab is available as a 100 mg/10 mL single-use vial and should be stored 
under refrigeration at 2ºC to 8ºC (36ºF-46ºF) in the original package until time of 
use in order to protect from light.  Nivolumab should not be frozen or shaken.  
After preparation, the nivolumab infusion can be stored at room temperature for 
no more than 4 hours (including time for administration), or under refrigeration at 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
34 
2ºC to 8ºC (36ºF-46ºF) for no more than 24 hours from the time of infusion 
preparation. 
 
8.2.4 
Protocol dose specifics 
The initial starting dose of nivolumab will be the standard dose of 240mg IV every 
2 weeks with a dose de-escalation dose of 80mg IV every 2 weeks in the event 
of unacceptable toxicity.  
 
 
8.2.5 
Preparation 
Dilute nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP, to prepare an infusion with a final concentration ranging 
from 1 mg/mL to 10 mg/mL.  Mix diluted solution by gentle inversion.   
 
 
 
8.2.6 
Route of administration for this study 
Nivolumab will be given as an infusion over 30 minutes through an intravenous 
line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size 
of 0.2 micrometer to 1.2 micrometer).  The intravenous line should be flushed at 
the end of the infusion.  
 
8.2.7 
Incompatibilities 
 
 
Other drugs should not be co administered through the same intravenous line. 
 
8.2.8 
Availability & Supply  
Nivolumab is commercially available, although not FDA approved for Ph+ ALL, 
and therefore will be supplied by the sponsor.  The drug should be shipped to 
each site directly.  
 
Drug can be ordered using the Drug Request Form provided by BMS. The form 
is provided as a separate document and should be submitted electronically at 
least 7 business days before the expected delivery date. Contact and submission 
details can be found directly on the Drug Request Form. Deliveries will be made 
Tuesday through Friday. 
 
8.2.9 
Side effects 
Most Frequent Adverse Events (≥20%): rash, fatigue, dyspnea, musculoskeletal 
pain, decreased appetite, cough, nausea, and constipation. 
 
Less Likely (≤20%): Hyperthyroidism; Injection site reaction; Lymphocyte count 
decreased; Platelet count decreased; Skin hypopigmentation 
 
Rare but Serious (<3%): Cardiac disorders - Other (cardiomyopathy); Cytokine 
release syndrome; Encephalopathy; Eye disorders - Other (Graves 
ophthalmopathy); Facial nerve disorder; Gastritis; Immune system disorders - 
Other (sarcoid granuloma); Musculoskeletal and connective tissue disorder - 
Other (polymyositis); Musculoskeletal and connective tissue disorder - Other 
(rhabdomyolysis); Myocarditis; Nervous system disorders - Other (demyelination 
myasthenic syndrome); Nervous system disorders - Other (myasthenia gravis); 
Peripheral sensory neuropathy; Respiratory, thoracic and mediastinal disorders - 
Other (bronchiolitis obliterans with organizing pneumonia) 
 
8.2.10 Return and Retention of Study Drug 
At the completion of all patients’ treatment, all unused drugs, partially used, or 
empty containers must be destroyed at the site according to the institution’s 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
35 
policy for drug destruction. Please maintain appropriate records of the disposal, 
including dates and quantities. 
 
 
9.0 
CORRELATIVES/SPECIAL STUDIES 
The pharmacokinetic profile of dasatinib and nivolumab will be studied by measuring the serum 
level of dasatinib 24 hours after the start of cycle 1, and both dasatinib and nivolumab serum 
levels on treatment days 8, 15, and 22 prior to treatment during cycle 1.   In order to address the 
effects of nivolumab on dasatinib’s ability to induce T-cell expansion and activation, lymphocyte 
subpopulations, specifically T-cells, will be quantitatively measured on cycle 1 day 1, 2, 8, 15, and 
22.  Bone marrow aspirate samples that are required for response assessment will also be used 
to characterize T-cell receptor clonal expansion/diversity. Studies will be performed at 
Northwestern University in the core facilities. Samples will be collected and stored with PathCore. 
Refer to separate lab manual for additional details. 
 
9.1 
Sample Collection Guidelines 
Peripheral blood will be collected to quantitatively measure T-cell subsets and serum 
concentrations of dasatinib and nivolumab on cycle 1, day 1, 2, 8, 15, and 22, prior to 
receiving treatment dose.  6 mL (approximately 1 tablespoon) of blood will be collected 
for each sample in heparin coated collection tubes (i.e. sodium heparin green top tubes).  
Bone marrow aspirate collected prior to treatment, during response assessment and at 
the time of treatment failure or end of treatment will be used to characterize T-cell 
receptor clonal expansion/diversity by PCR and sequencing. 5 mL (approximately 1 
tablespoon) of aspirate will be collected for each sample in heparin coated collection 
tubes (i.e. sodium heparin green top tubes).  
 
9.2 
Assay Methodology 
 
Peripheral blood mononuclear cells will be isolated by an adapted Ficoll density 
gradient separation.  The cells will then be stained with fluorescence-labeled 
antibodies against characteristic cell markers as follows:  
o 
T cells: 𝛾δTCR, CD3, CD4, CD8, CD56  
o 
T-cell activation: CD69, CD25, HLA-DR; CD8+  
o 
T-cell subsets: CD45RA, CD28, CD197  
o 
CD4+ regulatory T cells: CD25, Foxp3 
 
Cells will also be assessed for PD-1 receptor occupancy by the antibody on 
circulating CD3+ T-cells by flow cytometry. 
 
These studies will be performed by Northwestern University Flow Cytometry and 
Genomics Core Facilities and analyzed in the Department of Pathology.  
 
9.3 
Specimen Banking 
Unused samples will be stored for future unspecified use. Specimens will be stored 
indefinitely in the Northwestern University Biorepository until exhausted or a patient 
withdraws his or her consent for sample storage.  
 
10.0 STATISTICAL CONSIDERATIONS 
 
10.1 
Study Design/Study Endpoints 
This is a phase 1b open-label, multi-center prospective study which uses a modified 3+3 
design (i.e. 3+3 followed by a 10 patient expansion cohort) to evaluate the safety and 
tolerability of nivolumab when given in combination with dasatinib in adults with relapsed 
or refractory Ph+ ALL.  The primary endpoint will be dose-limiting toxicity, as defined by 
the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.  The 
secondary endpoints are the clinical response defined as complete remission rate and/or 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
36 
molecular remission after 3 cycles of nivolumab and dasatinib, the PD1 expression levels 
in the peripheral blood and bone marrow before and after treatment, and the T-cell levels 
and activation in the peripheral blood after treatment.  Exploratory endpoints include the 
overall survival, progression free survival and duration of remission, as well as a 
comparison of the overall survival between patients who receive a hematopoietic stem 
cell transplant and those who receive no further therapy following remission, and the 
presence of resistance mutations at the time of disease progression.  
 
10.2 
Sample Size and Accrual 
The total number of patients will depend on toxicities observed during the dose de-
escalation phase, although a maximum of 12 patients is possible.  The dose expansion 
phase will then enroll up to a total of 10 patients for an estimated total of 16-22 patients, 
with the justification of improving efficacy and toxicity estimates.  While it is theoretically 
possible to expand each dose with 10 patients so that the possible maximum sample size 
is 32, it is expected that the dose expansion will occur only at the MTD so that the total 
expected sample size is 16-22 patients.  Sample size is based on accrual feasibility, not 
on statistical power.  The expected accrual rate will be 1-2 patients per month across 3-5 
sites with the goal of achieving 100% accrual by 2 years.  The MTD is that dose at which 
fewer than 4 DLTs are seen in the total number of 16 patients observed at that dose.  If 
the true DLT rate is 13%, then there is less than a 5% chance that 4 or fewer DLTs out of 
16 will be observed. 
 
10.3 
Data Analyses Plans 
Toxicity profiles will be presented by rate of overall toxicity with rates of ≥ grade 3 
toxicities analyzed separately and combined.  Adverse events will be summarized and 
accompanied by 95% confidence intervals using binomial distribution.  Patient 
characteristics will be summarized using mean, median, and standard deviation for 
continuous variables, and tables for discrete variables.  We will descriptively report 
observed secondary and exploratory endpoints, including rates of complete remission, 
duration of remission, progression free survival, overall survival, and the outcomes for 
patients that go on to receive hematopoietic stem cell transplant versus those who 
receive no further therapy after achieving remission.  Rates will be estimated using exact 
binomial probabilities and 95% confidence intervals.  Molecular remission will be 
estimated using an exact binomial confidence interval.  Progression free survival and 
overall survival will be estimated using Kaplan-Meier curves.  T-celllevels after treatment 
will be assessed using the paired t-test or the signed rank test.  Levels of PD1 expression 
will be compared between responders versus non-responders using a Wilcoxon rank sum 
test.  Basic pharmacokinetic parameters will be calculated and summarized using means, 
medians and ranges. 
 
11.0 STUDY MANAGEMENT 
11.1 
Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
37 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion. 
 
 
11.2 
Amendments 
The Principal Investigator will formally initiate all amendments to the protocol and/or 
informed consent. All amendments will be subject to the review and approval of the 
appropriate local, institutional, and governmental regulatory bodies, as well as by 
Janssen Scientific Affairs. Amendments will be distributed by the lead institution 
(Northwestern) to all affiliate sites upon approval by the Northwestern University IRB. 
 
11.3 
Registration Procedures 
For potential patients, study teams are asked to inform the QAM of the date and time that 
the patient will need to be registered (croqualityassurance@northwestern.edu).   
 
BEFORE a patient can be treated on study, please complete and submit the following 
items to confirm eligibility and receive an identification number: 
 
Patient’s signed and dated informed consent form (upload to NOTIS and keep 
original hard copy in a secure location/study chart) 
 
Eligibility checklist (signed and dated by the treating physician – upload to NOTIS) 
 
Eligibility eCRF (complete in NOTIS) 
 
Copy of the pathology report (upload to NOTIS) 
 
The QAM will review all source documentation required to confirm eligibility that is readily 
available in the patient’s electronic medical record (EMR).  Any information that is not 
available in the EMR must be de-identified and emailed to the QAM. Once the QAM 
confirms the patient is eligible, he or she will register the patient, assign a subject 
identification number, provide a cohort assignment, and send a confirmation of 
registration to involved personnel. Registration will then be complete and the patient may 
begin study treatment.  
 
11.4 
Data Submission 
Once a subject is confirmed and registered to the study, eCRFs should be submitted 
according to the detailed data submission guidelines (provided in a separate document).  
Generally, all data for phase I patients during the time period patients are evaluated for 
Dose Limiting Toxicities (DLTs) must be submitted on a weekly basis.   Generally, for all 
phase II patients, data are due at the end of every cycle.   
 
This is a general template.  Data Submission language can be revised as make sense for 
each protocol.  A detailed data submission guideline must be included as a separate 
document for all NU IITs determined to require high or moderate level intensity 
monitoring.  To develop your data submission guideline, contact 
croqualityassurance@northwestern.edu. 
 
11.5 
Data Management and Monitoring/Auditing 
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please 
refer to Appendices for additional information). The level of risk attributed to this study 
requires High Intensity Monitoring, as outlined in the DSMP. The assigned QAM, with 
oversight from the Data Monitoring Committee, will monitor this study in accordance with 
the study phase and risk level. Please refer to the study-specific data submission 
instructions for timelines and requirements.   
 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
38 
11.6 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  
 
 
11.6.1  Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, an IRB modification form 
must be completed within 5 business days of making the change, and the QAM 
must be notified within 24 hours of such change.  
 
11.6.2 Other Protocol Deviations 
All other deviations from the protocol must be reported to the assigned QAM 
using the appropriate form. 
 
A protocol deviation is any unplanned variance from an IRB approved protocol 
that:  
 Is generally noted or recognized after it occurs. 
 Has no substantive effect on the risks to research participants. 
 Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected. 
 Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
A protocol deviation may be considered an instance of Promptly Reportable Non 
Compliance (PRNC) if it: 
 Has harmed or increased the risk of harm to one or more research 
participants. 
 Has damaged the scientific integrity of the data collected for the study. 
 Results from willful or knowing misconduct on the part of the investigator(s). 
 Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
11.7 
Investigator Obligations 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The PI is responsible for personally overseeing the treatment of all study 
patients. The PI must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected, entered onto the appropriate eCRFs, and submitted 
within the study-specific timeframes. Periodically, monitoring visits may be conducted and 
the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. The study may also be subject to routine audits by the 
Audit Committee, as outlined in the DSMP.  
 
11.8 
Publication Policy 
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance with the 
policies and processes set forth in the Lurie Cancer Center DSMP. The assigned QAM 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
39 
will prepare a preliminary data summary (to be approved by the DMC) no later than 3 
months after the study reaches its primary completion date (the date that the final subject 
is examined or receives an intervention for the purposes of final data collection for the 
primary endpoint). If the investigator’s wish to obtain DMC-approved data prior to this 
point (or prior to the point dictated by study design), the PI must send a written request 
for data to the QAM which includes justification. If the request is approved, data will be 
provided no later than 4 weeks after this request approval. The data will be presented to 
the DMC at their next available meeting, and a final, DMC-approved dataset will be 
released along with any DMC decisions regarding publication. The investigators are 
expected to use only DMC-approved data in future publications. The investigators should 
submit a copy of the manuscript to the biostatistician to confirm that the DMC-approved 
data are used appropriately.  Once the biostatistician gives final approval, the manuscript 
may be submitted to external publishers. 
 
 
 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
40 
 
                                                     
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IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
41 
                                                                                                                                                              
14 Zhang L, Gajewski T, and Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a 
murine acute myeloid leukemia model. Blood. 2009 114: 1545-1552. 
 
15 Mumprecht S, Schurch C, Schwaller J, et al. Programmed death 1 signaling on chronic myeloid 
leukemia-specific T cells results in T-cell exhaustion and disease progression. Blood. 2009;114(8):1528-
36.    
16 Zhou Q, Munger M, Highfill S, et al. Program death-1 signaling and regulatory T cells collaborate to 
resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia. 
Blood. 2010; 116: 2484-2493. 
17 Brahmer JR, Drake CG, Wollner I, et al: Phase I study of single-agent anti-programmed death-1 (MDX-
1106) in refractory solid tumors: Safety, clinical activity, pharmacodynamics, and immunologic correlates. 
J Clin Oncol. 2010; 28:3167-3175. 
18 Topalian SL, Hodi FS. Safety, activity and immune correlates of anti-PD-1 antibody in Cancer. The New 
England Journal of Medicine. 2012;366:2443-54.    
19 Ansell S, Lesokhin A, Borrello I, et al. PD-1 Blockade with Nivolumab in Relapsed or Refractory 
Hodgkin’s Lymphoma. N Engl J Med 2015;372:311-9. 
20 Lesokhin A, Ansell S, Armand P, et al. Preliminary Results of a Phase I Study of Nivolumab (BMS-
936558) in Patients with Relapsed or Refractory Lymphoid Malignancies. Blood. 2014;124: Abstract 291. 
 
21 Mustjoki S, Ekblom M, Arstila TP,et al. Clonal expansion of T/NK-cells during tyrosine kinase inhibitor 
dasatinib therapy. Leukemia 2009;8:1398-405.   
22 Kreutzman A, Juvonen V, Kairisto V, et al. Mono/oligoclonal T and NK cells are common in chronic 
myeloid leukemia patients at diagnosis and expand during dasatinib therapy. Blood 2010;116(5):772-82. 
  
23 Kreutzman A, Ladell K, Koechel C, et al. Expansion of highly differentiated CD8+ T-cells or NK-cells in 
patients treated with dasatinib is associated with cytomegalovirus reactivation. Leukemia 2011;10:1587-
97. 
24 Mustjoki S, Auvinen K, Kreutzman A, et al. rapid mobilization of cytotoxic lymphocytes induced by 
dasatinib therapy. Leukemia 2013;4:914-24.   
25 Kim DH, Kamel-Reid S, Chang H, et al. Natural killer or natural killer/T cell lineage large granular 
lymphocytosis associated with dasatinib therapy for Philadelphia chromosome positive leukemia. 
Haematologica. 2009;94(1):135-9. 
 
 
 
 
 
 
 
 
 
 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
42 
                                                                                                                                                              
 
 
 
 
 
 
 
 
 
APPENDIX 1: 
Recommended management algorithms for suspected nivolumab related endocrinopathy, gastrointestinal 
toxicity, hepatotoxicity, neurologic toxicity, pulmonary toxicity, renal toxicity and skin toxicity. 
 
 
 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
43 
                                                                                                                                                              
 
 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
44 
                                                                                                                                                              
 
 
 
 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
45 
                                                                                                                                                              
 
 
 
 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
46 
                                                                                                                                                              
 
 
 
 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
47 
                                                                                                                                                              
 
 
 
 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
48 
                                                                                                                                                              
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
49 
                                                                                                                                                              
 
 
APPENDIX 2:  
The following lists describe medications and foods which are common substrates, inducers or inhibitors of 
CYP3A4.  This list should not be considered all inclusive.  Consult individual drug labels for specific 
information on a compound’s propensity to induce or inhibit CYP3A4. 
  
Common CYP3A4 Substrates: 
Anti-arrhythmics: quinidine  
Antihistamines: astemizole, chlorpheniramine, terfenidine  
Benzodiazepines: alprazolam, diazepam, dronedarone, midazolam, triazolam  
Calcium Channel Blockers: amlodipine, diltiazem, felodipine, lercanidipine, nifedipine nisoldipine, 
nitrendipine, verapamil  
Immune Modulators: Cyclosporine, sirolimus, tacrolimus (FK506)  
Macrolide Antibiotics: clarithromycin, erythromycin, telithromycin, NOT: zithromycin  
HIV Antivirals: darunavir, indinavir, lopinavir, maraviroc, nelfinavir, ritonavir, saquinavir, tipranavir  
HMG CoA Reductase Inhibitors: atorvastatin, cerivastatin, lovastatin, NOT: pravastatin NOT: 
Simvastatin  
Steroid 6beta-OH: budesonide, estradiol, fluticasone, hydrocortisone, progesterone, testosterone  
Others: Alfentanyl, aripiprazole, aprepitant, boceprevir, buspirone, cafergot, caffeine, cilostaxol, 
cisapride, cocaine, conivaptan, dapsone, docetaxel, domperidone, codeine-Ndemethylation, darifenacin, 
dexamethasone, dextromethorphan, dihydroergotamine, eletriptan, eplerenone, ergotamine, everolimus, 
fentanyl, finasteride, gleevec, haloperidol, irinotecan, LAAM, Lidocaine, lurasidone, methadone, 
nateglinide, odanestron, pimozide, propranolol, quinine, quetiapine, risperidone, salmetrerol, sildenafil, 
sorafinib, tamoxifen, taxol, tolvaptan, torisel, trazodone, vardenafil, vincristine, zaleplon, ziprasidon, 
zolpidem 
 
Common CYP3A4 Inducers: 
HIV Antivirals: Efavirenz, nevirapine  
Others: Amprenavir, Aprepitant, armodafinil, barbiturates, bosentan, carbamazepine, Echinacea, 
etravirine, glucocorticoids, modafinil, nafcillin, Phenobarbital, phenytoin, rifabutin, rifampin, rufinamide, St. 
John’s wort, troglitazone 
 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
50 
                                                                                                                                                              
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
51 
                                                                                                                                                              
 
 
 
APPENDIX 3:  
Pregnancy and Contraception Requirements 
 
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% 
per year when used consistently and correctly. 
At a minimum, subjects must agree to the use of two methods of contraception, with one method being 
highly effective and the other method being either highly effective or less effective as listed below: 
 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
Male condoms with spermicide 
a) Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, 
injectables, implants, and intrauterine devices (IUDs) such as Mirena® by WOCBP subject or 
male subject’s WOCBP partner. Female partners of male subjects participating in the study may 
use hormone based contraceptives as one of the acceptable methods of contraception since they 
will not be receiving study drug. 
b) Nonhormonal IUDs, such as ParaGard® 
c) Tubal ligation 
d) Vasectomy. 
e) Complete Abstinence* 
 
*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. 
 
LESS EFFECTIVE METHODS OF CONTRACEPTION 
a) 
Diaphragm with spermicide 
b) 
Cervical cap with spermicide 
c) 
Vaginal sponge 
d) 
Male Condom without spermicide* 
e) 
Progestin only pills by WOCBP subject or male subject’s WOCBP partner 
f) 
Female Condom* 
*A male and female condom must not be used together 
 
Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from 
contraceptive requirements. However they must still undergo pregnancy testing as described in this 
section. 
 
 
 
 
 
 
 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
52 
                                                                                                                                                              
 
 
 
APPENDIX 4  
 
Amendment 1 (Version 2.0) –  April 6June 2, 2016 
Section(s) 
Affected 
1.0 Version 
2.0 Version 
Rationale 
8.2.9 
(Nivolumab 
side effects) 
Only listed most 
common side effects 
of nivolumab (>20%)  
Includes less frequent side effects included in 
updated investigator’s brochure, as follows: 
 
Less Likely (≤20%): Hyperthyroidism; Injection 
site reaction; Lymphocyte count decreased; 
Platelet count decreased; Skin hypopigmentation 
 
Rare but Serious (<3%): Cardiac disorders - Other 
(cardiomyopathy); Cytokine release syndrome; 
Encephalopathy; Eye disorders - Other (Graves 
ophthalmopathy); Facial nerve disorder; Gastritis; 
Immune system disorders - Other (sarcoid 
granuloma); Musculoskeletal and connective 
tissue disorder - Other (polymyositis); 
Musculoskeletal and connective tissue disorder - 
Other (rhabdomyolysis); Myocarditis; Nervous 
system disorders - Other (demyelination 
myasthenic syndrome); Nervous system disorders 
- Other (myasthenia gravis); Peripheral sensory 
neuropathy; Respiratory, thoracic and mediastinal 
disorders - Other (bronchiolitis obliterans with 
organizing pneumonia) 
CTEP Action 
Letter issued 
on 3/17/16 
with updated 
safety 
information 
Heading 
Other study number 
was not available 
BMS Study number listed as: CA209-613 
 
Amendment 2 (Version 3.0) –  September 2, 2016 
SRC Approved:  
Section(s) 
Affected 
1.0 Version 
2.0 Version 
Rationale 
2.0 
(Objectives & 
Endpoints) 
Sections numbered 
inaccurately 
Re-numbers sections appropriately 
Typographical 
error 
2.2.2 
(Secondary 
Endpoints); 
6.2 
(Secondary & 
Exploratory 
Endpoints) 
n/a 
Adds that adverse events will be recorded from 
consent until 30 days after treatment (100 days 
for SAE’s) 
Specification 
4.2.1 
(Dasatinib) 
“Treatment with 
dasatinib will begin 7 
days prior to starting 
nivolumab. This 7- 
day period will be 
referred to as ‘Cycle 
0’.” 
Removes language in bold. There is no “Cycle 0” 
– dasatinib treatment will begin on Cycle 1 Day 8 
Discrepancy 
 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.


NU Study Number: NU 15H13 
BMS Study Number: CA209-613 
Initial Version Date: June 2, 2016 
Amendment 2: September 2, 2016 
 
53 
                                                                                                                                                              
5.0 (Study 
Procedures) 
 Nivolumab infusion 
was marked at 
C1D1 and C1D15 
 #3: The end-of-
study visit was to 
take place within 28 
days after the last 
dose of study drug 
 #11: “AE’s will be 
monitored 
throughout the 
study” 
 Moves X’s to C1D8 and C1D22 
 #3: Changes the end-of-study visit to 30 days 
(±7 days) after the last dose of study drug 
 #11: Removes “throughout the study” and 
adds: “from the time of consent until 30 days 
after completing study treatment (100 days for 
SAE’s)” 
 
 To fix 
discrepanci
es in other 
sections of 
the protocol 
 Discrepancy 
 Adds more 
specific 
detail for 
clarity 
7.2.3 (Serious 
Adverse 
Events) 
SAE’s were to be 
reported for 30 days 
after the last 
administration of 
study drug 
Changes SAE collection to 100 days after last 
administration of study drug 
To align with 
BMS reporting 
requirements 
7.3.3.4 
(Reporting to 
BMS) 
n/a 
Adds language to state that SAE reports will 
include death and will be reported regardless of 
attribution 
Also adds the BMS study number and a 
reminder that study coordinator is responsible for 
reporting 
Clarifications 
 
IRB #: STU00202846-CR0002 Approved by NU IRB for use on or after 2/26/2019 through 2/25/2020.