Clinical trial NCT02066532
Conditions: Metastatic Breast Cancer Breast Carcinoma HER-2 Positive Breast Cancer
Keywords: Breast Neoplasms Breast Cancer Breast Carcinoma Breast tumors Cancer of the Breast Malignant tumor of the breast HER2 positive erythroblastosis virus oncogene B-2 (erbB-2) Metastatic Breast Cancer Secondary Breast Cancer
Sponsor: Dawn L. Hershman
Start date: 2014-06-01; Completion date: 2020-10-14
Enrollment: 32 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to examine the safety and efficacy of Ruxolitinib in combination with Trastuzumab in treatment of HER2 positive metastatic breast cancer. Ruxolitinib (Jakafi) is an Food and Drug Administration (FDA) approved treatment for myelofibrosis (a disease of the bone marrow), but its safety and efficacy in breast cancer patients is not known. Trastuzumab (Herceptin) is an FDA-approved treatment for HER2 positive breast cancer. The safety and efficacy of both treatments given in combination is not known. It is hypothesized that Ruxolitinib in combination with Trastuzumab will demonstrate efficacy in treating Metastatic HER2 Positive Breast Cancer subjects, and will have a tolerable safety profile in this patient population.

Detailed description:
Breast cancer is the most common female cancer and the second most common cause of cancer death in women. Approximately 1,150,000 cases and 410,000 deaths from breast cancer occur annually worldwide, and, in the U.S., there are an estimated 184,450 new cases and 40,480 deaths from breast cancer every year. The vast majority of patients who die from breast cancer succumb to metastatic disease. The human epidermal growth factor receptor type 2 gene (HER2) is amplified in 20% to 30% of breast cancers.

HER2+ breast cancers are associated with earlier recurrence and shorter overall survival and are associated with other adverse prognostic markers, such as high tumor grade, high rates of cell proliferation, increased nodal metastases, and relative resistance to certain types of chemotherapy. The HER family of receptors is a group of related transmembrane receptor tyrosine kinases that regulate normal cell survival, proliferation, differentiation, and migration.

Arms: arm 1: Jakafi (Ruxolitinib) and Trastuzumab (Herceptin) - 21 day cycle until disease progression
Interventions: intervention 1: Ruxolitinib intervention 2: Trastuzumab
Intervention descriptions: intervention 1: 25 mg bid, 20 mg bid, 15 mg bid, or 10 mg bid, (oral, twice a day) on days 1 through 21 of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops. intervention 2: 6 mg/kg every 3 weeks (cycle = 21 days). If no trastuzumab \> 28 days, patients will be initially re-loaded at 8 mg/kg, then 6 mg/kg.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
Phase I/II Trial of Ruxolitinib in Combination with Trastuzumab in 
Metastatic HER2 Positive Breast Cancer 
 
 
 
Version: September 19, 2019 
National Clinical Trial Identifier: NCT02066532  
 


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Local Protocol#:  AAAM1906 
 
TITLE:   
Phase I/II Trial of Ruxolitinib in Combination with 
Trastuzumab in Metastatic HER2 Positive Breast Cancer 
 
Coordinating Center: 
 
 Columbia University Medical Center  
 
Principal Investigator:   
 Kevin Kalinsky, MD 
                                                 161 Fort Washington Avenue, Room 1069 
 
 
             New York, NY 10032 
 
 
             Phone 212-305-1945/Fax 212-305-0178 
 
 
             E-mail: kk2693@columbia.edu  
 
Site Principal Investigator and Contact Information: 
Columbia Presbyterian Medical Center 
Kevin Kalinsky, MD, MS 
161 Fort Washington Ave, NY, NY 10032 
Phone: 212-305-1945  
Email: kk2693@columbia.edu; mm2058@columbia.edu 
Montefiore Medical Center 
Della Makower, MD 
1695 Eastchester Rd, Bronx, NY 10461 
Phone: 718-405-8529  Email: dmakower@montefiore.org 
Mount Sinai Medical Center 
Amy Tiersten, MD 
1 Gustave L. Levy Place, Box 1079, NY, NY 10029  
Phone: 212-241-2299 Email: amy.tiersten@mssm.edu  
New York Hospital 
Tessa Cigler, MD  
Weill Medical College-Cornell, 425 E. 61st Street, 8th Floor, 
NY, NY 10065 
Phone 212-821-0644 Email: elc2007@med.cornell.edu 
 
Statistician: 
Shing Lee, PhD 
Department of Biostatistics  
Mailman School of Public Health 
722 West 168th Street, 6th Floor 
New York, New York 10032 
Tel: 212-305-9398  
Email: sml2114@columbia.edu  
  
Incyte-Supplied Agent(s):  Ruxolitinib (Jakafi), INCB018424, INC424, Incyte  
Other Agent(s):  Trastuzumab (Herceptin), NSC 688097, Commercial   
 
 


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SYNOPSIS 
 
Phase I/II Trial of Ruxolitinib in Combination with Trastuzumab in Metastatic HER2 
Positive Breast Cancer (32-40 patients) 
 
Patient Selection (see section 3 for complete eligibility criteria)  
1. HER2+ Metastatic Breast Cancer 
2. Patients must have received at least two lines of HER2-directed therapy in the metastatic 
setting, and prior therapy for metastatic disease should include both pertuzumab and ado-
trastuzumab unless contraindicated or declined by the patient. 
3. ECOG performance status 0-2 
4. Measurable or non-measurable disease 
5. Adequate bone marrow and organ function  
6. Left Ventricular Ejection Fraction > 50%   
7. No prior history of IL-6, JAK or STAT inhibitor, such as ruxolitinib  
8. No HIV+ or active infection 
9. No concurrent medications that are potent CYP3A4 inhibitors or inducers 
 
Phase I (n=10: Section 5): The dose of trastuzumab will be fixed at 6 mg/kg every 3 weeks 
(with 8 mg/kg initial re-load if no trastuzumab in > 28 days). The dose levels of ruxolinitib: 
 
Dose Level 
Ruxolitinib Dose 
1 
25 mg bid 
0 
20 mg bid 
-1 
15 mg bid 
-2 
10 mg bid 
The maximum tolerated dose (MTD) combination is defined as the dose combination associated 
with a target probability of dose limiting toxicity of 0.25. The MTD will be estimated using the 
time-to-event continual reassessment method (TITE-CRM) as detailed in Section 13. 
 
Phase II (n=30 evaluable pts: Section 5): Recommended phase II dose of ruxolitinib (oral bid 
dosing) plus trastuzumab 6 mg/kg every 3 weeks (cycle = 21 days).  If no trastuzumab > 28 days, 
patients will be initially re-loaded at 8 mg/kg, then 6 mg/kg. Pts treated in Phase I at recommended 
Phase II dose will be considered evaluable. 
Design: Non-randomized, open-label trial 
Stratification: Hormone Receptor Status (+/-) 
 
Evaluations 
Disease Assessment: 
CT chest, abdomen, and pelvis plus (OR) PET/CT will be obtained every 3 cycles (9 weeks of 
treatment +/- 4 days, allowing for protocol specified dose delays).  Baseline bone scan required in 
all patients and will be performed every 3 cycles as clinically indicated. If patients have known 
brain metastases and are eligible for this trial, a head CT or brain MRI MUST be performed along 
with systemic imaging.  If a patient does not have known brain metastases and is asymptomatic, no 
baseline brain imaging is required. 
Blood: Samples will be obtained for biomarker analysis pre-treatment, on-treatment on cycle 2 day 
1, and then at progression  
Tumor Tissue: Pre-treatment biopsies from archival tissue or new biopsy, prior to cycle 2 day 1, 
and upon progression of disease will be discussed with pts with accessible disease (Optional) 


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Table of Contents 
1. 
OBJECTIVES ..........................................................................................................6 
1.1 
Primary Objectives ................................................................................. 6 
1.2 
Secondary Objectives ............................................................................. 6 
1.3 
Exploratory Objectives .......................................................................... 6 
2. 
BACKGROUND .....................................................................................................6 
2.1 
HER2 Overexpressed Breast Cancer ..................................................... 6 
2.2 
Trastuzumab ........................................................................................... 6 
2.3 
Incyte-Supplied Investigational Drug .................................................... 7 
2.3.1 Ruxolitinib ................................................................................. 7 
b. 
Non-Clinical Pharmacology .................................................... 7 
c. 
Animal Toxicity ........................................................................ 8 
2.4 
Rationale .............................................................................................. 13 
2.5 
Preliminary Results .............................................................................. 14 
2.5.1 Target Validation ..................................................................... 14 
Target Modulation ............................................................................. 15 
2.6 
Correlative Studies Background .......................................................... 17 
2.6.1 Transcriptional Profiling .......................................................... 17 
2.6.2 Reverse Phase Proteomic Array (RPPA) ................................. 17 
3. 
PATIENT SELECTION ........................................................................................18 
3.1 
Inclusion Criteria ................................................................................. 18 
3.2 
Exclusion Criteria ................................................................................ 19 
4. 
REGISTRATION PROCEDURES .......................................................................20 
5. 
TREATMENT PLAN ............................................................................................24 
5.1 
Agent Administration ........................................................................... 24 
5.2 
General Concomitant Medication and Supportive Care Guidelines .... 25 
5.3 
Duration of Therapy ............................................................................. 25 
5.4 
Duration of Follow Up ......................................................................... 26 
5.5 
Criteria for Removal from Study ......................................................... 26 
6. 
DOSING DELAYS/DOSE MODIFICATIONS....................................................26 
6.1 
Management of Cardiac Toxicity ........................................................ 28 
6.2 
Asymptomatic Decrease in LVEF (Left Ventricular Ejection 
Fraction) ............................................................................................... 29 
6.3 
Symptomatic Decrease in LVEF ......................................................... 29 
6.4 
Cardiac Ischemia/ Infarction ................................................................ 29 
6.5 
Arrhythmia ........................................................................................... 30 
6.6 
Management of Corrected QTc Prolongation ...................................... 30 
6.7 
Management of Trastuzumab Infusion Reaction ................................. 30 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ................30 
7.1 
Comprehensive Adverse Events and Potential Risks List ................... 31 
7.2 
Definitions and Reporting .................................................................... 36 
7.2.1 Dose Limiting Toxicity (DLT) ................................................ 36 
7.2.2 Adverse Event (AE) ................................................................. 36 


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7.2.3 Serious adverse event (SAE) ................................................... 37 
7.2.4 Unanticipated Problem............................................................. 38 
7.2.5 Suspected Adverse Reaction .................................................... 38 
7.2.6 Expectedness ............................................................................ 39 
7.2.7 Attribution ................................................................................ 39 
7.2.8 Expedited Adverse Event Reporting ........................................ 39 
7.2.9 Serious Adverse Event Reporting ............................................ 40 
7.2.10 Pregnancy ................................................................................. 41 
7.2.11 Non-Serious Adverse Event Reporting .................................... 42 
7.2.12 Reporting to the Institutional Review Board (IRB) ................. 42 
7.2.13 Reporting to the Food and Drug Administration (FDA) ......... 42 
7.2.14 Reporting to Incyte Corporation .............................................. 43 
7.2.15 Guidelines for Processing IND Safety Reports ................... 44 
7.2.16 Reporting to Hospital Risk Management ................................. 44 
7.2.17 Monitoring of Adverse Events and Period of Observation ...... 44 
7.3 
Secondary Malignancy ......................................................................... 44 
8. 
PHARMACEUTICAL INFORMATION ..............................................................44 
8.1 
Investigational Agent(s) ....................................................................... 44 
8.1.1 Ruxolitinib ............................................................................... 45 
8.1.2 Trastuzumab ............................................................................. 45 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ............................46 
10. 
STUDY CALENDAR ...........................................................................................49 
11. 
MEASUREMENT OF EFFECT............................................................................51 
11.1 
Antitumor Effect – Solid Tumors ........................................................ 51 
11.1.1 Definitions................................................................................ 51 
11.1.2 Disease Parameters .................................................................. 51 
11.1.3 Methods for Evaluation of Measurable Disease ...................... 52 
11.1.4 Response Criteria ..................................................................... 54 
11.1.5 Duration of Response ............................................................... 56 
11.1.6 Progression-Free Survival ........................................................ 56 
11.1.7 Response Review ..................................................................... 56 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...............................57 
12.1 
Data Collection .................................................................................... 57 
12.2 
Data Reporting ..................................................................................... 57 
Responsibility for Data Submission..................................................... 57 
12.3 
Data and Safety Monitoring Committee .............................................. 64 
12.4 
Quality Control and Quality Assurance ............................................... 64 
12.5 
Confidentiality ..................................................................................... 65 
12.6 
Source Documents ............................................................................... 65 
12.7 
Reporting to Incyte Corporation .......................................................... 66 
12.8 
Records Retention ................................................................................ 66 
13. 
STATISTICAL CONSIDERATIONS...................................................................66 
13.1 
Study Design/Primary Endpoint (Sample Size) ................................... 67 
13.2 
Accrual Rate......................................................................................... 69 
13.3 
Stratification Factors ............................................................................ 69 


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13.4 
Analysis of Secondary Endpoints ........................................................ 69 
13.4.1 Clinical Benefit Rate, Percent Progression-Free at 24 
weeks, Objective Response Rate: .......................................... 69 
13.4.2 Toxicity Evaluation ................................................................ 70 
13.4.3 Correlative Studies ................................................................. 70 
13.5 
Reporting and Exclusions .................................................................... 70 
13.5.1 Evaluation of toxicity. ............................................................ 70 
14. 
Protection of Human Subjects ...............................................................................70 
15. 
REFERENCES ......................................................................................................71 
APPENDIX A:  PERFORMANCE STATUS CRITERIA ............................................................74 
APPENDIX B: PATIENT’S Medication Diary ............................................................................75 
APPENDIX C: Strong KNOWN CYP 3A4 INHIBITORS AND INDUCERS. ...........................76 
APPENDIX D: Archived Tissue and Biopsy Collection and Shipment ........................................77 
APPENDIX E:  BLOOD BIOMARKER COLLECTION ............................................................79 
APPENDIX G: GUIDELEINES FOR AFFILIATE INSTITUTIONS IN MULTICENTER STUDIES
........................................................................................................................................................90 
 


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1. OBJECTIVES 
Refer to Section 13: Statistical Considerations for definition of the endpoints below. 
1.1 
Primary Objectives  
• 
To evaluate the safety and tolerability of ruxolitinib in combination with 
trastuzumab 
• 
To determine the MTD of ruxolitinib with a fixed dose of trastuzumab (Phase 1)  
• 
To estimate the efficacy end point of progression free survival (PFS) of the 
combination of ruxolitinib and trastuzumab in patients with HER2+ metastatic 
breast cancer who have progressed on a trastuzumab-containing regimen (Phase 2)  
 
1.2 
Secondary Objectives 
• 
To assess the pharmacokinetics (PK) and pharmacodynamics (PD) of combination 
ruxolitinib and trastuzumab (Phase 1) 
• 
To assess the objective response rate (ORR) and clinical benefit rate (CBR) in the 
study population (Phase 2) 
 
1.3 
Exploratory Objectives 
• 
To explore differences in clinical outcome (PFS, ORR, and CBR) based on 
clinicopathologic features, such as hormone receptor status 
• 
To explore the characteristics of the tumor and peripheral blood as potential 
pharmacodynamic or predictive biomarkers.  Potential biomarkers will include 
tumor evaluation of pSTAT3 expression, serum IL-6, IL-8, and C-reactive protein.   
• 
To conduct genomic profiling of serial tumor samples of subjects through RNA-
Seq to explore mechanisms of acquired resistance and response 
 
2. 
BACKGROUND 
2.1 
HER2 Overexpressed Breast Cancer 
Breast cancer is the most common female cancer and the second most common cause of 
cancer death in women.  Approximately 1,150,000 cases and 410,000 deaths from breast 
cancer occur annually worldwide (Parkin et al, 2005), and, in the U.S., there are an estimated 
184,450 new cases and 40,480 deaths from breast cancer every year (Jemal et al, 2008).  The 
vast majority of patients who die from breast cancer succumb to metastatic disease.  The 
human epidermal growth factor receptor type 2 gene (HER2) is amplified in 20% to 30% of 
breast cancers (Revillion et al. 1998).  
 
HER2+ breast cancers are associated with earlier recurrence and shorter overall survival and 
are associated with other adverse prognostic markers, such as high tumor grade, high rates of 
cell proliferation, increased nodal metastases, and relative resistance to certain types of 
chemotherapy (Slamon et al. 1987; Paik et al. 1990).  The HER family of receptors, HER1, 
HER2, HER3, HER4 (also referred to as epidermal growth factor receptors ErbB-1, ErbB-2, 
ErbB-3, ErbB-4), is a group of related transmembrane receptor tyrosine kinases that regulate 
normal cell survival, proliferation, differentiation, and migration (Hudis, 2007).  
 
2.2 
Trastuzumab 
Trastuzumab, a recombinant humanized monoclonal antibody against the extracellular 
domain of HER2, prevents cell proliferation and has greatly improved the treatment of 
HER2+ breast cancer.  Clinical studies demonstrate that trastuzumab can dramatically 
improve disease-free and overall-survival in HER2+ patients in both the curable and 
advanced disease settings (Slamon et al. 2001; Romond et al. 2005).   
 


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A single arm, 222 patient, multinational study of trastuzumab monotherapy in HER2+ 
metastatic breast cancer patients who had progressed after one or two treatment regimens 
showed a 14% response rate (2% complete responses) and a median duration of response of 
13 months (Cobleigh et al,1999; Herceptin (Trastuzumab) USPI, 2008).  Although response 
rates of HER2+ metastatic breast cancer to trastuzumab monotherapy are low (11 - 34%), the 
combination of chemotherapy, including taxanes and vinorelbine, plus trastuzumab yield 
response rates which approach 70% in the first line setting (Slamon et al. 1987; Seidman et 
al. 2001; Esteva et al. 2002; Burstein et al. 2007).   
 
In a pivotal trial in which women with previously untreated HER2+ MBC were randomized 
to chemotherapy versus chemotherapy with trastuzumab, the addition of trastuzumab 
increased time to progression from 4.6 months to 7.4 months (Slamon et al. 2005).  
Trastuzumab as a single agent is approved for treatment of HER2-overexpressing breast 
cancer in patients who have received one or more chemotherapy regimens (U.S. approval) or 
at least two chemotherapy regimens (European approval) for metastatic disease.  
Trastuzumab received approval in the U.S. for HER2+ metastatic breast cancer either as 
monotherapy or in combination with paclitaxel. Trastuzumab is also approved for the 
adjuvant treatment of HER2-overexpressing, node positive or node negative breast cancer.  
While the treatment effects of trastuzumab were seen in patients treated with anthracycline 
plus cyclophosphamide (AC) or paclitaxel, the size of the treatment effect was greater in the 
paclitaxel subgroup, with less cardiotoxicity.  The incidence of New York Heart Association 
class III or IV cardiac dysfunction was 16% in patients treated with AC and trastuzumab 
compared with 2 % among those who had received paclitaxel and trastuzumab (Herceptin 
(Trastuzumab) USPI, 2008; Slamon et al, 2001).  
 
2.3 
Incyte-Supplied Investigational Drug 
2.3.1 Ruxolitinib    
 
a. Mechanism of Action 
Ruxolitinib (INCB018424 phosphate, INC424, ruxolitinib phosphate) represents a potent, and 
selective inhibitor of JAK1 (Janus kinase 1) (inhibition concentration 50% [IC50]=3.3 ± 1.2 
nM) and JAK2 (IC50=2.8 ± 1.2 nM) with modest to marked selectivity against TYK2 
(tyrosine kinase 2) (IC50=19 ± 3.2 nM) and JAK3 (IC50=428 ± 243 nM), respectively. 
Ruxolitinib interferes with the signaling of a number of cytokines and growth factors that are 
important for hematopoiesis and immune function. JAK signaling involves recruitment of 
signal transducers and activators of transcription (STATs) to cytokine receptors, activation, 
and subsequent localization of STATs to the nucleus leading to modulation of gene 
expression. Dysregulation of the JAK-STAT pathway has been associated with several types 
of cancer and increased proliferation and survival of malignant cells.  
 
b. Non-Clinical Pharmacology 
Ruxolitinib has high aqueous solubility and high permeability in vitro based on Caco-2 cell 
culture study.  In single oral dose PK studies, ruxolitinib was absorbed rapidly with mean 
Tmax values ranging from 0.5 to 2 h. In mice, dogs, minipigs and humans, there were 
minimal gender differences in the exposure of ruxolitinib and its metabolites. In rats, the 
Cmax and AUC (area under the concentration-time curve) values were several-fold higher in 
females compared to males, due to metabolism by male rat specific isozymes 2C11, 2C13 
and CYP3A2. The terminal half-life, routes and rate of excretion for ruxolitinib-derived 
radioactivity and metabolites observed between male and female rats were similar. The oral 
bioavailability was variable across species, ranging from 22% in male monkeys to virtually 


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complete in female rats consistent with the species dependent clearance observed following 
IV dosing.  
 
Following IV administration of ruxolitinib, the plasma clearance was species-dependent and 
ranged from moderate in male dogs (0.48 L/h/kg) to very high in male rats (9.4 L/h/kg). 
Based on the apparent steady-state volume of distribution, ruxolitinib was not distributed 
extensively beyond body water in dogs (1.1 L/kg) and monkeys (0.81 L/kg), but may be 
distributed to a greater degree in rats (1.6-3.8 L/kg) and minipigs (6.4 L/kg). The terminal 
elimination half-life ranged from 0.4 h (rat) to 2.5 h (dog). In monkeys, the PK parameters of 
ruxolitinib were comparable with and without the pretreatment of agents that increase gastric 
pH, indicating that elevated gastric pH is not likely to affect the oral exposure of ruxolitinib. 
 
c. Animal Toxicity 
Ruxolitinib was evaluated in several in animal based toxicology studies and did not exhibit 
significant toxicities at target concentrations.  Cardiovascular evaluation in dogs 
demonstrated lowered blood pressure and increased heart rate at the highest dose of 
ruxolitinib (30 mg/kg).  Effects noted in multiple-dose toxicity studies in mice (up to 4 
weeks), rats (up to 6 months), and dogs (up to 12 months) were primarily those associated 
with the mechanism of action of ruxolitinib, a potent and reversible inhibitor of JAK-STAT 
signaling. Decreases in red blood cells, reticulocytes, eosinophils and lymphocytes have been 
observed along with lymphoid depletion in bone marrow and lymphoid organs. In addition, in 
dogs, demodectic mange, bacterial pneumonia and viral-induced papillomas, expected 
consequences of the pharmacology of JAK inhibition, were noted. 
 
Embyro-fetal assessments in rat and rabbit, maternal toxicity and minimal embryo-fetal 
toxicity were noted at the highest doses.  No teratogenicity was noted in rat or rabbit animal 
models.  There were no reported effects on fertility or early embryonic development.  In an 
evaluation of fertility and early embryonic development, no effects were noted on 
reproductive performance or fertility in male or female rats. Increases in post-implantation 
loss were noted at the higher doses. In a pre- and post-natal development and maternal 
function study in rats there were no adverse findings for fertility indices or for maternal and 
embryo-fetal survival, growth, and developmental parameters. Ruxolitinib passed into the 
milk of lactating rats with an exposure that was 13-fold higher than maternal plasma 
exposure.  
 
d. Absorption, bioavailability, and pharmacokinetics 
Ruxolitinib is a potent and selective inhibitor of the JAKs with selectivity for JAK1 and 
JAK2 (Quintás-Cardama et al, 2010). Ruxolitinib potently inhibits JAK1 and JAK2 
(IC50<5nM), yet it does not significantly inhibit a broad panel of 28 kinases (<30% 
inhibition) when tested at 200 nM (approximately 100 × the average IC50 value for JAK1 
and JAK2 enzyme inhibition). In cell-based assays relevant to the pathogenesis of MPNs 
(myeloproliferative neoplasms), such as JAK/STAT signaling and the growth of cytokine-
dependent tumor cell lines, ruxolitinib demonstrates IC50 values of 80-300 nM. This effect is 
not due to general cytotoxicity, because ruxolitinib (up to 25 μM) had no significant effect on 
the growth of a cytokine-independent, BCR-ABL-driven cell line. In addition, ruxolitinib 
inhibited JAK/STAT signaling and growth of a cell line expressing the constitutively active 
JAK2 mutant (JAK2V617F) that has been implicated in the pathogenesis of the majority of 
Philadelphia chromosome negative MPNs. Ruxolitinib was also tested in cell-based assays 
relevant to the increased inflammatory cytokine levels observed in MPNs that contribute to 
MPN-related systemic symptoms. Ruxolitinib potently inhibited IL-23 stimulated IL-22 


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production in human T cells (IC50=50 nM), as well as IL-6, GM-CSF and TPO induced 
STAT3 phosphorylation in human peripheral blood mononuclear cells with IC50 values < 
100 nM. Ruxolitinib also inhibited GCSF stimulated STAT3 phosphorylation in human 
neutrophils (IC50=28 ± 9 nM), as well as TPO induced STAT3 phosphorylation in human 
whole blood (IC50=281 ± 62 nM).  Finally, ruxolitinib inhibited the production of IL-17 in 
response to IL-23 in T cells, and the production of monocyte chemotactic protein-1 in 
response to IL-6 in peripheral blood mononuclear cells with IC50 values of ≤120 nM 
(Fridman et al, 2011).  
 
Ruxolitinib inhibited splenomegaly in mice resulting from intravenous (IV) inoculation of 
cells expressing the clinically relevant JAK2V617F mutation (Quintás-Cardama et al, 2010). 
After 3 weeks of treatment, more than 90% of vehicle-treated mice had succumbed to disease 
while more than 90% of ruxolitinib -treated mice survived. Treatment with ruxolitinib also 
reduced inflammatory cytokine levels in these mice. The effects of ruxolitinib were also 
tested in a mouse disease model of polycythemia vera-like disease, based on transplantation 
of a 1:1 ratio of JAK2 wild type green fluorescent protein (GFP)-expressing murine bone 
marrow cells with JAK2V617F-positive murine bone marrow cells, which have a 
repopulation advantage. In this model, oral ruxolitinib treatment at doses of 30 or 90 mg/kg 
twice a day for 21 consecutive days reduced levels of phosphorylated STAT5 (pSTAT5) in 
the spleen, as well as the spleen size. Ruxolitinib also effectively reduced the red cell 
parameters (RBC count, Hgb, Hct and reticulocyte count) and neutrophil count. The 
treatment was well tolerated as assessed by monitoring body weight, and histological 
assessments of spleen and bone marrow samples post-therapy revealed a decrease of 
hypercellularity (erythroid and myeloid lineages) in ruxolitinib treated groups as compared to 
vehicle treated animals. However, no significant decrease in the mutant allele burden 
surrogate readout (percentage of GFP-negative cells, i.e. cells expressing JAK2V617F) was 
observed, as assessed by flow cytometry. Treatment of mice with ruxolitinib in a cytokine-
dependent multiple myeloma (MM) xenograft model resulted in a dose-dependent 
suppression of phosphorylated STAT3 (pSTAT3) and tumor growth. Efficacy was also 
observed in additional preclinical tumor models representing both hematologic and solid 
tumors. Taken together, these data indicate that ruxolitinib will be able to inhibit wild-type 
and mutant JAKs in the clinical setting and are consistent with its observed efficacy in 
patients with MPNs. 
 
e. Clinical Trials 
The clinical database (safety set) in solid tumor and hematologic malignancies consists of 
787 patients treated in 6 studies evaluating patients with myelofibrosis (MF) (n=679), 
prostate cancer (n=22), MM (n=13), essential thrombocythemia (ET), and polycythemia vera 
(PV) (n=73), of whom 617 patients received ruxolitinib.  Hematologic events are the most 
frequently reported adverse events (AEs) and include thrombocytopenia and anemia. The 
majority of these AEs are of Grades 1-2, seldom led to study drug discontinuation (<1% of 
patients), and can be usually managed through dose reduction or interruption. Increased rates 
of anemia resulted in an increase in packed red blood cell (PRBC) transfusion requirements 
for some ruxolitinib-treated patients. Platelet transfusions while on ruxolitinib were rare. 
Biochemistry laboratory abnormalities of alanine aminotransferase (ALT), aspartate 
aminotransferase (AST) and cholesterol were reported. The majority of these increases were 
Grade 1 or 2. No Grade 4 events were reported. 
 
Safety in clinical pharmacology studies 


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The safety profile for ruxolitinib in the Phase I development program was assessed in 
over145 healthy subjects for single doses from 5 mg to 200 mg, and in 53 healthy subjects for 
repeat doses from 15 mg to 50 mg b.i.d. and 50 to 100 mg q.d. Ruxolitinib has also been 
administered to 32 subjects with various degrees of renal impairment, 24 subjects with 
various degrees of hepatic impairment, and 50 subjects with RA (rheumatoid arthritis). AEs 
were, in general, mild and resolved without interventions. In the first in human study one 
subject had hyponatremia after receiving 5 mg ruxolitinib. The hyponatremia was assessed as 
severe in intensity, unrelated to study medication, reversed within 5 days, and was reported as 
a serious adverse event (SAE). A Phase I dose escalation study and a study to evaluate food 
effect in Japanese healthy volunteers showed that administration of ruxolitinib with a high-fat 
meal led to results that were in line with results from the North American study.  A Phase I 
dose escalation study in Chinese healthy volunteers showed similar overall results over a 
dose range of 10-50 mg.  The pharmacokinetics of ruxolitinib was linear in the dose range 
studied, with a short half-life of 2-4 hours resulting in no notable drug accumulation 
following multiple doses. 
 
In the repeat-dose study in healthy subjects, the intensity of an adverse event was graded 
according to the protocol-defined toxicity criteria based on Rheumatology Common Toxicity 
Criteria V 1.0. The dose-limiting AE was neutropenia, which occurred at a dose of 50 mg 
b.i.d. Neutropenia as an AE was noted in three subjects, all receiving the highest dose of 
ruxolitinib, 50 mg b.i.d. Neutropenia at the Grade 4 level, assessed as severe, led to study 
drug discontinuation on Day 5 in one subject, and was reported as a SAE. Neutrophil count 
returned to a normal level 12 days after the final dose of study medication. In two other 
subjects, neutropenia was Grade 1 or 2, and resolved with dose interruption or during 
continued dosing. The AE profile was similar for single- and multiple-dose studies, and no 
differences were observed between males and females. The most frequent (≥2 subjects) 
treatment-emergent AEs (TEAEs) occurring in the Phase I multiple-dose study were: 
neutropenia (4.2%), dizziness (2.8%), headache (2.8%) and nausea (2.8%). Overall, in 
healthy volunteer studies where frequent sampling of the neutrophil count was performed, a 
transient, reversible decrease in neutrophil count was frequently seen following dosing, 
which reversed after 12-24 hours off drug. 
 
Two clinical pharmacology studies are ongoing to evaluate the effect of ruxolitinib on the 
pharmacokinetics of orally administered midazolam in healthy males subjects and of 
monophasic oral contraceptives in health female subjects.   
 
The first Periodic Safety Update Report (PSUR) for ruxolitinib covered the reporting period 
from 16 Nov 2011 to 22 Feb 2013.  A critical analysis of the efficacy and safety data revealed 
that the overall benefit-risk assessment of ruxolitinib remains favorable.  Based on a single 
confirmed case of PML in an MF patient treated with ruxolitinib, this condition has been 
identified as an important potential risk.  Reports of tuberculosis continue to be received in 
ruxolitinib-treated subjects in clinical trials.  While the cumulative incidence of these 
tuberculosis reports appears to decline since the original Phase III trials, given the potential 
impact of JAK1/JAK2 inhibition upon immune defense, the risk tuberculosis will be 
monitored closely in subsequent PSURs. 
 
 
 
 
 


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Phase III studies in patients with myelofibrosis 
The Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment I, (COMFORT-I) 
was a randomized, double-blind, placebo-controlled, multicenter study comparing the 
efficacy and safety of ruxolitinib tablets to a matched placebo in 309 patients with MF. The 
primary objective was to evaluate the efficacy, safety and tolerability of ruxolitinib given 
b.i.d. compared to placebo in patients with MF. Patients were randomized in a 1:1 ratio of 
ruxolitinib: placebo with no stratification. Ruxolitinib starting dose was based on baseline 
platelet count as follows: patients with baseline platelet count >200 x109/L started at 20 mg 
b.i.d. and patients with baseline platelet count >100 x 109/L to ≤200 x 109/L started at 15 mg 
b.i.d. The primary endpoint for this study was the percentage of patients with ≥35% reduction 
in spleen volume assessed by imaging (MRI or CT) from baseline, at Week 24.  The 
Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment II (COMFORT II) was an 
open-label, randomized, active-comparator, multicenter study comparing the efficacy and 
safety of ruxolitinib tablets versus best available therapy as selected by the investigators in 
219 adults patients with myelofibrosis.  Key eligibility criteria were as follows: adult MF 
patients, not candidates for stem cell transplantation, with two or more risk factors identified 
by IPSS, palpable spleen length ≥5 cm below the left costal margin, peripheral blast count 
<10%. The primary endpoint for this study was the percentage of patients with ≥35% 
reduction in spleen volume assessed by imaging (MRI or CT) from baseline, at Week 48. 
These trials identified statistically significantly larger proportion of patients randomized to 
ruxolitinib achieved a ≥35% reduction from baseline in spleen volume compared to patients 
randomized to control. This effect was seen at both Week 24 (primary endpoint in 
COMFORT-I) and Week 48 (primary endpoint in COMFORT-II). For patients who remained 
on study, the median percent reduction from baseline in spleen volume in both ruxolitinib 
arms was approximately 30%, was reached as early as Week 12 and was maintained 
throughout the study. The control arms had a median percent increase from baseline in spleen 
volume throughout the study. 
 
For additional information see the ruxolitinib Investigator’s Brochure, Edition 12, dated 11 
September, 2013. 
 
Phase III study in patients with polycythemia vera 
The RESPONSE Trial is a global, randomized, open label phase III pivotal study comparing 
ruxolitinib (starting dose of 10 mg b.i.d.) with best available therapy (HU, pipobroman, 
immunomodulatory drugs, pegylated interferon or interferon, anagrelide, observation only) in 
PV patients. The protocol is designed for patients with evidence of need for phlebotomy and 
splenomegaly, either resistant or intolerant to HU. The primary endpoint is a composite one 
with phlebotomy control (absence of phlebotomy from Week 8 to 32) and reduction in spleen 
volume by MRI (or CT if MRI is clinically contraindicated) of at least 35% measured at 32 
weeks. Two key secondary endpoints include durability of the primary endpoint and 
complete hematologic remission. There are multiple, non-key secondary endpoints including 
modified clinico-hematologic response (overall response rate, durability and duration), as 
defined by the European Leukemia Net (ELN). The study is ongoing and 147 patients have 
been enrolled so far (as of 1 August 2012). 
 
Phase I/II study in patients with multiple myeloma 
Ruxolitinib is being evaluated in a phase II, multicenter, Simon-two-stage, open label, 
clinical trial to) in patients with relapsed or refractory MM. This was a multi-center, Simon 2-
stage, open-label clinical trial. Patients were to receive ruxolitinib 25 mg orally b.i.d. on each 
day of each 28-day cycle. Tumor responses were assessed every cycle. Responding patients 


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Page 12 of 96 
 
could continue on ruxolitinib monotherapy. The patients who were assessed to have 
progressed at any time or were assessed to have stable disease after 3 cycles of ruxolitinib 
monotherapy had the addition of 40 mg oral dexamethasone daily on Days 1-4, 9-12, and 17-
20 of each 28-day cycle (combination phase of the trial). Each cycle of dexamethasone was 
repeated every 28 days for 4 cycles. After the fourth cycle, 40 mg of dexamethasone was to 
be administered only on Days 1-4 of subsequent cycles. Treatment could be continued until 
occurrence of progressive disease or unacceptable toxicity. A total of 13 MM patients have 
been enrolled in Stage 1 to receive ruxolitinib as monotherapy (11 were evaluable for 
response). Seven of these subjects received ruxolitinib in combination with high dose 
dexamethasone after their disease progressed or after having had stable disease on ruxolitinib 
monotherapy. No MM patient has been enrolled in stage 2. None of the 11 MM evaluable 
subjects achieved a response according to the IRC (International uniform Response Criteria) 
when treated with ruxolitinib monotherapy. However, with combination therapy of high dose 
dexamethasone added to ruxolitinib, two out of seven subjects achieved a partial response 
and one subject had long-term stable disease. 
 
Phase I/II study in patients with prostate cancer 
A Phase II, open label study of ruxolitinib administered orally to patients with androgen 
independent metastatic prostate cancer (AIPC) was performed. The primary endpoint was 
PSA50 (prostate-specific antigen) response rate, a clinically validated endpoint associated 
with clinical benefit in patients with metastatic prostate cancer. This endpoint is defined as a 
PSA decline from baseline of 50% or greater, confirmed by measurement on two occasions at 
least 4 weeks apart. The study used a Simon 2-stage optimal design. The first stage of the 
trial (Part 1) was designed to enroll 21 patients. If fewer than two PSA50 responses were 
observed in the first 
21 patients (no later than 10 weeks after the last patient in the first stage is enrolled), the trial 
would be closed and the agent will be declared inactive as a monotherapy. If two or more 
PSA50 responses are seen in the first stage, an additional 20 patients would be enrolled in the 
second stage (Part 2) for a total of 41 patients. The study in patients with advanced prostate 
cancer completed enrollment of 22 subjects in the first stage of the study. The study endpoint 
permitting advancement to a second stage of the study was not reached. Seventeen of 22 
subjects enrolled experienced death or protocol-defined progressive disease while on study.  
 
Given that all patients discontinued the study due to protocol-specified lack of efficacy, the 
primary efficacy endpoint of PSA50 response rate was not assessed. Similarly, the secondary 
endpoints of median time to progression and tumor response rates were not assessed. All 
patients provided samples for the secondary endpoints of evaluating population PK and 
plasma PD markers; however, the samples were not assessed as part of this analysis. 
The primary endpoint of safety and tolerability was assessed in this analysis. All patients 
experienced at least one TEAE, and the majority of patients (16 patients; 72.7%) experienced 
treatment-related TEAEs. The events associated with ruxolitinib treatment included anemia, 
fatigue, diarrhea, nausea, leukopenia and peripheral edema, all of which were not unexpected 
events in this patient population of metastatic androgen AIPC, as were the most frequently 
reported severe or life-threatening TEAEs (anemia, thrombocytopenia, peripheral edema, 
increased blood alkaline phosphatase, bone pain). 
Treatment with ruxolitinib was generally well-tolerated. Among the 11 SAEs reported by 
nine patients, the only SAE that was reported by more than one patient was anemia (two 
patients), and only two SAEs were considered to be possibly or definitely related to study 


Local Protocol#:  AAAM1906 
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Page 13 of 96 
 
medication by the investigator (cardiac arrest and anemia, respectively). Further, only one 
patient discontinued treatment as a result of an AE (anemia). Among the four deaths, cardiac 
arrest was deemed by the investigator as possibly related to study medication in one patient, 
but the patient had other risk factors that may have also contributed to the event; the other 
three deaths were likely associated with medical history and metastatic AIPC. 
Eight patients had laboratory abnormalities that resulted in serious, severe, or life-threatening 
AEs, which included the following events: anemia, increased blood alkaline phosphatase, 
increased γGT, thrombocytopenia, hyperuricemia, and leukopenia. There was no specific 
trend among patients with regards to laboratory abnormalities or ECG values out of the 
normal range. Overall, there were no specific safety concerns associated with ruxolitinib. 
Phase IIa study in patients with rheumatoid arthritis (RA) 
A total of 50 patients were enrolled to a double-blind, placebo-controlled study exploring the 
safety, tolerability, and efficacy of a 4-week course of ruxolitinib in subjects with active 
RA.This trial consisted of Cohort 1: 16 patients (12 received 15 mg b.i.d. of ruxolitinib, and 
four received placebo), Cohort 2: 34 patients (nine received 5 mg b.i.d. of ruxolitinib, 10 
received 25 mg b.i.d. of ruxolitinib, 10 received 50 mg q.d. of ruxolitinib, and five received 
placebo).  Efficacy demonstrated in this study has been notable. Efficacy greater than placebo 
was demonstrated in the top three doses in this study, with ACR20 (American College of 
Rheumatology 20% improvement response criteria) responses ranging from 50-83% of 
subjects, ACR50 responses in 40-50% of subjects, ACR70 responses in 25-30% of subjects, 
and ACR90 responses in 10-17% of subjects, while the placebo group and 5 mg b.i.d. group 
exhibited ACR20 responses of 33% and ACR50 responses of 11% with no ACR70 or 90 
responses. 
 
Ruxolitinib was well tolerated in RA patients dosed for 28 days with regimens including 5 
mg b.i.d, 15 mg b.i.d., 25 mg b.i.d., and 50 mg q.d. AEs were seen in similar frequency in 
patients receiving ruxolitinib as in patients receiving placebo. The intensity of AEs was 
graded according to the protocol-defined toxicity criteria based on the Rheumatology 
Common Toxicity Criteria (Version 1.0). In general, AEs were mild and self-limited usually 
resolving with continued dosing. There were no clinically significant changes in mean Hgb or 
platelet counts, and mean neutrophil counts remained within the normal range. One patient 
dosed with 25 mg b.i.d. exhibited Grade 3 neutropenia, which improved with continued 
dosing, and one patient, who had a prior history of thrombocytopenia, probably immune-
mediated thrombocytopenia, exhibited Grade 3 thrombocytopenia. SAEs of interstitial lung 
disease and congestive heart failure occurred with onset 20 days following the last dose of 
study medication (50 mg q.d.) in a patient taking methotrexate with coronary artery disease. 
The SAE resolved with treatment and was assessed as possibly related to study medication. 
2.4 
Rationale 
In addition to trastuzumab, other HER2 therapies that specifically target upstream HER2 
activity have been approved in HER2+ metastatic breast cancer, including pertuzumab, 
lapatinib, and T-DM1.  Unfortunately, the control of tumor progression is only temporary and 
the majority of the patients’ tumors eventually acquire resistance and progress (Hynes et al, 
2005). Thus, there is the need to find alternative tumor targets to develop specific, more 
efficient, treatments for patients with ErbB2+ breast cancer. By combining RNAi loss-of-
function screens with system biology interactome models, we completed a genome-wide 
screen searching for gene/pathways that are essential for the survival of ErbB2 
overexpressing breast tumor cells but dispensable for normal cells (synthetic lethal 


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2.6 
Correlative Studies Background 
Patient’s tumor tissues will be collected including archived tissue as well as optional biopsy 
before treatment, C2D1, and after treatment metastatic biopsies.  RNAseq will be performed 
on all tumor tissues to assess intrinsic molecular subtype, mutations, and interactome 
modeling for JAK/SAT pathway dependence. Metastatic biopsies will also be sent for 150 
protein reverse phase protein analysis (RPPA). These unbiased approaches will allow for 
integrated exploration of candidate resistance and sensitivity biomarkers.  In addition, 
specific candidate biomarkers will be assessed including IHC for pSTAT3 (Cell Signaling), 
serum IL-6 and IL-8 (Immulite 1000, Siemens Healthcare Diagnostics), and serum C-reactive 
protein (Cobas Integra 400 Plus, Roche Dx). 
2.6.1 Transcriptional Profiling 
RNA sequencing [RNA-seq] has emerged as the single most powerful genomic profiling 
technology.  It can be performed from less tissue [requires only 100-200ng RNA] and at 
lower cost than whole genome sequencing and delivers identification of both mutational 
events and gene expression. Unlike traditional RNA microarray analysis, RNA-seq is 
unbiased with respect to potential content, so it can detect previously unidentified genes or 
transcripts which may be involved in the phenotype of interest.  One of the biggest 
advantages of RNA-seq over microarray analysis is the ability to detect single nucleotide 
variants, small insertions and deletions (InDels) and transcript isoforms. RNA-seq also offers 
improved specificity than microarrays, so it can detect different isoforms of a transcript, and 
offers increased dynamic range of expression over microarray analysis.  Given the power of 
RNA-seq it is our chosen method of transcriptional profiling.  The quality of RNA isolated 
from FFPE samples is potentially compromised by loss in poly-A tails, fragmentized, and 
chemical modification, with possible additional deterioration from prolonged storage times.  
However, even with these limitations, RNAseq from FFPE breast cancers has been successful 
[PMID: 22808097].  In addition, the Columbia University genome center has compared RNA 
sequencing from the same samples, fresh frozen and PPFE, and found highly concordant 
sequencing. 
 
2.6.2 Reverse Phase Proteomic Array (RPPA) 
Reverse phase protein array (RPPA) is a high-throughput antibody-based technique developed 
for functional proteomics studies to evaluate protein activities in signaling networks. RPPA 
has been developed and validated as a quantitative, sensitive, and reproducible proteomic 
technology. It is inexpensive, automated, and only requires 30 micrograms of sample.  Over 
150 total and phosphospecific antibodies can be assessed. RPPA study has major strengths in 
identification and validation of cellular targets, characterization of signaling pathways and 
networks, as well as determination of on and off target activity of novel drugs. Among the 
cancer pathways represented in the RPPA data are the pathways most important for analysis of 
the combined treatment with trastuzumab and ruxolitinib, including the JAK/STAT, PI3K, and 
MAPK pathways. Each sample is analyzed for cell cycle progression, apoptosis, functional 
proteomics, and signaling network activity. RPPA is the current technology being used for 
proteomic profiling in the cancer genome atlas (TCGA) project.  Importantly, RPPA has 
recently been validated using FFPE tissues (Guo, Wang et al. 2007, Guo, Liu et al. 2012).   In 
addition, the molecular pathology core at Columbia University Medical Center has experience 
preparing RPPA samples and analyzing the results [unpublished results].   
 
Fig 3. Ruxolitinib treatment impairs transformation of MCF-10A/ErbB2 cells. (A) Western blot showing the effect of 
incubation with ruxolitinib 10uM in phosphorylation of STAT3. Treatment with the JAK inhibitor affects the expression 
of S100A8 and S100A9 while promoting PARP and caspase3 cleavage. (B) and (C) Soft agar and matrigel assays in MCF-
10A/ErbB2 cells treated with increasing doses of ruxolitinib. (D) Growth of MCF-10A/ErbB2 tumors in 
immunocompromised mice when treated with ruxolitinib. The right graph shows the final weight of the extracted tumors. 
(E) Growth of MCF-10A/ErbB2 tumors when mice were treated with different drug combinations. 


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3. PATIENT SELECTION 
 
3.1 
Inclusion Criteria  
A subject must meet all of the following criteria to be eligible for the study. 
 
1. Subjects must have histologically or cytologically confirmed adenocarcinoma of the 
breast with locally recurrent or metastatic disease.  Locally recurrent disease must not 
be amenable to any local treatment with curative intent.  Metastatic disease must be 
demonstrated either radiographically or histologically.   
2. Primary tumors and/or metastatic lesions must demonstrate HER2-neu 
overexpression, per the 2013 recommendations (Wolff, Hammond et al. JCO 2013), 
i.e.  immunohistochemistry (IHC 3+) or amplification by in situ hybridization based 
on the following: 
a. Single-probe average HER2 copy number ≥6.0 signals/cell 
b. Dual-probe HER2/CEP17 ratio ≥2.0 with an average HER2 copy number ≥4.0 
signals/cell 
C. Dual-probe HER2/CEP17 ratio ≥2.0 with an average HER2 copy number <4.0 
signals/cell 
d.  Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number > 
6.0 signals/cell 
 
Patients may be estrogen and/or progesterone positive (>1%) or negative (<1%).  
Hormone receptor status will be a stratification factor. 
 
3. Patients must have received at least two lines of HER2-directed therapy in the 
inoperable locally advanced and/or metastatic setting.  Prior therapy for inoperable 
locally advanced/metastatic disease should include trastuzumab plus pertuzumab as 
well as  ado-trastuzumab.  Pertuzumab and ado-trastuzumab should have been 
previously used, unless for reasons that include, but are not limited, to the following: 
intolerance to pertuzumab and/or ado-trastuzumab, medical contraindication, regimen 
declined by patient, treating investigator discretion, or medical insurance coverage 
issues which prevented administration of pertuzumab or ado-trastuzumab.  These 
reasons must be reviewed with the study chairs and documented in the medical record 
and care report form.   Patients who relapse within 12 months of completing 
neoadjuvant/adjuvant pertuzumab or ado-trastuzumab would be considered as having 
progressed on that regimen. 
 
Patients may have measurable disease only, non-measurable disease only, or both (RECIST 
1.1).   Concomitant treatment with bone-targeted therapies such as RANKL inhibitors or 
bisphosphonates is allowed.  It is anticipated that most patients will have measurable disease, 
given the behavior of HER2+ metastatic breast cancer.  
 
4. Because no dosing or adverse event data are currently available on the use of 
ruxolitinib in combination with trastuzumab in patients <18 years of age, children are 
excluded from this study. 
 
5. Women and men of all races and ethnic groups are eligible for this trial. 
 
6. ECOG performance status 0-2 (Karnofsky ≥60%, see Appendix A). 
 


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7. Left ventricular ejection fraction > 50% by transthoracic echocardiography or multi-
gated acquisition scan (MUGA) within 28 days prior to the first dose of the study 
drug. 
 
8. The subject has a baseline corrected QT interval < 480ms.  
 
9. Patients must have normal organ and marrow function as defined below: 
 
leukocytes 
≥ 3,000/mcL 
 
absolute neutrophil count 
≥ 1,500/mcL 
 
platelets 
≥ 100,000/mcL 
 
hemoglobin 
≥ 9 g/dL 
 
total bilirubin 
≤ 1.5 × the upper limit of normal 
 
AST(SGOT)/ALT(SGPT) 
≤ 2.5 × institutional upper limit of normal 
 
Serum creatinine   
 
≤ 1.5 × the upper limit of normal or  
 
 
 
 
 
 
 
calculated creatinine clearance ≥ 60 mL/min 
 
10. Women of childbearing potential and men must use adequate contraception prior to 
study entry and for the duration of study participation.  Contraception should continue 
to be used for a minimum of 5 mean half-lives after the last dose of study drugs (mean 
Trastuzumab half-life at 6 mg/kg 16 days; mean half-life Ruxolitinib: 3 hours) 
 
11. Patient is able to swallow, retain, and absorb oral medication. 
 
12. Life expectancy of at least 12 weeks 
 
13. Informed Consent.  Ability to understand and the willingness to sign a written  
            informed consent document. 
 
3.2 
Exclusion Criteria 
A subject who meets any of the following criteria is ineligible for the study: 
 
1. Patients who have had chemotherapy, hormonal therapy, or radiotherapy within 2 
weeks prior to entering the study or those who have not recovered from adverse 
events due to agents administered more than 2 weeks earlier. 
 
2. Patients who are receiving any other investigational agents or have received other 
investigational agents within 2 weeks or 5 half-lives of the compound or active 
metabolites, whichever is longer before the first dose of the study treatment. 
 
3. Patients who have previously been treated with an IL-6, JAK or STAT inhibitor for 
any indication, such as ruxolitinib or tocilizumab.  
 
4. Symptomatic or unstable brain metastases. (Note: Asymptomatic patients with 
metastatic brain disease who have been on a stable dose of corticosteroids for 
treatment of brain metastases for at least 14 days prior to randomization are eligible to 
participate in the study). 
 
5. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to ruxolitinib or trastuzumab.   
 


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6. The effects of ruxolitinib on the developing human fetus are unknown.  For this 
reason and because JAK2 inhibitor agents as well as other therapeutic agents used in 
this trial are known to be teratogenic, women of child-bearing potential and men must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation.  Should a 
woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform the principal investigator immediately. 
   
7. Patients receiving any medications or substances that are strong inhibitors of CYP450 
3A4 isoenzyme are ineligible.  Please refer to Appendix C for list of common strong 
inhibitors of the CYP 3A4 isoenzyme.  This list is not meant to be comprehensive, but 
provides an example of medications. If there it remains unclear as whether the 
medication is a strong inhibitor, check the prescribing information of the medication 
for accurate details.  Patients must be off the strong inhibitor for at least 1 week prior 
to being deemed eligible. 
 
8. Patients may not have an uncontrolled intercurrent illness including, but not limited 
to, ongoing or active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness that would limit compliance with 
study requirements. 
 
9. Patients must not have clinically significant cardiovascular disease (New York Heart 
Association Class III or IV heart failure), uncontrolled clinically significant atrial or 
ventricular cardiac arrhythmias, or any of the following within the past 6 months: 
myocardial infarction, new evidence of transmural infarction on ECG, unstable 
angina, coronary angioplasty.  
 
10. Pregnant women are excluded from this study because ruxolitinib is a Class C agent 
with the potential for teratogenic or abortifacient effects.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with ruxolitinib, breastfeeding must be discontinued if the 
mother is treated with ruxolitinib.  These potential risks also apply to trastuzumab, 
which can cause fetal harm when administered to a pregnant woman.  
 
11. Active Infections.  Patients with known active infections with human 
immunodeficiency virus (HIV), hepatitis A virus (HAV), hepatitis B (HBV), and 
hepatitis C virus (HCV) infections will not be considered for this trial.  HIV+ patients 
on combination antiretroviral therapy are ineligible because of the potential for 
pharmacokinetic interactions with ruxolitinib.  In addition, these patients are at 
increased risk of lethal infections when treated with marrow-suppressive therapy.  
Testing for HIV or hepatitis is not required. 
 
4. REGISTRATION PROCEDURES 
 
CUMC Research Participant Registration  
Confirm eligibility as defined in the section entitled Criteria for Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures, along with applicable institutional policies and federal regulations. 
 


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Only Investigators/Research personnel properly trained and delegated to consent subjects for 
this protocol will participate in the consenting process. Furthermore, properly 
delegated/trained Physician Investigators (i.e., MD, MD PhD) are required to sign/verify a 
protocol specific Eligibility Checklist for each subject enrolled on the study, in addition to 
providing the relevant source documentation to confirm subject eligibility. 
 
All participants must be centrally registered through the Central Registration Office 
within Herbert Irving Comprehensive Cancer Center at CUMC prior to initiation of 
study treatment. 
 
Registration hours are available Monday through Friday from 9:00am – 5:00pm EST 
(excluding holidays and weekends). Same day patient registrations (and after hour 
registrations) will be accommodated on a case-by-case basis provided that the study team has 
expressed all time sensitive registration concerns/cases in a timely manner to the Central 
Registration Office.  
 
CPDM Central Registration Procedures: 
Within 48 hours of obtaining consent (excluding holidays and weekends), a completed/signed 
IRB approved informed consent HIPAA form, and demographics forms must be submitted to 
the CPDM Central Registration Office via an email to CPDMRegistration@columbia.edu or 
fax to 212.305.5292, with the subject line “AAAM1906 Pending Subject Registration 
Request (PHI)”.  Upon receipt, applicable subject information as well as a “pending 
eligibility” status will be entered into HICCC’s institutional database.  This status will remain 
until further source documentation is made available to confirm overall patient eligibility. 
Required materials for all pending registration submissions are as follows: 
 
 Completed/signed IRB approved/stamped Informed Consent Forms, including 
additional study ICFs (i.e. tissue, DNA, etc.) as applicable 
 The completed/signed IRB approved HIPAA Authorization form 
 Completed/signed CPDM ICF checklist 
 Completed/signed HICCC personal census form 
 Completed/signed CPDM Demographics Note to File 
In order to confirm eligibility status, Investigators/designees (i.e., study specific Clinical 
Research Coordinator/Research Nurse, etc.) must submit the following documentation to the 
Central Registration Office via email or fax: 
 
 The completed/signed study specific Eligibility Checklist  (signed by a Physician 
level Investigator) 
 Copies of source documentation necessary for each item to be verified on the CUMC 
specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (i.e., hematology, 
serum chemistry, pregnancy test when applicable, MRI reports, CT/bone scans 
or PET/CT, etc.) 
o Copy of pathology and surgical reports 
o Copy of clinic note(s) or other appropriate medical records capturing the 
consent process information, along with providing source documentation of 


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Page 22 of 96 
 
any other items needed for screening/eligibility that are not captured in other 
source document forms (e.g., positive investigator statements of unique 
eligibility items not captured via other direct source documentation, 
concomitant medication lists, etc) 
o Protocol deviation/waiver approvals (if applicable) 
 Please note: subject line of email or fax should include the following: “AAAM1906 
Complete Subject Registration Request (PHI).” 
Upon Receipt of the above-mentioned documentation, participant eligibility information will 
be verified by a qualified Central Registration Registrar. If any questions arise during the 
review process, queries in the form of emails will be addressed to the applicable study team 
personnel for clarification prior to enrollment.  All applicable finalized registration/eligibility 
information will then be entered into HICCC’s institutional database by the Central 
Registration Registrar.  Upon completion, an official subject registration notification email 
will be sent to the PI/research team, which will include eligibility/enrollment status, as well 
as subject ID information.  Protocol therapy may not be initiated prior to receipt of this 
notification from the Central Registration Office. 
 
All screenfail/ineligible subjects, as well as subjects who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration office 
in a manner analogous to the procedures noted above. Applicable source documentation will 
be required within the corresponding submissions. 
 
Central Registration Procedures- Affiliate Institution Research Participant Registration 
Process:  
 
All Affiliate Institutions must register subjects with the coordinating center (CUMC) prior to 
any administration of study drug/intervention/local institution registration.  Please see 
instructions below: 
 
Within 48 hours of obtaining consent (excluding holidays and weekends), the Affiliate 
Institution CRN and/or CRC is required to submit the following documents to the 
coordinating center’s designee (CUMC’s Multicenter Core) via the study email at 
m1906@columbia.edu.  The coordinating center’s designee will review the documents for 
accurateness, and subsequently submit the documents to the CPDM Central Registration 
Office via email at CPDMRegistration@columbia.edu (or via fax at 212.305.5292), with a 
request to register the patient “pending eligibility.” The title of the email should read, 
“AAAM1906 Pending Subject Registration Request (PHI)”.  The following documents 
should be submitted with the pending registration request: 
 Redacted Completed/signed IRB approved/stamped Informed Consent Forms, 
including additional study ICFs (i.e. tissue, DNA, etc.) as applicable 
 Redacted Signed HIPAA (or institutional equivalent) 
 MCT CPDM Demographics Note to File form  
 
The Affiliate Institution’s investigator/research nurse/data manager/coordinator must contact 
the coordinating center’s designee (CUMCMulticenter Core) via telephone or email at 
m1906@columbia.edu to communicate the following: 


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 Notify of pending registration request  
 Confirm method of registration request submission (email or fax) 
 Communicate expected time-line of registration request submission (i.e., same 
day, next day, within the hour, etc.) 
 
To complete registration, the Affiliate Institution’s investigator/research nurse/data 
manager/coordinator should then submit the following documents to the CUMC study 
specific designee: 
 A signed Affiliate Site Eligibility Checklist (signed by the investigator) 
 Copies of redacted source documentation necessary for each item to be verified on 
the CUMC specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (i.e., hematology, 
serum chemistry, pregnancy test when applicable, MRI reports, CT/bone 
scans, etc.) 
o Copy of pathology and surgical reports 
o Copy of clinic note(s) capturing the consent process information, along with 
providing source documentation of any other items needed for 
screening/eligibility that are not captured in other source document forms. 
(e.g., positive investigator statements of unique eligibility items not captured 
via other direct source documentation, concomitant medication lists, etc.) 
o Protocol deviation/waiver approvals (if applicable) 
 
Please note: subject line of email or fax should include the following: “AAAM1906 
Complete Subject Registration Request (PHI)”. 
 
Upon receipt of the above mentioned documents, the designated study specific Clinical 
Research Coordinator will review all documents and verify patient eligibility.  If any 
questions arise during the review process, queries in the form of emails will be addressed to 
the applicable affiliate site study team personnel for clarification prior to enrollment.  Upon 
verification, the CUMC study specific designee will then forward all documents to the 
CPDM Central Registration Office for central registration (as described above). The CPDM 
Central Registration Registrar will review all applicable documents and communicate to the 
CUMC study specific designee in order to clarify any items.  The CUMC study specific 
designee will communicate with the applicable site study team personnel for additional 
clarifications necessary prior to enrollment. 
 
Upon receipt of the subject registration notification email, the CUMC study specific designee 
will forward the notification email (which will include the study specific patient ID) to the 
affiliate site’s Principal Investigator, Consenting Professional, and applicable research 
personnel.  This notification should be filed in the patient research binder accordingly. 
Protocol therapy may not be initiated prior to receipt of this notification from the 
coordinating center. 
 


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All screenfail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration office 
in a manner analogous to the procedures noted above. Applicable source documentation will 
be required within the corresponding submissions. 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
Treatment will be administered on an outpatient basis.  Expected adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  
No investigational or commercial agents or therapies other than those described below may 
be administered with the intent to treat the patient's malignancy. 
 
Table 1: Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Ruxolitinib 
None 
 
Phase I (assigned): 
BID dosing (10 mg, 
15 mg, 20 mg, or 25 
mg) 
Phase II: Based upon 
MTD from phase I 
PO 
Days 1-
21  
21 days  
(3 weeks) 
 
 
 
Trastuzumab None (unless 
prior reaction) 
6 mg/kg in 250 cc NS 
(8 mg/kg initial re-
load if no 
trastuzumab > 28 
days) 
IV over 90 
minutes for 
initial dose.  
IV over 30-90 
minutes for 
subsequent 
doses 
Day 1, 
Week 1 
 
 
Treatment Cycle 
The duration of a treatment cycle will be 21 days.  Ruxolitinib will be taken orally twice 
daily, every day for 21 days.  Trastuzumab will be administered IV on Day 1 out of a 21-day 
cycle.  The initial dose of trastuzumab will be 8 mg/kg (loading dose) if the patient has not 
received trastuzumab in > 28 days.  If the patient has received a dose of trastuzumab within 
the prior 28 days then the initial dose will be 6 mg/kg. Subsequent doses will be 6 mg/kg 
(maintenance dose). 
 
If the patient has a history of infusion reaction to trastuzumab, the pre-medications will be 
administered 30 minutes prior to administration of trastuzumab.  Pre-medications are allowed 
and should be followed by institutional standards.  These can include acetaminophen 650mg 
po once, diphenhydramine 25-50mg po/IV once 30 minutes prior to administration of drug, 
and/or a H2 receptor antagonist (such as famotidine 20 mg po/IV). 
 
Patient compliance with ruxolitinib will be assessed by medication diary.  The patient will be 
requested to record each dose of medication.  The medication diary will be returned to 
research staff at the end of each cycle. 
 


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Ruxolitinib 
Ruxolitinib is an FDA-approved treatment for intermediate to high-risk myelofibrosis, 
including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-
essential thrombocythemia myelofibrosis. It does not require specific prophylactic or 
supportive regimens.  It is an oral therapy and can be administered with or without 
food according to manufacturer’s recommendations.  Subjects in the phase I study 
will be given a 3-week supply of medication.  Dosing will start at 20 mg b.i.d. for the 
phase I. 
 
Trastuzumab 
Trastuzumab is FDA-approved for HER2+ breast cancer and gastric cancer.  It does 
not require specific prophylactic or supportive regimens.  It is an intravenous therapy 
that should be prepared according to manufacturer’s recommendations.  It can be 
administered with or without food.  
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
Ruxolitinib is an FDA approved treatment for myelofibrosis and is commercially available.  
Per manufacturer Prescribing Information (PI), there are no concurrent supportive or 
prophylactic regimens recommended. 
 
Ruxolitinib is predominantly metabolized by CYP3A4. When administering ruxolitinib with 
strong CYP3A4 inhibitors, a dose reduction is recommended.  Thus, co-administration of 
ruxolitinib with strong CYP3A4 inhibitors will not be allowed.  Patients should be closely 
monitored and the dose titrated based on safety and efficacy. No dose adjustment is 
recommended when ruxolitinib is co-administered with mild or moderate CYP3A4 inhibitors 
(i.e. erythromycin) or a CYP3A4 inducer – and patients on these medications will not be 
excluded.  Appendix C presents guidelines for identifying medications/substances that could 
potentially interact with the study agent(s). 
 
If a subject requires additional anti-cancer therapy, the subject must be withdrawn from study 
treatment, with the exception of palliative radiotherapy (ie, to bone metastasis or for subjects 
who have disease progression limited to the CNS but who are otherwise benefiting from 
study treatment), which may be allowed during the study but must be discussed with the 
overall principal investigator. Study treatment should be withheld until palliative 
radiotherapy is terminated. This treatment break should not be considered as treatment 
interruption in determining the DLT. Palliative radiotherapy to metastatic disease sites is 
allowed provided there are other sites of disease and ≥ 1 week has elapsed since the 
completion of radiotherapy and all treatment-related toxicities have resolved or are at a new 
stable baseline. Subjects who have received radiation to the spine, pelvis, ribs, or femur 
should be discussed and approved by one of the overall principal investigator prior to study 
re-entry.  If anti-cancer treatment follows discontinuation of study treatment due to clinical 
progression determined by the investigator, the basis for this determination should be 
documented. 
5.3 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue until one 
of the following criteria applies: 
 
Disease progression 


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 
Intercurrent illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Patient decides to withdraw from the study  
 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. OR 
 
Pregnancy 
 
In the absence of one of the events listed above, there is no pre-defined limit on the number 
of potential cycles. 
 
5.4 
Duration of Follow Up 
Patients will no longer be followed after removal unless adverse event(s) occur.  All adverse 
events, both serious and non-serious, and deaths that are encountered during the study and 
within 30 days of the last study intervention should be followed.  See Section 7.4.7.  
 
5.5 
Criteria for Removal from Study 
Patients will be removed from study when any of the criteria listed in Section 5.3 applies.  
The reason for study removal and the date the patient was removed must be documented in 
source documentation and the Case Report Form. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
The most common adverse events are listed below.  Definitions of grading of each Adverse 
Events are defined per CTCAE 4.0.  Doses of ruxolitinib that are missed will not be made up, 
and upon resumption of dosing, the cycle will stay on schedule.  If the dose is reduced for 
hematologic toxicities, a repeat complete blood count with differential should be performed 
within 7 days (+/- 2 days) of dose reduction.  Management for each grade of AE is outlined 
below.   
 
Dosing delays/ dose modifications should occur only if adverse event is deemed possibly, 
probably, or definitely related to study drug.  
 
Table 2: Dose Levels 
Dose Level 
Ruxolitinib Dose 
1 
25 mg bid 
0 
20 mg bid 
-1 
15 mg bid 
-2 
10 mg bid 
 
Table 3: Neutropenia 
Neutrophil Count 
Decreased 
Management/Next Dose for 
Ruxolitinib 
Management/Next Dose for 
Trastuzumab 
Grade 1 
<LLN – 1500 
No change in dose 
No change in dose 
Grade 2 
<1500 – 1000 
No change in dose 
No change in dose 
Grade 3 
<1000 – 500 
Hold* until ≤ Grade 2.  Resume at 
one dose level lower, per 
investigator discretion** 
No change in dose 
Grade 4 
Hold* until ≤ Grade 2. Resume at 
No change in dose 


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Neutrophil Count 
Decreased 
Management/Next Dose for 
Ruxolitinib 
Management/Next Dose for 
Trastuzumab 
<500 
one dose level lower** 
*Patients requiring a ruxolitinib delay of > 28 days should go off protocol therapy.  Growth 
factor support is allowed, per investigator discretion. 
**Patients requiring > 2 dose reductions of ruxolitinib should go off protocol therapy. 
 
Table 4: Thrombocytopenia 
Platelet Count 
Decreased 
Management/Next Dose for 
Ruxolitinib 
Management/Next Dose for 
Trastuzumab 
Grade 1 
<LLN - 75,000 
No change in dose 
No change in dose 
Grade 2 
<75,000 – 50,000 
No change in dose 
No change in dose 
Grade 3 
<50,000 - 25,000 
Hold* until ≤ Grade 2.  Resume at 
one dose level lower, per 
investigator discretion** 
No change in dose 
Grade 4 
<25,000 
Hold* until ≤ Grade 2.  Resume at 
one dose level lower** 
No change in dose 
*Patients requiring a ruxolitinib delay of > 28 days should go off protocol therapy.  
**Patients requiring > 2 dose reductions of ruxolitinib should go off protocol therapy. 
 
Table 5: Anemia 
Hemoglobin 
Decreased 
Management/Next Dose for 
Ruxolitinib 
Management/Next Dose for 
Trastuzumab 
Grade 1 
<LLN – 10 
No change in dose 
No change in dose 
Grade 2 
<10 – 8 
No change in dose 
No change in dose 
Grade 3 
<8 
Transfuse PRBC as clinically 
indicated.  Hold* until ≤ Grade 2.  
Resume at one dose level lower, 
per investigator discretion** 
No change in dose 
Grade 4 
Transfuse PRBC as clinically 
indicated.  Hold* until ≤ Grade 2.  
Work up for alternative causes of 
blood loss.  First occurrence: 
Resume at one dose level lower.  
Second occurrence: off therapy. 
No change in dose 
*Patients requiring a ruxolitinib delay of > 28 days should go off protocol therapy.  Growth 
factor support is allowed, per investigator discretion. 
**Patients requiring > 2 dose reductions of ruxolitinib should go off protocol therapy. 
 
Table 6: Febrile Neutropenia 
Febrile Neutropenia 
Management/Next Dose for 
Ruxolitinib 
Management/Next Dose for 
Trastuzumab 
Grade 1 
N/A 
N/A 
Grade 2 
N/A 
N/A 
Grade 3 
Hold* until ≤ Grade 2.  Resume at 
No change in dose 


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Febrile Neutropenia 
Management/Next Dose for 
Ruxolitinib 
Management/Next Dose for 
Trastuzumab 
one dose level lower ** 
Grade 4 
Hold* until ≤ Grade 2.  First 
occurrence: Resume at one dose 
level lower.  Second occurrence: 
off therapy. 
No change in dose 
*Patients requiring a ruxolitinib delay of > 28 weeks should go off protocol therapy.  Growth 
factors support is allowed, per investigator discretion. 
**Patients requiring > 2 dose reductions should go off protocol therapy. 
 
Table 7: Non-Hematologic Toxicities 
Non-Hematologic 
Toxicities  
(non-Cardiac) 
Management/Next Dose for 
Ruxolitinib 
Management/Next Dose for 
Trastuzumab 
Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold* until ≤ Grade 1.  
Recommend resume at same dose 
level, but per investigator 
discretion.  If the toxicity is 
deemed possibly, probably, or 
definitely related to ruxolitinib – 
and not reduced after the first 
occurrence - a dose reduction 
should be considered after a second 
recurrence, if still deemed 
possibly, probably, or definitely 
related. 
No change in dose 
Grade 3 
Hold* until ≤ Grade 1.  Resume at 
one dose level lower** 
No change in dose 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management if diarrhea:  loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-
free for 12 hours (maximum dosage:  16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
Recommended management if nausea/vomiting: anti-emetics 
 
6.1 
Management of Cardiac Toxicity 
Frequent cardiac evaluations will be performed in this study because cardiotoxicity has been 
reported in patients treated with single-agent trastuzumab and in combination with targeted 
therapies.  Initiation of trastuzumab will depend on review of the initial multiple-gated 
acquisition (MUGA) scan/echocardiogram (ECHO) results. It is recommended patients have 
their MUGA scans/ECHOs performed at the same radiology facility to eliminate variability 
between facilities. The same method for assessment should be used throughout the study.  A 
MUGA/ECHO should be performed at baseline, prior to cycle 2 (during phase I), and then 
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The cardioprotective drug dexrazoxane may not be taken by subjects participating in this 
trial. 
 
6.2 
Asymptomatic Decrease in LVEF (Left Ventricular Ejection Fraction) 
Decision to continue or stop trastuzumab treatment is based on the measured ejection fraction 
as it relates to the radiology facility’s lower limit of normal (LLN) and change in ejection 
fraction from baseline. Guidelines for performing MUGA scan/ECHO and management of 
patients who have an asymptomatic decrease in LVEF from baseline are provided below: 
 
Table 8: Guidelines for Trastuzumab Suspension 
Relationship of 
LVEF to Radiology 
Facility’s LLN 
Decrease of < 10 
Percentage Points 
From Baseline 
Decrease of 10 to 
15 Percentage Points 
From Baseline 
Decrease of 
≥ 16 Percentage 
Points From Baseline 
Within normal limits 
Continue 
Trastuzumab 
Continue 
Trastuzumab 
Hold Trastuzumaba,b 
1-5 percentage points 
below 
LLN 
Continue 
Trastuzumab 
Hold Trastuzumaba,b 
Hold Trastuzumaba,b 
≥ 6 percentage points 
below 
LLN 
Continue 
Trastuzumaba 
Hold Trastuzumaba,b 
Hold Trastuzumaba,b 
LLN, lower limit of normal; LVEF, left ventricular ejection fraction; MUGA, multiple gated 
acquisition scan.  Source: Cardiac management during adjuvant trastuzumab therapy (Mackey et 
al. 2008). 
a Repeat MUGA/ECHO after 4 weeks. 
b After two consecutive holds permanently discontinue trastuzumab. 
 
If trastuzumab is held or discontinued during therapy, treatment with ruxolitinib may be 
continued, per the investigator. Trastuzumab must be permanently discontinued if withheld 
for more than 9 weeks or earlier per discretion of the investigator. If LVEF is maintained at a 
“continue and repeat MUGA/ECHO” or improves from a “hold” to a “continue and repeat 
MUGA/ECHO” category, additional MUGA scans/ECHO prior to the next scheduled 
MUGA scan/ECHO will be at the discretion of the investigator. 
 
6.3 
Symptomatic Decrease in LVEF 
For symptomatic Grade 3 and Grade 4 congestive heart failure (CHF), hold treatment with 
study drugs. A cardiology consult should be obtained and treatment per institutional 
standards should be initiated. Confirm diagnosis of CHF with either a MUGA scan/ECHO. A 
chest x-ray is also required. Once a diagnosis of CHF is confirmed, treatment with study 
drugs must be permanently discontinued and reported as an AE.  
 
6.4 
Cardiac Ischemia/ Infarction  
Grade 1: Continue treatment with frequent monitoring. 
 
Grade 2: Hold treatment with study drugs and conduct cardiac evaluation. Based on this 
evaluation, treatment may be continued at the discretion of the investigator. 
 
Grade 3 or 4: Discontinue treatment with study drugs. 
 


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6.5 
Arrhythmia  
Grade 1: Continue treatment with study drugs with careful monitoring OR hold treatment and 
conduct cardiac evaluation. Based on cardiac evaluation, treatment with study drugs may 
continue or discontinue at the discretion of the investigator. 
 
Grade 2: Hold treatment with study drugs and conduct cardiac evaluation. Based on cardiac 
evaluation, treatment with study drugs may continue or discontinue at the discretion of the 
investigator. 
 
Grade 3 or 4: Discontinue treatment with study drugs. 
 
6.6 
Management of Corrected QTc Prolongation 
At any time point, if there is an increase in the QTc intervals (using Bazett or Fridericia 
correction formula) to > 500 msec (ie, Grade 3 QTc prolongation), an additional ECG should 
be performed. If the average QTc is > 500 msec, study treatment should be withheld.  If the 
subject is asymptomatic (ie, does not have palpitations, dizziness, syncope, orthostatic 
hypotension, a significant ventricular arrhythmia on ECG, or a change in vital signs), the 
following actions should be taken: 
• 
Hold ruxolitinib.  Can continue trastuzumab. 
• 
Check electrolytes, especially magnesium and potassium; correct abnormalities as 
clinically indicated 
• 
Modify the dose as a Grade 3, Non-hematologic AE as described in Table 7 after 
the QTc elevation has resolved. 
 
Subjects with QTc prolongation and symptoms must be monitored closely. Cardiology 
consultation is recommended for evaluation and subject management. No additional study 
treatment will be given to the subject until after the event has resolved.   
 
6.7 
Management of Trastuzumab Infusion Reaction 
Infusion reactions consist of a symptom complex, such as fever and chills, and on occasion 
nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, 
hypotension, rash, and asthenia. Infusion reactions should be managed by standard clinical 
practice. Stop infusion and give antipyretics if fever occurs within 24 hours of trastuzumab 
infusion. Once the temperature is < 38°C, resume infusion at a slower rate and monitor the 
patient according to institutional standard practice. Chills triggered by trastuzumab infusion 
can be treated with acetaminophen and/or diphenhydramine hydrochloride. Meperidine may 
be given at the investigator’s discretion. 
 
Pulmonary toxicity including dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural 
effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute 
respiratory distress syndrome, and pulmonary fibrosis can occur as sequelae of infusion 
reactions. Management of pulmonary toxicity should follow clinical standard practice. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
An Adverse Event (AE) is any undesirable sign, symptom or medical condition or experience 
that develops or worsens in severity after starting the first dose of study treatment or any 
procedure specified in the protocol, even if the event is not considered to be related to the 
study. 
 


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Abnormal laboratory values or diagnostic test results constitute adverse events only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests. 
 
Adverse events will be monitored from the time the subject signs informed consent. Subjects 
will be instructed to report all AEs during the study and subjects will be assessed for the 
occurrence of AEs throughout the study. All AEs (serious and nonserious) must be recorded 
on the source documents and case report forms regardless of the assumption of a causal 
relationship with the study drug. 
 
Adverse Events that begin or worsen after informed consent should be recorded in the 
Adverse Events section of the case report form (CRF). Conditions that were already present 
at the time of informed consent should be recorded in the baseline symptoms section of the 
CRF. Adverse Event monitoring should be continued for at least 30 days following the last 
dose of study treatment. Adverse Events (including lab abnormalities that constitute AEs) 
should be described using a diagnosis whenever possible, rather than individual underlying 
signs and symptoms. When a clear diagnosis cannot be identified, each sign or symptom 
should be reported as a separate AE. 
 
The following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 
7.2) will determine whether the event requires expedited reporting in addition to routine 
reporting. 
 
7.1 
Comprehensive Adverse Events and Potential Risks List 
 
Adverse Event List for Ruxolitinib 
Adverse Events with Possible Relationship to Ruxolitinib 
(CTCAE 4.0 Term)  
Likely (> 20%)  
Less Likely (≤ 20%)  
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS  
 
1. Anemia 
1. Febrile neutropenia  
 
 
CARDIAC DISORDERS 
 
1. Atrial Flutter 
2. Atrial Fibrillation 
Cardiac Failure 
GASTROINTESTINAL DISORDERS  
 
1. Diarrhea  
 
1. Abdominal pain 
2. Abd Distension 
3. Constipation 
4. Dyspepsia 
5. Flatulence 
6. Nausea  
1. Colitis 
2. Gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS  
 
1. Fatigue  
 
2. Fever  
 
3. Pain  
4. Edema limb 
 
 
INFECTIONS AND INFESTATIONS  


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   1. Infection 
1.  Posterior multifocal 
leukoencephalopathy 
INJURY, POISONING, AND PROCEDURAL COMPLICATIONS 
1. Bruising 
 
 
INVESTIGATIONS  
1. Platelet count decreased 
1. Aspartate aminotransferase 
increased  
2. Bilirubin increased 
3. GGT increased  
4. Neutrophil count decreased2  
5. Weight Gain 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS  
 
1. Arthralgia  
2. Back pain  
 
NERVOUS SYSTEM DISORDERS  
 
1. Headache 
2. Dizziness  
 
 
 
PSYCHIATRIC DISORDERS 
 
  1. Confusion 
  2. Insomnia 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS  
 
 
1. Cough  
2. Dyspnea 
3. Epistaxis 
1. Pleural Effusion  
  
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS  
 
1. Rash  
Rash acneifo
 
 
VASCULAR DISORDERS  
 
 
1. Hematoma 
 
The comparison of the control groups to the ruxolitinib patients showed that headache was 
more frequent in ruxolitinib-treated patients (13.6% vs. 6.0% on placebo and 5.5% on best 
available therapy: BAT). Most AEs of headache were Grade 1 or 2. Similarly, dizziness 
(12.0% vs. 6.6% on placebo and 6.8% on BAT) was more frequent in ruxolitinib-treated 
patients, again mostly Grade 1 or 2. When adjusted for patient-year exposure, the differences 
are still present for headache and dizziness. 
 


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Weight increase was also more frequent in ruxolitinib-treated patients than in the control 
groups (9.6% vs. 1.3% on placebo and 1.4% on BAT). Although some of these patients had 
co-reported AEs of edema, many had a past medical history of weight loss and the weight 
gain usually gradually accumulated over the course of one year of treatment. The majority of 
weight gain AEs were Grade 1 and 2. It is worth noting that weight gain may be a beneficial 
effect in patients with MF, given the catabolic nature of the disease and the frequency of 
weight loss reported as a constitutional symptom. Other preferred terms with increased 
frequency in the ruxolitinib arms included bruising (2.6% vs. 1.3% on placebo), contusion 
(8.6% vs. 5.3% on placebo and 1.4% on BAT), urinary tract infection (7.3% vs. 4.6% on 
placebo and 2.7% on BAT), herpes zoster (4.0% vs. 0.7% on placebo and 0% on BAT) and 
flatulence (3.3% vs. 1.3% on placebo and 0% on BAT). 
 
Abdominal pain was more frequent in the control groups than in the ruxolitinib group (43% 
on placebo and 13.7% on BAT vs. 12% on ruxolitinib), as were weight decrease (8.6% on 
placebo and 8.2% on BAT vs. 1% on ruxolitinib), early satiety (8.6% on placebo and 0% on 
BAT vs. 0.3% on ruxolitinib) and splenic infarction (6.0% on placebo and 0% on BAT vs. 
1.0% on ruxolitinib). 
 
A total of 13 reports of tuberculosis (TB) during ruxolitinib treatment had been received from 
all clinical trials, as of February 2013.  The cumulative incidence of TB reported in subjects 
treated with ruxolitinib (13/4755; 0.27%) is less than that originally observed in the Phase III 
clinical trials (3/301; 1.0%), possibly due to differences in time of exposure to ruxolitinib and 
a more heterogeneous study population.  The Phase III clinical trial sample size did not allow 
detection of a statistically significant difference in the incidence of tuberculosis between the 
treatment and control arms.  The cumulative incidence of these TB reports appears to have 
declined since the original Phase III trials. 
 
Progressive multifocal leukoencephalopathy (PML) was reported in a myelofibrosis patient 
receiving ruxolitinib, with an atypical feature of a short time to onset (approximately 1 
month) after initiation of ruxolitinib treatment.  Because of its mechanism of action, 
ruxolitinib may be associated with a higher risk of infections.  However, infections are also 
well known complications of myelofibrosis and the occurrence of PML has been described in 
myeloproliferative diseases in the absence of ruxolitinib treatment.  Whereas a contribution 
of ruxolitinib therapy cannot be formally ruled out, the available information with the 
observation of a single case of PML is currently insufficient to formally establish a causal 
association of PML with the drug therapy.  Based on this report and provided the potentially 
disabling outcome of this condition, the potential risk of PML is closely monitored. 
 
Non-melanoma skin cancers (NMSC) have been reported in patients treated with ruxolitinib. 
These are highly uncommon.  Most of these patients had histories of extended treatment with 
hydroxyurea (a chemotherapy associated with skin cancer) and prior NMSC or pre-malignant 
skin lesions.  Hydroxyurea is not a standard chemotherapy given to patients with breast 
cancer. A causal relationship to ruxolitinib has not been established. 
 
Updated Risk Section, including update on NMSC and the following statement: “Ruxolitinib 
is currently under clinical development for the treatment of solid tumors in combination with 
cytotoxic chemotherapy. To date there have been no specific adverse drug reactions have 
been identified that are unique to ruxolitinib combination therapies under study, and the 
relative strength index derived primarily from treatment of myeloproliferative neoplasms is 
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Adverse Event List for Trastuzumab 
Adverse Events with Possible Relationship to Trastuzumab  
(CTCAE 4.0 Term)  
 
Likely (> 20%)  
Less Likely (≤ 20%)  
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS  
 
 
1. Anemia  
 
2. Febrile neutropenia2  
 
CARDIAC DISORDERS 
 
1. Cardiomyopathy  
2. Left ventricular systolic 
dysfunction  
 
3. Pericardial effusion  
4. Pericarditis  
5. Sinus tachycardia  
 
6. Supraventricular tachycardia  
 
GASTROINTESTINAL DISORDERS  
 
 
1. Abdominal pain  
2. Diarrhea  
3. Mucositis oral  
4. Nausea  
5. Vomiting  
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS  
 
1. Chills  
 
2. Fatigue  
 
3. Fever  
 
4. Flu like symptoms  
 
5. Infusion related reaction  
6. Non-cardiac chest pain  
 
7. Pain  
 
IMMUNE SYSTEM DISORDERS  
 
1. Allergic reaction3  
2. Anaphylaxis  
 
INFECTIONS AND INFESTATIONS  
 
   1. Infection4  
 
INVESTIGATIONS  
 
1. Alkaline phosphatase 
increased  
2. Aspartate 
aminotransferase increased  
3. GGT increased  
4. Neutrophil count 
decreased2  
 
METABOLISM AND NUTRITION DISORDERS  
 
1. Anorexia  
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS  
 
1. Arthralgia  
2. Back pain  
3. Bone pain  
4. Myalgia  
 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)  
 
1. Tumor pain  
 
NERVOUS SYSTEM DISORDERS  
 
1. Headache   
2. Peripheral sensory 
 neuropathy  
 


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RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS  
 
1. Allergic rhinitis   
2. Cough  
 
3. Dyspnea3  
 
4. Hypoxia3  
 
5. Pneumonitis3  
6. Pulmonary edema  
7. Pulmonary fibrosis  
  1. Adult respiratory   distress syndrome3 
  2. Bronchospasm3 
3. Pneumonitis3  
4. Pulmonary edema  
5. Pulmonary fibrosis  
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS  
 
1. Rash acneiform  
Rash acneiform (Gr. 3)  
2. Rash maculo-papular  
Rash maculo-papular (Gr. 3)  
3. Urticaria  
Urticaria (Gr. 3)  
 
VASCULAR DISORDERS  
 
1. Hypertension5  
2. Hypotension5  
 
1This table will be updated as the toxicity profile of the agent is revised.  
2Fatal event when given in combination with Xeloda® (capecitabine) and Taxotere® (docetaxel).  
3Severe hypersensitivity reactions including angioedema and pulmonary adverse events (e.g., hypoxia, dyspnea, 
pulmonary infiltrates, pleural effusion, and acute respiratory distress syndrome) have been reported.  
4Infection may include any of the 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC.  
5Associated with infusion reactions.  
 
Additional adverse events:  
The following are adverse events which have been reported on trastuzumab trials; however, 
the relationship to trastuzumab is currently undetermined.  
 Cardiac Disorders – acute coronary syndrome, atrial fibrillation, cardiac arrest, 
myocardial infarction; ventricular arrhythmia; ventricular fibrillation; ventricular 
tachycardia  
 Ear and Labyrinth Disorders - hearing impaired  
 Endocrine Disorders – hypothyroidism  
 Eye Disorders - blurred vision; extraocular muscle paresis  
 Gastrointestinal Disorders - colitis; dyspepsia; enterocolitis; esophageal ulcer; 
gastritis; pancreatitis; upper gastrointestinal hemorrhage  
 General Disorders and Administration Site Conditions - sudden death NOS  
 Immune System Disorders - immune system disorders - Other (autoimmune 
thyroiditis)  
 Investigations - alanine aminotransferase increased; blood bilirubin increased; cardiac 
troponin-I; creatinine increased; platelet count decreased  
 Metabolism and Nutrition Disorders - hypomagnesemia; hyponatremia  
 Musculoskeletal and Connective Tissue Disorders - avascular necrosis; generalized 
muscle weakness; muscle weakness left-sided; muscle weakness lower limb; muscle 
weakness right-sided; muscle weakness trunk; muscle weakness upper limb; 
musculoskeletal and connective tissue disorder - Other (myopathy)  
 Nervous System Disorders - ataxia; cognitive disturbance; depressed level of 
consciousness; dizziness; hydrocephalus; ischemia cerebrovascular; neuralgia; 
seizure; syncope  
 Psychiatric Disorders - anxiety; confusion; depression; psychosis  
 Renal and Urinary Disorders - acute kidney injury; hematuria; proteinuria; urinary 
tract obstruction  
 Reproductive System and Breast Disorders - fallopian tube obstruction; prostatic 
obstruction; spermatic cord obstruction; uterine obstruction; vaginal obstruction  


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 Respiratory, Thoracic and Mediastinal Disorders - apnea; laryngeal edema; 
pharyngolaryngeal pain; pleural effusion; pneumothorax; pulmonary hypertension; 
voice alteration  
 Skin and Subcutaneous Tissue Disorders - nail loss; pruritus; skin ulceration  
 Vascular Disorders - thromboembolic event 
 
Note: Trastuzumab in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result 
in events never previously associated with either agent.  
Additional adverse events from the FDA-approved October 2010 Prescribing 
Information for Herceptin® (Trastuzumab)  
General Disorders – edema limbs, edema trunk  
Infections and Infestations – pharyngitis  
Nervous System Disorders – dizziness  
Psychiatric Disorders – depression, insomnia  
Renal and Urinary Disorders – other (glomerulopathy) 
 
7.2 
Definitions and Reporting 
 
7.2.1 Dose Limiting Toxicity (DLT) 
A dose-limiting toxicity is defined as any grade 3 non-hematologic toxicities despite maximal 
supportive care or any grade 4 hematologic toxicity directly related to study drug.  In order 
for a patient to be completely evaluable for DLT, the patient must incur a DLT during the 
first 21 days of actively taking ruxolitinib plus trastuzumab.  If, for instance, the patient 
temporarily stops ruxolitinib due to uncomplicated hematologic toxicities, the patient can 
resume ruxolitinib at the same dose and the DLT period will remain defined as the first 21 
days of actively taking the study medication.  In order to be considered completely followed, 
the DLT period (i.e. 21 days of actively taking ruxolitinib plus trastuzumab) must be 
completed within 30 days of the first dose of ruxolitinib.  If a patient is not completely 
followed due to dropout, treatment discontinuation, or death which is unrelated to study drug, 
we will replace that patient so that the sample size refers to those with complete DLT follow-
up.  However, patients with partial follow-up will be included up to their last assessment 
while on treatment. 
 
7.2.2 Adverse Event (AE) 
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. The occurrence of AEs should be sought by non-directive questioning 
of the subject during the screening process after signing informed consent and at each visit 
during the study. As far as possible, each AE should be evaluated to determine: 
• The severity grade (CTCAE Grade 1-5) 
• Reasonable possibility that AE is related to the study treatment: Definite, Probable, 
Possible, Unlikely, Unrelated (Section 7.3.4) 
• Start and end dates, unless unresolved at final exam 
 
Action taken with respect to study drug (i.e., none, dose adjusted, temporarily interrupted, 
permanently discontinued, unknown, not applicable) 
• Outcome (eg, not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown) 
• Whether it is serious, as per Serious Adverse Event (SAE) definition provided in Section 
7.2.2. 


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Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements, see Section 7.2.2. 
 
All AEs should be treated appropriately. If a concomitant medication or non-drug therapy is 
given, this action should be recorded on the AE CRF as well as the Prior/Concomitant 
medications CRF. 
 
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent; assessment should be made at each visit (or more frequently if necessary) of any 
changes in severity, the suspected relationship to the study drug, the interventions required to 
treat it, and the outcome. 
 
Disease progression should not be regarded or reported as an AE itself, unless it is associated 
with a separate AE. 
 
Laboratory abnormalities that constitute an AE in its own right (are considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the AE CRF. Whenever possible, a 
diagnosis, rather than a symptom should be provided (i.e., anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for AEs should be followed 
until they have returned to normal or an adequate explanation of the abnormality is found. 
 
When an abnormal laboratory or test result corresponds to a sign or symptom of a previously 
reported AE, it is not necessary to separately record the lab/test result as an additional event.  
 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as 
AEs. A Grade 3 or 4 (severe) event, as per CTCAE, does not automatically indicate a SAE 
unless it meets the definition of serious, as defined below, and/or as per the investigator’s 
discretion. 
 
7.2.3 Serious adverse event (SAE) 
A serious adverse event (SAE) is any adverse event, occurring at any dose and 
Regardless of causality that: 
 
• Results in death. 
 
• Is life-threatening. Life-threatening means that the person was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically might 
have caused death had it occurred in a more severe form. 
 
• Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-hour 
hospitalization or prolonged a hospitalization beyond the expected length of stay). 
Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry are not considered SAEs if the illness or disease 
existed before the person was enrolled in the trial, provided that it did not deteriorate in an 
unexpected manner during the trial (e.g., surgery performed earlier than planned). 
 
• Results in persistent or significant disability/incapacity. Disability is defined as a substantial 
disruption of a person’s ability to conduct normal life functions. 


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• Is a congenital anomaly or birth defect; or 
 
• Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.  
 
Events not considered to be serious adverse events are hospitalizations for: 
 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures. 
 
• Elective or pre-planned treatment for a pre-existing condition that did not worsen. 
 
• Emergency outpatient treatment for an event not fulfilling the serious criteria outlined above 
and not resulting in inpatient admission. 
 
• Respite care 
 
7.2.4 Unanticipated Problem 
An Unanticipated Problem (UP) is any incident, experience or outcome involving risk to 
subjects or others in any human subjects research that meets all of the following criteria:  
 Unexpected (in terms of nature, severity or frequency) given (a) the research 
procedures that are described in the IRB-approval protocol and informed consent 
document, and (b) the characteristics of the subject population being studied;  
 Related or possibly related to participation in such research (i.e., there is a reasonable 
possibility that the incident, experience or outcome may have been caused by the 
procedures involved in such research); and  
 Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic or social harm) than was previously known or 
recognized.   
 
7.2.5 Suspected Adverse Reaction 
A Suspected Adverse Reaction (SAR) is any AE for which there is a reasonable possibility 
that it was caused by the drug. 
Reasonable possibility means that there is evidence to suggest a causal relationship between 
the drug and the AE.  Examples of reasonable possibility are: 
 A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure. 
 One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug. 
 An aggregate analysis of specific events observed in a clinical trial that indicates that 
those events occur more frequently in the drug treatment group than in a concurrent or 
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7.2.6 Expectedness 
Adverse events can be 'Expected' or 'Unexpected.' 
 
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered 
expected when it appears in the current adverse event list, the Investigator’s Brochure, the 
package insert or is included in the informed consent document as a potential risk. 
 
For the purposes of this study, an adverse event is considered unexpected when it varies in 
nature, intensity or frequency from information provided in the current adverse event list, the 
Investigator’s Brochure, the package insert or when it is not included in the informed consent 
document as a potential risk. 
 
7.2.7 Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the 
study treatment. Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment. 
• Unlikely - The AE is doubtfully related to the study treatment. 
• Unrelated - The AE is clearly NOT related to the study treatment. 
 
7.2.8 Expedited Adverse Event Reporting 
Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study. 
 
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, will be 
recorded in the participant’s medical record and on the appropriate study specific case report 
forms. 
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  A copy 
of the CTCAE version 4.0 can be downloaded from the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
For multi-site trials where a Columbia University Medical Center investigator is serving as 
the principal investigator, each participating investigator is required to abide by the reporting 
requirements set by Columbia University Medical Center. The study must be conducted in 
compliance with FDA regulations, local safety reporting requirements, and reporting 
requirements of the principal investigator. 
 
Each investigative site will be responsible to report SAEs that occur at that institution to their 
respective IRB. It is the responsibility of each participating investigator to report serious 
adverse events to the study sponsor (i.e. Kevin Kalinsky, MD, MS and Incyte representative) 
as described below. 
 
In addition to the reporting requirements for SAEs, a separate case report form will be made 
for reporting of any grade adverse events attributable to research biopsies. These events will 


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not require expedited reporting unless they also meet the requirements for SAE reporting, as 
detailed below. 
 
Copies of all IND safety reports submitted to the FDA and/or institutional IRB by the 
institution under the institution’s IND will be shared with Incyte Pharmacovigilance 
representative, so that these reports can be evaluated and included in the Investigator 
Brochure and future Incyte IND safety submissions per regulations. 
 
7.2.9 Serious Adverse Event Reporting 
All serious adverse events that occur after the initial dose of study treatment, during 
treatment, or within 30 days of the last dose of treatment must be reported to Columbia 
University Medical Center Overall Principal Investigator on the local institutional SAE form. 
This includes events meeting the criteria outlined in Section 7.2.2, as well as the following: 
 
•   All Grade 4 (life-threatening or disabling) Events – Unless expected AND 
specifically listed in the protocol as not requiring reporting. 
 
•   All Grade 5 (fatal) Events – When the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the last study 
intervention. 
 
Note: If the participant is in long term follow up, report the death at the time of 
continuing review.  
 
Participating investigators must report each serious adverse event to the Columbia University 
Medical Center Overall Principal Investigator within 24 hours of learning of the occurrence. 
In the event that the participating investigator does not become aware of the serious adverse 
event immediately (e.g., participant sought treatment elsewhere), the participating 
investigator is to report the event within 24 hours after learning of it and document the time of 
his or her first awareness of the adverse event. Report serious adverse events by telephone, 
email or facsimile to: 
 
Name of Contact:  
 
Kevin Kalinsky, MD  
Address:  
 
Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center  
161 Fort Washington Avenue 
New York, NY 10032 
Email:  
 
 
M1906@columbia.edu 
Phone:  
 
 
212-305-1945 
Fax: 
 
 
212-305-0178 
 
 
Within the following 24-48 hours, the participating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether the 
event has resolved or continues, if and how the event was treated, and whether the participant 
will continue or discontinue study participation. 
 
Follow-up information is sent to the same person to whom the original SAE 
Report Form was sent, using a new SAE Report Form stating that this is a follow- up to the 
previously reported SAE and giving the date of the original report. Each re-occurrence, 
complication, or progression of the original event should be reported as a follow-up to that 


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event regardless of when it occurs. The follow-up information should describe whether the 
event has resolved or continues, if and how it was treated, and whether the subject continued 
or withdrew from study participation or if study drug was interrupted or discontinued. 
 
If the SAE is not previously documented in the Investigator’s Brochure for the study drug 
(new occurrence) and is thought to be related to the Sponsor’s study drug, a Sponsor’s 
associate may urgently require further information from the Investigator for reporting to 
Health Authorities. 
 
The Sponsor may need to issue an Investigator Notification (IN) to inform all Investigators 
involved in any study with the same drug that this SAE has been reported. Suspected 
Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries. If the study 
is open-label, no special unblinding procedures are needed for exceptional circumstances or 
medical emergencies. 
 
7.2.10 Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE, unless there is suspicion that study drug 
may have interfered with the effectiveness of a contraceptive medication or method.  The 
procedures that will be followed based on whether a pregnancy is confirmed by a positive 
serum or urine test result are listed below: 
 
• 
Investigator and subject must notify each other immediately.  
 
o Investigator must notify the Principal Investigator and Incyte within 24 
hours of learning of the occurrence 
 
• 
Study drug must be discontinued immediately.  
 
• 
Subject must be withdrawn from the study.  
 
• 
Investigator must complete and submit the Pregnancy Initial and Follow-up report 
forms to the Principal Investigator and to Incyte.  
 
• 
A serum pregnancy test must be performed to confirm the urine test result. (The 
serum test should be performed at the investigative site to ensure the test will be 
performed promptly and the result available immediately for review.) 
 
 
If a negative serum test does not confirm the urine test result, then: 
 
•   The Investigator will use his/her expert judgment, based on an assessment  
of the potential benefit/risk to the subject, to determine if it is in the subject’s 
best interest to resume study drug and continue participation in the study. 
 
To ensure subject safety, each pregnancy in a subject during maternal or paternal 
exposures to study drug must be reported within 24 hours of learning of its 
occurrence.  Data on fetal outcome and breast-feeding are collected for regulatory reporting 
and drug safety evaluation. The pregnancy should be followed- up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications by following until the first well-baby visit. Pregnancy should be recorded on 
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follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study drug of any pregnancy outcome and follow-up to the first 
well-baby visit. Any SAE experienced during pregnancy must be reported on the SAE 
Report Form and to Incyte Corporation. 
 
7.2.11 Non-Serious Adverse Event Reporting 
 
Non-serious adverse events will be reported to the Columbia University Medical Center 
Overall Principal Investigator on the toxicity Case Report Forms. 
 
7.2.12 Reporting to the Institutional Review Board (IRB) 
Unanticipated Problems (Ups) are to be reported to the IRB.  SAEs not constituting UPs are 
to be reported to the HICCC DSMC.   
 
Other investigative sites should report serious adverse events to their respective IRB 
according to the local IRB’s policies and procedures in reporting adverse events. A copy 
of the submitted institutional SAE form should be forwarded to: 
 
Name of Contact:  
 
Kevin Kalinsky, MD  
Address:  
 
Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center  
161 Fort Washington Avenue 
New York, NY 10032 
Email:  
 
 
M1906@columbia.edu 
Phone:  
 
 
212-305-1945 
Fax: 
 
 
212-305-0178 
 
SAEs are to be reported to the HICCC DSMC, if they are considered UPs, then they must be 
submitted to CUMC IRB per institutional policies. 
 
Unanticipated Problems must be reported promptly, but not later than 7 calendar days 
following the occurrence of the UP or the Principal’s Investigator’s acquiring knowledge of 
the UP. 
 
Expected AEs must be reported at the time of continuing review of a protocol. 
 
7.2.13 Reporting to the Food and Drug Administration (FDA) 
Columbia University Medical Center Overall Principal Investigator (Sponsor-Investigator), as 
holder of the IND, will be responsible for all communication with the FDA. Columbia 
University Medical Center Principal Investigator will report to the FDA, regardless of the site 
of occurrence, any adverse event that is serious, unexpected and reasonably related (i.e., 
possible, probable, definite) to the study treatment. 
 
The Columbia University Medical Center Sponsor Investigator must report the following 
SARs: 
• 
To the FDA, as soon as possible, but no later than 7 calendar days after the S-I's 
initial receipt of the information, any unexpected fatal or life-threatening SAR. 
• 
To the FDA and all participating investigators, as soon as possible but no later 
than 15 calendar days after the S-I determines that information qualifies for 


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reporting, in an IND safety report, any SAR that is both serious and unexpected. 
• 
To the FDA and all participating investigators, as soon as possible but no later 
than 15 calendar days after the S-I determines that the information qualifies for 
reporting, any findings from epidemiological studies, pooled analysis of multiple 
studies or clinical studies, whether or not conducted under an IND or by the S-I, 
that suggest a significant risk in humans exposed to the drug.  
• 
To the FDA and all participating investigators, as soon as possible, but no later 
than 15 calendar days after the S-I determines that the information qualifies for 
reporting, any findings from animal or in vitro testing, whether or not conducted 
by the S-I, that suggest a significant risk in humans exposed to the drug.  
• 
To the FDA and all participating investigators, as soon as possible, but no later 
than 15 calendar days after the S-I determines that the information qualifies for 
reporting, any clinically important increase in the rate of a Serious SAR over that 
listed in the protocol or Investigator Brochure. 
• 
Expected SAEs and AEs should be included in the IND Annual Reports. 
 
Follow-up information to a safety report should be submitted as soon as the relevant 
information is available.  However, if the results of a sponsor’s investigation show that an 
adverse drug experience not initially determined to be reportable are so reportable, the 
sponsor must report such experience as soon as possible, but no later than 15 calendar days 
after the determination is made. 
 
All other serious unexpected experiences associated with the use of the study treatment will 
be reported to FDA as soon as possible but in no event later than 15 calendar days after 
initial receipt of the information. 
 
Events will be reported to the FDA by telephone (1-800-FDA-1088) or by fax (1-800- 
FDA-0178) using Form FDA 3500A (Mandatory Reporting Form for investigational 
agents) or FDA Form 3500 (Voluntary Reporting Form for commercial agents). Forms are 
available at http://www.fda.gov/medwatch/getforms.htm. 
 
7.2.14 Reporting to Incyte Corporation 
The Overall Principal Investigator will report to Incyte Corporation any serious adverse 
events within 24 hours of learning of the event. Reporting will occur by emailing the 
completed Serious Adverse Event Reporting Form to IncytePhVOpsIST@incyte.com.  
 
The Overall Principal Investigator send copies of any IND Safety reports submitted to the 
FDA will be sent to Incyte so that these reports can be evaluated and included in the 
Investigator’s Brochure or Incye IND safety submissions. These will be sent via email to 
IncytePhVOpsIST@incyte.com. 
 
,Every six months, the overall Principal Investigator will submit copies of IND safety reports 
in the format of a lie listing with details regarding the reports that were submitted to the FDA. 
These will be inclusive of all sites to they will be sent via email to 
IncytePhVOpsIST@incyte.com.  
 
The Overall Principal investigator will provide complete data transfers for AEs listings, 
including AEs, on labs, on a quarterly basis for the duration of the study. The data transfer 
will not include any Protected Health Information as defined by HIPAA.  


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7.2.15 Guidelines for Processing IND Safety Reports  
The U.S. Food and Drug Administration (FDA) regulations require sponsors of clinical 
studies to notify the FDA and all participating investigators of any serious and unexpected 
adverse experiences that are possibly related to the investigational agent. The CUMC 
Principal Investigator will review all applicable IND Safety Reports and has the responsibly 
for forwarding the IND Safety Reports to the Affiliate Institutions. The Affiliate Institution 
investigators are to review, send a copy to their IRB according to their local IRB’s policies 
and procedures, and file a copy with their regulatory documents. All Affiliate site INDSR 
submissions, along with IRB acknowledgment (per local policies and procedures) are to be 
forwarded to CUMC for placement within the trial master file. 
 
 
7.2.16 Reporting to Hospital Risk Management 
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
 
7.2.17 Monitoring of Adverse Events and Period of Observation 
All adverse events, both serious and non-serious, and deaths that are encountered from 
initiation of study intervention, throughout the study, and within 30 days of the last study 
intervention should be followed to their resolution, or until the participating investigator 
assesses them as stable, or the participating investigator determines the event to be 
irreversible, or the participant is lost to follow-up. The presence and resolution of AEs and 
SAEs (with dates) should be documented on the appropriate case report form and recorded in 
the participant’s medical record and subject binder to facilitate source data verification. 
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately evaluate 
the SAE report (e.g., hospital discharge summary, consultant report, or autopsy report). 
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should notify 
Columbia University Medical Center Overall Principal Investigator and their respective IRB 
of any unanticipated death or adverse event occurring after a participant has discontinued 
or terminated study participation that may reasonably be related to the study. 
 
7.3 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.   Second malignancies 
require ONLY routine reporting unless otherwise specified.  
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 7. 
 
8.1 
Investigational Agent(s) 
This study will evaluate the effects of a novel combination of two commercially available, 


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FDA-available medications.  Ruxolitinib has been approved by the FDA for treatment of 
intermediate and high risk myelofibrosis.  Trastuzumab has been approved by the FDA for 
the treatment of HER2+ breast cancer.  Both medications have been widely used and have 
considerable safety data.  To our knowledge, this combination has been not been evaluated in 
patients with breast cancer.   
 
8.1.1 Ruxolitinib 
8.1.1.1 
Product Description  
Ruxolitinib (INCB018424 phosphate, INC424, ruxolitinib phosphate) represents a novel, 
potent, and selective inhibitor of JAK1 (Janus kinase 1) (inhibition concentration 50% 
[IC50]=3.3 ± 1.2 nM) and JAK2 (IC50=2.8 ± 1.2 nM) with modest to marked selectivity 
against TYK2 (tyrosine kinase 2) (IC50=19 ± 3.2 nM) and JAK3 (IC50=428 ± 243 nM), 
respectively. Ruxolitinib interferes with the signaling of a number of cytokines and growth 
factors that are important for hematopoiesis and immune function. 
 
Ruxolitinib phosphate is a kinase inhibitor with the chemical name (R)-3-(4-(7H-pyrrolo[2,3- 
d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate and a molecular 
weight of 404.36. Ruxolitinib phosphate is a white to off-white to light pink powder and is 
soluble in aqueous buffers across a pH range of 1 to 8. 
 
8.1.1.2 
Product Formulation 
Ruxolitinib is an oral medication supplied as 5 mg tablets for this study.  
 
8.1.1.3 
Route of Administration  
Tablets are for oral administration. Each tablet contains ruxolitinib phosphate equivalent to 5 
mg of ruxolitinib free base together with microcrystalline cellulose, lactose monohydrate, 
magnesium stearate, colloidal silicon dioxide, sodium starch glycolate, povidone and 
hydroxypropyl cellulose. 
 
8.1.1.4 
Agent Ordering  
Ruxolitinib is an investigational agent supplied to investigators by Incyte Pharmaceuticals. 
Ruxolitinib supplied for this protocol is intended for clinical trial use only and is not 
commercially available. Ruxolitinib is shipped directly from the company to the participating 
institution (see Appendix H for Drug Order Form). For further details molecule 
characterization, see the ruxolitinib Investigator’s Brochure. 
 
8.1.2 Trastuzumab 
8.1.2.1 
Product Description  
Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that selectively 
binds with high affinity in a cell-based assay (Kd=5 nM) to the extracellular domain of the 
human epidermal growth factor receptor 2 protein, HER2. The antibody is an IgG1 kappa that 
contains human framework regions with the complementarity-determining regions of a 
murine antibody (4D5) that binds to HER2.  
The humanized antibody against HER2 is produced by a mammalian cell (Chinese Hamster 
Ovary [CHO]) suspension culture in a nutrient medium containing the antibiotic gentamicin. 
Gentamicin is not detectable in the final product.  
 
Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder for 
intravenous (IV) administration. The nominal content of each trastuzumab vial is 440 mg 


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trastuzumab, 400 mg α,α-trehalose dihydrate, 9.9 mg L-histidine HCl, 6.4 mg L-histidine, 
and 1.8 mg polysorbate 20, USP. Reconstitution with 20 mL of the supplied Bacteriostatic 
Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative, yields a 
multi-dose solution containing 21 mg/mL trastuzumab, at a pH of approximately 6. 
 
8.1.2.2 
Solution Preparation  
Vials of trastuzumab are stable at 2°–8°C (36°–46°F) prior to reconstitution. Do not use 
beyond the expiration date stamped on the vial. A vial of trastuzumab reconstituted with 
BWFI, as supplied, is stable for 28 days after reconstitution when stored refrigerated at 2°–
8°C (36°–46°F), and the solution is preserved for multiple use. Discard any remaining multi-
dose reconstituted solution after 28 days. If unpreserved SWFI (not supplied) is used, the 
reconstituted trastuzumab solution should be used immediately and any unused portion must 
be discarded. Do not freeze trastuzumab that has been reconstituted. The solution of 
trastuzumab for infusion diluted in polyvinylchloride or polyethylene bags containing 0.9% 
Sodium Chloride Injection, USP, may be stored at 2°–8°C (36°–46°F) for up to 24 hours 
prior to use. Diluted trastuzumab has been shown to be stable for up to 24 hours at room 
temperature 2°–25°C. However, because diluted trastuzumab contains no effective 
preservative, the reconstituted and diluted solution should be stored refrigerated 2°–8°C. 
 
8.1.2.3 
Route of Administration  
Trastuzumab is administered intravenously. When administering trastuzumab to a patient 
with a known hypersensitivity to benzyl alcohol, trastuzumab must be reconstituted with 
SWFI, and only one dose per trastuzumab vial should be used. Trastuzumab, which has been 
reconstituted, with SWFI must be used immediately and any unused portion must be 
discarded. Use of other reconstitution diluents should be avoided.  
Shaking the reconstituted trastuzumab or causing excessive foaming during the addition of 
diluent may result in problems with dissolution and the amount of trastuzumab that can be 
withdrawn from the vial. Use appropriate aseptic technique when performing the following 
reconstitution steps:  
− Using a sterile syringe, slowly inject the 20 mL of diluent into the vial containing the 
lyophilized cake of trastuzumab. The stream of diluent should be directed into the lyophilized 
cake.  
− Swirl the vial gently to aid reconstitution. Trastuzumab may be sensitive to shear-induced 
stress, e.g., agitation or rapid expulsion from a syringe. DO NOT SHAKE.  
 
8.1.2.4 
Agent Ordering  
Trastuzumab is commercially available. 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Given that this is a proof-of-concept phase I/II study there will be no assessment of integral 
biomarkers (essential for conducting the study) or integrated biomarkers (testing a hypothesis 
based on preexisting data).  Instead, all correlative studies for this trial will be exploratory 
and used for either hypothesis generation and/or assay development and testing.  Hypotheses 
generated from these studies will then be tested as integrated biomarkers in follow-up clinical 
studies.  
 
All analyses will be performed in batched fashion at the end of the study.  Plasma and serum 
samples will be prepared (Appendix E) on the same day they are drawn and stored locally.  
Biopsies will be obtained, processed, and stored as a clinical specimen by the participating 


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sites clinical pathology labs (Appendix D).  At the end of the study freshly cut slides will be 
requested from each site for all the appropriate biopsy specimens.  Slides will be cut for all 
specimens at the same time at the end of the study. Pathology reports for all samples assessed 
for the study will be entered into the clinical research form.  For the blood based biomarkers 
samples will be shipped directly to the lab performing the analysis at the end of study accrual 
and sample collection [see appendices for shipping and labeling instructions]. 
 
For patients with accessible tumor, 2 punch biopsies (for skin) or 3 core biopsies are 
recommended.  The following will be requested: 10 immunoblanks [each having 4 
micron sections on charged slides], one intervening H&E stained slide, and 12 regular 
slides each with 10 microns sections. 
 
  
DNA 
Blood 
Biomarkers 
PK 
IHC 
RNAseq 
RPPA 
Primary tumor biopsy (archived) * 
  
  
  
x 
x 
x 
Biopsy upon recurrence (archived)* 
  
  
  
x 
x 
x 
Pre-treatment biopsy (Optional) 
  
  
  
x 
x 
x 
On-treatment biopsy (Optional)** 
  
  
  
x 
x 
x 
Biopsy upon progression (Optional) 
  
  
  
x 
x 
x 
Pre-treatment whole blood 
x 
  
  
  
  
  
Pre-treatment plasma and serum 
  
x 
  
  
  
  
On-treatment plasma and serum** 
  
x 
  
  
  
  
Plasma and serum upon progression 
  
x 
  
  
  
  
On-treatment plasma** 
  
  
x 
  
  
  
 
*If available 
**On-treatment assessments will be performed on C2D1.  For PK analysis plasma will be 
drawn before the C2D1 dose and again two hours after. 
 
Transcriptional profiling 
RNA-Sequencing will be performed by the Columbia University Genome Center using current 
best technologies with a goal of at least 40 million reads per sample.  RNAseq has been 
validated from FFPE breast cancer samples.  In addition, the quality of sequencing reads from 
FFPE has been verified by the Columbia University Genome Center.  Data analysis will be 
performed by the Columbia University bioinformatics core under the direction of Andrea 
Califano.  Using the master regulator methodologies pioneered by Dr. Califano and used as the 
basis for the preclinical studies, they will perform interactome modeling for JAK/SAT pathway 
dependence. In addition, intrinsic molecular subtype of each sample will be identified, as well 
as mutation assessment and pathway analysis. 
 
RPPA 
We will explore the baseline proteomic profile of patients entered on this study, the profile in 
the setting of trastuzumab resistance, and the effect on the proteomic profile with treatment 
with combined trastuzumab and ruxolitinib. We will use is the current technology being used 
for proteomic profiling in the cancer genome atlas (TCGA) project. Samples will be sent to 
and analyzed by the MDA Anderson RPPA Functional Proteomics Core Facility.   
 


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Protein extracts from FFPE tumor blocks (3-8 untreated 10 micron slides) will be prepared 
from appropriately isolated regions (as determined by an experienced pathologist).  
Following deparaffinization, at least 30-40 micrograms of protein per sample will be 
extracted using an extraction buffer of 20 mM Tris HCl buffer at pH 9, with 2%(w/v)SDS, as 
previously described. RPPA will be conducted using a total of 161 antibodies 
(www.mdanderson.org/education-and-research/resources-for-professionals/scientific-
resources/core-facilities-and-services/functional-proteomics-rppa-core/index.html), including 
markers of proliferation (PCNA) and apoptosis (e.g., cleaved caspase-3), as well as 
antibodies against STAT3, EGFR, HER2, c-MET, IGF-1R, PI3K, PTEN, AKT, mTOR, and 
their phosphorylated isoforms.  These antibodies have been fully validated by direct 
correlation between RPPA and Western blotting results.  Specifically, tumor lysates will be 
diluted in five 2-fold serial dilutions and arrayed on nitrocellulose-coated slides (Whatman, 
Schleicher & Schuell BioScience, Inc., Keene, NH).  Samples will be probed with validated 
primary antibodies and biotin-conjugated secondary antibodies and visualized by DAB 
colorimetric reaction.  Slides will be scanned and quantified for raw signal intensities by 
using MicroVigene automated RPPA software (VigeneTech, Inc., North Billerica, MA).  
Dilution curves will be fitted to the logistic model “Supercurve Fitting” 
(http://bioinformatics.mdanderson.org/OOMPA).  Relative protein levels for each sample 
were derived from the supercurve for each lysate by curve-fitting, will be normalized for 
protein loading, and the log2-scaled protein concentrations will be normalized by global 
sample median normalization.  
 
IHC 
Ten freshly cut slides from each biopsy and archived tissue will be analyzed by the Columbia 
University Molecular Pathology Lab for immunhistochemical (IHC) staining.  IHC for 
phosphorylated STAT3, Ki67, and cleaved caspase-3, as well as other potential markers 
identified through transcriptional and/or proteomic profiling, will be performed based on the 
standard protocol published for each antibody.  Standard protocols, institutional and from the 
antibody vender, will be assessed and modified as needed.  Phospho-Stat3 (Tyr705) (D3A7) 
XP® Rabbit mAb  [CellSignaling #9145].  Phospho-Stat3 staining will be measured with an 
H score calculated from the percent and intensity of staining. 
 
Peripheral blood samples 
Peripheral blood samples will be obtained from each patients prior to starting study drug, 
prior to the observed C2D1 dose and at the time of progression. Plasma and serum 
biomarkers will be assessed by Biomarkers Core of the Irving Institute for Clinical and 
Translational Research at Columbia University Medical Center.  At minimum, IL-6, IL-8, 
and C-reactive protein levels will be assessed. 
 
Pharmacokinetics 
Ruxolitinib exhibits near complete oral absorption, achieving maximal plasma concentration 
at approximately 1-2 h post-dose with linear PK over a dose range of 5-200 mg.  Full PK 
analyses will not be performed given the low likelihood of interactions between the 
trastuzumab and ruxolitinib.  However, steady state trough and peak levels [2 hours post 
dose] of ruxolitinb will be assessed on C2D1 for the first 10 patients on study.  Once the 
samples from the first 10 patients have been obtained they will be sent to Incyte for analysis.  
If the results are not within expected ranges then the protocol will be amended to include full 
PK sampling on the remaining patients.  The time the trough level is drawn, the time the 
C2D1 dose is taken, and the time the peak level is drawn must be entered into the clinical 
research form. 


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10. STUDY CALENDAR 
 
Baseline evaluations, except for scans and x-rays, are to be conducted within 14 days prior to 
start of protocol therapy.  Scans, including CT scans and MUGA/ECHO, and x-rays must be 
done < 28 days prior to the start of therapy.   
 
 
 
Cycle 1c 
Cycle 2c 
Cycle 3c 
Cycle 4+c 
Off Study 
Visit Day 
Pre-
Study 
Day 
1 
Day 
8 
Day 
15 
Day 1 
Day 1 
Day 1 
Within 28 
days of the 
last dose 
Visit Window 
(Days) 
 
 
± 2d 
± 2d 
± 4d 
± 4 
± 4 
 
Ruxolitiniba 
 
X 
X 
X 
X 
X 
X 
 
Trastuzumab 
 
X 
 
 
X 
X 
X 
 
Informed consente 
X 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion Criteria 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Concurrent medsf 
 
X 
X 
X 
X 
X 
Xg 
X 
History and 
Physical exam 
X 
X 
X 
X 
X 
X 
Xg 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Xg 
X 
Height 
X 
 
Weight 
X 
X 
X 
X 
X 
X 
Xg 
X 
Performance status 
X 
X 
X 
X 
X 
X 
Xg 
X 
Adverse event 
evaluation 
X 
X 
X 
X 
X 
X 
Xg 
X 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
Xg 
X 
Serum chemistry, 
liver function testsh 
X 
X 
X 
X 
X 
X 
Xg 
X 
Lipid panel 
Xi 
 
 
 
 
 
Xi 
X 
B-HCG 
Xj 
 
Pharmacokinetics 
 
 
 
 
Xk 
 
 
 
ECG 
X 
 
Xl 
 
Xl 
 
Xm 
X 
EF Assessment 
(Echo or MUGA) 
X 
 
 
 
Xn 
 
Xo 
X 
CT C/A/P or 
PET/CTp 
X 
 
 
 
Xm 
X 
Bone Scanq 
Xq 
 
 
 
Xq 
Xq 
Review Pill Diary 
 
 
X 
X 
X 
X 
Xg 
X 
Blood Biomarker 
X 
 
 
 
X 
 
 
X 


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Cycle 1c 
Cycle 2c 
Cycle 3c 
Cycle 4+c 
Off Study 
Visit Day 
Pre-
Study 
Day 
1 
Day 
8 
Day 
15 
Day 1 
Day 1 
Day 1 
Within 28 
days of the 
last dose 
Visit Window 
(Days) 
 
 
± 2d 
± 2d 
± 4d 
± 4 
± 4 
 
(Section 9) 
Whole blood for 
DNA 
X 
 
 
 
 
 
 
 
Tumor Analysis: 
Predictive 
Biomarker 
(Section 9) 
Xr 
 
 
 
Xs 
 
 
Xs 
a. 
Ruxolitinib:  Dose as assigned (phase I dose level 0: 20 mg b.i.d.; phase II dose will be based upon the phase I 
Maximum Tolerated Dose).  Patients will be instructed not take ruxolitinib until seen by study team on 
days of study visits.  Ideally, the first dose of ruxolitinib will be in the morning so that the first day allow 
for b.i.d. On D1 of every cycle prior to drug dispensation and dose administration, subject’s disease 
status/non-progression will be confirmed by the treating investigator, including clinical and radiographic 
assessment. RECIST restaging will be confirmed for the most recent scans received, including documentation 
of investigator sign off on calculation of percentage change from baseline and nadir and overall response, prior 
to treatment. If the new scan information becomes available mid cycle, the study team will inform the subject 
if treatment discontinuation is required per protocol in real time, and document date of treatment 
discontinuation. 
b. Trastuzumab:  Fixed dosing.  If no trastuzumab > 28 days from initiating trastuzumab: load 8 mg/kg IV.  
Otherwise, 6 mg/kg IV.  If loaded, patient should remain on 6 mg/kg IV every 21 days (+/- 3 days). 
c:    Cycle = 21 days (+/-4 days from Day 1 of the prior cycle) 
d.    During cycle 1, patients will be seen on day 1, 8 (+/- 2 days), 15 (+/- 2 days).  Cycle 2 day 1 should be within 
21 days (+/- 4 days) from Cycle 1 day 1. 
e.    Radiographic assessments and EF (ejection fraction) testing may be done before consenting, if performed as 
part of the subject’s routine care/procedures, and if done within the screening window per the protocol-defined 
method time period. 
f.     Patients on strong CYP3A4 inhibitors are not eligible.  Must be off for at least 1 week prior to being deemed 
eligible. 
g.    Every 21 days (+/- 4 days) during phase I and phase II 
h.    Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
i.     Lipids should be conducted at baseline, prior to cycle 4, and then every 3 cycles (~9 weeks+/- 1 week).  
Hyperlipidemia is not an exclusion criterion.  Lipids do not need to be fasting.  If abnormalities are detected, 
fasting blood lipid levels (at least 8 hours fasting) should be considered and patients should be treated per 
standard of care. 
j.     Serum pregnancy test (women of childbearing potential). 
k.    Trough (prior) and peak (2 hours post) levels should be drawn at Cycle 2 Day 1 (+/- 2 days) during phase I 
only. 
l.     ECG prior to dose at Cycle 1 Day 8 (+/- 2 days) and prior to Cycle 2 Day 1 during phase I only. 
m.   Every 3 cycles (~9 weeks of treatment +/- 4 days) during phase I and phase II. Scans to be conducted every 9 
weeks (+/- 4 days) from start of study treatment. 
n.    During phase I only, EF assessment should occur prior to Cycle 2 Day 1. 
o.    EF assessment should be performed prior to Cycle 4 Day 1.  EF assessment should be repeated 3 cycles (~9 
weeks+/- 4 days) prior to treatment with trastuzumab. 
p.    If patients have known brain metastases and are eligible for this trial, a head CT or brain MRI MUST be 
performed along with systemic imaging.  If a patient does not have known brain metastases and is asymptomatic, 
no baseline brain imaging is required. . Scans to be conducted every 9 weeks (+/- 4 days) from start of study 
treatment. Corresponding RECIST restaging will be conducted in real time following scans and signed 
(electronically or wet ink) by the investigator, including confirmation of overall disease status per RECIST v.1.1 
q.    Baseline bone scan required in all patients. 
NOTE: If bone scan done ≤ 6 weeks prior to registration showed no evidence suggesting bone metastases and no 


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Cycle 1c 
Cycle 2c 
Cycle 3c 
Cycle 4+c 
Off Study 
Visit Day 
Pre-
Study 
Day 
1 
Day 
8 
Day 
15 
Day 1 
Day 1 
Day 1 
Within 28 
days of the 
last dose 
Visit Window 
(Days) 
 
 
± 2d 
± 2d 
± 4d 
± 4 
± 4 
 
clinical indication of skeletal pain or other evidence suggesting bone metastases, a repeat baseline bone scan is 
not required.  If there is evidence of disease on the bone scan, bone scans should be continued every 3 cycles 
(~9 weeks of treatment +/- 4 days), as clinically indicated. 
r.    From archived primary and/or metastatic biopsy  if patient is amenable and has accessible disease repeat 
biopsy (optional) 
s.    If patient is amenable and has accessible tumor, repeat biopsy (optional).  These biopsies should be considered 
in patients with accessible disease. 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
For the purposes of the phase I/II study, patients should be re-evaluated for response every 3 
cycles (~9 weeks of treatment +/- 4 days).  In addition to a baseline scan, confirmatory scans 
should also be obtained 9 (not less than 4) weeks (+/-  4 days) following initial 
documentation of an objective response. 
 
Response and progression will be evaluated in this study using the international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
11.1.1 Definitions 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first 
treatment with ruxolitinib and trastuzumab. 
 
Evaluable for objective response:  Only those patients who have measurable disease present 
at baseline, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for response.  These patients will have their response 
classified according to the definitions stated below.  (Note:  Patients who exhibit objective 
disease progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
non-target disease.  The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray or as 
≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 


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Note:  Tumor lesions that are situated in a previously irradiated area may be considered 
measurable, as long as they meet the criteria above.   
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are 
considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline.  Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements.  It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters.  If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should also 
be recorded at baseline.  Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow-
up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 


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Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the same type 
of scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements.  
However, if the site believes that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the 
PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.  Note, however, that the 
PET portion of the CT introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next.  If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation 
is not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 


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initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.   
 
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side 
effect of the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation corrected 
image. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is 


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the smallest on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or more 
new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, not a 
single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 


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Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first.  
 
Percent progression-free at 24 weeks is defined as the proportion of patients who remain 
progression-free at 24 weeks from study entry day #1 (binary proportion). 
 
11.1.7 Response Review 
All responses are reviewed by an expert(s) independent of the study at the study’s 
completion. Simultaneous review of the patients’ files and radiological images is the best 
approach. 


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12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).  The Data Safety Monitoring Plan is 
described in Section 12.2. 
 
12.1 
Data Collection 
The Herbert Irving Comprehensive Cancer Center has an electronic clinical trials and data 
management system that will be used for data collection. CRFs for the study will be built into 
Velos for data entry. The system has full auditing capabilities which is web-based and housed 
on a server in a fully HIPAA compliant server room with restricted access and video camera 
monitoring.  All users must login with their own application username and password.  Users 
off campus must first access the Virtual Private Network with their assigned campus 
username and password and then use their application credentials.  Users are only able to 
view study information if they are indicated as study personnel in our electronic IRB system, 
or an affiliate IRB system. Users are limited to access based on the role assigned in their 
corresponding protocol.  Subject data is entered directly into the system, which (in the case of 
Columbia subjects) confirms the correct identity of patients via an interface with the 
electronic medical patient index.  Staff with the appropriate IRB defined roles can run reports 
within the system for reporting purposes. 
 
12.2 
Data Reporting 
Responsibility for Data Submission 
Case Report Forms will be completed for each subject enrolled into the clinical study through 
Velos eResearch. It is the investigator’s responsibility for ensuring that all clinical and 
laboratory data entered on the corresponding CRFs are complete, accurate and authentic. 
 
Refer to the table below regarding the form completion and source document submission 
guidelines. 


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Page 58 of 96 
 
 
Phase I: 
 
Redacted 
Source 
Documents 
(if 
applicable) 
Case Report Form 
Pre-Study 
(Required 
for Central 
Registration) 
Baseline 
Cycle 1 
Day 1 
Cycle 1 
Day 8 
Cycle 1 
Day 15 
Cycle 2 
Cycle 3 
Cycle 4 
Off Study 
SAEs 
Required Submission Schedules 
Within 2 
business 
days of 
visit 
 
At time of 
Central 
Registration 
submission 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 24 
hours and 
ongoing as 
available and 
applicable  
x 
Registration and 
Demographics 
 
x 
 
x 
Eligibility (Inclusion and 
Exclusion) 
 
x 
 
x 
Medical and Surgical History 
 
x 
 
x 
Breast Biopsy and Histology 
 
x 
 
x 
Metastatic Breast Cancer Prior 
to Study 
 
x 
 
x 
HER2 Status Prior to Study 
 
x 
 
x 
Previous Therapy 
 
x 
 
x 
Baseline Physical Exam 
 
x 
 
 
 
 
 
 
 
 
x 
Baseline Cardiac Assessments 
 
x 
 
x 
Baseline Laboratory & 
Biomarker Collection (Heme 
and chemistry) 
 
x 
 
x 
Baseline Imaging 
 
x 
 
x 
Baseline Disease Assessment 
 
x 
 


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Page 59 of 96 
 
Redacted 
Source 
Documents 
(if 
applicable) 
Case Report Form 
Pre-Study 
(Required 
for Central 
Registration) 
Baseline 
Cycle 1 
Day 1 
Cycle 1 
Day 8 
Cycle 1 
Day 15 
Cycle 2 
Cycle 3 
Cycle 4 
Off Study 
SAEs 
Required Submission Schedules 
Within 2 
business 
days of 
visit 
 
At time of 
Central 
Registration 
submission 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 24 
hours and 
ongoing as 
available and 
applicable  
x 
On Study Physical Exam 
 
x 
x 
x 
x 
x 
x 
 
x 
On Study Cardiac Assessment 
 
x 
x 
x1 
 
x 
On Study Hematology 
 
x 
x 
x 
x 
x 
x 
 
x 
On Study Biochemistry 
 
x 
x 
x 
x 
x 
x 
 
x 
Cycle Form 
 
x 
x 
x 
x 
x 
x 
 
x 
Agent Interruption Form 
 
x 
x 
x 
x 
x 
x 
 
x 
Phase I Observation Period 
 
x2 
 
x 
On Study Lipid Panel 
 
x3 
x 
 
x 
Pharmacokinetics 
 
x 
 
x 
Follow Up On Study Tumor 
Assessment 
 
x 
 
x 
On Study Biomarker 
Collection 
 
x 
 
x 
Research Related Biopsies 
 
x 
x 
x 
 
x 
Adverse Events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant Medications, 
Supplements, Et. Al.  
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
Off Study Medical History 
 
x 
 
x 
Off Study Physical Exam 
 
x 
 


Local Protocol#:  AAAM1906 
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Page 60 of 96 
 
Redacted 
Source 
Documents 
(if 
applicable) 
Case Report Form 
Pre-Study 
(Required 
for Central 
Registration) 
Baseline 
Cycle 1 
Day 1 
Cycle 1 
Day 8 
Cycle 1 
Day 15 
Cycle 2 
Cycle 3 
Cycle 4 
Off Study 
SAEs 
Required Submission Schedules 
Within 2 
business 
days of 
visit 
 
At time of 
Central 
Registration 
submission 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 24 
hours and 
ongoing as 
available and 
applicable  
x 
Off Study Laboratory Data 
(Hematology) 
 
x 
 
x 
Off Study Laboratory Data 
(Biochemistry) 
 
x 
 
x 
Off Study Cardiac Assessment 
 
x 
 
x 
Off Study Biomarkers 
 
x 
 
x 
Off Study 
 
x 
 
x 
Death Report4 
 
 
 
Comments* 
 
 
 
Verification 
 
 
x 
Off Schedule Imaging* 
 
 
x 
Follow Up On Study Tumor* 
Assessment 
 
 
 
1 On study cardiac assessments to be completed prior to C4D1 and every 3 cycles thereafter; CRF to be completed with C4D1 assessments, C7D1 assessments, C10D1 assessments, etc. 
2 If subject does not complete entire 3 week phase I observation period, a Phase I Observation CRF should be inserted with last day of study assessments to note time point of DLT. 
3 On study lipid panel to be completed prior to C4D1 and every 3 cycles thereafter: CRF to be completed with C4D1 assessments, C7D1 assessments, C10D1 assessments, etc. 
4 Complete at Death Report CRF only if subject dies while on study or within 30 days of last study intervention.  
* Certain CRF pages can be inserted into any Velos eResearch calendar time point such as Comments or Off Schedule Imaging. Please provide applicable redacted source in these instances. 
 


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Page 61 of 96 
 
Phase II: 
 
Redacted 
Source 
Documents 
(If 
applicable) 
Case Report Form 
Pre-Study 
(Required 
for Central 
Registration) 
Baseline 
Cycle 1 
Day 1 
Cycle 1 
Day 8 
Cycle 1 
Day 15 
Cycle 2 
Cycle 3 
Cycle 4 
Off Study 
SAEs 
Required Submission Schedules 
Within 2 
business 
days of 
visit 
 
At time of 
Central 
Registration 
submission 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 24 
hours and 
ongoing as 
available and 
applicable  
x 
Registration and 
Demographics 
 
x 
 
x 
Eligibility (Inclusion and 
Exclusion) 
 
x 
 
 
 
 
 
 
 
 
x 
Medical and Surgical History 
 
x 
 
x 
Breast Biopsy and Histology 
 
x 
 
x 
Metastatic Breast Cancer Prior 
to Study 
 
x 
 
x 
HER2 Status Prior to Study 
 
x 
 
x 
Previous Therapy 
 
x 
 
x 
Baseline Physical Exam 
 
x 
 
x 
Baseline Cardiac Assessments 
 
x 
 
x 
Baseline Laboratory & 
Biomarker Collection (Heme 
and chemistry) 
 
x 
 
x 
Baseline Imaging 
 
x 
 
x 
Baseline Disease Assessment 
 
x 
 
x 
On Study Physical Exam 
 
x 
x 
x 
x 
x 
x 
 


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Page 62 of 96 
 
Redacted 
Source 
Documents 
(If 
applicable) 
Case Report Form 
Pre-Study 
(Required 
for Central 
Registration) 
Baseline 
Cycle 1 
Day 1 
Cycle 1 
Day 8 
Cycle 1 
Day 15 
Cycle 2 
Cycle 3 
Cycle 4 
Off Study 
SAEs 
Required Submission Schedules 
Within 2 
business 
days of 
visit 
 
At time of 
Central 
Registration 
submission 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 24 
hours and 
ongoing as 
available and 
applicable  
x 
On Study Cardiac Assessment 
 
x1 
 
x 
On Study Hematology 
 
x 
x 
x 
x 
x 
x 
 
x 
On Study Biochemistry 
 
x 
x 
x 
x 
x 
x 
 
x 
Cycle Form 
 
x 
x 
x 
x 
x 
x 
 
x 
Agent Interruption Form 
 
x 
x 
x 
x 
x 
x 
 
x 
On Study Lipid Panel 
 
x2 
x 
 
x 
Follow Up On Study Tumor 
Assessment 
 
x 
 
x 
On Study Biomarker 
Collection 
 
x 
 
x 
Research Related Biopsies 
 
x 
x 
x 
 
x 
Adverse Events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant Medications, 
Supplements, Et. Al.  
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
Off Study Medical History 
 
x 
 
x 
Off Study Physical Exam 
 
x 
 
x 
Off Study Laboratory Data 
(Hematology) 
 
x 
 
x 
Off Study Laboratory Data 
(Biochemistry) 
 
x 
 


Local Protocol#:  AAAM1906 
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Page 63 of 96 
 
Redacted 
Source 
Documents 
(If 
applicable) 
Case Report Form 
Pre-Study 
(Required 
for Central 
Registration) 
Baseline 
Cycle 1 
Day 1 
Cycle 1 
Day 8 
Cycle 1 
Day 15 
Cycle 2 
Cycle 3 
Cycle 4 
Off Study 
SAEs 
Required Submission Schedules 
Within 2 
business 
days of 
visit 
 
At time of 
Central 
Registration 
submission 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 2 
business 
days of 
visit 
Within 24 
hours and 
ongoing as 
available and 
applicable  
x 
Off Study Cardiac Assessment 
 
x 
 
x 
Off Study Biomarkers 
 
x 
 
x 
Off Study 
 
x 
 
x 
Death Report3 
 
 
 
Comments* 
 
 
 
Verification 
 
 
x 
Off Schedule Imaging* 
 
 
x 
Follow Up On Study Tumor* 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
1 On study cardiac assessments to be completed prior to C4D1 and every 3 cycles thereafter; CRF to be completed with C4D1 assessments, C7D1 assessments, C10D1 assessments, etc. 
2 On study lipid panel to be completed prior to C4D1 and every 3 cycles thereafter: CRF to be completed with C4D1 assessments, C7D1 assessments, C10D1 assessments, etc. 
3 Complete at Death Report CRF only if subject dies while on study or within 30 days of last study intervention.  
* Certain CRF pages can be inserted into any Velos eResearch calendar time point such as Comments or Off Schedule Imaging. Please provide applicable redacted source in these instances. 
 
 


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12.3 
Data and Safety Monitoring Committee 
The NCI-approved Data Safety and Monitoring Committee (DSMC) of the Herbert 
Irving Comprehensive Cancer Center (HICCC) will monitor every subject who 
receives treatment on this protocol for toxicity. This protocol will adhere to the 
policies of the currently approved HICCC Data and Safety Monitoring Plan (DSMP), 
which is in accordance with NCI and CUMC-IRB policy and guidelines.  The 
committee is led by Dr. J. Gregory Mears and consists of HICCC faculty and staff 
with expertise in oncology, research pharmacy, research nursing, and data 
management. The DSMC convenes twice a month to review patient safety and the 
conduct of the trial. The PI will submit data and safety monitoring reports to the 
DSMC at a frequency to be determined by the DSMC based on risk to the subjects. 
(Appendix F) 
 
At the time of renewal, the study team will submit the most recent DSMC approval 
letter for safety review to the CUMC IRB. Any modifications that are required by the 
DSMC to ensure patient safety will be submitted to the IRB. All protocol deviations, 
violations, and eligibility waivers will be submitted to and approved by the DSMC 
prior to being reported to the IRB. All study data reviewed and discussed during these 
meetings will be kept confidential.  
 
The Coordinating Site will assure that there is a mechanism in place to distribute the 
report to all participating investigators for submission to their local IRB.  The report 
will document that a review of data and outcomes across all centers took place on a 
given date.  It will summarize the DSMC’s review of the cumulative toxicities 
reported from all participating sites without specific disclosure by treatment arm.  It 
will also inform site investigators of the study the DSMC’s conclusion with respect to 
progress or need for modification of the protocol.   
 
12.4 
Quality Control and Quality Assurance 
Independent monitoring of the clinical study for protocol and GCP compliance will be 
conducted periodically by the CPDM Compliance Core on behalf of the HICCC 
DSMC.  Additionally, the Compliance Oversight Committee of the IRB at Columbia 
University Medical Center may audit the study at any time, per institutional policies 
and procedures. 
 
The investigator-sponsor and Columbia University Medical Center will permit direct 
access of the study monitors and appropriate regulatory authorities to the study data 
and to the corresponding source data and documents to verify the accuracy of this 
data. 
 
A risk-based approach will be used by the Compliance Core to determine the frequency, 
number of subject charts, and data elements to be monitored. The Compliance 
Coordinator will review the study status and summarize enrollment, toxicities, 
SAEs/UPs, dose escalation, statistical endpoints (e.g., stopping rules), etc. for the full 
DSMC membership at the regularly scheduled meetings.   
 
Internal On-site Monitoring: 
 
1. Initial, recurrent, and close-out on-site monitoring visits will also be conducted 
at remote clinical sites, as appropriate/feasible. Other sites will have 
monitoring performed remotely (see below for further details). 


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a. The study Monitoring Visit Log will be completed and signed by the 
monitor and the PI/CRNP/CRN and/or CRC and will be filed in the 
regulatory binder. 
 
2. The Compliance Coordinator will communicate with the site coordinator/Site 
Principle Investigator to schedule the monitoring visit and arrange for access 
to study materials and documentation. 
 
3. The assigned Compliance Coordinator will monitor IIT trials within 1 month 
after the first subject is enrolled and throughout the life of the study to ensure 
that the study is being conducted in accordance with the protocol, GCP, 
applicable federal and local regulations, and per all applicable SOPs. The 
Compliance Coordinator is responsible to notify the PI and CRNP/CRN/CRC 
of upcoming monitor visits and convey what information and documentation 
will be required for the visit(s).  The Compliance Coordinator is responsible 
for verifying that informed consent is properly obtained, eligibility is met (via 
the central registration process), and all study procedures are conducted 
according to the study protocol. The Compliance Coordinator will also verify 
that the data reported in the CRF’s accurately reflect source documents, that 
all toxicities have been reported to date, and that all 
SAE’s/UPs/deviations/violations have been reported according to local IRB 
and HICCC DSMC requirements. The Compliance Coordinator will issue 
queries and ensure resolution in a timely and efficient manner.  The 
Compliance Coordinator will also monitor for applicable regulatory 
compliance and research pharmacy compliance (if applicable) and 
communicate any deficiencies as appropriate. 
 
12.5 
Confidentiality 
Information about study subjects will be kept confidential and managed according to 
the requirements of the Health Insurance Portability and Accountability Act (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the 
following:  
1. What protected health information (PHI) will be collected from subjects in this 
study 
2. Who will have access to that information and why 
3. Who will use or disclose that information 
4. The rights of a research subject to revoke their authorization for use of their 
PHI  
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation 
of subject authorization.  For subjects who have revoked authorization to collect or 
use PHI, attempts should be made to obtain permission to collect at least vital status 
(i.e. that the subject is alive) at the end of their scheduled study period. 
12.6 
Source Documents 
Source data is all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial.  Source data are contained in source documents   Examples of these original 
documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 


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dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the 
clinical trial. 
 
12.7 
Reporting to Incyte Corporation 
The Overall Principal Investigator will send complete Data transfers every six months 
during the course of the study to Incyte Corporation. Incyte Corporation may request 
additional data transfers over the course of the study. The data will be provided in a 
readable format for all study participants. The data will not include any protected health 
information as defined under HIPAA. 
 
Additionally, Incyte Corporation will be provide monthly study status updates 
including a summary of: 
 Recruitment (screened, enrolled, discontinued and on-going with dates and 
study drug dosing regimens, 
 SAEs and safety reports to regulatory authorities 
 Regulatory correspondence include IRB approval letters, IRB approved 
protocol, informed consent documents, and documents related to Inycte.  
 Investigational product Inventory 
 Payment milestones.  
 
12.8 
Records Retention 
Records relating to a specific research activity, including research records collected 
by investigators, must be maintained for at least three years after completion of the 
research (45 CFR 46.115(b); 21 CFR 56.115(b); 21 CFR 312.62). This minimum 
retention period applies whether or not any subjects were enrolled in the study. 
If the research is FDA regulated, records should be retained for at least two years after 
approval of the investigational agent by FDA; if it is not approved, records should be 
retained at least two years after the study is terminated and FDA is notified (note the 
additional requirement below for clinical research studies);  
Clinical records, including consent forms that document clinical intervention or 
clinical diagnostic procedure research-related procedures, must be retained in medical 
records by the institution for at least seven years, per CUMC and NYP policy, which 
is based on state law. 
 
Guidelines for Processing IND Safety Reports  
The U.S. Food and Drug Administration (FDA) regulations require sponsors of 
clinical studies to notify the FDA and all participating investigators of any serious and 
unexpected adverse experiences that are possibly related to the investigational agent. 
The CUMC Principal Investigator will review all applicable IND Safety Reports and 
has the responsible for forwarding the IND Safety Reports to the Affiliate Institutions. 
The Affiliate Institution investigators are to review, send a copy to their IRB 
according to their local IRB’s policies and procedures, and file a copy with their 
regulatory documents. All Affiliate site INDSR submissions, along with IRB 
acknowledgment (per local policies and procedures) are to be forwarded to CUMC for 
placement within the trial master file. 
 
13. STATISTICAL CONSIDERATIONS 
 


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13.1 
Study Design/Primary Endpoint (Sample Size) 
 
Phase I (n=10 patients):  
The objective of the phase I portion of this study is to determine an acceptable dose of 
ruxolitinib in combination with trastuzumab.  The dose of trastuzumab will be fixed at 
6 mg/kg every 3 weeks IV for all patients.  If patients have not received trastuzumab 
for > 28 days prior to the initiation of study drugs, a loading of 8 mg/kg IV should be 
used.  After this dose, patients should remain on 6 mg/kg every 21 days (+/- 4 days).  
We evaluate four doses of ruxolitinib PO during the phase I. The ordering of these 
doses is as follows:  
 
The maximum tolerated dose (MTD) combination is defined as the dose combination 
associated with a target probability of dose limiting toxicity of 0.25. A dose-limiting 
toxicity is defined as the MTD with DLTs defined as any grade 3 non-hematologic 
toxicities despite maximal supportive care or any grade 4 hematologic toxicity directly 
related to study drug.  In order for a patient to be evaluable for DLT assessments, the 
patient must incur a DLT during the first 21 days of actively taking ruxolitinib plus 
trastuzumab.  If, for instance, the patient temporarily stops ruxolitinib due to 
uncomplicated hematologic toxicities, the patient can resume ruxolitinib at the same 
dose and the DLT period will remain defined as the first 21 days of actively taking the 
study medication.  In order to be considered eligible, the DLT period (i.e. 21 days of 
actively taking ruxolitinib plus trastuzumab) must be completed within 30 days of the 
first dose of ruxolitinib. 
 
The MTD will be estimated using the time to event continual reassessment method 
(TITE-CRM).  The TITE-CRM will use an empirical dose-toxicity model, with a 
sample size of 10.  The dose-toxicity model is calibrated such that the method will 
eventually select a dose that yields between 16% and 34% DLT (Lee and Cheung 2009, 
Cheung and Chappell 2002).  The advantage of the TITE-CRM is that it uses the 
patient’s partial information before a complete follow-up is achieved.  As a result, we 
can conduct the trial in a continuous fashion without having patients being turned away 
due to waiting time.  However, since the MTD will be estimated from partial data, final 
data may show that patients will have been treated with a dose exceeding the MTD. 
Given the toxicities reported on previous studies using this drug, we anticipate very low 
rates of DLTs at 10 and 15 mg.  Most likely the MTD will be 25mg or 20mg. In addition, 
another advantage is an increased likelihood of getting the true MTD with this 
methodology, as opposed to utilizing a 3+3 dose-finding design.  We will start the trial 
with a dose of 20mg based on the Incyte Investigator’s Brochure and assess the 
performance of the TITE-CRM under two most likely scenarios. 
 
To evaluate the performance of the method, 2000 simulations under the two mostly 
likely scenarios of toxicity profiles were done.  The operating characteristics of our 
design under these scenarios are displayed in the Table 8.  With 10 patients, the design 
Dose Level 
Dose 
1 
25 mg bid 
0 (starting dose level) 
20 mg bid 
-1 
15 mg bid 
-2 
10 mg bid 


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selects the correct MTD with probabilities over 50%.   These simulations assume that 
the patients arrive at a rate of 2 patients every 3 weeks, especially at the initiation of the 
clinical trial, and that a DLT occurs randomly and uniformly within the observation 
window.  
Table 8: Selection Probabilities of the TITE-CRM  
Doses of 
Ruxolitinib  
10mg 
15mg 
20mg 
25mg 
Scenario 1 
 
 
 
 
DLT rate 
1% 
5% 
5% 
25% 
P(Selection)  
0% 
2% 
20% 
78% 
 
 
 
 
 
Scenario 2 
 
 
 
 
DLT rate 
1% 
5% 
  25% 
40% 
P(Selection) 
1% 
21% 
51% 
27% 
 
Table 9 displays a simulation of a sample design using the method where the 
MTD is at dose level 1 (i.e. 25 mg po b.i.d.)    Given the low likelihood of 
overlapping toxicities with ruxolitinib plus trastuzumab and favorable side effect 
profile of ruxolitinib, we anticipate that the table below is the most likely 
scenario. 
 
Table 9: Sample simulated design with n=10 
Patient 
Arrival Time 
Dose Level 
Assigned 
Toxicity (Y/N) 
Time of Toxicity 
1 
1.5 weeks 
0 
N 
- 
2 
3 weeks 
0 
N 
- 
3 
4.5 weeks 
1 
N 
- 
4 
6 weeks 
1 
N 
- 
5 
7.5 weeks 
1 
N 
- 
6 
9 weeks 
1 
N 
- 
7 
10.5 weeks 
1 
Y 
1.11 weeks 
8 
12 weeks 
1 
N 
- 
9 
13.5 weeks 
1 
N 
- 
10 
15 weeks 
1 
N 
- 
 


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Phase II (n=30 patients – evaluable patients from phase I at the recommended 
phase II trial may be included):  
The primary endpoint of the phase II portion of this study is to define the progression 
free survival (PFS) of the combination of ruxolitinib plus trastuzumab in patients with 
HER2+ metastatic breast cancer who have previously received HER2 targeted 
therapy.  PFS will be defined as the time from patient registration until objective or 
disease progression or death from any cause. Assuming a historical PFS of 8 weeks 
with single-agent agent HER2-targeted therapy in metastatic HER2+ breast cancer 
after progressing on trastuzumab-based therapy (Blackwell JCO 2010), we predict 
that patients receiving the combination of ruxolitinib at the MTD dose] plus 
trastuzumab will have a PFS of at least 13 weeks.  With a 2-sided alpha of 0.05, we 
have 80% power to detect a difference with 30 pts.   
 
The PFS distribution of the treatment arm will be estimated by Kaplan-Meier survival 
analysis. Ninety-five percent confidence intervals for the Kaplan-Meier PFS estimates 
will be calculated using Greenwood’s formulae. Patients will be analyzed regardless 
of therapy initiation or compliance for this analysis. A secondary analysis will be 
performed comparing “evaluable” patients. We will define “evaluable” patients as 
patients who met eligibility requirements, have initiated therapy, and were not 
removed from the study for non-compliance or patient withdrawal.  Evaluation of 
disease will be made according to RECIST criteria (version 1.1) in patients with 
measurable disease. Patients with hormone receptor positive metastatic breast cancer 
may not have easily measurable disease as defined by RECIST criteria, in particular 
bone and soft tissue metastases. In these patients CR or PR are not easily assessed. 
Thus, we have chosen Progression Free Survival as our primary endpoint. The 
Clinical Benefit Rate (CBR), defined as complete response, partial response or stable 
disease for > 24 weeks, is our secondary endpoint. In addition, overall response rate, 
CR and PR will be analyzed in evaluable patients. 
 
13.2 
Accrual Rate 
Four centers will accrue patients to the phase I/II portions of this trial.  These centers 
are: New York Presbyterian Hospital – Columbia University, Albert Einstein College 
of Medicine, New York Presbyterian Hospital - Cornell University, and Mount Sinai 
Medical Center.  We anticipate that each site will be able to accrue 5 patients per year 
and believe that the accrual period will be 2 years.  If the accrual is lower than 
expected within the first 6 months, we will consider expanding the study. 
 
13.3 
Stratification Factors 
Patients will be stratified by hormone receptor status (binary: positive or negative).  
Positivity will be defined as estrogen receptor and/or progesterone receptor status > 
1% by immunohistochemistry. 
 
13.4 
Analysis of Secondary Endpoints 
 
13.4.1 Clinical Benefit Rate, Percent Progression-Free at 24 weeks, Objective 
Response Rate:  
Secondary endpoints include clinical benefit rate (CR + PR + SD > 24 weeks) 
(estimated via binomial proportions) and percent progression-free at 24 weeks.  
Ninety-five percent confidence intervals will be calculated for the clinical benefit 
response proportion and the percent progression-free at 24 weeks via binomial 
proportions. The analysis of objective response rate will be conducted on the 


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Measurable Disease at baseline analysis set. Exact binomial 2-sided 95% confidence 
intervals will be generated for the objective response rate.   
 
13.4.2 Toxicity Evaluation  
The frequency of subjects experiencing toxicities will be tabulated.  
The CTEP Active Version of the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be utilized for AE reporting. The CTEP Version 4.0 of the 
CTCAE is identified and located on the CTEP website at 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
All appropriate treatment areas should have access to a copy of the CTEP Active 
Version of CTCAE. All patients will be evaluable for toxicity from the time of their 
first treatment with the study drugs. 
 
13.4.3 Correlative Studies  
Transcriptional profiling will be assessed by our bioinformatics core under the 
direction of Dr. Califano using standard analyses, as well as Interactome modeling.  
Comparisons between pre-treatment to on-treatment will be assessed for significance 
and trend using the paired t-tests. 
 
13.5 
Reporting and Exclusions 
  
13.5.1 Evaluation of toxicity.  
All patients included in the study must be assessed for response to treatment, even if 
there are major protocol treatment deviations or if they are ineligible. Each patient 
will be assigned one of the following categories: 1) complete response, 2) partial 
response, 3) stable disease, 4) progressive disease, 5) early death from malignant 
disease, 6) early death from toxicity, 7) early death because of other cause, or 9) 
unknown (not assessable, insufficient data). [Note: By arbitrary convention, category 
9 usually designates the “unknown” status of any type of data in a clinical database.]  
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate. Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression). Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  
 
14. PROTECTION OF HUMAN SUBJECTS 
This study is to be conducted in accordance with applicable government regulations 
and Institutional research policies and procedures. AN IND annual report will be 
submitted to the FDA in accordance with 21.CFR 312.33. 
 
This protocol and any amendments will be submitted to a properly constituted 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for 
formal approval of the study conduct.  The decision of the IRB concerning the 
conduct of the study will be made in writing to the investigator and a copy of this 
decision will be provided to the sponsor before commencement of this study.  
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study. This consent form will be submitted with the protocol for 
review and approval by the IRB for the study.  The formal consent of a subject, using 


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the IRB-approved consent form, must be obtained before that subject is submitted to 
any study procedure.  This consent form must be signed by the subject or legally 
acceptable surrogate, and the investigator-designated research professional obtaining 
the consent.  
 
 
15. REFERENCES 
1. 
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA 
Cancer J Clin 2005;55(2):74–108.  
2. 
Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 
2008;58(2):71–96.  
3. 
Revillion F, Bonneterre J, Peyrat JP.  ERBB2 oncogene in human breast cancer 
and its clinical significance. European Journal of Cancer 1998;34(6):791–808.  
4. 
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human 
breast cancer: correlation of relapse and survival with amplification of the 
HER-2/neu oncogene. Science 1987;235(4785):177–82.  
5. 
Paik S, Hazan R, Fisher ER, et al. Pathologic findings from the National 
Surgical Adjuvant Breast and Bowel Project: prognostic significance of erbB-2 
protein overexpression in primary breast cancer. J Clin Oncol 1990;8(1):103–
12.  
6. 
Hudis CA. Trastuzumab--mechanism of action and use in clinical practice. 
NEJM 2007;357(1):39–51.  
7. 
Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a 
monoclonal antibody against HER2 for metastatic breast cancer that 
overexpresses HER2. NEJM 2001;344(11):783–92.  
8. 
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant 
chemotherapy for operable HER2-positive breast cancer. NEJM 
2005;353(16):1673–84.  
9. 
Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy 
and safety of humanized anti-HER2 monoclonal antibody in women who have 
HER2-overexpressing metastatic breast cancer that has progressed after 
chemotherapy for metastatic disease. J Clin Oncol 1999;17(9):2639–48.  
10. 
Seidman AD, Fornier MN, Esteva FJ, et al. Weekly trastuzumab and paclitaxel 
therapy for metastatic breast cancer with analysis of efficacy by HER2 
immunophenotype and gene amplification. J Clin Oncol 2001;19(10):2587–95.  
11. 
Esteva FJ, Valero V, Booser D, et al. Phase II study of weekly docetaxel and 
trastuzumab for patients with HER-2–overexpressing metastatic breast cancer. 
J Clin Oncol 2002;20(7):1800–8.  
12. 
Burstein HJ, Keshaviah A, Baron AD, et al. Trastuzumab plus vinorelbine or 
taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the 
trastuzumab and vinorelbine or taxane study. Cancer 2007;110(5):965–72.  


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13. 
Slamon D, Eiermann W, Robert N, et al. Phase III randomized trial comparing 
doxorubicin and cyclophosphamide followed by docetaxel (AC→ T) with 
doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab 
(AC→ TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 
positive early breast cancer patients: BCIRG 006 study. Breast Cancer Res 
Treat 2005;94(Suppl 1):S5.  
14. 
Fridman JS, Scherle PA, Collins R, et al. Preclinical evaluation of local JAK1 
and JAK2 inhibition in cutaneous inflammation. J Investig Dermatol 
2011;131(9):1838–44.  
15. 
Quintás-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the 
selective JAK1/2 inhibitor INCB018424: therapeutic implications for the 
treatment of myeloproliferative neoplasms. Blood 2010;115(15):3109–17.  
16. 
Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted 
inhibitors. Nat Rev Cancer 2005;5(5):341–54.  
17. 
Basso K, Margolin AA, Stolovitzky G, Klein U, Dalla Favera R, Califano A. 
Reverse engineering of regulatory networks in human B cells. Nat Genet 
2005;37(4):382–90.  
18. 
Carro MS, Lim WK, Alvarez MJ, et al. The transcriptional network for 
mesenchymal transformation of brain tumours. Nature 2009;463(7279):318–
25.  
19. 
Margolin AA, Nemenman I, Basso K, et al. ARACNE: an algorithm for the 
reconstruction of gene regulatory networks in a mammalian cellular context. 
BMC Bioinformatics 2006;7 Suppl 1:S7.  
20. 
Wang K, Saito M, Bisikirska BC, Alvarez MJ, al E. Genome-wide 
identification of post-translational modulators of transcription factor activity in 
human B cells. Nature 2009; 
21. 
Silva JM, Mizuno H, Brady A, Lucito R, Hannon GJ. RNA interference 
microarrays: high-throughput loss-of-function genetics in mammalian cells. 
Proc Natl Acad Sci USA 2004;101(17):6548–52.  
22. 
Silva JM, Marran K, Parker JS, et al. Profiling essential genes in human 
mammary cells by multiplex RNAi screening. Science 2008;319(5863):617–
20.  
23. 
Silva JM, Ezhkova E, Silva J, et al. Cyfip1 is a putative invasion suppressor in 
epithelial cancers. Cell 2009;137(6):1047–61.  
24. 
Paddison PJ, Silva JM, Conklin DS, et al. A resource for large-scale RNA-
interference-based screens in mammals. Nature 2004;428(6981):427–31.  
25. 
Akca H, Tani M, Hishida T, Matsumoto S, Yokota J. Activation of the AKT 
and STAT3 pathways and prolonged survival by a mutant EGFR in human 
lung cancer cells. Lung Cancer 2006;54(1):25–33.  
26. 
Byers LA, Sen B, Saigal B, et al. Reciprocal regulation of c-Src and STAT3 in 


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non-small cell lung cancer. Clin Cancer Res 2009;15(22):6852–61.  
27. 
Weerasinghe P, Garcia GE, Zhu Q, et al. Inhibition of Stat3 activation and 
tumor growth suppression of non-small cell lung cancer by G-quartet 
oligonucleotides. Int J Oncol 2007;31(1):129–36.  
28. 
Zhang X, Guo A, Yu J, et al. Identification of STAT3 as a substrate of receptor 
protein tyrosine phosphatase T. Proc Natl Acad Sci USA 2007;104(10):4060–
4.  
29. 
Darnell JE. Validating Stat3 in cancer therapy. Nat Med 2005;11(6):595–6.  
30. 
Sansone P, Bromberg J. Targeting the interleukin-6/Jak/stat pathway in human 
malignancies. Journal of Clinical Oncology 2012;30(9):1005–14.  
31.     Guo, H., W. Liu, Z. Ju, P. Tamboli, E. Jonasch, G. Mills, Y. Lu, B. Hennessy 
and D.  Tsavachidou (2012). "An efficient procedure for protein extraction 
from formalin-fixed,  paraffin-embedded tissues for reverse phase protein 
arrays." Proteome Science 10(1): 56. 
32.      Guo, T., W. Wang, P. Rudnick, T. Song, J. Li, Z. Zhuang, R. Weil, D. DeVoe,  
C. Lee and  B. Balgley (2007). "Proteome analysis of microdissected formalin-
fixed and paraffin-embedded tissue specimens." J Histochem Cytochem 55(7): 
763 - 772. 
 
33. 
Mackey JR, Clemons M, Côté MA, et al. Cardiac management during adjuvant 
trastuzumab therapy: recommendations of the Canadian Trastuzumab Working 
Group. Curr Oncol 2008;15(1):24–35.  
34. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria 
in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer. 
2009;45(2):228–47.  
 
 


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APPENDIX A:  PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated.  Death 
not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B: SUBJECT’S MEDICATION DIARY 
 
SUBJECT’S MEDICATION DIARY 
 
Today’s date _____________________ 
Agent:  Ruxolitinib ______ mg 
 
Subject Name_____________________ (initials acceptable)  
  
Subject Study ID __________________________ 
 
 
Cycle  
 
Day 
 
Date 
 
Time of 
dose  
(AM)  
 
Number 
of Pills 
(AM) 
 
Time of 
dose  
(PM) 
 
Number 
of Pills 
(PM) 
Comments 
Side effects  
 
1 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
 
______________________                       _____________________                  
SUBJECT SIGNATURE 
 
DATE       
 
 
 
 
 
 


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APPENDIX C: STRONG KNOWN CYP 3A4 INHIBITORS AND INDUCERS. 
Inhibitors 
boceprevir 
clarithromycin 
chloramphenicol 
conivaptan 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
mibefradil 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
 
Patients should limit grapefruit juice intake 
 
Source: Jakafi prescribing information, 2013.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX D: ARCHIVED TISSUE AND BIOPSY COLLECTION AND 
SHIPMENT  
 
All formalin-fixed paraffin embedded (FFPE) from archived tumor and study-related 
biopsies will be stored onsite until requested by the coordinating center. Ideally, all 
slides will be cut at the same time, within 6 weeks of time of request, and sent to the 
coordinating center to distribute for analysis at the Columbia University Genome 
Center, Columbia University Molecular Pathology Core, and MD Anderson 
Functional Proteomics Core Facility.  
Ship to: 
Kevin Kalinsky, MD, MS 
Attn: Stephanie Aguilar 
Columbia University Medical Center  
161 Fort Washington Ave – Mezzanine 
New York, NY 10032 
Phone: 212-342-4591 
Complete these forms separately for each subject; enclose with shipment along with 
accompanying pathology report.  
 
I. 
Archived Diagnostic Tissue 
Subject ID: ______________________ 
Archival tissue, diagnostic biopsy                                                                               
 Not available  
Number of 
slides 
Slide preparation 
Slide IDs 
 
 10 immunoblanks [each having 4 micron sections on 
charged slides] 
 1 intervening H&E stained 
 12 regular slides each with 10 microns sections 
 
Enclose redacted accompanying pathology report. 
Archival tissue, biopsy at recurrence                                                           
 Not 
available/applicable  
Number of 
slides 
Slide preparation 
Slide IDs 
 
 10 immunoblanks [each having 4 micron sections on 
charged slides] 
 1 intervening H&E stained 
 12 regular slides each with 10 microns sections 
 
Enclose redacted accompanying pathology report. 
Date  
Name of person responsible for this shipment 
 
 


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II.  Optional study-related biopsies 
For patients with accessible tumor, 2 punch biopsies (for skin) or 3 core biopsies are 
recommended.  The following will be requested: 10 immunoblanks [each having 4 
micron sections on charged slides], one intervening H&E stained slide, and 12 regular 
slides each with 10 microns sections. 
Subject ID: ______________________ 
FFPE tissue, Pre-treatment biopsy   
 Core biopsies (3 preferred)  
 Punch biopsies  (2 preferred)                                                    
Number 
of slides 
Slide preparation 
Date 
Collected 
Slide IDs 
 
 10 immunoblanks [each having 4 micron sections on 
charged slides] 
 1 intervening H&E stained 
 12 regular slides each with 10 microns sections 
 
 
Enclose redacted accompanying pathology report (if available). 
FFPE tissue, On-treatment biopsy from C2D1 (prior to treatment) 
 Core biopsies (3 preferred)  
 Punch biopsies  (2 preferred)                                                  
Number 
of slides 
Slide preparation 
Date 
Collected 
Slide IDs 
 
 10 immunoblanks [each having 4 micron sections on 
charged slides] 
 1 intervening H&E stained 
 12 regular slides each with 10 microns sections 
 
 
Enclose redacted accompanying pathology report (if available). 
Date  
Name of person responsible for this shipment 
 
 
 
III. 
Optional biopsy upon progression 
For agreeable patients with accessible tumor upon progression, 2 punch biopsies (for 
skin) or 3 core biopsies are recommended.  The following will be requested: 10 
immunoblanks [each having 4 micron sections on charged slides], one intervening 
H&E stained slide, and 12 regular slides each with 10 microns sections. 
Subject ID: ______________________ 
FFPE tissue, biopsy upon progression 
 Core biopsies (3 preferred)  
 Punch biopsies  (2 preferred)                                                  
Number 
of slides 
Slide preparation 
Date 
Collected 
Slide IDs 
 
 10 immunoblanks [each having 4 micron 
sections on charged slides] 
 1 intervening H&E stained 
 12 regular slides each with 10 microns 
sections 
 
 
Date  
Name of person responsible for this shipment 
 
 


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APPENDIX E:  BLOOD BIOMARKER COLLECTION 
 
I.  Plasma and Serum Biospecimen Collection 
Samples should be obtained at protocol specified time points, using supplies available 
onsite. All specimens will be stored onsite and shipped out when requested (usually at 
inception of analysis). Samples are collected according to the calendar in section 9.  
I. 
Whole Blood 
Collect 
Invert 
Store 
 
 
 
At least 3 ml whole blood 
in EDTA tube (lavender 
top) 
Invert 8 to 10 times. 
Freeze in -80 freezer 
until ready to ship; 
alternatively, freeze in -
20 freezer up to 4 weeks 
prior to transferring to -
80 freezer for long-term 
storage.  
 
Whole blood is collected pre-study only for all subjects.  
 Be sure to label tube with subject ID, date and time point 
 When requested, ship to:  
Regina Santella Laboratory 
Attn: Irina Gurvich 
Columbia University Medical Center 
630 West 168th St Room 16-410 
New York, NY 10032 
Phone: 212-305-8158 
 Ship on dry ice for overnight delivery; FedEx airbill can be supplied by study 
team. 
 Email m1906@columbia.edu and ig112@columbia.edu to inform study team 
and Irina of incoming samples 


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II. 
Plasma PK – C2D1 only 
Plasma PK is collected C2D1 prior to treatment only for all phase I subjects. 
Trough (prior) and peak (2 hours post) levels should be drawn at Cycle 2 Day 1. 
Collect 
Invert 
Ice/Water 
Bath 
Centrifuge 
Aliquot & 
label 
Store 
 
 
 
 
 
 
 
4 ml whole 
blood in 
K2EDTA 
tube 
(lavender 
top) 
Invert ≥ 5 
times. 
Place tube on 
ice or in 
water bath. 
Within 45 
min. of 
collection, 
centrifuge 
2000 x g for 
15 minutes at 
~5ᴏC. 
With pipette, 
aliquot equal 
amounts 
plasma into 2 
cryotubes.  
Ship Plasma 
aliquot A 
same day as 
collection or 
store both in -
20 to -80 
freezer until 
ready for 
shipment.  
 
 Label the cryotubes with protocol number, patient ID, time of collection and 
Plasma aliquot A or Plasma aliquot B. Place transparent tape over the cryotube 
labels. 
 When prepared, ship Plasma aliquot A samples to:  
Incyte Corporation 
Attn: Tom Emm 
Route 141 & Henry Clay Rd 
Building 400-3431 
Wilmington, DE 19880 
Phone: 302-498-6775 
 Ship on plenty of dry ice for overnight delivery; FedEx airbill can be supplied 
by study team. 
 Plasma aliquot B samples will remain in frozen storage at the site until 
specified by Incyte or the study PI to ship 
 Email temm@incyte.com and smalhotra@incyte.com with tracking 
information to inform them of incoming samples 
 
 


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III. 
Plasma (C-reactive protein, et. al) 
Collect 
Invert 
Centrifuge 
Aliquot 
Store 
 
 
 
 
 
At least 4 ml 
whole blood 
in lithium 
heparin tube 
(dark green top);  
alternatively, 
sample can be 
collected in pink 
top K2EDTA 
tube. 
Invert 8 to 10 
times (do not 
shake). Keep 
at room 
temperature or 
on regular ice 
after inverted. 
Within 1 hour 
of collection, 
centrifuge 
2000 x g for 15 
minutes at 4ᴏC. 
With pipette, 
aliquot ~1.0 ml 
of plasma into 3 
to 5 cryovials. 
(max. volume of 
cryovials should 
be 2 ml) 
Freeze in -80 
freezer until ready 
to ship.  
 
Plasma is collected pre-study, C2D1 prior to treatment, and at progression for all 
subjects.  
 Be sure to label cryovials with subject ID, date, specimen type and time point 
 When requested, ship to:  
Regina Santella Laboratory 
Attn: Irina Gurvich 
Columbia University Medical Center 
630 West 168th St Room 16-410 
New York, NY 10032 
Phone: 212-305-8158 
 Ship on dry ice for overnight delivery; FedEx airbill can be supplied by study 
team. 
 Email m1906@columbia.edu and ig112@columbia.edu to inform study team 
and Irina of incoming samples 
 
 
 
 
 
 
 


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IV. 
Serum (IL6, IL8 cytokines & additional serum biomarkers) 
Collect 
Invert 
Centrifuge 
Aliquot 
Store 
 
 
 
 
 
Up to 10 ml 
whole blood 
in serum tube 
(red top, no gel 
separator); 
alternatively, 
sample can be 
collected in 
multiple serum 
tubes less than 10 
ml. to have 
adequate 
aliquots. 
Invert 8 to 10 
times. Keep at 
room 
tempature until 
adequately 
clotted (at least 
30 minutes). 
Within 1 hour 
of collection, 
centrifuge 
2000 x g for 15 
minutes at 4ᴏC. 
With pipette, 
aliquot ~1.0 ml 
of serum into 4 
to 6 cryovials. 
(max. volume of 
cryovials should 
be 2 ml) 
Freeze in -80 
freezer until ready 
to ship.  
 
Serum Plasma is collected pre-study, C2D1 prior to treatment, and at progression for 
all subjects.  
 Be sure to label cryovials with subject ID, date, specimen type and time point 
 When requested, ship to:  
Regina Santella Laboratory 
Attn: Irina Gurvich 
Columbia University Medical Center 
630 West 168th St Room 16-410 
New York, NY 10032 
Phone: 212-305-8158 
 Ship on dry ice for overnight delivery; FedEx airbill can be supplied by study 
team. 
 Email m1906@columbia.edu and ig112@columbia.edu to inform study team 
and Irina of incoming samples 
 
 


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V. 
Plasma (Additional plasma biomarkers) 
Collect 
Invert 
Centrifuge 
Aliquot 
Store 
 
 
 
 
 
At least 4 ml 
whole blood 
in EDTA tube 
(lavender top)  
Invert 8 to 10 
times.  
Within 1 hour 
of collection, 
centrifuge 
2000 x g for 15 
minutes at 4ᴏC. 
With pipette, 
aliquot ~1.0 ml 
of plasma into 3 
to 5 cryovials. 
(max. volume of 
cryovials should 
be 2 ml) 
Freeze in -80 
freezer until ready 
to ship.  
 
Plasma for biomakers is collected pre-study and C2D1 prior to treatment for all 
subjects.  
 Be sure to label cryovials with subject ID, date, specimen type and time point 
 When requested, ship to:  
Regina Santella Laboratory 
Attn: Irina Gurvich 
Columbia University Medical Center 
630 West 168th St Room 16-410 
New York, NY 10032 
Phone: 212-305-8158 
 Ship on dry ice for overnight delivery; FedEx airbill can be supplied by study 
team. 
 Email m1906@columbia.edu and ig112@columbia.edu to inform study team 
and Irina of incoming samples 
 
 


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VI. 
Shipping Document for Biospecimens 
Store all biospecimens onsite until they are requested from the coordinating site. 
Enclose this document with all biospecmen shipments. You may ship multiple 
specimen types and subjects together, but keep time points and subjects grouped 
together (i.e. all pre-treatment samples grouped together for one subject; all C2D1 
samples for one subject grouped together). 
All biospecimens will be shipped to:  
Regina Santella Laboratory 
Attn: Irina Gurvich 
Columbia University Medical Center 
630 West 168th St Room 16-410 
New York, NY 10032 
Phone: 212-305-8158 
Keep a copy or multiples copies of this document on site with study subject records.  
Send shipments on dry ice for overnight delivery. 
 
Subject 
ID 
Whole 
Blood 
Plasma 
CRP 
Serum 
Plasma 
Total # of 
cryovials 
Comments 
 
 Pre-
treatment 
 Pre-
treatment 
 C2D1 
 Pre-
treatment 
 C2D1 
 Pre-
treatment 
 C2D1 
 
 
 
 Pre-
treatment 
 Pre-
treatment 
 C2D1 
 Pre-
treatment 
 C2D1 
 Pre-
treatment 
 C2D1 
 
 
 
 Pre-
treatment 
 Pre-
treatment 
 C2D1 
 Pre-
treatment 
 C2D1 
 Pre-
treatment 
 C2D1 
 
 
 
 Pre-
treatment 
 Pre-
treatment 
 C2D1 
 Pre-
treatment 
 C2D1 
 Pre-
treatment 
 C2D1 
 
 
 
 Pre-
treatment 
 Pre-
treatment 
 C2D1 
 Pre-
treatment 
 C2D1 
 Pre-
treatment 
 C2D1 
 
 
Use additional shipping documents if needed. 
Date  
Name of person responsible for this shipment 
 
 
 


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VII. 
Shipping Document for PK’s 
 
Ship PK’s directly to Incyte for processing.  
Ship same day if possible on dry ice or store in -80 freezer until ready for shipment.  
All PK’s will be shipped to:  
Thomas Emm 
Sr. Director, Drug Metabolism and Biopharmaceutics 
Incyte Corporation 
1801 Augustine Cut Off 
Wilmington, DE 19803 
 
Email temm@incyte.com and smalhotra@incyte.com with tracking information to 
inform them of incoming samples 
Keep a copy of this document on site with study subject records.  
Sites should use their own courier services for this activity.  
Send shipments on dry ice for overnight delivery; shipments may be completed 
Monday to Thursday only as Saturday delivery is not available. 
 
Subject 
ID 
Plasma PK 
 
Number of tubes 
being sent 
Comments 
 
 C2D1 only prior to 
treatment 
 
 
 
 C2D1 only prior to 
treatment 
 
 
 
 C2D1 only prior to 
treatment 
 
 
Use additional shipping documents if needed. 
Date  
Name of person responsible for this shipment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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HERBERT IRVING COMPREHENSIVE 
CANCER CENTER 
Data and Safety Monitoring Committee 
 
SERIOUS ADVERSE EVENT REPORTING FORM  
 
1 – Trial Information  
SPONSOR  
 
OVERALL PRINCIPAL INVESTIGATOR  
 
LOCAL PRINCIPAL INVESTIGATOR  
 
IRB NUMBER 
 
STUDY TITLE 
 
Study team member reporting event 
 
 
 
2 – Type of event  
Are you reporting a UP? (Unanticipated Problem) 
Yes 
 
No 
 
 
3 – SAE report type  
Report type 
Initial notification  
 
Follow up 
 
 
 
4 – Timeline of the event 
Date Investigator informed 
 
Date of report 
 
Date of Onset 
 
Date Resolved 
 
 
 
 
5 – Participant information  
SUBJECT ID NUMBER 
 
Age 
 
Gender 
Male 
 
Female 
 
 
6 – Description of the Event(s)  
Seriousness 
Causality 
Expectedness 
Death 
 
Not related 
 
Expected 
 
Life threatening 
 
Unlikely 
 
Not expected 
 
Hospitalization or prolongation of hospital stay 
 
Possibly 
 
 
Persistent or significant disability or incapacity 
 
Probably 
 
 
Congenital abnormality or birth defect 
 
Definitely 
 
 
Otherwise considered serious 
 
 
Primary Diagnosis  
CTCAE term for Primary SAE 
 
Grade 
Attribution 
Start date of Primary SAE 
 
End date of Primary AE 
 
Secondary SAEs during hospitalization/prolongation of hospitalization (if applicable) 
CTCAE term 
Grade 
Start date of AE 
End date of AE 
Attribution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Brief description and treatment of events 
 
 
 
Outcome 
Fatal 
 
On-going 
 
Recovered with 
sequelae 
 
Recovered 
 
If recovered (or recovered with sequelae) selected, enter date of recovery 
 
If fatal enter date of death 
 
Cause of death:  
 
 
 
 


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7 – Medication details  
Information about the CHEMOTHERAPY/ STUDY DRUG 
Drug (please specify action taken next to the agent) Legend is in the last column 
Dose 
Route 
Start date 
Stop date 
Action Taken 
 
 
 
 
 
1- Dose stopped 
2- Dose reduced 
3- Dose unchanged 
4- Dose increased 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant Concomitant Medication 
Drug (please specify action taken) 
Indication 
Dose 
Route 
Start date 
Stop date 
Action Taken 
 
 
 
 
 
 
1- Dose stopped 
2- Dose reduced 
3- Dose unchanged 
4- Dose increased 
5- N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other clinical information, including relevant tests (laboratory, CT, ECG etc.) **Please include relevant redacted source documentation. 
 
 
 
 
 
 


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89 
 
 
 
 
 
 
CONTACT DETAILS 
Clinical Research Coordinator or 
Research Nurse 
 
Signature and date 
 
Email 
 
Fax 
 
Telephone 
 
CONTACT DETAILS 
CUMC Principal Investigator or  
Co-Investigator providing 
coverage 
 
Signature and date 
 
Email 
 
Fax 
 
Telephone 
 
CONTACT DETAILS 
Sub-Site Principal Investigator 
 
Signature and date 
 
Email 
 
Fax 
 
Telephone  
 


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APPENDIX G: GUIDELEINES FOR AFFILIATE INSTITUTIONS IN MULTICENTER 
STUDIES  
 
 
1. Multi-site Communication: 
The CPDM office at CUMC provides administration, data management, and organizational 
support for the affiliate sites in the conduct of a multicenter clinical trial.  The CPDM office will 
coordinate regularly scheduled conference calls with affiliate sites.  
The following issues will be discussed as appropriate:  
 Enrollment information  
 Cohort updates (i.e. DLTs) 
 Adverse events (i.e. new adverse events and updates on unresolved adverse events and 
new safety information) 
 Protocol violations 
 Other issues affecting the conduct of the study 
 
2. New Protocol Distribution, IRB Submission, Modifications and Annual Renewals 
 Protocol specific documents are distributed to affiliate sites once CUMC IRB approval 
has been obtained.  
 The affiliate site must submit a draft of site specific revisions to protocol and/or consent 
form documents for review and approval by the sponsor-investigator prior to submission 
to the local IRB. Draft documents should be sent to the study specific email address. The 
site will be provided confirmation that they are approved to submit to their local IRB.  
 Protocol amendments must be approved by the affiliate site’s local IRB within 90 days of 
distribution to the site by the sponsor-investigator.  
 
3. Regulatory Documents: 
3.1 Prior to Site Initiation: 
Sponsor-Investigator will ensure that proper requests are made of sites and that the following 
documentation is collected prior to the initiation of an affiliate site.   
 CV of PI, Sub-I’s and other research staff listed on FDA 1572 (signed and dated copy 
within 2 years) 
 Medical Licenses of PI and Sub-I’s (current copy) 
 Human subjects training certificates for PI and Sub-I’s 
 CLIA/Laboratory  Certifications for Local Laboratories listed on FDA 1572 
 Local Laboratory Director’s CV and License 
 Local Laboratory Reference Ranges  
 IRB roster or statement of compliance 
 FDA Form 1572, if applicable (wet ink originals required) 
 Financial Disclosure forms for all members listed on FDA 1572 (wet ink originals 
required) 
 


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3.2 Ongoing Regulatory Documentation:  Sponsor-Investigator will ensure that proper requests 
are made of sites and that the following documentation is collected throughout the course of the 
study. 
 IRB approval letters for all protocol modifications and all renewals 
 IRB-approved consent forms 
 Current IRB roster, if statement of compliance is not provided as part of site initiation  
 FDA Form 1572, if applicable as updates are required 
 Updated investigator and site information where relevant (e.g., CV, medical licensure 
and Financial Disclosure for new sub-investigator, local laboratory information) 
 
Regulatory documents may be sent to M1906@columbia.edu or to the following address if wet 
ink originals are required: 
 
Clinical Protocol & Data Management Office 
161 Fort Washington Ave. 
Herbert Irving Pavilion 
Mezzanine Level, M-203 
New York, NY 10032 
 
4. Protocol Deviation/Subject Waiver request for Affiliate Sites: 
The Affiliate site MUST submit a prospective deviation request to the CUMC lead PI for review 
and submission to the HICCC DSMC and CUMC IRB. Approvals must be obtained from all 
entities prior to implementation at the Affiliate site.  If a prospective protocol deviation request is 
submitted for review (from an Affiliate site), the PI/site memo(s), HICCC DSMC approval(s) and 
correspondence and CUMC IRB eligibility deviation approval letter(s) should be forwarded to the 
Affiliate site for documentation. The Affiliate site is also required to obtain prospective local IRB 
approval as per institutional policies/procedures prior to implementing the proposed deviation and 
registering/enrolling the subject via CUMC Central Registration. All documents and 
determinations must be clearly documented in the study subject’s medical record, research chart 
and regulatory binder, as described. 
 
 
5. Guidelines for Affiliate Site Monitoring  
 
6.1 On-Site MCT Monitoring:  
1. Initial, recurrent, and close-out on-site monitoring visits will also be conducted at 
Affiliate sites, as appropriate/feasible. Other sites will have monitoring performed 
remotely (see below for further details). 
 The study Monitoring Visit Log will be completed and signed by the 
monitor and the PI/CRNP/CRN and/or CRC and will be filed in the 
regulatory binder. 
 
2. The Compliance Coordinator will communicate with the Affiliate site coordinator/Site 
 Principle Investigator to schedule the monitoring visit and arrange for access to study 
materials and documentation. 
 


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3. The Compliance Coordinator will monitor IIT trials within 1 month after the first subject 
is enrolled at the Affiliate site and throughout the life of the study to ensure that the study 
is being conducted in accordance with the protocol, GCP, applicable federal and local 
regulations, and per all applicable SOPs. The Compliance Coordinator is responsible to 
notify the participating site PI and CRNP/CRN/CRC of upcoming monitor visits and 
convey what information and documentation will be required for the visit(s).  The 
Compliance Coordinator is responsible for verifying that informed consent is properly 
obtained, eligibility is met (via the central registration process), and all study procedures 
are conducted according to the study protocol. The Compliance Coordinator will also 
verify that the data reported in the CRF’s accurately reflect source documents, that all 
toxicities have been reported to date, and that all SAE’s/UPs/deviations/violations have 
been reported according to Coordinating Center, local IRB and HICCC DSMC 
requirements. The Compliance Coordinator will issue queries and ensure resolution in a 
timely and efficient manner.  The Compliance Coordinator will also monitor for 
applicable regulatory compliance and research pharmacy compliance (if applicable) and 
communicate any deficiencies as appropriate. 
 
4. An SIV (or) teleconference will be scheduled and conducted prior to study drug being 
made available (if applicable) and before any subjects are enrolled on a study at the 
Affiliate site. 
 
6.2 MCT Remote Monitoring:  
 
1. 
When necessary (due to logistical constraints), Affiliate sites will be monitored 
remotely by a designated Compliance Coordinator. Sites will be informed of this remote 
monitoring process on a site by site basis. 
 
2. 
Affiliate sites will be monitored by the Compliance Coordinator on both a regulatory 
level, as well as a clinical data/source documentation review level. 
 
3. 
Redacted source documents (applicable to supporting the protocol specific CRF data 
requirements) will be sent to the designated Compliance Coordinator via fax or secure email 
for all subjects enrolled at Affiliate sites. Timelines for submission procedures will be 
defined on a case-by-case basis.   
 
4. 
The Compliance Coordinator will review all submitted redacted source documents 
against the data entered on the protocol specific CRFs. The Compliance Coordinator will 
issue queries when/if necessary. 
 
5. The Affiliate site research staff will respond to queries within 30 days. If queries remain 
outstanding, the Compliance Coordinator will send a delinquent query reminder for the 
outstanding items. 
 
3. The remote monitoring procedures will include review of applicable redacted source 
documentation and supporting applicable documents to determine compliance regarding: 
 Informed consent procedures 


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 Eligibility criteria 
 Protocol specific treatment compliance 
 Protocol specific toxicity/outcome documentation/compliance 
 Protocol specific schedule of events (e.g., baseline visits, pre-treatment, on 
study, follow-up) 
 Participating site IRB documents (e.g., IRB amendment approvals, annual 
renewals, SAE/UP submissions, violation/deviation submissions, INDSR 
submissions, etc). 
 Required specimen submissions (e.g., tissue specimens, research blood 
specimens, etc.) 
 Pharmacy accountability records 
 Adherence to the CRF submission timeframes to CUMC (within the 
protocol specified timeframes) 
 
4. Affiliate site remote monitoring reports will be sent to the lead PI, HICCC DSMC, and 
Affiliate sites after each remote monitoring review. Reports will include information 
regarding data submission timeliness/accuracy, protocol adherence items, query 
resolution status, regulatory status, and overall Affiliate site performance. These reports 
will be generated by the Compliance Coordinator and reviewed with the Compliance 
Core Manager prior to dissemination. 
 
 
6. Dose Level Determinations: 
 
The sponsor-investigator will review enrollment for each dose level cohort during the regularly 
scheduled conference call with the affiliate sites.  
 
The dose level for newly enrolled subjects will be determined by the study statistician upon 
notification that a subject has signed informed consent to participate in the study. The assigned 
dose level for any subject to begin study treatment will be communicated to the affiliate site 
along with the determination by Central Registration that the subject is eligible for enrollment in 
the study.  
 
If a Dose Limiting Toxicity (DLT) is identified in a subject, the affiliate site must notify the 
sponsor-investigator via email at the study specific email address within 1 business day of 
identification. The lead site will communicate that a DLT has been experienced within 1 
business day.  
 
 
7. Confidentiality 
Each affiliate site will be assigned a site number. Each subject that signs consent should be 
assigned a unique code number consisting of site number followed by a number with each new 
subject being assigned the next sequential number (e.g. 04-10). All sites will be required to enter 
their data in the Velos eResearch, the Clinical Trial Management System used for all Cancer-
related clinical research at CUMC. All users must login with their own application username and 
password.  Users off campus must first access the Virtual Private Network with their assigned 
campus username and password and then use their application credentials.   


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Subject confidentiality must be maintained according to HIPAA regulations and GCP 
recommendations.  
 
Except when required by law, study information shared with persons and organizations outside 
of Columbia University Medical Center must not identify the patient by name, social security 
number, address, telephone number, or any other direct personal identifier. 
If the results of this research project are published or presented at a scientific or medical meeting, 
the patient not be identified. Otherwise, all results will be kept confidential and will not be 
divulged (except as required by law) without permission.  
 
Data Reporting Plan 
Columbia University Medical Center (CUMC) is deeply committed to research integrity and 
strong credibility when it comes to the discovery of new treatment concepts, implementation of 
new clinical research techniques, and acceptance of its researcher's findings by the medical 
establishment. In accord with these ethics, CUMC encourages and supports its investigators in 
the sharing of final research data and/or details of newly developed clinical treatments. 
 
CUMC's policies that pertain to patient data sharing conform to CUMC IRB rules, local and state 
laws, and HIPAA privacy regulations. The primary reason for this is to protect the privacy of 
patients who participate in clinical trials. The data can be made available for continuing review 
by federal agencies upon request and for ongoing study safety reviews by the Principal 
Investigator, Statistician, Data Safety and Monitoring Board (DSMC), and, in other instances, 
the CUMC IRB. 
 
Data collected during the course of this clinical trial will primarily be shared with other 
investigators and University staff, the IRB, FDA, and other reporting agencies, and/or transferred 
to other collaborators.  Prior to transfer, the data collected must comply with, and must be 
limited by, the CUMC's guidelines for Protecting the Rights and Privacy of Human Subjects.   
 
Data Acquisition and Submission 
Informed consent, including HIPPA authorization, must be obtained on all subjects prior to their 
participation. Always keep the original signed and dated consent form, with the redacted source 
documents and eligibility checklist. Velos eResearch will be used as the electronic clinical trials 
and data management system. Affiliate sites will enter data directly into Velos eResearch via 
customized case report forms for the study. The research staff will generate reports from Velos 
eResearch to ensure timely submission of data by affiliate sites. This resource allows for the 
timely analysis of particular data sets for safety analysis. 
 
 
 


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APPENDIX H: DRUG ORDER FORM 
 
Completed Form should be e-mailed to: gmb-pci-clinicalrequests@catalent.com and cc: 
Evyonne.Shands@catalent.com  or fax to (215)613-3360.  
INVESTIGATIONAL SUPPLIES SHIPMENT AND RECEIPT VERIFICATION FORM 
Incyte: Protocol: I-RUX-13-02 (Site Protocol  # AAAM1906) 
Section I: (PRINT/TYPE) 
Authorized 
Requestor: 
Sales Order #: 9015870 
Today’s Date: 
 
 
Date needed on site: 
 
Domestic Carrier: Catalent 
Preferred Carrier 
Site No.: 1 
Investigator Information:  
Full Ship To Address: (No P.O. Boxes) 
Name:  
 
Attention to:   
 
 
 
 Telephone:   
Authorized Requestor:  
Date:  
 
 
Description  
 
Catalent Part # 
Quantity 
Requested to 
Ship 
I-RUX-13-02 5MG 60CT BT 
LABELED 
CLR-FG-9015870-001 
 
 
 
     
1.0 Attachment 3  Shipment Checklist 
Section II: (to be completed by Pharmacy, Site Coordinator or Investigator) 
 
Date Shipment 
Received: 
 
 
Inventoried By: 
 
Discrepancies:   
Authorized Site 
Signature: 
 
 
Date: 
 
Upon Receipt, please conduct an inventory of the above shipment and file a 
copy of this form with the drug accountability records. 
      


Local Protocol#:  AAAM1906 
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Incyte Corporation 
I-RUX-13-02 
Pack Slip#: 
SO#: 9015870 
Consign# 
Shipment Condition: Ambient 
 
Carrier: FedEx  
 
Documents Included w/shipment: 
 Packing Slip 
 Shipment Request Form 
 
 
International Requirements: N/A 
 
Shipping Timelines: 
 
48 hour turnaround unless expedited services requested by client. 
 
Special Instructions: 
 
Study Material is CL1 
 
 
 
Packout: Standard Corrugated Shipper