Clinical trial NCT03240016
Conditions: Urothelial Carcinoma
Sponsor: University of Michigan Rogel Cancer Center
Start date: 2018-02-08; Completion date: 2023-06-23
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase 2, single arm, two-stage study of abraxane with an anti-PD1/PDL1 (pembrolizumab) in cisplatin-ineligible patients with advanced urothelial cancer.

Each cycle last 21-days. All subjects will receive pembrolizumab via IV on day 1, and abraxane via IV on Day 1 and Day 8 of each cycle. Subjects may continue to receive the study regimen until they experience disease progression or unacceptable toxicity.

Detailed description:

Arms: arm 1: Pembrolizumab 200mg IV D1 Abraxane 100mg/m\^2 IV D1 and D8 21 Day Cycles
Interventions: intervention 1: Pembrolizumab intervention 2: Abraxane
Intervention descriptions: intervention 1: 200mg IV D1 intervention 2: 100mg/m\^2 D1 and D8

Protocol documents:
Prot_SAP_000.pdf: 
ID: UMCC 
2017.077 
    Abraxane With Anti-PD1/PDL1 in Patients With 
Advanced Urothelial Cancer 
    NCT03240016 
 


 
 
UMCC 2017.077 
ABLE: PHASE 2, SINGLE ARM, TWO-STAGE STUDY OF ABRAXANE WITH ANTI-PD1/PDL1  
IN PATIENTS WITH ADVANCED UROTHELIAL CANCER 
Principal Investigator: 
Ajjai Alva, MD 
Internal Medicine/Hematology-Oncology 
University of Michigan  
7316 Cancer Center 
1500 E. Medical Center Drive 
Ann Arbor, MI 48109 
Phone: (734) 936-0091 
Fax:  (734) 615-2719 
Email: ajjai@umich.edu 
Co-Investigator(s): 
Megan Caram, MD 
Internal Medicine/Hematology-Oncology 
Phillip Palmbos, MD, PhD 
Internal Medicine/Hematology-Oncology 
Zachery Reichert, MD 
Internal Medicine/Hematology-Oncology 
David Smith, MD 
Internal Medicine/Hematology-Oncology 
Ulka Vaishampayan, MD 
Internal Medicine/Hematology-Oncology 
Sarah Yentz, MD 
Internal Medicine/Hematology-Oncology 
 
Aaron Udager, MD, PhD 
Department of Pathology 
 
Lubomir Hadjiyski, PhD 
Department of Radiology 
 
Biostatistician: 
Veerabhadran Baladandayuthapani 
University of Michigan  
Phone: (734) 615-4788 
Email: veerab@umich.edu 
 
Study Drug:  
 
Other Drug: 
nab-paclitaxel (Abraxane) – Investigational 
Pembrolizumab (Keytruda®) – Standard of care


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Initial version: 
September 5, 2017 
Amended: 
November 15, 2017 
February 8, 2018 
November 19, 2019 
August 14, 2020 
March 22, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
ABBREVIATIONS ...........................................................................................................................1 
STUDY SCHEMA ............................................................................................................................2 
STUDY SYNOPSIS..........................................................................................................................3 
1.0 
BACKGROUND AND RATIONALE......................................................................................8 
  1.1 
Disease Background........................................................................................................8 
1.2 Rationale...............................................................................................................................12  
1.3 Correlative Studies ...............................................................................................................12 
2.0 
STUDY OBJECTIVES .........................................................................................................13 
  2.1 
Objectives......................................................................................................................13 
  2.2 
Endpoints.......................................................................................................................13 
3.0 
PATIENT ELIGIBILITY........................................................................................................14 
  3.1 
Inclusion Criteria............................................................................................................14 
  3.2 
Exclusion Criteria...........................................................................................................16 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES ......................................17 
5.0 
TREATMENT PLAN ............................................................................................................18 
  5.1 
Treatment Dosage and Administration..........................................................................18 
  5.2 
Toxicities and Dosing Delays/Dose Modifications.........................................................18 
  5.3 
Concomitant Medications/Treatments...........................................................................28 
  5.4 
Other Modalities or Procedures.....................................................................................28 
  5.5 
Duration of Therapy.......................................................................................................29 
  5.6 
Off Treatment Criteria....................................................................................................29 
  5.7 
Duration of Follow-Up....................................................................................................29 


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  5.8 
Off Study Criteria...........................................................................................................29 
  5.9 
Patient Replacement .....................................................................................................30 
6.0 STUDY PROCEDURES...........................................................................................................31  
6.1 Schedule of Assessments ...................................................................................................31 
7.0 
MEASUREMENT OF EFFECT............................................................................................32 
7.1 Antitumor Effect- Solid Tumors.............................................................................................32  
7.2 Safety/Tolerability.................................................................................................................36 
8.0 
ADVERSE EVENTS.............................................................................................................37 
  8.1 
Adverse Event Reporting Requirements.......................................................................38 
  8.2 
Definitions......................................................................................................................38 
  8.3 
Adverse Event Characteristics ......................................................................................40 
  8.4 
Serious Adverse Event Reporting Guidelines ...............................................................40 
  8.5 
Expedited Reporting by Investigator to Celgene...........................................................41 
  8.6 
Routine Reporting..........................................................................................................42 
  8.7 
Reporting of Unanticipated Problems............................................................................42 
  8.8 
Reference Safety Information........................................................................................42 
9.0 
DRUG INFORMATION ........................................................................................................46 
 9.1 
nab-paclitaxel (Abraxane®) - Investigational.................................................................46 
 9.2 
Pembrolizumab (Keytruda®) - Standard of Care……………………………….................52 
10.0 CORRELATIVES/SPECIAL STUDIES................................................................................52 
  10.1 
Sample Collection Guidelines........................................................................................53 
  10.2 
Specimen Banking.........................................................................................................53 
11.0 
STATISTICAL CONSIDERATIONS..................................................................................54 
  11.1 
Study Design .................................................................................................................54 


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11.2 Sample Size and Accrual ..................................................................................................54  
11.3 Data Analyses Plans..........................................................................................................54 
12.0 INVESTIGATOR REPORTING RESPONSIBILITIES ..........................................................55 
13.0 DATA MANAGEMENT .........................................................................................................56 
14.0 DATA AND SAFETY MONITORING.....................................................................................56 
15.0 QUALITY ASSURANCE…………………………………………………………………………...56 
16.0 
REFERENCES...................................................................................................................57 
17.0 
APPENDICES……………………………………………………………………………………60 
 
Appendix 1 
ECOG Performance Scale 
 
Appendix 2 
EQ-5D-5L Health Questionnaire 


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ABBREVIATIONS 
  AE 
Adverse Event 
  ALT 
Alanine Aminotransferase 
  ALC 
Absolute Lymphocyte Count 
  Anti-PD1/PDL1 
Pembrolizumab for purposes of this protocol 
  AST 
Aspartate Aminotransferase 
  BUN 
Blood Urea Nitrogen 
  CBC 
Complete Blood Count 
  CMP 
Comprehensive Metabolic Panel 
  CR 
Complete Response 
  CT 
Computed Tomography 
  CTCAE 
Common Terminology Criteria for Adverse Events 
  CTSU 
Clinical Trials Support Unit 
  DLT 
Dose Limiting Toxicity 
  DSMC 
Data and Safety Monitoring Committee 
  H&P 
History & Physical Exam 
  HRPP 
Human Research Protections Program 
  IND 
Investigational New Drug 
  IRB 
Institutional Review Board 
  IV (or iv) 
Intravenously 
  MTD 
Maximum Tolerated Dose 
  NCI 
National Cancer Institute 
  ORR 
Overall Response Rate 
  OS 
Overall Survival 
  PBMCs 
Peripheral Blood Mononuclear Cells 
  PD 
Progressive Disease 
  PFS 
Progression Free Survival 
   PI 
 
           Principal Investigator  
   p.o. 
 
           per os/by mouth/orally 
  PR 
Partial Response 
  PRC 
Protocol Review Committee 
  SAE 
Serious Adverse Event 


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  SD 
Stable Disease 
  SGOT 
Serum Glutamic Oxaloacetic Transaminase 
  SPGT 
Serum Glutamic Pyruvic Transaminase 
  UaP 
Unanticipated Problem 
  UMCCC 
University of Michigan Comprehensive Cancer Center 
  WBC 
White Blood Cells 
STUDY SCHEMA 
 
STUDY SYNOPSIS 
Title 
ABLE: PHASE 2, SINGLE ARM, TWO-STAGE STUDY OF ABRAXANE  
WITH ANTI-PD1/PDL1 IN PATIENTS WITH ADVANCED UROTHELIAL 
CANCER 
Phase 
II 
Methodology 
Single arm 
Study Duration 
24 months of accrual; up to 24 months of follow-up per subject/death 
Study Center(s) 
Single center 
Until Progression (therapy  
beyond one radiologic  
progression allowed if  
criteria  
met)/death/intolerable  
toxicity 
Advanced Urothelial  
Cancer 
Pembrolizumab 200 mg IV  
D1  
+   
Abraxane 100 mg IV D1 and  
D8  
in 21 d cycles 
Optional Tumor Biopsy 


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Objectives and Endpoints 
OBJECTIVES: 
• 
PRIMARY: 
• 
To determine the efficacy of pembrolizumab and 
abraxane in patients with advanced urothelial cancer. 
• 
SECONDARY: 
• 
To assess the safety and toxicity of pembrolizumab and 
abraxane in patients with advanced urothelial cancer. 
• 
To estimate secondary measures of efficacy with 
pembrolizumab and abraxane in patients with advanced 
urothelial cancer. 
• 
CORRELATIVE:  
• 
To correlate PD-L1 expression on tumor cells and TILs in 
baseline archival tumor tissue with primary and 
secondary efficacy measures. 
• 
EXPLORATORY:  
• 
To develop a therapy response predictor based on 
baseline immune parameters in tumor tissue. 
• 
To determine the quality of life of patients enrolled on the 
study as reflected in patient-reported outcomes 
ENDPOINTS: 
• 
PRIMARY: 
• 
ORR (Overall Response Rate) proportion in patients with 
advanced urothelial carcinoma treated with 
pembrolizumab and abraxane. 
• 
SECONDARY: 
• 
Adverse events by CTCAE criteria of the pembrolizumab 
and abraxane combination in patients with advanced 
urothelial carcinoma. 
• 
PFS (Progression-Free Survival) and OS (Overall 
Survival) in patients with advanced urothelial carcinoma 
treated with pembrolizumab and abraxane; CR 
(Complete Response) proportion, DOR (Duration of 
Response) and DOT (Duration of Therapy). 
• 
CORRELATIVE:  
• 
PD-L1 expression in tumor tissue and TILs at baseline 
(and in optional tumor biopsy at progression) correlated 
to response, PFS, OS, DOR, DOT. 
 
 
• 
EXPLORATORY 
• 
Development of a Therapy Response Predictor based on 
baseline immune parameters in tissue. 
• 
Quality of Life with patient-reported outcomes (EQ-5D5L) 
before, during and at end of treatment. 


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Number of Subjects 
36 evaluable subjects 
Inclusion Criteria 
1. 
Patients with recurrent unresectable locally advanced or 
metastatic urothelial carcinoma (aka transitional cell carcinoma). 
If unresectable locally advanced urothelial cancer: could have 
been previously radiated, but must have RECIST 1.1 measurable, 
untreated progression of disease component. 
2. 
Subjects may be either cisplatin-ineligible or platinum-refractory. 
 
Cisplatin ineligibility is defined as meeting at least one of 
the following criteria:  
a. Creatinine clearance (calculated or measured) <60 
ml/min (but> 30mL/min) calculated by Cockcroft-Gault 
equation (using actual body weight) or by measured 
24hour urine collection of creatinine for determination 
b. Common Terminology Criteria for Adverse Events  
(CTCAE) Grade >2 audiometric hearing loss 
c. New York Heart Association Class III/IV heart failure. 
d. ECOG Performance Status of 2 as determined by 
treating investigator. 
 
Platinum-refractory is defined as subjects who have 
progression of disease after receiving platinum-containing 
chemotherapy (chemotherapy could have been given in the 
neoadjuvant, adjuvant or metastatic setting). 
3. 
Histological or cytologically proven urothelial carcinoma. Mixed 
urothelial/non-urothelial cell histologies are allowed but pure 
non-urothelial cell carcinoma is NOT allowed.    
4. 
Have measurable disease based on RECIST 1.1 as determined 
by the investigator/radiology assessment. Target lesions 
situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such 
lesions. 
5. 
Has urothelial cancer that is not suitable for local therapy 
administered with curative intent if not already administered. An 
example of local therapy with curative intent is treatment with 
chemotherapy and radiation for Stage 3 disease. If unresectable 
locally advanced urothelial cancer, could have been previously 
radiated, but must have progression of disease component that 
is untreated and RECIST 1.1 measurable. 
6. 
Must have recovered (i.e., AE < Grade 1 or stable) from AEs 
due to a previously administered agent. 
 


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7. ECOG Performance Status of 0, 1 or 2.  
8. Prior neoadjuvant or adjuvant systemic therapy or local 
intravesical chemotherapy or immunotherapy is permitted.  
9. Adequate organ function including hematologic, renal and 
neurologic function (see Section 3.1.9). 
10. Women of child-bearing potential (WOCBP-defined as a sexually 
mature woman who (1) has not undergone hysterectomy [the 
surgical removal of the uterus] or bilateral oophorectomy [the 
surgical removal of both ovaries] or (2) has not been naturally 
postmenopausal for at least 24 consecutive months [i.e., has had 
menses at any time during the preceding 24 consecutive months]) 
must: 
i. Either commit to true abstinence from heterosexual contact 
(which must be reviewed on a monthly basis), or agree to use, 
and be able to comply with, effective contraception without 
interruption, 28 days prior to starting study medication therapy 
(including dose interruptions), and for 6 months after last dose of 
study medication. 
ii. Have a negative serum or urine pregnancy test (β-hCG) result at 
screening - this applies even if the subject practices true 
abstinence* from heterosexual contact. 
11. Male subjects must practice true abstinence* or agree to use a 
condom during sexual contact with a pregnant female or a female 
of childbearing potential while participating in the study, during 
dose interruptions and for 6 months following study drug 
discontinuation, even if he has undergone a successful 
vasectomy. 
* True abstinence is acceptable when this is in line with the 
preferred and usual lifestyle of the subject. [Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of 
contraception]. 
12. Patients must have < Grade 2 pre-existing peripheral neuropathy 
(per CTCAE). 
13. Be > 18 years of age as of date of signing informed consent. 
14. Ability to understand and the willingness to sign a written informed 
consent. 


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Exclusion Criteria 
 
 
 
1. Prior exposure to immune-mediated therapy, including but not limited 
to, other anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA 4), 
anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, including therapeutic 
anticancer vaccines is NOT permitted. 
2. History of allogenic organ transplantation that requires use of 
immunosuppressive agents is NOT permitted. 
 


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3. Active or prior documented autoimmune or inflammatory disorders 
are NOT permitted. The following are exceptions to this criterion: 
a) Patients with vitiligo or alopecia. 
b) Patients with hypothyroidism (e.g., following Hashimoto 
syndrome). 
c) Any chronic autoimmune or inflammatory skin condition that does 
not require systemic therapy. 
d) Patients without active disease requiring treatment in the last 3 
years may be included but only after consultation with principal 
investigator. 
e) Patients with celiac disease controlled by diet alone may be 
included but only after consultation with principal investigator. 
4. Current or prior use of immunosuppressive medication(s) within 14 
days before study treatment is NOT permitted. The following are 
exceptions to this criterion:  
a) Intranasal, inhaled, topical steroids, or local steroid injections 
(e.g., intra articular injection). 
b) Systemic corticosteroids at physiologic doses not to exceed 10 
mg/day of prednisone or its equivalent. 
c) Steroids as premedication for hypersensitivity reactions (e.g., CT 
scan premedication). 
5. Brain metastases or spinal cord compression are NOT permitted 
unless treated with the patient's condition being stable clinically and 
radiologically for at least 28 days and off steroids for at least 14 days 
prior to the start of study treatment. Patients with suspected or known 
brain metastases at screening should have an MRI (preferred) or CT, 
preferably with IV contrast, to access baseline disease status. 
6. Active infection including tuberculosis, hepatitis B, hepatitis C, or 
human immunodeficiency virus (HIV) is NOT permitted. 
7. Receipt of live attenuated vaccine within 30 days prior to the first 
study treatment is NOT permitted. 
8. Is currently participating and receiving study therapy or has 
participated in a study of an investigational agent and received study 
therapy or used an investigation device within 28 calendar days of 
the first dose of treatment. 
9. Grade > 1 peripheral neuropathy (CTCAE criteria) is NOT permitted. 
10. If subjects received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the 
intervention prior to starting trial therapy. 
11. Has a known additional malignancy that is progressing or requires 
active treatment. 
12. Has a history of severe hypersensitivity reaction (e.g., generalized 
rash/erythema, hypotension, bronchospasm, angioedema or 
anaphylaxis) to nab-paclitaxel or anti-PD1/PDL1 or human albumin. 


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13. Has a history or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of the trial, 
interfere with the subject’s participation for the full duration of the 
trial, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator. 
14. Has known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. At the 
time of signing informed consent is a known regular user (including 
"recreational use") of any illicit drug(s) or had a recent history (within 
the last year) of drug or alcohol abuse.  
15. Pregnancies: 
a. Females:  nab-paclitaxel can cause harm to an unborn child if 
given to a pregnant woman.  Females may not take part in this study 
if pregnant or breast-feeding for 6 months after last dose of study 
drug.  Because of the possible risks to an unborn child, women of 
child-bearing potential (WOBCP) will be asked to take a pregnancy 
test prior to starting study medication. 
b. Males: Male subjects should avoid fathering a child while 
receiving study medication and for 6 months after the last dose of 
study medication. Males must agree to complete abstinence from 
heterosexual contact or use a condom during sexual contact with a 
female of child bearing potential while receiving study medication 
and within 6 months after last dose of study medication. If a female 
partner of a male subject taking investigational product becomes 
pregnant, the male subject taking the product should notify the 
principal investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately. 
c. Subjects (both males and female) should practice effective 
contraception during study and for 6 months after the last dose of 
study medication (Section 3.1.8 i, ii). 
16. Patients with biliary obstruction or biliary stent are excluded. 
17. Patients with a history of prior thoracic radiation >30 Gy. 
Study Product(s), Dose, 
Route, Regimen 
Pembrolizumab 200 mg IV on Day 1 and Abraxane (nab-paclitaxel) 100 
mg/m2 IV on Days 1 and 8 in every 21-day cycles. 
Duration of Administration 
Until disease progression/intolerable toxicity/death. Abraxane may be 
stopped after 6 cycles per investigator discretion. 
Reference Therapy 
Pembrolizumab as monotherapy (historical control) 
Statistical Methodology 
The primary aim of this single-arm phase II trial is to determine the 
efficacy of the combination of pembrolizumab and abraxane in patients 
with advanced urothelial carcinoma. The primary endpoint is the ORR 
(Overall Response Rate = Complete Response + Partial Response per 
RECIST 1.1) proportion. 


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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Disease Background 
In the United States, bladder cancer is a common malignancy with an estimated 74,690 new 
cases and 15,580 deaths projected for the year 20141. Although a chemo-sensitive disease 
initially, the median overall survival of patients with metastatic urothelial carcinoma (UC) treated 
with first-line cisplatin-based combination chemotherapy is only approximately 15 months 2. 
Outcomes for cisplatin-ineligible patients is even more disappointing with median overall survival 
around 8 months3. Hence, patients with advanced UC who are ineligible for cisplatin represent an 
area of unmet need in urothelial cancer. Platinum-refractory urothelial cancer also continues to be 
exceedingly lethal disease despite the recent data on activity of checkpoint inhibitor 
immunotherapy as the response rates are approximately 16-20% only. 
Pembrolizumab (also known as MPDL3280A; anti-PDL1) is a blocking monoclonal antibody 
against anti-PDL1 and PD1 respectively designed to disrupt the interactions of PD1 with PDL1. 
By inhibiting PDL1-PD1 interaction, such therapies, PDL1 may enable the activation of T cells. 
1.1.1 Activity of anti-PD therapy in UC:  
Recently, checkpoint inhibitor immunotherapy has been clinically validated in metastatic UC as 
well in other cancer types4,5. The PD-1 receptor-ligand interaction is a major immune checkpoint 
hijacked by tumors to suppress immune control. The normal function of PD-1, expressed on the 
cell surface of activated T-cells under healthy conditions, is to down-modulate unwanted or 
excessive immune responses, including autoimmune reactions. PD-1 (encoded by the gene 
Pdcd1) is an immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 
(CD28) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PDL2).  
On May 18, 2017, the U.S. Food and Drug Administration granted regular approval to 
pembrolizumab (KEYTRUDA, Merck and Co., Inc.) for patients with locally advanced or 
metastatic urothelial carcinoma who have disease progression during or following platinum 
containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum 
containing chemotherapy. 
FDA also granted approval to pembrolizumab for patients with locally advanced or metastatic 
urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. The FDA 
approval was based on a single-arm trial in 370 patients (KEYNOTE-052) with locally advanced 
or metastatic urothelial carcinoma who were deemed not eligible for cisplatin-containing 
chemotherapy. 
1.1.2 Activity of anti-PD therapy in cisplatin-ineligible patients with advanced UC – 
Pembrolizumab 
The regular approval for the second-line indication was based on data from Trial KEYNOTE-045, 
a multicenter, randomized, active-controlled trial in patients with locally advanced or metastatic 
urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. 
Patients were randomly assigned (1:1) to receive either pembrolizumab 200 mg every 3 weeks 
(n=270) or investigator’s choice of a chemotherapy regimen (paclitaxel [n=84], docetaxel [n=84], 
or vinflunine [n=87]) every 3 weeks (n=272). The trial demonstrated statistically significant 
improvements in overall survival (OS) and objective response rate (ORR) for patients assigned to 
pembrolizumab as compared to chemotherapy. Median OS was 10.3 and 7.4 months in the 
pembrolizumab and chemotherapy arms, respectively (HR 0.73; 95% CI: 0.59, 0.91, p=0.004). 
ORR was 21% for pembrolizumab and 11% for chemotherapy (p=0.002). No statistically 
significant difference in progression-free survival between the two arms was observed. 


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The accelerated approval for the first-line indication was based on data from KEYNOTE-052, a 
single-arm, open-label trial in 370 patients with locally advanced or metastatic urothelial 
carcinoma who were deemed not eligible for cisplatin-containing chemotherapy. Patients received 
pembrolizumab 200 mg every 3 weeks. With a median follow-up time of 7.8 months, the ORR 
was 28.6% (95% CI 24, 34) and the median response duration was not reached (range 1.4+, 
17.8+ months). 
1.1.3 Chemoimmunotherapy: 
For many tumors, checkpoint blockade alone has not provided significant benefits or been 
suboptimal6,7. It has been suggested that the immune system could be potentiated with “priming” 
prior to or in conjunction with an immunotherapy agent8. Although numerous chemotherapy 
agents have known immunosuppressive adverse events, some may possess this “priming” effect 
to the host immune system, helping to elicit an antitumor T-cell response. Cytotoxic killing of 
tumors provides a natural source of cancer-associated antigens. Therefore, combining 
chemotherapy with a checkpoint inhibitor could create an immunogenic “feedback loop”, 
increasing antigen presentation and immune response8. 
In addition to direct cytotoxic killing of tumor cells, standard chemotherapeutic agents can elicit 
immunogenicity through various mechanisms8-10. In brief, many cytotoxic agents have been 
shown to recruit immune cells (i.e., dendritic cells, macrophages, and natural killer cells) to the 
tumor microenvironment, enhance tumor-cell death by converting dying tumor cells into 
endogenous vaccines, stimulate natural killer-dependent antitumor immunity and T-cell 
responses, induce phagocytosis of cell debris by dendritic cells and antigen presentation to T 
cells, sensitize tumor cells to cytotoxic T lymphocytes, and disrupt immune suppressor 
mechanisms by selectively depleting myeloid-derived suppressor cells and suppressing 
regulatory T cells. These immunomodulatory properties make chemotherapy agents ideal 
candidates for combination with immunotherapies. 
Although high doses of chemotherapy can be immunosuppressive, chemotherapy agents can 
enhance the antitumor activity of immunotherapy when given at an optimal dose (i.e., lower dose 
such as weekly regimens)11-13. In a preclinical mouse model of relapsed ovarian cancer, a dose 
dense regimen of low-dose paclitaxel/carboplatin versus the maximum-tolerated-dose regimen 
was less toxic to the immune system, reduced immunosuppression by components of the tumor 
microenvironment, and stimulated recruitment of macrophages and CD8+ T cells to tumors14. 
Preclinical evidence also supports giving chemotherapy prior to immunotherapy and at doses 
slightly higher than the dose levels that begin to induce cytopenias12. In a clinical study of patients 
with metastatic breast cancer, low doses of cyclophosphamide/doxorubicin enhanced the immune 
response to an allogeneic, HER2-positive, GMCSF-secreting breast-tumor vaccine in patients 
with breast cancer15. In the same study, higher doses of cyclophosphamide were shown to 
suppress immunity. Therefore, when given at an optimal dose (such as weekly lower doses rather 
than higher monthly dose), chemotherapy may enhance the immune response rather than 
suppress it.  
1.1.4 Immunomodulatory properties of taxanes: 
Taxanes may provide long-term immune benefits, have been shown to increase tumor-infiltrating 
lymphocytes, and have demonstrated a positive effect on T-cell proliferation and natural killer 
mediated tumor-cell lysis in breast cancer tumors16,17. Paclitaxel may be a particularly strong 
immune stimulant, as it is able to both activate CD8+ T cells and reduce immunosuppressive 
cells, such as regulatory T cells18. Docetaxel has been shown to increase CD8+ T-cell production 
RI,)1ȖDVWLPXODWRURIWXPRU-cell killing), but docetaxel does not appear to inhibit the 
suppressor function of regulatory T cells19. In a preclinical model, lower-dose taxanes appeared 
to induce maturation of myeloid-derived suppressor cells into more mature dendritic cells 


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independently of TLR420. In patients with advanced breast cancer, treatment with paclitaxel or 
docetaxel was also associated with enhanced natural killer-cell activity21. In addition, a study 
showed that the antitumor effects of paclitaxel may be mediated by myeloid-derived suppressor 
cells22. Taxanes regulate many aspects of immune function, including lymphocyte recruitment 
and activation and production of immune-enhancing cytokines, including IL-12, IFNγ, TNFα, and 
GMCSF, all of which may augment the antitumor activity of immunotherapies23. Tumor cell-
derived TGFβ has been shown to inhibit paclitaxel-induced macrophage activation; therefore, 
depletion of TGFβ may provide a mechanism for restoring the immunomodulatory properties of 
taxanes24. 
1.1.5 Abraxane (nab-paclitaxel): nab-Paclitaxel (ABRAXANE® for Injectable Suspension [Abraxis 
BioScience, LLC, a wholly owned subsidiary of Celgene Corporation, Summit, New Jersey, 
United States; hereafter referred to as “Celgene”], ABI-007) is a proprietary solvent-free, protein-
stabilized formulation of paclitaxel comprised of paclitaxel in a noncrystalline amorphous state 
and human albumin with a mean particle size of approximately 130 nanometers. nab-Paclitaxel 
has been developed to improve the therapeutic index of paclitaxel, also reducing the toxicities 
associated with Taxol and the CrEL and ethanol vehicle.  This may be achieved in part by taking 
advantage of endogenous transport pathways to deliver higher doses of paclitaxel to the tumor. 
Because nab-paclitaxel does not contain a solvent vehicle, micellar entrapment observed with 
Taxol does not occur 25-27. nabPaclitaxel displays linear pharmacokinetic (PK) characteristics. The 
novel albumin-bound particle formulation of paclitaxel in nab-paclitaxel conferred the ability to 
achieve a higher maximum tolerated dose (MTD) based on every 3-weeks dosing: 300 mg/m2 for 
nab-paclitaxel (Study DM97-123) versus 175 mg/m2 for Taxol (Nyman, 2004)28. The use of 
albumin-bound paclitaxel also enables nab-paclitaxel to be given in a shorter, more convenient 
infusion time of 30 - 40 minutes compared with 3 hours to 24 hours with Taxol.  Due to its distinct 
pharmacological and PK properties and therapeutic index, nab-paclitaxel has been approved by 
regulatory authorities worldwide in over 40 countries/regions as a new product, rather than as a 
generic formulation of Taxol. nab-Paclitaxel may be given without steroid and anti-histamine 
premedication, which is required for Taxol to prevent solvent-related HSRs (Taxol US prescribing 
information). Cremophor EL has been shown to leach plasticizers, specifically di(2-
ethylhexyl)phthalate (DEHP), from polyvinyl chloride (PVC) bags and polyethylene-lined tubing 29-
34. Although no controlled epidemiologic toxicity studies have been conducted in humans exposed 
to DEHP, severe effects (e.g., carcinogenicity, cardiopulmonary toxicity, hepatotoxicity, and 
nephrotoxicity) have been observed in experimental models.  The Taxol prescribing information 
instructs users to prepare, store, and administer solutions in glass, polypropylene, or polyolefin 
containers; nonPVC-containing infusion sets (e.g., those with polyethylene lining) should be used 
(Taxol US prescribing information). By comparison, standard tubing and intravenous (IV) bags 
may be used for the IV administration of nab-paclitaxel 25,28. 
As of October 2016, nab-paclitaxel is approved under the trade name of ABRAXANE in 65 
countries worldwide for the treatment of patients with metastatic breast cancer. ABRAXANE is 
also approved in 54 countries worldwide for the first-line treatment of locally advanced or 
metastatic non-small cell lung cancer (NSCLC), in 57 countries for the first-line treatment of 
metastatic adenocarcinoma of the pancreas, and in Japan for treatment of advanced gastric 
cancer. 
1.1.6 Activity of Abraxane in platinum-refractory UC: 
The activity of Abraxane (ABI-007) against platinum-refractory advanced UC was recently 
described35. The multi-institutional phase II study evaluated the efficacy and tolerability of abraxane 
as a single agent in patients with platinum-refractory metastatic UC. Abraxane was given at 260 
mg/m2 IV q3weekly until progression to the 48 patients enrolled. Baseline characteristics included 
40 being male; median age of 68 years; ECOG Performance Status 0:1:2 was present in 15:24:8 


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patients respectively. A median of 5.5 cycles was administered per patient with 17/48 pts (35%) 
requiring dose reductions. Most frequent adverse events (AE) were alopecia (12%), fatigue (12%), 
pain (12%), neuropathy (9%) and nausea (4%). The most frequent grade > 3 AEs were pain (45%), 
hypertension (14%), fatigue (8%), joint stiffness (5%), neuropathy (4%) and weakness (4%). Forty 
patients are evaluable for response: 1 (2.5%) complete response (CR), 11 (28%) partial responses 
(PR), 9 (23%) stable disease (SD) and 20 (49%) progressive disease. One patient was inevaluable 
for response, 7 patients are too early for evaluation. Single agent abraxane was therefore well 
tolerated with a response rate (CR+PR) of 33% (12/36) and a clinical benefit rate (CR+PR+SD) of 
58% (21/36), representing one of the highest reported response rates to date in the second-line 
UC setting. A NCIC Clinical Trials Group (NCIC CTG) led intergroup trial with the Australian and 
New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) comparing abraxane to 
paclitaxel in platinum-refractory advanced urothelial cancer (NCT02033993) is ongoing. 
 
1.1.7 Taxane-based chemotherapy with immune-checkpoint inhibitors: 
Experience with nab-paclitaxel in combination with checkpoint inhibitors are emerging, but early 
data suggest that nab-paclitaxel-based therapy could augment the antitumor activity of these 
agents. In a preliminary analysis of a Phase IB trial of patients with various solid tumors, a cohort 
of 16 efficacy-evaluable patients with advanced NSCLC treated with the combination of 
atezolizumab (15 mg/kg q3w) plus nab-paclitaxel (100 mg/m2 weekly) plus carboplatin achieved 
an ORR of 56% and a complete response rate of 25% 36,37. Two other trial arms of atezolizumab 
plus either paclitaxel/carboplatin (efficacy evaluable, n=8) or pemetrexed/carboplatin (efficacy 
evaluable, n=17) also demonstrated favorable ORRs of 50% and 76%, respectively, but no 
patients receiving the paclitaxel- or pemetrexed-containing regimens have achieved a complete 
response to date. The most common grade 3 or 4 adverse event was neutropenia (35% in the 
nab-paclitaxel arm, 29% in the paclitaxel arm, and 25% in the pemetrexed arm). Initial analysis of 
a cohort of patients with triple-negative breast cancer treated with atezolizumab (800 mg q2w) 
plus nab-paclitaxel (125 mg/m2 weekly for first 3 of 4 weeks) within the same Phase IB trial 
demonstrated a best ORR of 71% (42% confirmed) in 24 patients evaluable for efficacy38. 
Patients with metastatic triple-negative breast cancer who received the atezolizumab plus nab-
paclitaxel regimen as first-line therapy derived the greatest benefit (best ORR, 46% confirmed). A 
total of 32 patients with triple-negative breast cancer were evaluable for safety. Neutropenia and 
decreased neutrophil count were the most common grade 3/4 AE, occurring in 47% of patients 
receiving atezolizumab plus nab-paclitaxel. The investigators also found that expression of PDL1 
was mostly restricted to immune cells in excised tumors, but the level of expression did not 
appear to correlate with response. Based on the positive results of this Phase IB trial, the 
combination of atezolizumab and nab-paclitaxel is being evaluated in Phase III trials in triple 
negative breast cancer and NSCLC. 
Interim analysis from a triple negative breast cancer study of a microtubule inhibitor eribulin in 
combination with pembrolizumab, an anti-PD1 drug, was recently presented at the San Antonio 
Breast Cancer Symposium 201639. Study 218 is a Phase Ib/II clinical study which examined the 
activity and safety of eribulin in combination with pembrolizumab in 95 patients with metastatic 
triple-negative breast cancer previously treated with 0-2 lines of chemotherapy in the metastatic 
setting. The primary objective of the Phase Ib part was safety and tolerability, and the primary 
objective of the Phase II part was objective response rate (ORR). At the time of the interim 
analysis of 39 evaluable patients out of the 89 patients enrolled in the study as of July 2016, ORR 
was 33.3% (1 patient experienced a complete response and 12 patients experienced a partial 
response). In addition, the ORR was similar between PD-L1 positive and negative cohorts. 
Treatment with the PD-L1 inhibitor atezolizumab (MPDL3280A) plus nab-paclitaxel (Abraxane) 
showed a confirmed objective response rate (ORR) of 66.7% in patients with metastatic triple 
negative breast cancer (TNBC), according to data presented at the 2015 San Antonio Breast 
Cancer Symposium40. In the phase Ib study, atezolizumab plus nab-paclitaxel was explored 
across several lines of treatment regardless of PD-L1 status for patients with metastatic TNBC. In 
the second-line setting, the confirmed ORR was 25% and in the third-line and beyond the ORR 


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was 28.6%. Across the full trial, the ORR was 41.7%. In the ongoing study, 32 patients received 
concurrent treatment with nab-paclitaxel at 125 mg/m2 and atezolizumab at 800 mg. In the initial 
safety cohort of the study (n = 8), atezolizumab was administered on days 1 and 15 along with 
nab-paclitaxel on days 1, 8, and 15 in a 28-day cycle. In a serial biopsy cohort, 24 patients 
received nab-paclitaxel on days 1 and 8 for the first cycle followed by concurrent treatment with 
both agents using the safety cohort schedule. In the serial biopsy arm, a pretreatment biopsy was 
taken > 7 days before the first cycle. Additional biopsies were obtained between days 10 and 15 
during the first cycle then again 4 weeks after the first dose of atezolizumab. Responses were 
confirmed if seen on two or more sequential scans. The primary endpoint of the study was safety, 
with key secondary endpoints focused on ORR, duration of response, progression-free survival, 
and biomarker analyses. The median age of patients in the study was 55.5 years, and most had 
an ECOG PS of 0 (19%) or 1 (81%). The number of prior systemic therapies received was 5, 
although a group of patients were enrolled in the frontline setting (n = 9). Prior to entering the 
study, 87% of patients had received a taxane. At the time of the data cutoff, 24 patients with a 
minimum follow-up of > 3 months were evaluable for efficacy. Across all groups, when 
considering unconfirmed responses, the ORR was 70.8%, which included a complete response 
rate of 4.2%. Additionally, the stable disease rate was 20.8%, for an overall disease control rate 
of 91.6%. At the time of the analysis, 11 of 17 responses (65%) remained ongoing.  
 
1.2 
Rationale 
Given the dire unmet clinical need to improve outcomes for patients who are cisplatin ineligible as 
well as those who are platinum-refractory in advanced urothelial cancer, the preliminary evidence 
of robust activity of abraxane in advanced urothelial cancer, the proven activity of pembrolizumab 
in both platinum-refractory and cisplatin-ineligible patients with advanced urothelial cancer, and 
the emerging data from ongoing studies showing excellent tolerance and promising combinatorial 
activity of the two agents when combined in other cancer types including potential synergy 
between the two agents, we hypothesize that the addition of abraxane to pembrolizumab in 
advanced urothelial cancer would augment the anti-cancer immune response to 
pembrolizumab and result in greater clinical efficacy and benefit to patients from both 
agents in a synergistic manner. 
We therefore propose a single arm phase 2 study of abraxane in combination with 
pembrolizumab in cisplatin ineligible as well as platinum-refractory patients with advanced 
urothelial cancer (metastatic or locally advanced unresectable).  
Rationale for reduction in starting dose of abraxane: Experience in the first 17 subjects enrolled 
revealed: Grade ≥3 adverse events (AE) occurred in 15/17 pts including fatigue (n=5), peripheral 
neuropathy (n=3), anemia (n=3), and oral mucositis (n=3). Five pts discontinued treatment due to 
AEs, all attributed to abraxane. Hence, we believe a dose reduction in starting dose of abraxane 
to 100 mg/m2/dose down from 125 mg/m2/dose is appropriate. 
1.3 
Correlative Studies41  
PD-L1 expression is prevalent in many human tumors, and elevated PD-L1 expression on tumor 
cells is associated with a poor prognosis in patients with UBC 41, 42. Tumor tissue will be archived 
for future testing including PD-L1 status by IHC.  
In the IM vigor 210 trial of atezolizumab in urothelial cancer, PD-L1 expression on immune cells 
infiltrating tumor tissue did correlate with response. Twenty-six percent of patients whose tumor 
immune cells were highly positive by IHC responded whereas only 8% of patients whose tumor 


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immune cells were PDL1 negative had a response. While displaying an important trend, PD-L1 
expression is not an optimal discriminatory biomarker by itself, as evidenced by the fact that 2% 
of patients in the PD-L1 negative group did have a complete response to atezolizumab. Data for 
pembrolizumab PD-L1 is similar5. 
We would like to correlate response with PD-L1 status in patients treated with abraxane and 
pembrolizumab. We plan to test for PD-L1 expression with the corresponding PD-L1 IHC 22C3 
pharmDx assay per the commercial assay specifications in the future after trial accrual is 
complete. 
2.0 
STUDY OBJECTIVES 
 
2.1 
OBJECTIVES: 
PRIMARY: 
• 
To determine the efficacy of abraxane and pembrolizumab antibody in advanced 
urothelial cancer. 
SECONDARY: 
• 
To assess the safety and toxicity of abraxane and pembrolizumab antibody in patients 
with advanced urothelial cancer. 
• 
To estimate secondary measures of efficacy with abraxane and pembrolizumab antibody 
in advanced urothelial cancer. 
EXPLORATORY/CORRELATIVE:  
• 
To correlate PD-L1 expression on tumor cells and TILs in baseline archival tumor tissue 
with primary and secondary efficacy measures. 
• 
To develop a therapy response predictor based on immune parameters in tumor tissue 
and blood. 
• 
To determine the quality of life of patients enrolled on the study as reflected in patient 
reported outcomes. 
 
2.2 
ENDPOINTS: 
PRIMARY: 
• 
ORR (Overall Response Rate) proportion in patients with advanced urothelial carcinoma 
treated with pembrolizumab and abraxane.    
SECONDARY: 
• 
Safety and Toxicity of the combination in patients with advanced urothelial carcinoma. 
• 
PFS (Progression-Free Survival), OS (Overall Survival), CR (Complete Response) 
proportion, DOR (Duration of Response) and DOT (Duration of Therapy) in patients with 
advanced urothelial carcinoma treated with abraxane and pembrolizumab. 
EXPLORATORY/CORRELATIVE:  


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• 
Future testing of PD-L1 expression in tumor tissue and TILs at baseline (and in optional 
tumor biopsy at progression) correlated to objective response, PFS, OS, DOR, DOT. 
• 
Development of a Therapy Response Predictor based on immune parameters in tumor 
tissue and blood. 
• 
Quality of Life with patient-reported outcomes (EQ-5D-5L) before, during and at end of 
treatment. 
3.0 
PATIENT ELIGIBILITY 
Subjects must meet all of the inclusion and exclusion criteria to be enrolled to the study. Study 
treatment may not begin until a subject is enrolled. 
 
3.1 
Inclusion Criteria 
3.1.1  
Patients with recurrent unresectable locally advanced or metastatic urothelial 
carcinoma (aka transitional cell carcinoma). 
If unresectable locally advanced urothelial cancer, could have been previously 
radiated, but must have RECIST 1.1 measurable, untreated progression of 
disease component. 
 
3.1.2 
Subjects may be either cisplatin-ineligible or platinum-refractory. 
• Cisplatin ineligibility is defined as meeting at least one of the following 
criteria:  
a. Creatinine clearance (calculated or measured) <60 ml/min (but> 
30mL/min) calculated by Cockcroft-Gault equation (using actual body 
weight) or by measured 24-hour urine collection of creatinine for 
determination 
b. Common Terminology Criteria for Adverse Events (CTCAE) Grade > 
2 audiometric hearing loss 
c. New York Heart Association Class III/IV heart failure. 
d. ECOG Performance Status of 2 as determined by treating 
investigator. 
• Platinum-refractory is defined as subjects who have progression of  
disease after receiving platinum-containing chemotherapy  
(chemotherapy could have been given in the neoadjuvant, adjuvant or 
metastatic setting). 
3.1.3 
Histological or cytologically proven urothelial carcinoma. Mixed urothelial/non-
urothelial cell histologies are allowed but pure non-urothelial cell carcinoma is 
NOT allowed.   
3.1.4 
Have measurable disease based on RECIST 1.1 as determined by the 
investigator/radiology assessment. Target lesions situated in a previously 
irradiated area are considered measurable if progression has been 
demonstrated in such lesions. 
3.1.5 
Has urothelial cancer that is not suitable for local therapy administered with 
curative intent if not already administered. An example of local therapy with 
curative intent is treatment with chemotherapy and radiation for Stage 3 disease. 


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If unresectable locally advanced urothelial cancer, could have been previously 
radiated, but must have progression of disease component that is untreated and 
RECIST 1.1 measurable. 
3.1.6 
Must have recovered (i.e., AE ≤Grade 1 or stable) from AEs due to a previously 
administered agent. 
 
3.1.7 
ECOG Performance Status of 0, 1 or 2.  
3.1.8 
Prior neoadjuvant or adjuvant systemic therapy or local intravesical 
chemotherapy or immunotherapy is permitted.  
 
3.1.9 
Adequate organ and marrow function as defined below: 
System 
Laboratory Value 
Hematological 
 
Absolute Neutrophil Count 
(ANC) 
≥1500/mm3 
Hemoglobin (Hgb) 
>9 g/dL with or without pRBC transfusion 
Platelets (Plt) 
> 100,000/mm3 
Renal 
 
Calculated or measured 
creatinine clearance 
>30 mL/min calculated by Cockcroft-Gault 
equation (using actual body weight) or by 
measured 24-hour urine collection of 
creatinine for determination. 
Hepatic 
 
Bilirubin 
<1.5 x upper limit of normal (ULN) 
Aspartate aminotransferase 
(AST) 
<2.5 x ULN 
Alanine aminotransferase (ALT) 
<2.5 x ULN 
Total Bilirubin  
<1.5 x ULN 
 
3.1.10 
Women of child-bearing potential (WOCBP-defined as a sexually mature woman 
who (1) has not undergone hysterectomy [the surgical removal of the uterus] or 
bilateral oophorectomy [the surgical removal of both ovaries] or (2) has not been 
naturally postmenopausal for at least 24 consecutive months [i.e., has had 
menses at any time during the preceding 24 consecutive months]) must: 
i. Either commit to true abstinence* from heterosexual contact (which must be 
reviewed on a monthly basis), or agree to use, and be able to comply with, 
effective contraception without interruption, 28 days prior to starting study 
medication therapy (including dose interruptions), and for 6 months after last 
dose of study medication. 
ii. Have a negative serum or urine pregnancy test (β-hCG) result at screening 
this applies even if the subject practices true abstinence* from heterosexual 
contact. 
3.1.11 Male subjects must practice true abstinence* or agree to use a condom during 
sexual contact with a pregnant female or a female of childbearing potential while 


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participating in the study, during dose interruptions and for 6 months following 
study drug discontinuation, even if he has undergone a successful vasectomy. 
* True abstinence is acceptable when this is in line with the preferred and usual 
lifestyle of the subject. [Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception]. 
3.1.12 Patients must have < Grade 2 pre-existing peripheral neuropathy (per CTCAE). 
3.1.13 Be > 18 years of age as of date of signing informed consent. 
 
3.1.14 Ability to understand and the willingness to sign a written informed consent. 
 
3.2 
Exclusion Criteria 
3.2.1 
Prior exposure to immune-mediated therapy, including but not limited to, other 
anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA 4), anti-PD1, anti –PDL1, 
or anti-PD-L2 antibodies, including therapeutic anticancer vaccines is NOT 
permitted.  
3.2.2 
History of allogenic organ transplantation that requires ongoing use of 
immunosuppressive agents is NOT permitted. 
3.2.3 
Active or prior documented autoimmune or inflammatory disorders are NOT 
permitted. The following are EXCEPTIONS to this criterion and are allowed: 
a. Patients with vitiligo or alopecia, Type I diabetes mellitus. 
b. Patients with hypothyroidism (e.g., following Hashimoto syndrome). 
c. Any chronic autoimmune or inflammatory skin condition that does not 
require systemic therapy. 
d. Patients without active disease requiring treatment in the last 3 years 
may be included but only after consultation with principal investigator. 
e. Patients with celiac disease controlled by diet alone may be included but 
only after consultation with principal investigator. 
3.2.4 
Current or prior use of immunosuppressive medication(s) within 14 days before 
study treatment is NOT permitted. The following are EXCEPTIONS to this 
criterion and are allowed: 
a. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra 
articular injection). 
b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day 
of prednisone or its equivalent. 
c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication). 
3.2.5 
Brain metastases or spinal cord compression are NOT permitted unless they 
have been treated with the patient's condition being stable clinically and 
radiologically for at least 28 calendar days and off steroids for at least 14 
calendar days prior to the start of study treatment. Patients with suspected or 
known brain metastases at screening should have an MRI (preferred) or CT 
brain/head, preferably with IV contrast, to assess baseline disease status. 


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3.2.6  
Active infection requiring systemic therapy including tuberculosis, hepatitis B, 
hepatitis C, or human immunodeficiency virus (HIV) is NOT permitted. 
3.2.7 
Receipt of live attenuated vaccine within 28 calendar days prior to the first study 
treatment is NOT permitted.  
3.2.8 
Is currently participating and receiving study therapy or has participated in a 
study of an investigational agent and received study therapy or used an 
investigation device within 28 calendar days of the first dose of treatment. 
3.2.9  
CTCAE Grade > 1 peripheral neuropathy is NOT permitted.  
3.2.10  If subjects received major surgery they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting trial therapy. 
3.2.11  Has a known additional malignancy that is progressing or requires active 
treatment. 
3.2.12  Has a history of severe hypersensitivity reaction (e.g., generalized 
rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to nab 
paclitaxel or anti-PD1/PDL1 or human albumin. 
3.2.13  Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the subject’s 
participation for the full duration of the trial, or is not in the best interest of the 
subject to participate, in the opinion of the treating investigator.  
3.2.14  Has known psychiatric or substance abuse disorders that would interfere with  
cooperation with the requirements of the trial. At the time of signing informed 
consent is a known regular user (including "recreational use") of any illicit drug(s) 
or had a recent history (within the last year) of drug or alcohol abuse. 
3.2.15 Pregnancies  
a. Females:  nab-paclitaxel can cause harm to an unborn child if given to a 
pregnant woman.  Females may not take part in this study if pregnant or 
breast-feeding for 6 months after last dose of study drug.  Because of the 
possible risks to an unborn child, women of child-bearing potential (WOBCP) 
will be asked to take a pregnancy test prior to starting study medication. 
b. Males: Male subjects should avoid fathering a child while receiving study 
medication and for 6 months after the last dose of study medication. Males 
must agree to complete abstinence from heterosexual contact or use a 
condom during sexual contact with a female of child bearing potential while 
receiving study medication and within 6 months after last dose of study 
medication. If a female partner of a male subject taking investigational product 
becomes pregnant, the male subject taking the product should notify the 
principal investigator, and the pregnant female partner should be advised to 
call their healthcare provider immediately. 
c. Subjects (both males and female) should practice effective contraception 
during study and for 6 months after the last dose of study medication (Section 
3.1.8 i, ii). 


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3.2.16 
Patients with biliary obstruction or biliary stent are excluded. 
3.2.17    Patients with a history of prior thoracic radiation >30 Gy. 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES 
After informed consent is obtained and PRIOR to the initiation of protocol therapy all patients 
satisfying the inclusion/exclusion criteria must have eligibility confirmed by the Oncology Clinical 
Trials Support Unit (OCTSU). The patient will not be considered registered and enrolled in the 
study until all information is confirmed by the OCTSU Data Manager. 
A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be assigned a Patient Study ID number and documented on a Screening 
and Enrollment Log. 
It is the responsibility of the principal investigator to determine patient eligibility prior to submitting 
patient registration request to the OCTSU. The eligibility worksheet and all pertinent source 
documents will be maintained in the patient’s chart. 
Patients found to be ineligible for participation after being consented will be considered screen 
failures and documented as such in the Screening and Enrollment Log. 
5.0 
TREATMENT PLAN 
 
5.1 
Treatment Dosage and Administration 
Protocol treatment must start within 14 business days of enrollment to the study. 
5.1.1 
REGIMEN DESCRIPTION 
 
 
Agent 
Premedications; 
Precautions 
Starting  
Dose 
Route 
Schedule 
Cycle 
Length  
Abraxane (nab 
paclitaxel) 
Prochlorperazine 
10 mg once  
oral/IV if unable 
to tolerate oral 
route 
100 
mg/m2/dose  
IV over 30-40 
minutes 
Days 1, 8  
21 days 
Pembrolizumab 
None mandated 
200 mg/dose 
IV over 60 
minutes (+/-5 
minutes). If 
the first 
infusion is 
tolerated, all 
subsequent 
infusions may 
be delivered 
over 30 
minutes. 
Day 1 
 


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• 
Administer abraxane first followed by pembrolizumab. 
• 
Abraxane infusion completed in less than 25 minutes will meet the infusion rate 
criterion for an overdose. 
• 
Abraxane can be discontinued after 6 cycles at investigator discretion, or for 
intolerable toxicities and pembrolizumab alone could be continued. 
• 
Abraxane alone can be continued if pembrolizumab is stopped for pembrolizumab 
related toxicities, and vice versa. 
 
5.1.2 
Dose levels 
Dose level 
Pembrolizumab Dose 
Abraxane Dosing 
0 
200 mg 
100 mg/m2 
-1 
200 mg 
75 mg/m2 
-2 
200 mg 
50 mg/m2 
 
5.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
Table (Section 6.4). Toxicity will be assessed according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0. Dose adjustments should be made 
according to the system showing the greatest degree of toxicity. 
5.2.1 Hematological Toxicities (only applicable to abraxane dosing) 
Hematological Toxicity Dose Reductions for Abraxane 
ANC1 
Platelets 
Action 
•PL or 
>100,000/PL 
None. 


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-1st Occurrence: Hold current dose until 
ANC > 1,500/μL and platelets > 
100,000/μL. Do not replace missed doses. 
Restart next treatment at TBD dose. 
1000-1499/PL or 
75,000-99,000/PL 
-2nd Occurrence: Hold current dose until 
ANC > 1,500/μL and platelets > 
100,000/μL. Do not replace missed doses. 
Restart next treatment at 1 dose level lower 
if possible. If no lower dose level possible, 
stop abraxane. 
 
-3rd Occurrence: Hold current dose until  
ANC > 1,500/μL and platelets > 
100,000/μL. Do not replace missed doses. 
Restart next treatment at 1 dose level 
lower if possible. If no lower dose level 
possible, stop abraxane. 
-4th Occurrence: Discontinue abraxane 
-1st Occurrence: Hold current dose until  
500-999/PL or 
50,000-74,000/PL 
ANC > 1,500/μL and platelets > 
100,000/μL. Do not replace missed doses. 
Restart next treatment at 1 dose level 
lower if possible. If no lower dose level 
possible, stop abraxane. 
 
-2nd Occurrence: Hold current dose until 
ANC > 1,500/μL and platelets > 100,000/μL. 
Do not replace missed doses. Restart next 
treatment at 1 dose level lower if possible. If 
no 
lower 
dose 
level 
possible, 
stop 
abraxane. 
 
-3rd Occurrence: Discontinue abraxane. 
-1st Occurrence: Hold current dose until  
<500/PL or 
<50,000/PL                     ANC > 1,500/μL and platelets > 100,000/μL. 
Restart next treatment at 1 dose level lower 
if possible. If no lower dose level possible, 
stop abraxane. 
 
-2nd Occurrence: Discontinue abraxane. 
1Note: G-CSF (Filgrastim) may be added for low ANC on day of treatment BEFORE a dose 
reduction is instituted at treating physician’s discretions. Neulasta® on day 9 of a cycle is allowed 
if preferred. 
 
5.2.2 Non-hematological Toxicities (except neuropathy) Dosing level changes 
NCI CTCAE Grade 
Pembrolizumab 
Abraxane (nab-paclitaxel) 


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1 
Please see Section 5.2.4 
No change from original 
starting dose  
2 
Please see Section 5.2.4 
Hold until improved to < 
Grade 1, then reduce 
abraxane by 1 dose level 
when resuming. If no lower 
dose level possible, stop 
abraxane. 
3 
Please see Section 5.2.4 
Hold until improved to < 
Grade 1, then reduce 
abraxane by 1 dose level 
when resuming. If no lower 
dose level possible, stop 
abraxane. 
Second or greater episode 
of grade 3 or 1st or greater 
episode of grade 4 toxicity 
Please see Section 5.2.4 
Discontinue abraxane. 
 
For Abraxane induced neuropathy as a special event: 
Grade 1: Dose reduce abraxane by -1 level and continue; recommend adding gabapentin or 
pregabalin 
Grade 2: Hold abraxane till grade 1 or less; then dose reduce abraxane by -1 level and resume; 
recommend adding gabapentin or pregabalin 
Grade 3: Discontinue abraxane permanently; recommend adding gabapentin or pregabalin 
Grade 4: Discontinue abraxane permanently; recommend adding gabapentin or 
pregabalin  
 
N.B.: Can continue pembrolizumab if abraxane is held or discontinued. 
N.B.: If abraxane is held or discontinued, can cancel day 8 visit along with associated 
labs/procedures and infusion. 
5.2.3 Recommendations for Dose of Abraxane on C1 D8 and beyond in Patients with 
Hepatic Impairment. 
 
SGOT (AST) 
OR SGPT  
(ALT) Levels 
 
Bilirubin 
Levels 
ABRAXANE Dose 
Mild 
< 10 x ULN 
AND 
>ULN to < 1.5 x    
ULN 
100 mg/m2 
Moderate 
< 10 x ULN 
AND 
>1.5 to < 2.5 x ULN 
HOLD 
Severe 
< 10 x ULN 
AND 
>3 to < 5 x ULN 
HOLD 
< 10 x ULN 
OR 
>5 x ULN 
HOLD 
 
5.2.4 Dosing delays and holds for Pembrolizumab: 


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•     No dose delays for pembrolizumab are needed for hematologic changes. 
•     Doses that are held will be skipped, not made up later. 
•  
With any grade 2 or higher non-hematologic toxicity deemed to be related to 
pembrolizumab, hold pembrolizumab and refer to section 5.2.1. If adverse event is not an 
event of interest and improves to grade 1 or better, pembrolizumab may be resumed. 
•  
If non-hematologic toxicity does not improve to grade 1 or better in 12 weeks from prior dose, 
discontinue pembrolizumab. 
•  
Infusion-Related Reaction: Pembrolizumab can cause severe or life-threatening infusion 
related reactions, including hypersensitivity and anaphylaxis, which have been reported in 6 
(0.2%) of 2799 patients receiving pembrolizumab. Monitor patients for signs and symptoms of  
infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, 
hypotension, hypoxemia, and fever. For severe (Grade 3) or life-threatening (Grade 4) 
infusion-related reactions, stop infusion and permanently discontinue Pembrolizumab. 
Certain adverse events that are possibly immune mediated warrant special monitoring and 
management and are outline below to guide investigators. 
5.2.4.1 Pulmonary: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
protocol therapy. Evaluate with imaging and pulmonary consultation. 
Grade of 
pneumonitis (NCI 
CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
Radiographic Changes 
Only 
 
Consider delay of  pembrolizumab 
 
Monitor for symptoms every 2-3 days 
 
Consider pulmonary and infectious 
disease consultations 
 
Re-image at least every 
3 weeks 
 
If worsening, treat as 
grade 2, 3 or 4 
Grade 2 
Mild to moderate new  
symptoms 
 
 
Delay pembrolizumab  
 
Consult pulmonary and 
infectious disease  
 
Monitor symptoms daily, 
consider hospitalization  
 
1.0-2.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent 
 
Consider bronchoscopy and/or 
lung biopsy 
 
 
 
Re-image every 1-3 
days 
 
Consider 
prophylactic 
antibiotics while on 
steroids 
 
If improves: 
 
When symptoms 
return to near 
baseline, 
taper 
steroids over at 
least one month 
 
When steroids 
are at 10mg oral 
prednisone (or 
equivalent) or 
below, resume 
pembrolizumab 
 
If not improving 
after 2 weeks or 


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worsening, treat 
as grade 3 or 4 
 
 
 
  
Grade 3 or 4 
Severe new 
symptoms and/or new 
or worsening hypoxia 
 
 
 
 
 
Discontinue pembrolizumab 
 
Hospitalize 
 
Consult pulmonary 
and infectious 
disease  
 
1-2 mg/kg/day 
methylprednisolone 
IV or IV equivalent 
 
Add prophylactic  
antibiotics for opportunistic  
infections like PCP/PJP 
 
Consider 
bronchoscopy 
and/or lung biopsy 
 
 
 
If improves to 
baseline: 
 Taper steroids 
over 4 weeks 
 
If not improving 
after 48 hours or 
worsening 
Add additional 
immunosuppressive 
agent(s) (e.g. 
infliximab, 
cyclophosphamide, 
intravenous 
immunoglobulin or 
mycophenolate mofetil) 
 
5.2.4.2 Gastrointestinal: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
protocol therapy. Opiates or narcotics may mask symptoms of perforation. Infliximab should not 
be used in case of perforation or sepsis. 
Grade of diarrhea/colitis 
 (NCI CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
 
Diarrhea of less 
than 4 stools per 
day over baseline 
or 
asymptomatic 
colitis 
 
Continue 
pembrolizumab 
 
Symptomatic treatment 
such as loperamide 
 
Close monitoring for 
worsening symptoms 
 
Educate patient to report 
worsening immediately 
 
If worsening, treat as grade 
2,3 or 4 
Grade 2 
 
Diarrhea of 4-6 
stools per day 
 
Hold pembrolizumab 
and start symptomatic 
treatment such as 
loperamide 
 
If improves to grade 1, 
resume pembrolizumab 
o 
Resume pembrolizumab 
if the event improves to 


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over baseline 
OR  
 
IV fluids needed < 
24 hours due to 
diarrhea 
OR 
 
Colitis with 
abdominal pain or 
blood in stool 
o 
1-2 mg/kg per day 
of oral prednisone 
or equivalent 
o 
Consider 
prophylactic 
antibiotics for 
opportunistic 
infections like 
PCP 
 
 
grade 0 or 1 within 12 
weeks and 
corticosteroids have 
been reduced to the 
equivalent of ≤ 10mg 
oral prednisone per day 
o 
When symptoms 
improve to grade 1, 
taper steroids over at 
least one month 
 
If worsening, treat as grade 3 
or 4 
Grade 3  
 
Diarrhea ≥ 7 
stools per day 
over baseline 
OR 
 
IV fluids needed 
for ≥ 24 hours due 
to diarrhea 
OR 
 
Colitis with severe 
abdominal pain or 
medical 
intervention 
indicated 
 
 
Delay pembrolizumab 
 
1-2mg/kg/day 
methylprednisolone IV 
or IV equivalent 
 
Start prophylactic 
antibiotics for 
opportunistic infections 
such as PCP 
 
Consider lower 
endoscopy 
 
 
If improves 
 
Continue steroids until 
symptoms are grade 1, then 
taper over at least one month 
 
Resume pembrolizumab if the 
event improves to grade 0 or 
1 within 12 weeks and 
corticosteroids have been 
reduced to the equivalent of ≤ 
10mg oral prednisone per day 
 
If persists for >3-5 days or 
recurs after improvement, add 
infliximab 5mg/kg if no 
contraindication (Note: 
infliximab should not be used 
in cases of perforation or 
sepsis) 
Grade 4 
Life threatening or 
perforation 
 
Discontinue 
pembrolizumab 
 
1-2mg/kg/day 
methylprednisolone IV 
or IV equivalent 
 
Start prophylactic 
antibiotics for 
opportunistic infections 
such as PCP 
 
Consider lower 
endoscopy 
 
If improves 
 
Continue steroids until 
symptoms are grade 1, then 
taper over at least one month 
 
If persists for >3-5 days or 
recurs after improvement, add 
infliximab 5mg/kg if no 
contraindication (Note: 
infliximab should not be used 
in cases of perforation or 
sepsis) 
 
5.2.4.3 Endocrinopathy: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
protocol therapy. Consider visual field testing, endocrinology consultation and imaging. 
Endocrinopathy 
Management 
Follow-up 


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Asymptomatic thyroid-
stimulating hormone (TSH) 
elevation 
 
Continue pembrolizumab 
 
If TSH <0.5 x LLN or 
TSH >2x ULN, or 
consistently out of range 
in subsequent 
measurements, include 
free T4 in subsequent 
measurements as 
clinically indicated 
 
Consider endocrinology 
consult 
 
Symptomatic 
Hypothyroidism 
 
Initiate thyroid 
replacement 
 
Symptomatic 
Hyperthyroidism 
 
Delay pembrolizumab 
 
Consider endocrinology 
consult 
 
Initiate anti-thyroid drug 
 Resume pembrolizumab 
when symptoms of 
hyperthyroidism are 
controlled and thyroid 
function is improving 
Hypophysitis 
 
Administer 
corticosteroids and 
hormone replacement as 
clinically indicated 
 
Delay pembrolizumab 
for grade 2 or 3 
hypophysitis 
 
Permanently discontinue 
pembrolizumab for 
grade 4 hypophysitis 
 
Symptomatic Adrenal 
Insufficiency 
 
Delay Pembrolizumab 
 
 
Administer 
methylprednisolone 1-2 
mg/kg/day IV followed 
by oral prednisone 1-
2mg/kg per day or 
equivalent once 
symptoms improve 
 
Add prophylactic 
antibiotics for 
opportunistic infections 
 
If improves to ≤ grade 1, 
taper steroids over at least 
one month 
 
Resume pembrolizumab if 
the event improves to grade 
0 or 1 within 12 weeks and 
corticosteroids have been 
reduced to the equivalent of 
≤10 mg oral prednisone per 
day and the patient is on 
stable replacement therapy 
if required 
 
5.2.4.4 Hepatic: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
protocol therapy. Consider imaging for obstruction. 
Grade of Liver Test 
Elevation 
(NCI CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
AST or ALT >ULN to 3x 
ULN and/or total 
 
Continue 
pembrolizumab 
 Continue 
liver 
function 
test 
monitoring per protocol 
 If worsening, treat as grade 2,3, or 
4 


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bilirubin >ULN to 1.5x 
ULN 
Grade 2 
AST or ALT >ULN to 3-
5x ULN and/or total 
bilirubin >ULN to 1.5-3x 
ULN 
 
Delay 
pembrolizumab 
 
Administer 
corticosteroids at a 
dose of 
0.51mg/kg/day oral 
prednisone 
 Resume pembrolizumab if returns 
to baseline 
 If persists >5-7 days or worsens, 
treat as grade 3 or 4 
Grade 3 or 4 
AST or ALT >5x ULN 
and/or total bilirubin >3x 
ULN 
 
Discontinue 
pembrolizumab 
 
Increase frequency 
of monitoring to 
every 1-2 days 
 
1-2mg/kg/day 
methylprednisolone 
IV or IV equivalent 
for grade 3 and 2 
mg/kg/day 
methylprednisolone 
IV for grade 4 
 
Add prophylactic 
antibiotics for 
opportunistic 
infections like PCP 
 
Consult 
gastroenterologist 
 If improves to grade 2, taper 
steroids over at least one month 
 If does not improve within 3-5 
days or worsens after 
improvement: 
o 
Add mycophenolate 
mofetil 1g twice daily 
o 
If no response within an 
additional 3-5 days, 
consider other 
immunosuppressive 
agents per local 
guidelines 
 
5.2.4.5 Pancreatic/Renal: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
protocol therapy. Consider imaging for obstruction. 
Grade of pancreatic 
toxicity  
(NCI CTCAE v4.03) 
Management 
Follow-up 
Grade 1-2 
Amylase or Lipase 
up to 2x ULN 
 
Continue  
pembrolizumab 
 


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Grade 2 or 3 
Pancreatitis or 
Grade 3 serum 
amylase or lipase 
level (>2x ULN) 
 
Delay pembrolizumab  
 
Treat with 1-2mg/kg IV 
methylprednisolone or 
equivalent per day 
 Once symptoms improve, follow 
with 1-2mg/kg of oral prednisone or 
equivalent per day 
 Resume pembrolizumab if 
amylase/lipase improves to ≤ 
grade 1 within 12 weeks, 
symptoms of pancreatitis have 
resolved, and corticosteroids have 
been reduced to ≤ 10 mg oral 
prednisone or equivalent per day 
Grade 4 or recurrent 
pancreatitis 
 
Discontinue 
pembrolizumab 
 
Treat with 1-2mg/kg IV 
methylprednisolone or 
equivalent per day 
 Once symptoms improve, follow 
with 1-2mg/kg of oral prednisone or 
equivalent per day and taper for ≥ 1 
month 
 
5.2.4.6 Neurological: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
protocol therapy. 
Grade of neurological 
toxicity 
(NCI CTCAE v 4.03) 
Management 
Follow-up 
Grade 1 
 
Asymptomatic or 
mild symptoms 
 
Intervention not 
indicated 
 
Continue  pembrolizumab 
 Continue to monitor 
the 
patient, 
if 
worsening treat as 
grade 2, 3, or 4 
Grade 2 
 
Moderate symptoms 
 
Limiting instrumental 
ADLs 
 
Delay pembrolizumab 
 
Treat symptoms per 
institutional guidelines 
 
Consider 0.5-1mg/kg per 
day methylprednisolone IV 
or oral equivalent 
 
If returns to baseline, 
resume 
pembrolizumab 
 
If worsens, treat as 
grade 3 or 4 
Grade 3 or 4 
 
Severe symptoms 
 
Limiting self-care 
ADLs 
 
Discontinue 
pembrolizumab 
 
Consult Neurology 
 
Treat symptoms per 
institutional guidelines 
 
1-2mg/kg per day IV 
methylprednisolone or IV 
equivalent 
 
Add prophylactic antibiotics 
for opportunistic infections 
 
If improves to grade 
2, taper steroids over 
at least one month 
 
If worsens, consider 
IVIG or other 
immunosuppressive 
therapies per 
institutional 
guidelines 
Meningitis or Encephalitis 
 
Discontinue 
pembrolizumab 
 
1-2mg/kg 
per 
day 
IV 
methylprednisolone or IV 
equivalent 
 
Add prophylactic antibiotics 
for opportunistic infections 
 
If improves, convert 
to oral steroids 
(prednisone 
60mg/day or 
equivalent) 
 
When symptoms 
improve to ≤ grade 


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1, taper steroids 
over at least one 
month 
 
5.2.4.7 Skin: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
protocol therapy 
Grade of Rash 
(NCI CTCAE v4.03) 
Management 
Follow-up 
Grade 1-2 
Covering ≤ 30% body 
surface area (BSA) 
 
Symptomatic therapy 
(such as antihistamines, 
topical steroids) 
 
Continue pembrolizumab 
 
If persists 1-2 weeks or recurs 
o 
Consider skin biopsy 
 
Delay pembrolizumab 
o 
Consider 0.5-1mg/kg/day 
methylprednisolone IV or 
oral equivalent 
o 
Once improving, taper 
steroids for at least one 
month 
o 
Consider prophylactic 
antibiotics for 
opportunistic infections 
like PCP/PJP 
o 
Resume pembrolizumab 
if rash improves to ≤ 
grade 1 within 12 weeks 
and corticosteroids have 
been reduced to ≤ 10 mg 
oral prednisone or 
equivalent per day 
 
If worsens, treat as grade 
3 or 4 
Grade 3-4 
Covering >30% BSA or 
life threatening 
consequences 
 
Delay or discontinue 
pembrolizumab. If SJS or 
TEN, permanently 
discontinue 
pembrolizumab. 
 
Consider skin biopsy 
 
Consult dermatology 
 
1-2mg/kg/day 
methylprednisolone IV or IV 
equivalent 
 
Add prophylactic 
antibiotics for opportunistic 
infections 
 
If improves to grade 1: 
o 
Taper steroids over at 
least one month  
o 
Resume 
pembrolizumab if rash 
improves to ≤ grade 1 
within 12 weeks and 
corticosteroids have 
been reduced to ≤ 10 
mg oral prednisone or 
equivalent per day 
 
If Steven Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN) develops, 
permanently discontinue Pembrolizumab. 
5.2.4.8 Renal: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
protocol therapy 


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Grade of elevation in 
serum creatinine 
(NCI CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
Serum creatinine >ULN 
and >baseline but ≤1.5x 
baseline 
 Continue 
pembrolizumab  
 Monitor serum 
creatinine weekly 
 
If returns to baseline, resume 
creatinine monitoring per 
protocol 
 
If worsens, treat as grade 2, 
3, or 4 
Grade 2 
Serum creatinine ≤ 6 x 
ULN 
 Delay or discontinue 
pembrolizumab 
 Monitor serum 
creatinine every 2-3 
days 
 1-2 mg/kg/day 
methylprednisolone IV 
or oral equivalent 
 Add prophylactic 
antibiotics for 
opportunistic infections 
 Consider renal biopsy 
 
If improves to grade 1 
o Taper steroids over at 
least one month  
o Resume  
pembrolizumab if 
improves to ≤ grade 1 
within 12 weeks and 
corticosteroids have 
been reduced to ≤ 10 
mg oral prednisone or 
equivalent per day 
 
If elevation persists >7 days 
or worsens, treat as grade 4 
 
Grade 3 or 4 
Serum creatinine > 6x 
ULN 
 Discontinue 
pembrolizumab 
 Monitor serum 
creatinine daily 
 1-2mg/kg/day 
methylprednisolone IV 
or IV equivalent 
 Add prophylactic 
antibiotics for 
opportunistic infections 
 Consult nephrology 
 Consider renal biopsy 
 
If improves to grade 1 
o Taper steroids over at 
least one month  
o Resume 
pembrolizumab if 
improves to ≤ grade 1 
within 12 weeks and 
corticosteroids have 
been reduced to ≤ 10 
mg oral prednisone or 
equivalent per day 
 
 
5.3 
Concomitant Medications/Treatments 
Systemic corticosteroids greater than the equivalent of 10 mg of prednisone or equivalent 
alternative steroid (except physiologic dose for adrenal replacement therapy) or other 
immunosuppressive agents (such as cyclosporine or methotrexate) and any other 
medications that could potentially impact the efficacy or safety of the study as judged by 
the treating investigator are NOT permitted from time of registration to subjects 
completing protocol therapy unless clinically indicated to manage adverse events or life 
threatening or serious conditions as determined by the treating investigator. 
Use caution when concomitantly administering ABRAXANE with inhibitors or inducers of 
either CYP2C8 or CYP3A4. 
 
5.4 
Other Modalities or Procedures 
Pembrolizumab should be held (no specified time period, at discretion of treating 
investigator) for any surgery until subject is judged to be stable to resume by treating 


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investigator as adequate information does not exist on its effects on wound healing. 
When resumed, same dose level will be maintained.  
Abraxane should be held (no specified time period, at discretion of treating investigator) 
for any surgery until subject is judged to be stable to resume by treating investigator. 
When resumed, same dose level will be maintained.  
Percutaneous procedures like imaging guided biopsies and central line placements do 
not require pembrolizumab or abraxane to be necessarily held unless treating 
investigator judges it may increase risk of complications. 
 
5.5 
Duration of Therapy 
Treatment may continue until one of the following criteria apply: 
• Disease progression by RECIST1.1 as defined in Section 7.1.4. Subject may 
be continued on same regimen beyond one objective progression by 
RECIST 1.1 if clinically stable at the discretion of treating investigator and 
with the permission of the principal investigator. 
• Inter-current illness that prevents further administration of treatment 
• Unacceptable adverse event(s)  
• Patient voluntarily withdraws from treatment  
• General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 
5.6 
Off Treatment Criteria  
Patients will be removed from protocol therapy when any of the criteria listed in Section 
5.5 apply. Document in the source the reason for ending protocol therapy and the date 
the patient was removed from treatment. All patients who discontinue treatment should 
comply with protocol specific follow-up procedures as outlined in Section 5.7 and in 
section 6.0. The only exception to this requirement is when a subject withdraws consent 
for all study procedures or loses the ability to consent freely (Section 5.8). 
 
5.7 
Duration of Follow-Up 
Patients will be followed for up to 24 months after removal from treatment or until death, 
whichever occurs first. Patients removed from treatment for unacceptable adverse events 
will be followed with a phone call or clinic visit until resolution or stabilization of the 
adverse events.  
 
5.8 
Off Study Criteria 
Patients can be taken off study at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral or administrative 
reasons. The reason(s) for discontinuation from study will be documented and may 
include: 
 
5.8.1 
Patient withdraws consent (termination of treatment and follow-up); 
5.8.2  
Loss of ability to freely provide consent through imprisonment or 
involuntary incarceration for treatment; 
 
5.8.3 
Patient is unable to comply with protocol requirements; 
5.8.4 
Treating physician determines continuation on the study would not be in 
the patient’s best interest; 


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5.8.5 
Patient becomes pregnant (pregnancy to be reported along same 
timelines as a serious adverse event); 
5.8.6 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which 
would interfere with this study; 
 
5.8.7 
Lost to Follow-up. 
 
5.8.8 
Termination of the study by The University of Michigan; 
 
5.8.9 
Patient completes protocol treatment and follow-up criteria. 
 
5.9 
Patient Replacement 
Patients who do not receive any dose of the study drug will be replaced.  
 


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6.0 
STUDY PROCEDURES 
6.1 
SCHEDULE OF ASSESSMENTS: 
1 cycle (C) = 21 days (D) 
Assessment 
Screening 
C1 
D1 
C1 
D8 
C2 
D1 
C2 
D8 
C3 
D1 
C3 
D8 
Subsequent  
Cycles as 
per C1 
(duration of 
therapy per  
section 5.5,  
5.6, 5.8) 
EOT 
Follow-up 
every 12  
weeks8 +/- 7 
business  
days for 24 
months/death 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Tumor tissue specimen 
identified (15 FFPE 
unstained slides 
required; blocks 
preferred)  
X 
 
 
 
 
 
 
 
 
 
Whole blood, Plasma, 
serum for banking 
X 
 
 
 
 
 
 
 
 
 
History, PE,  
Concomitant Meds, 
Weight, Vital Signs1 
X 
X 
 
X 
 
X 
 
X (Day 1 
only) 
X 
 
ECOG Performance 
Status 
X 
X 
 
X 
 
X 
 
X (Day 1 
only) 
X 
 
QoL (EQ-5D-5L) 
X 
 
 
X 
 
X 
 
X 
X 
 
Toxicity Evaluation 
X 
X 
 
X 
 
X 
 
X (Day 1 
only) 
X 
 
Pregnancy 
Test 
for 
WOBCP, HIV, HBV,  
HCV serology 2 
X 
 
 
 
 
 
 
 
 
 
CBC with diff and plat 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
COMP 4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
TSH, free T3, free T4 (IF 
Clinically 
 
Indicated: FSH, 
LH, ACTH) 
X 
 
 
 
 
X 
 
X6 
X 
 
Amylase, Lipase 
X 
 
 
 
 
X 
 
X6 
X 
 
Tumor response 
assessment (CT chest, 
CT or MRI 
abdomen/pelvis; CT or 
MRI brain if indicated) 5 
X 
 
 
 
 
X 
 
X5 
 
X 
Optional Tumor Biopsy 
 
 
 
 
 
 
 
 
X7 
 
Pembrolizumab 
 
X 
 
X 
 
X 
 
X (D1) 
 
 
Abraxane 
 
X 
X 
X 
X 
X 
X 
X (D1, 8)  
 
 


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1. Vital signs will include temperature, pulse, respirations, blood pressure; height will be obtained at 
screening only. 
2. WOCBP: Women of child bearing potential; urine or serum pregnancy test. 
3. CBC with diff includes total WBC, hemoglobin, hematocrit and differential of the WBC including 
absolute counts. D15 CBC checks are at discretion of treating investigator. 
4. COMP or Comprehensive metabolic profile includes sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, AST, ALT, alkaline phosphatase, total bilirubin.  
5. With or without intravenous contrast, before or on associated visit. CT or MRI brain with (preferred) or 
without IV contrast if suspected or known brain metastases. Frequency of tumor assessments will be 
q2 cycles (i.e. q 6 weeks) for first 4 assessments beyond baseline and then q 3 cycles (i.e. 9 weeks) 
subsequently. If CR/PD, should be confirmed with repeat imaging after an interval of at least 4 weeks. 
6. Every 42 calendar days ± 7 business days. 
7. Optional tissue biopsy collection if subject consents; +/- 14 working days. 
8. Follow up with phone call or with clinic visit. 
NOTE: 
All assessments have a window of ± 3 business days unless otherwise mentioned. 
G-CSF (Filgrastim) may be added for low ANC on day of treatment BEFORE a dose reduction is 
instituted at treating physician’s discretion. Neulasta® on day 9 of a cycle is allowed if preferred. 
An Optional Tumor Biopsy would be performed, if subject has been consented to it, at progression. 
7.0 
MEASUREMENT OF EFFECT 
 
7.1 
Antitumor Effect- Solid Tumors 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [JNCI 92(3):205-216, 2000]. Changes in only the largest diameter  
(unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 criteria. 
 
7.1.1 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of 
their first treatment with study drug. 
Response Evaluable Population for primary endpoint: Only those patients who 
have had their disease re-evaluated by imaging after 2 cycles of therapy OR 
exhibit objective or unequivocal clinical disease progression prior to the end of 
cycle 2 will be considered evaluable for the primary endpoint. These patients will 
have their response classified according to the definitions stated below. 
 
7.1.2 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
• 10mm by CT scan (irrespective of scanner type) for studies with a slice 
thickness of <5mm or twice the slice thickness or MRI 
   • 10mm caliper measurement by clinical exam (lesions which cannot be 


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         accurately measured with calipers should be recorded as non-measurable)          
 • 20mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
                           
All tumor measurements must be recorded in millimeters (or decimal fractions of                             
centimeters). 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, 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. 
Note: Tumor lesions that are situated in a previously irradiated area might or 
might not be considered measurable, and the conditions under which such 
lesions should be considered may be defined in the protocol when appropriate. 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <20 mm with conventional techniques or <10 mm using 
CT scan), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all non-measurable. 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total 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 organ, 
but in addition should be those that lend themselves to reproducible repeated 
measurements. 
Lymph nodes merit special mention since they are normal anatomical structures 
which may be visible by imaging even if not involved by tumor. Pathological 
nodes which are defined as measurable and may be identified as target lesions 
must meet the criterion of a short axis of >15mm by CT scan. Only the short axis 
of these nodes will contribute to the baseline sum. The short axis of the node is 
the diameter normally used by radiologists to judge if a node is involved by solid 
tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI 
the plane of acquisition may be axial, sagittal or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node which is reported 
as being 20mm x 30mm has a short axis of 20mm and qualifies as a malignant, 
measurable node. In this example, 20mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis >10mm but <15 
mm) should be considered non-target lesions. Nodes that have a short axis 
<10mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters. If lymph nodes are to be included in the sum, then as noted above, 
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 pathological 
lymph nodes should be identified as non-target lesions and should also be 
recorded at baseline. Measurements are not required and these lesions should 


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be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g. 
‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
 
7.1.3 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as close as 
possible to the treatment start 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 should always be done rather than clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they 
are superficial and >10mm diameter as assessed using calipers (e.g. skin 
nodules). For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is suggested. As noted above, 
when lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when 
progression is an important endpoint, since CT is more sensitive than X-ray, 
particularly in identifying new lesions. However, lesions on chest X-ray may be 
considered measurable if they are clearly defined and surrounded by aerated 
lung. 
CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined 
measurability of lesions on CT scan based on the assumption that CT slice 
thickness is 5mm or less. When CT scans have slice thickness greater than 5 
mm, the minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
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, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in 
trials where recurrence following complete response or surgical resection is an 
endpoint. 


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Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. If markers are initially above the upper normal limit, however, they 
must normalize for a patient to be considered in complete response. Because 
tumor markers are disease specific, instructions for their measurement should be 
incorporated into protocols on a disease specific basis. Specific guidelines for 
both CA-125 response (in recurrent ovarian cancer) and PSA response (in 
recurrent prostate cancer), have been published. In addition, the Gynecologic 
Cancer Intergroup has developed CA125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian 
cancer. 
Cytology, Histology: These techniques can be used to differentiate between PR 
and CR in rare cases if required by protocol (for example, residual lesions in 
tumor types such as germ cell tumors, where known residual benign tumors can 
remain). When effusions are known to be a potential adverse effect of treatment 
(e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment can be considered if the measurable tumor has met criteria for 
response or stable disease in order to differentiate between response (or stable 
disease) and progressive disease. 
 
7.1.4 
Response Criteria 
7.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, 
determined by two separate observations conducted not less than 4 
weeks apart. There can be no appearance of new lesions. 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the baseline 
sum LD. There can be no appearance of new lesions. 
Progressive Disease (PD): At least a 20% increase in the sum of the LD 
of target lesions, taking as reference the smallest sum LD recorded since 
the treatment started, or the appearance of one or more new lesions. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started. 
7.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. 
Incomplete Response/Stable Disease (SD): 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. 


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7.1.4.3 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. 
Target 
Lesions 
Non-
Target  
Lesions 
New Lesions 
Overall  
Response 
Best  
Response for 
this Category 
Also  
Requires: 
CR 
CR 
No 
CR 
>4 wks. 
confirmation 
CR 
Non- 
CR/SD 
No 
PR 
>4 wks. 
confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at  
least once >4 
wks. from 
baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, 
PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
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. 
Note: If subjects respond to treatment and are able to have their disease 
resected, the patient’s response will be assessed prior to the surgery. 
 
7.1.5 
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 recurrent 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.  


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7.1.6 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression or death. 
 
7.2 
Safety/Tolerability 
Analyses will be performed for all patients having received at least one dose of study 
drug. The study will use the CTCAE version 4.0 for reporting of non-hematologic adverse 
events (http://ctep.cancer.gov/reporting/ctc.html) and modified criteria for hematologic 
adverse events. 
8.0 
ADVERSE EVENTS 
For the most recent safety update, please refer to the current package inserts for nab-paclitaxel 
and pembrolizumab. 
Overdose 
Overdose, as defined for this protocol, refers to ABRAXANE®, combination products and 
comparator dosing only.   
On a per dose basis, an overdose is defined as 10% over the protocol-specified dose of 
Abraxane® assigned to a given patient, regardless of any associated adverse events or sequelae. 
IV 
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency.   
On an infusion rate basis, an overdose is defined as any rate faster than the protocol-specified 
rate. For nab-paclitaxel, an infusion completed in less than 25 minutes may increase Cmax by 
approximately 20%, therefore a nab-paclitaxel infusion completed in less than 25 minutes 
will meet the infusion rate criterion for an overdose. 
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the case report form.    
Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on IP, or within 60 days are 
considered immediately reportable events.  IP is to be discontinued immediately. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, using the Pregnancy Initial Report Form, 
or approved equivalent form. The female subject may be referred to an obstetrician-gynecologist 
(not necessarily one with reproductive toxicity experience) or another appropriate healthcare 
professional for further evaluation. 
The principal investigator will follow the female subject until completion of the pregnancy, and 
must notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal 
or abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.  


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If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 
principal investigator should report the abnormal outcome as an AE.  If the abnormal outcome 
meets any of the serious criteria, it must be reported as an SAE to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the principal 
investigator’s knowledge of the event using the SAE Report Form, or approved equivalent form. 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the principal 
investigator’s knowledge of the event using the SAE Report Form, or approved equivalent form. 
 
8.1 
Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is 
done to ensure the safety of subjects enrolled in the studies as well as those who will 
enroll in future studies using similar agents. Data on adverse events will be collected 
from the time of the initial study treatment administration or intervention through 30 days 
after the last dose of study treatment or study intervention. Any serious adverse event 
that occurs more than 30 days after the last study treatment or intervention and is 
considered related to the study treatment or intervention must also be reported. Serious 
Adverse Events (SAEs) will continue to be followed until: 
• Resolution or the symptoms or signs that constitute the serious adverse event 
return to baseline; 
• There is satisfactory explanation other than the study treatment or intervention for   
the changes observed; or  
• Death. 
The investigator is responsible for the detection, documentation, grading and assignment 
of attribution of events meeting the criteria and definition of an AE or SAE. The definitions 
of AEs and SAEs are given below. It is the responsibility of the principal investigator to 
ensure that all staff involved in the trial is familiar with the content of this section. 
Any medical condition or laboratory abnormality with an onset date before initial study 
treatment administration or intervention is considered to be pre-existing in nature. Any 
known pre-existing conditions that are ongoing at time of study entry should be 
considered medical history. 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 8.2, 
occurring from the initial study treatment administration or intervention through 30 days 
following the last dose of the study treatment or study intervention must be recorded as 
an adverse event in the patient’s source documents and on the CRF regardless of 
frequency, severity (grade) or assessed relationship to the study treatment or 
intervention.  
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of 
a pre-existing condition that occurs after the patient begins study treatment or 
intervention is also considered an adverse event. 


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8.2 
Definitions 
 
8.2.1 Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an experimental intervention, whether or not related to the intervention.  
• Diagnostic and therapeutic non-invasive and invasive (i.e., surgical) procedures 
will not be reported as adverse events. However, the medical condition for 
which the procedure was performed must be reported if it meets the 
definition of an adverse event unless it is a pre-existing (prior to protocol 
treatment) condition. 
• Abnormal laboratory values or test results constitute adverse events if they 
induce clinical signs or symptoms or require therapy. They are to be captured 
under the signs, symptoms or diagnoses associated with them. 
 
8.2.2 Serious Adverse Event 
An adverse event is considered “serious” if, in the view of the principal 
investigator, it results in any of the following outcomes: 
o 
Death 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
o 
A life-threatening adverse event 
An adverse even is considered ‘life-threatening’ if, in the view of either the 
investigator, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event that, had it occurred in a more 
severe form, might have caused death.  
o 
Inpatient hospitalization or prolongation of existing hospitalization for > 24 
hours. 
o 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions  
o 
A congenital anomaly/birth defect 
o 
Important medical event 
Any event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition 
of “Serious Adverse Event”. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room 
or at home; convulsions that do not result in inpatient hospitalization or the 
development of drug dependency or drug abuse. 


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Previously planned (prior to signing the informed consent form) surgeries should 
not be reported as SAEs unless the underlying medical condition has worsened 
during the course of the study. Preplanned hospitalizations or procedures for 
preexisting conditions that are already recorded in the patient’s medical history at 
the time of study enrollment should not be considered SAEs. Hospitalization or 
prolongation of hospitalization without a precipitating clinical AE (for example, for 
the administration of study therapy or other protocol-required procedure) should 
not be considered SAEs. However, if the preexisting condition worsened during 
the course of the study, it should be reported as an SAE. 
 
8.2.3 Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
• For approved and marketed drugs or devices, those adverse events are 
described in the approved Package Insert (Label).  
• For investigational new drugs or devices, those adverse events are 
described in the FDA Investigator’s Brochure.  
• In clinical research studies, information on expected adverse events is also 
summarized in the protocol and in the consent document.  See section 
9.1 for the list of expected adverse events related to the drug under 
study. 
 
8.2.4 Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in the 
Package Insert, Investigator’s Brochure, in published medical literature, in the 
protocol, or in the informed consent document.  
 
8.3 
Adverse Event Characteristics 
 
8.3.1 CTCAE Term 
(AE description) and grade: The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be down 
loaded from the CTEP web site. (http://ctep.cancer.gov) 
 
8.3.2 Attribution of the AE 
The principal investigator or co-investigator is responsible for assignment of 
attribution. 
Definite – The AE is clearly related to the study [treatment/intervention]. 
Probable – The AE is likely related to the study [treatment/intervention]. 
Possible – The AE may be related to the study [treatment/intervention]. 
Unlikely – The AE is doubtfully related to the study [treatment/intervention]. 
Unrelated – The AE is clearly NOT related to the study [treatment/intervention]. 
 
8.4 
Serious Adverse Event Reporting Guidelines 
All serious adverse events (SAEs) and unanticipated problems (UPs), regardless of 
causality to study drug, will be reported to the principal investigator within 2 business 
days of study team’s knowledge of any event meeting the criteria and definition of a 


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serious adverse event, regardless of attribution, occurring during the study or within 30 
days of the last administration of the study related treatment. 
The investigator must report all events meeting the criteria and definition of a serious 
adverse events that are unexpected and possibly related (definite, probable or possible) 
to study treatment to the local IRB within 7 days of study team’s knowledge.  
All Serious Adverse Events that are unexpected and possibly related (definite, probable 
or possible) to study treatment will be reported to the IRB using the MEDWATCH 3500A 
form. 
Principal Investigator Contact Information for SAE reporting: 
Ajjai Alva, MD 
Hematology/Oncology 
University of Michigan  
7316 Cancer Center 
1500 E. Medical Center Drive 
Ann Arbor, MI 48109 
Phone: (734) 936-0091 
Fax: (734) 615-2719 
Email: ajjai@umich.edu 
 
8.5 
Expedited Reporting by Investigator to Celgene 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene 
in writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 
hours of being aware of the event.  The written report must be completed and supplied 
to Celgene by facsimile within 24 hours. The initial report must be as complete as 
possible, including an assessment of the causal relationship between the event and the 
investigational product(s).  Information not available at the time of the initial report (e.g., 
an end date for the adverse event or laboratory values received after the report) must be 
documented on a follow-up report.  A final report to document resolution of the SAE is 
required.  The Celgene tracking number (AX-BLD-12813- PI-Alva) and the institutional 
protocol number should be included on SAE reports (or on the fax cover letter) sent to 
Celgene.  A copy of the fax transmission confirmation of the SAE report to Celgene 
should be attached to the SAE and retained with the patient records. 
For the purpose of regulatory reporting, Celgene Drug Safety will determine the 
expectedness of events of being related to ABRAXANE® based on the Investigator 
Brochure.  In the United States, all suspected unexpected serious adverse reactions 
(SUSARs) will be reported in an expedited manner in accordance with 21 CFR 312.32. 
Report of Adverse Events to the Institutional Review Board 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) 
of a serious adverse event according to institutional policy.   
Investigator Reporting to the FDA 
Serious adverse events (SAEs) that are unlisted/unexpected, and at least possibly 
associated to the drug, and that have not previously been reported in the 
Investigators brochure, or reference safety information document should be reported 
promptly to the Food and Drug Administration (FDA) by telephone or by fax.  Fatal or 
life threatening SAEs that meet the criteria for reporting to the FDA must be reported to 
the FDA within 7 calendar days after awareness of the event.  All other SAEs that meet 


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the criteria for reporting to the FDA must be reported to the FDA within 15 calendar 
days after awareness of the event.  A clear description of the suspected reaction 
should be provided along with an assessment as to whether the event is drug or 
disease related.  
Adverse event updates/IND safety reports 
Celgene shall notify the Investigator via an IND Safety Report of the following 
information: 
• Any AE suspected of being related to the use of drug in this study or in other 
studies that is both serious and unexpected. 
• Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
The Investigator shall notify his/her IRB/EC promptly of these new serious and 
unexpected AE(s) or significant risks to subjects. 
The Investigator must keep copies of all pertinent safety information on file, including 
correspondence with Celgene and the IRB/EC. 
8.6       Routine Reporting 
All other adverse events- such as those that are expected, or are unlikely or definitely not 
related to the study participation- are to be reported annually as part of regular data 
submission. 
 
8.7 
Reporting of Unanticipated Problems 
There are types of incidents, experiences and outcomes that occur during the conduct of 
human subjects research that represent unanticipated problems but are not considered 
adverse events. For example, some unanticipated problems involve social or economic 
harm instead of the physical or psychological harm associated with adverse events. In 
other cases, unanticipated problems place subjects or others at increased risk of harm, 
but no harm occurs. 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse 
event) that may represent an unanticipated problem, the investigator should assess 
whether the incident, experience, or outcome represents an unanticipated problem. The 
incident, experience or outcomes is considered unanticipated if it meets all of the 
following criteria: 
1. Unexpected (in terms of nature, severity, or frequency); 
2. Related or possibly related to participation in the research; and 
3. Suggests that the research places subjects or others at a greater risk of harm 
than was previously known or recognized. 
If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator must report it to the IRB within 7 calendar days of 
the study team becoming aware of the problem. 


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8.8 
Reference Safety Information: Treatment-Emergent Adverse Drug Reactions 
Reported with nab-Paclitaxel 
System Organ Class 
MedDRA Preferred  
Term 
Frequency 
– 
CIOMS IV WG 
Criteriaa 
Seriousb 
Severity Life 
Threatening 
Severity 
Death 
New 
LPTd 
Blood and lymphatic system disorders 
 
 
 
 
Anemia 
Very common 
X 
 
 
 
Bone marrow 
depression 
Uncommon 
X 
 
 
 
Febrile neutropenia 
Common 
X 
 
 
 
Leukopenia 
Very common 
X 
 
 
 
Lymphopenia 
Common 
X 
 
 
 
Neutropenia 
Very common 
X 
 
 
 
Pancytopenia 
Common 
X 
 
 
 
Thrombocytopenia 
Very common 
X 
 
 
 
Thrombotic 
thrombocytopenic 
purpura 
Uncommon 
X 
 
 
 
Cardiac disorders 
 
 
 
 
Arrhythmia 
Uncommon 
X 
 
X 
 
Atrioventricular 
block 
Rare 
X 
 
 
 
Cardiac arrest 
Uncommon 
X 
 
X 
 
Cardiac failure 
congestive 
Common 
X 
 
X 
 
 
Left ventricular 
dysfunction 
Uncommon 
X 
 
 
 
Palpitations 
Common 
X 
 
 
 
Sinus bradycardia 
Uncommon 
X 
 
 
 
Supraventricular 
tachycardia 
Uncommon 
X 
 
 
 
Tachycardia 
Common 
X 
 
 
 
Eye disorders 
 
Conjunctivitis 
Uncommon 
 
 
 
 
Cystoid macular 
edema 
Uncommon 
X 
 
 
 


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Lacrimation 
increased 
Common 
 
 
 
 
Keratitis 
Uncommon 
X 
 
 
 
Maculopathy 
Uncommon 
X 
 
 
 
Visual impairment 
Common 
X 
 
 
 
Gastrointestinal disorders 
 
Abdominal pain 
Very common 
X 
 
 
 
Colitis 
Common 
X 
 
 
 
Constipation 
Very common 
X 
 
 
 
Diarrhea 
Very common 
X 
 
 
 
Dry mouth 
Common 
X 
 
 
 
Dyspepsia 
Common 
X 
 
 
 
Dysphagia 
Common 
X 
 
 
 
Intestinal 
obstruction 
Common 
X 
 
 
 
Nausea 
Very common 
X 
 
 
 
Stomatitis 
Very common 
X 
 
 
 
Vomiting 
Very common 
X 
 
 
 
General disorders and administration site conditions 
 
Asthenia 
Very common 
X 
 
 
 
Chest pain 
Common 
X 
 
 
 
Chills 
Very common 
X 
 
 
 
Fatigue 
Very common 
X 
 
 
 
Infusion site 
reactions 
Common 
X 
 
 
 
Lethargy 
Uncommon 
X 
 
 
 
Malaise 
Uncommon 
X 
 
 
 
Mucosal 
inflammation 
Common 
X 
 
 
 
Edema 
Very common 
X 
 
 
 
Pyrexia 
Very common 
X 
 
 
 


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Hepatobiliary disorders 
 
Cholangitis 
Common 
X 
 
 
 
Hyperbilirubinemia 
Common 
X 
 
 
 
Immune system disorders 
 
Hypersensitivity 
Uncommon 
X 
 
X 
 
Infections and infestations 
 
Lower respiratory 
tract infection 
including bronchitis 
Common 
X 
 
 
 
Candida infection 
Common 
X 
 
 
 
Folliculitis 
Common 
 
 
 
 
Injection site  
Uncommon 
 
 
 
 
 
infection 
 
 
 
 
 
Nail infection 
Common 
 
 
 
 
Neutropenic sepsis 
Uncommon 
X 
 
X 
 
Pneumonia 
Common 
X 
 
X 
 
Sepsis 
Common 
X 
 
X 
 
Upper 
respiratory 
tract infection 
Common 
X 
 
 
 
Urinary tract 
infection 
Common 
X 
 
 
 
Injury, Poisoning and Procedural Complications 
 
Radiation recall  
phenomenon e 
Not known 
 
 
 
 
Investigations 
 
Alanine 
aminotransferase 
increased 
Very common 
X 
 
 
 
Aspartate 
aminotransferase 
increased 
Common 
X 
 
 
 
Blood alkaline 
phosphatase 
increased 
Common 
X 
 
 
 
Blood creatinine 
increased 
Common 
X 
 
 
 


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Weight decreased 
Very common 
X 
 
 
 
Metabolism and nutrition disorders 
 
Decreased appetite 
Very common 
X 
 
 
 
Dehydration 
Very common 
X 
 
 
 
Fluid retention 
Uncommon 
X 
 
 
 
Hypokalaemia 
Very common 
X 
 
 
 
Musculoskeletal and connective tissue disorders 
 
Arthralgia 
Very common 
X 
 
 
 
Muscular weakness 
Common 
X 
 
 
 
Musculoskeletal 
pain 
Very common 
X 
 
 
 
Myalgia 
Very common 
X 
 
 
 
Nervous system disorders 
 
Ataxia 
Common 
X 
 
 
 
Cranial 
nerve 
palsies e 
Not known 
X 
 
 
 
Dizziness 
Very common 
X 
 
 
 
Dysgeusia 
Very common 
X 
 
 
 
Facial paralysis 
Uncommon 
X 
 
 
 
Headache 
Very common 
X 
 
 
 
Peripheral 
neuropathy f 
Very common 
X 
 
 
 
Vocal cord paresis e 
Not known 
X 
 
 
 
Psychiatric disorders 
 
Anxiety 
Common 
X 
 
 
 
Depression 
Very common 
X 
 
 
 
Insomnia 
Very common 
X 
 
 
 
Renal and urinary disorders 
 
Acute renal failure 
Common 
X 
 
X 
 
Hematuria 
Common 
X 
 
 
 


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Hemolytic uremic 
syndrome 
Uncommon 
X 
 
 
 
Respiratory, thoracic and mediastinal disorders 
 
Cough 
Very common 
X 
 
 
 
Dry throat 
Uncommon 
 
 
 
 
Dyspnea 
Very common 
X 
 
 
 
Epistaxis 
Very common 
X 
 
 
 
Hemoptysis 
Common 
X 
 
 
 
Nasal congestion 
Common 
X 
 
 
 
Nasal dryness 
Uncommon 
 
 
 
 
Oropharyngeal pain 
Common 
 
 
 
 
Pleural effusion 
Common 
X 
 
 
 
Pneumonitis g 
Common 
X 
 
X 
 
Pulmonary 
embolism 
Common 
X 
 
X 
 
Radiation 
pneumonitis 
Unknown 
X 
 
 
 
Skin and subcutaneous tissue disorders 
 
Alopecia 
Very common 
X 
 
 
 
Dermatitis allergic 
Uncommon 
X 
 
 
 
Dry skin 
Common 
X 
 
 
 
Erythema 
Common 
X 
 
 
 
Erythema 
multiforme 
Uncommon 
X 
 
 
 
Nail disorder 
including 
onycholysis and 
discoloration 
Very common 
X 
 
 
 
Palmar-plantar 
erythrodysesthesia 
syndrome 
Common 
X 
 
 
 
Photosensitivity 
reactione 
Not known 
 
 
 
 
Pruritus 
Very common 
X 
 
 
 
Rash including 
generalized 
Very common 
X 
 
 
 


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Skin exfoliation 
Uncommon 
 
 
 
 
Stevens – Johnson 
syndromee 
Not known 
X 
 
 
 
Toxic epidermal 
necrolysise 
Not known 
X 
 
 
 
Urticaria 
Uncommon 
X 
 
 
 
Vascular disorders 
 
Deep vein 
thrombosis 
Common 
X 
 
 
 
Flushing 
Common 
X 
 
 
 
Hypertension 
Common 
X 
 
X 
 
Hypotension 
Common 
X 
 
 
 
Lymphoedema 
Common 
X 
 
 
 
ADR = adverse drug reaction; CIOMS = Council for International Organizations of 
Medical Sciences; MedDRA = Medical Dictionary for Regulatory Activities; PT = 
preferred term; RSI = reference safety information; SMQ = standardized MedDRA 
query; WG = Working Group. 
a CIOMS IV WG Criteria are defined as Very Common: >10%; Common: >1% and <  
10%; Uncommon: >0.1% and <1%; Rare: >0.01% and < 0.1%; and Very Rare: < 0.01%. 
b Serious ADR from any source defined as resulting in death, is life-threatening, requires 
hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability or incapacity, or is a congenital anomaly or birth defect or considered 
an important medical event. c Severity corresponding to seriousness criteria of life-
threatening or death. d New PTs reported since the previous RSI version. e ADRs 
identified in the post-marketing setting are italicized. In cases where the ADR was 
observed from both post-marketing and clinical trials, the event is classified as clinical 
trial. 
f 
Peripheral neuropathy evaluated using the MedDRA SMQ neuropathy (broad 
scope); all PTs will be considered listed. 
g 
Pneumonitis evaluated using the MedDRA SMQ interstitial lung disease; all PTs 
will be considered listed. 
Note: When an ADR is reported as serious, or life-threatening or leads to death, the 
term will be considered unexpected for regulatory purposes, unless marked with an “X” 
under the corresponding column listed above. 
Note: All ADRs reported in this table have been reported more than once. 
Source: nab-Paclitaxel (Abraxane) Company Core Data Sheet (CCDS) Version 14, 29 
September 2014. 
9.0 
DRUG INFORMATION 
9.1 
nab-paclitaxel (Abraxane®) - Investigational 
Overview nab-Paclitaxel (ABRAXANE® for Injectable Suspension [Abraxis BioScience, LLC, a 
wholly owned subsidiary of Celgene Corporation, Summit, New Jersey, United States; hereafter 
referred to as “Celgene”], ABI-007) is a proprietary solvent-free, protein-stabilized formulation of 
paclitaxel comprised of paclitaxel in a noncrystalline amorphous state and human albumin with a 


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mean particle size of approximately 130 nanometers. nab-Paclitaxel has been developed to 
improve the therapeutic index of paclitaxel, also reducing the toxicities associated with Taxol and 
the CrEL and ethanol vehicle.  This may be achieved in part by taking advantage of endogenous 
transport pathways to deliver higher doses of paclitaxel to the tumor. Because nab-paclitaxel 
does not contain a solvent vehicle, micellar entrapment observed with Taxol does not occur 25-27. 
nabPaclitaxel displays linear pharmacokinetic (PK) characteristics. The novel albumin-bound 
particle formulation of paclitaxel in nab-paclitaxel conferred the ability to achieve a higher 
maximum tolerated dose (MTD) based on every 3-weeks dosing: 300 mg/m2 for nab-paclitaxel 
(Study DM97-123) versus 175 mg/m2 for Taxol 28. The use of albumin-bound paclitaxel also 
enables nab-paclitaxel to be given in a shorter, more convenient infusion time of 30 - 40 minutes 
compared with 3 hours to 24 hours with Taxol.  Due to its distinct pharmacological and PK 
properties and therapeutic index, nab-paclitaxel has been approved by regulatory authorities 
worldwide in over 40 countries/regions as a new product, rather than as a generic formulation of 
Taxol.   nab-Paclitaxel may be given without steroid and anti-histamine premedication, which is 
required for Taxol to prevent solvent-related HSRs (Taxol US prescribing information). 
Cremophor EL has been shown to leach plasticizers, specifically di(2-ethylhexyl) phthalate 
(DEHP), from polyvinyl chloride (PVC) bags and polyethylene-lined tubing 29-34.  Although no 
controlled epidemiologic toxicity studies have been conducted in humans exposed to DEHP, 
severe effects (e.g., carcinogenicity, cardiopulmonary toxicity, hepatotoxicity, and nephrotoxicity) 
have been observed in experimental models.  The Taxol prescribing information instructs users to 
prepare, store, and administer solutions in glass, polypropylene, or polyolefin containers; 
nonPVC-containing infusion sets (e.g., those with polyethylene lining) should be used (Taxol US 
prescribing information).  By comparison, standard tubing and intravenous (IV) bags may be used 
for the IV administration of nab-paclitaxel 25,28. 
As of October 2016, nab-paclitaxel is approved under the trade name of ABRAXANE in 65 
countries worldwide for the treatment of patients with metastatic breast cancer. ABRAXANE is 
also approved in 54 countries worldwide for the first-line treatment of locally advanced or 
metastatic non-small cell lung cancer (NSCLC), in 57 countries for the first-line treatment of 
metastatic adenocarcinoma of the pancreas, and in Japan for treatment of advanced gastric 
cancer. 
Indications and Usage: 
In the United States, ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles 
for injectable suspension) (albumin bound) is indicated for the treatment of metastatic breast 
cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 
months of adjuvant chemotherapy.  Prior therapy should have included an anthracycline unless 
clinically contraindicated. 
It is also indicated for the first-line treatment of locally advanced or metastatic NSCLC (non-small 
cell lung cancer), in combination with carboplatin, in patients who are not candidates for curative 
surgery or radiation therapy, and is indicated for the first-line treatment of patients with metastatic 
adenocarcinoma of the pancreas, in combination with gemcitabine. 
Other names for the drug: Abraxane (ABI-007 
ABRAXANE® Description 
ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable 
suspension) (albumin-bound) is paclitaxel formulated as albumin-bound nanoparticles with a 
mean particle size of approximately 130 nanometers.  Paclitaxel exists in the particles in a non-
crystalline, amorphous state.  ABRAXANE® is supplied as a white to yellow, sterile, lyophilized 
powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to 
intravenous infusion. 


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Clinical Pharmacology 
Pharmacokinetics and Drug Metabolism 
Absorption 
The pharmacokinetics of total paclitaxel following 30 and 180-minute infusions of ABRAXANE® at 
dose levels of 80 to 375 mg/m2 were determined in clinical studies. Dose levels of mg/m2 refer to 
mg of paclitaxel in ABRAXANE®.  Following intravenous administration of ABRAXANE®, 
paclitaxel plasma concentrations declined in a biphasic manner, the initial rapid decline 
representing distribution to the peripheral compartment and the slower second phase 
representing drug elimination. 
The drug exposure (AUCs) was dose proportional over 80 to 300 mg/m2 and the 
pharmacokinetics of paclitaxel for ABRAXANE® were independent of the duration of intravenous 
administration.  The pharmacokinetic data of 260 mg/m2 ABRAXANE® administered over a 
30minute infusion was compared to the pharmacokinetics of 175 mg/m2 paclitaxel injection over 
a 3-hour infusion. Clearance was larger (43%) and the volume of distribution was higher (53%) 
for ABRAXANE® than for paclitaxel injection. There were no differences in terminal half-lives. 
Pharmacokinetic Parameters 
Distribution 
Following ABRAXANE® administration to patients with solid tumors, paclitaxel is evenly 
distributed into blood cells and plasma and is highly bound to plasma proteins (94%). In a within 
patient comparison study, the fraction of unbound paclitaxel in plasma was 
significantly higher with ABRAXANE® (6.2%) than with solvent-based paclitaxel (2.3%). This 
contributes to significantly higher exposure to unbound paclitaxel with ABRAXANE® compared 
with solvent-based paclitaxel, when the total exposure is comparable. In vitro studies of binding to 
human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50μg/mL, indicated 
that the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect 
protein binding of paclitaxel. The total volume of distribution is approximately 1741 L; the large 
volume of distribution indicates extensive extravascular distribution and/or tissue binding of 
paclitaxel. 
Metabolism  
In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was  
metabolized primarily to 6α-hydroxypaclitaxel by CYP2C8; and to two minor metabolites, 3’-p-
hydroxypaclitaxel and 6α, 3’-p-dihydroxypaclitaxel by CYP3A4. In vitro, the metabolism of 
paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, 
diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the 
concentrations used exceeded those found in vivo following normal therapeutic doses. 
Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, 
also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel 
may also be altered in vivo as a result of interactions with compounds that are substrates, 
inducers, or inhibitors of CYP2C8 and/or CYP3A4. 
Elimination 
At the clinical dose range of 80 to 300 mg/m2, the mean total clearance of paclitaxel ranges from 
13 to 30 L/h/m2, and the mean terminal half-life ranges from 13 to 27 hours.  After a 30-minute 
infusion of 260 mg/m2 doses of ABRAXANE®, the mean values for cumulative urinary recovery 
of unchanged drug (4%) indicated extensive non-renal clearance. Less than 1% of the total 
administered dose was excreted in urine as the metabolites 6α-hydroxypaclitaxel and 3’-p-
hydropaclitaxel. Fecal excretion was approximately 20% of the total dose administered. 


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Specific Populations 
Pharmacokinetics in Hepatic Impairment 
The effect of hepatic impairment on the pharmacokinetics of paclitaxel following ABRAXANE® 
administration was studied in patients with advanced solid tumors. The results showed that mild 
hepatic impairment (total bilirubin >1 to <1.5 x ULN, AST <10 x ULN, n=8) had no clinically 
important effect on pharmacokinetics of paclitaxel. Patients with moderate (total bilirubin >1.5 to 
<3 x ULN, AST <10 x ULN, n=7) or severe (total bilirubin >3 to <5 x ULN, n=5) hepatic 
impairment had a 22% to 26% decrease in the maximum elimination rate of paclitaxel and 
approximately 20% increase in mean paclitaxel AUC compared with patients with normal hepatic 
function (total bilirubin < ULN, AST < ULN, n=130)   
 
Elimination of paclitaxel shows an inverse correlation with total bilirubin and a positive correlation 
with serum albumin.  Pharmacokinetic/pharmacodynamics modeling indicates that there is no 
correlation between hepatic function (as indicated by the baseline albumin or total bilirubin level) 
and neutropenia after adjusting for ABRAXANE® exposure. Pharmacokinetic data are not 
available for patients with total bilirubin >5 x ULN or for patients with metastatic adenocarcinoma 
of the pancreas. 
Pharmacokinetics in Renal Impairment 
The effect of pre-existing mild (creatinine clearance >60 to <90 mL/min, n=61) or moderate 
(creatinine clearance >30 to <60 mL/min, n=23) renal impairment on the pharmacokinetics of 
paclitaxel following ABRAXANE® administration was studied in patients with advanced solid 
tumors. Mild to moderate renal impairment had no clinically important effect on the maximum 
elimination rate and systemic exposure (AUC and Cmax) of paclitaxel. 
Other Intrinsic Factors 
Population pharmacokinetic analyses for ABRAXANE® show that body weight (40 to 143 kg), 
body surface area (1.3 to 2.4 m2), gender, race (Asian vs. White), age (24 to 85 years) and type 
of solid tumors do not have a clinically important effect on the maximum elimination rate and 
systemic exposure (AUC and Cmax) of paclitaxel. 
Pharmacokinetic Interactions between ABRAXANE® and Carboplatin 
Administration of carboplatin immediately after the completion of the ABRAXANE® infusion to 
patients with NSCLC did not cause clinically meaningful changes in paclitaxel exposure. The 
observed mean AUCinf of free carboplatin was approximately 23% higher than the targeted value 
(6 min*mg/mL), but its mean half-life and clearance were consistent with those reported in the 
absence of paclitaxel. 
Description 
Each single-use vial contains 100 mg of paclitaxel and approximately 900 mg of human albumin. 
Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel. 
Classification - type of agent: Antineoplastic Agent 
Mode of action: 
Paclitaxel protein-bound, an albumin-bound form of paclitaxel (a natural product obtained from 
Taxus media), works as an anti-microtubule agent by promoting microtubule assembly from 
tubulin dimers and stabilizing microtubules. Stabilizing microtubules prevents depolymerization 
and causes an inhibition of the normal dynamic reorganization of the microtubules which is 
necessary for important interphase and mitotic functions in the cell. Paclitaxel causes the 
formation of abnormal bundles of microtubules in many phases of the cell cycle and multiple 
asters of microtubules during mitosis 


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Pharmacokinetics: nab-Paclitaxel displays linear pharmacokinetic (PK) characteristics. 
Hepatic metabolism and biliary excretion are likely routes of paclitaxel elimination in 
humans. 
Patients with mild hepatic impairment (total bilirubin > 1 to <1.5 x Upper limit of normal [ULN]) 
have no clinically important changes in pharmacokinetics (PK) of paclitaxel while patients with 
moderate (total bilirubin >1.5 to <3 x ULN) or severe (total bilirubin >3 to <5 x ULN) hepatic 
impairment have a 22% to 26% decrease in the maximum elimination rate of paclitaxel and 
approximately 20% increase in mean paclitaxel AUC compared with patients with normal hepatic 
function. Mild to moderate renal impairment (creatinine clearance >30 and < 90 mL/min) has no 
clinically important effect on the maximum elimination rate and systemic exposure (AUC and 
Cmax) of paclitaxel. 
Elimination half-life, 13 to 27 hours 
Side effects: 
Common 
a) Cardiovascular: Edema (10%), Electrocardiogram abnormal (60%), Peripheral edema (non-
small cell lung cancer, 10%; pancreatic cancer, 46%)Dermatologic: Alopecia (breast 
cancer, 90%; non-small cell lung cancer, 56%; pancreatic cancer, 50%), Rash (non-small 
cell lung cancer, 10%; pancreatic cancer, 30%) 
b) Gastrointestinal: Constipation (non-small cell lung cancer, 16%), Diarrhea (breast cancer, 
27%; non-small cell lung cancer, 15%; pancreatic cancer, 44%), Loss of appetite (nonsmall 
cell lung cancer, 17%; pancreatic cancer, 36%), Nausea, Any grade (breast cancer,  
30%; non-small cell lung cancer, 27%; pancreatic cancer, 54%), Vomiting, Any grade 
(breast cancer, 18%; non-small cell lung cancer, 12%; pancreatic cancer, 36%) 
c) Hematologic: Anemia (breast cancer, 33%; non-small cell lung cancer, 98%), Neutropenia, 
Any grade (73% to 85%), Thrombocytopenia (breast cancer, 2%; non-small cell lung 
cancer, 68%; pancreatic cancer, 74%) 
d) Hepatic: Alkaline phosphatase raised (36%), AST/SGOT level raised (39%), Gamma- 
glutamyl transferase raised, Grade 3 or 4 (14%) 
e) Musculoskeletal: Arthralgia (11% to 13%), Myalgia (10%) 
f) Neurologic: Asthenia (breast cancer, 47%; non-small cell lung cancer, 16%; pancreatic 
cancer, 19%), Peripheral neuropathy (non-small cell lung cancer, 48%; pancreatic cancer, 
54%), Sensory neuropathy, Any grade (71%) 
g) Ophthalmic: Visual disturbance (13%) 
h) Renal: Serum creatinine raised (11%) 
i) Respiratory: Dyspnea (12%) 
j) Other: Dehydration (pancreatic cancer, 21%), Fatigue (non-small cell lung cancer, 25%; 
pancreatic cancer, 59%), Fever (pancreatic cancer, 41%) 
Serious 
a) Cardiovascular: Cardiac arrest, Cerebrovascular accident, Supraventricular tachycardia, 
Transient ischemic attack 


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b) Gastrointestinal: Nausea, Grade 3 or higher (breast cancer, 3%; pancreatic cancer, 6%), 
Vomiting, Grade 3 or higher (4% to 6%) 
c) Hematologic: Anemia, Severe (breast cancer, 1%; non-small cell lung cancer, 28%),  
Febrile neutropenia (2%), Hemorrhage (2%), Neutropenia, Grade 3 or 4 (breast cancer,  
9%; non-small cell lung cancer, 47%; pancreatic cancer, 38%), Thrombocytopenia, Severe  
(breast cancer, less than 1%; non-small cell lung cancer, 18%; pancreatic cancer, 13%), 
Thrombosis 
d) Immunologic: Anaphylaxis, Hypersensitivity reaction (4%), Infectious disease (24%) 
e) Neurologic: Cranial nerve disorder, Sensory neuropathy, Grade 3 (10%), Vocal cord palsy 
f) Respiratory: Pneumonia (3% to 4%), Pneumonitis (pancreatic cancer, 4%), Pneumothorax 
(less than 1%), Pulmonary embolism, Pulmonary thromboembolism 
g) Other: Neutropenic sepsis (less than 5%), Sepsis (pancreatic cancer, 5%) 
Drug Interactions 
The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. Pharmacokinetic drug-drug 
interactions between nab-paclitaxel and inhibitors or inducers of CYP2C8 or CYP3A4 have not 
been evaluated in humans. 
Storage and stability 
Unopened vials of nab-paclitaxel are stable until the date indicated on the package when stored 
in the original cartons at United States Pharmacopeia (USP) Controlled Room Temperature 
(20°C to 25°C, excursions permitted between 15° to 30°C), or as specified on the vial label and 
as per the country requirements. 
Preparation and Dispensing 
nab-Paclitaxel is supplied as a sterile lyophilized powder for reconstitution before use. Each mL of 
the reconstituted formulation will contain 5 mg/mL paclitaxel. Using a sterile syringe, slowly inject 
20 mL of sodium chloride 9 mg/mL (0.9%) solution for injection to a vial of nab-paclitaxel. Direct 
the solution flow onto the inside wall of the vial and take at least 1 minute for the introduction. Do 
not inject the solution directly onto the lyophilisate as this will result in foaming. Once the addition 
is complete, allow the vial to stand for a minimum of 5 minutes to ensure proper wetting of the 
solid. Then, gently swirl and/or invert the vial slowly for at least 2 minutes until complete 
dissolution of any lyophilisate occurs. Avoid the generation of foam. 
Calculate the exact total dosing volume of 5 mg/mL suspension required for the patient and 
slowly withdraw the dosing volume of the reconstituted nab-paclitaxel suspension from the vial(s) 
into a syringe. The exact total dosing volume of 5 mg/mL suspension required for the patient is 
calculated using the following formula: 
Dosing volume (mL) = Total dose (mg) / 5 (mg/mL) 
Administration 
Inject the appropriate amount of reconstituted nab-paclitaxel into an empty, sterile, intravenous 
bag (PVC or non-PVC type IV bag). The use of specialized DEHP-free solution containers or 
administration sets is not necessary to prepare or administer nab-paclitaxel infusions. The use of 
medical devices containing silicone oil as a lubricant (i.e., syringes and IV bags) to reconstitute 
and administer nab-paclitaxel may result in the formation of proteinaceous strands. Visually 
inspect the reconstituted nab-paclitaxel suspension in the IV bag prior to administration. If strands 
are observed, administer reconstituted nab-paclitaxel suspension through a 15 micron filter. Do 
not use a filter with a pore size less than 15 microns. A similar phenomenon has also been 


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observed with other protein-containing injectable products. Filtration of the nab-paclitaxel 
suspension using a 15 micron filter removes the proteinaceous strands and does not change the 
physical or chemical properties of nab-paclitaxel suspension. Based on data from clinical trials 
and post-marketing surveillance, there is no indication of an increased risk of embolic events 
should these strands be administered to patients. Refer to local product label or study notebook, 
as applicable, for complete directions regarding the use of a filter. 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
before administration whenever the solution and container permit. The reconstituted sample 
should be milky and homogenous without visible particulates. If particulates or settling are visible, 
the vial should be gently inverted again to ensure complete resuspension prior to use. 
Following administration of nab-paclitaxel, the intravenous line should be flushed with sodium 
chloride 9 mg/mL (0.9%) solution for injection to ensure administration of the complete dose, 
according to local practice. 
Dose Reduction / Discontinuation Recommendations 
Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, 
cutaneous, or gastrointestinal toxicities.  Please refer to the Prescribing Information which can be 
found in Section 2.5. 
Availability 
Provided by Celgene Corporation 
Under no circumstance will the study medication nab-paclitaxel be used other than as directed by 
the protocol. Do Not Use Commercially Available Product. 
Supplier(s) 
ABRAXANE® will be supplied by Celgene Corporation and labeled appropriately as 
investigational material for this study.  Labels will bear Celgene’s name and address, the protocol 
number AX-BLD-12813, product name, dosage form and strength, medication identification/kit 
number, lot number, expiry date, dosing instructions, storage conditions, the quantity of IP 
contained, and required caution statements and/or regulatory statements as applicable.  No 
supplies will be shipped to any site until regulatory approval has been obtained.  Investigational 
sites will be supplied with ABRAXANE® upon identification and screening of a potential trial 
subject. 
Upon identification of a potential subject, site must order Abraxane, depending on the study IND 
status. For IND studies, site should be order Abraxane through the Endpoint (IDOS) online drug 
ordering system. For IND Exempt studies, site must submit a completed Celgene USMA IND 
Exempt Drug Request Form, the most recent IRB approval letter, and the most current drug 
accountability log for your study to the following mailbox:  NonIMIDUSOrders@celgene.com (Fax 
number: 844-343-4312). Allow 5 working days for drug shipment and note there are no drug 
shipments on Fridays and holidays.   
Drug Accountability: 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of the investigational drug nab-paclitaxel. The drug 
accountability records will capture drug receipt, drug dispensing, drug return and final disposition.   
Receipt of study drug 
The Investigator or designee is responsible for taking an inventory of each shipment of study drug 
received, and comparing it with the accompanying study drug accountability form.  The  
Investigator will verify the accuracy of the information on the form, sign and date it, retain a copy 
in the study file, and return a copy to Celgene or its representative 


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The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of the investigational drug nab-paclitaxel. The drug 
accountability records will capture drug receipt, drug dispensing, drug return and final disposition.   
Return and Retention of Study Drug 
Celgene will instruct the Investigator on the return or destruction of unused study drug.  If any 
study drug is lost or damaged, its disposition should be documented in the source documents.  
Study drug supplies will be retained at the clinical site pending instructions for disposition by 
Celgene.  Patients will be instructed to return empty vials or unused vials to the clinic site.  
Drug Safety Contact Information: 
Celgene Corporation     
Global Drug Safety and Risk Management 
86 Morris Avenue, Building L 
Summit, New Jersey 07901 
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 
Telephone: 1-908-673-9667 
Toll Free:    1-800-640-7854                                                                                                         
9.2 
Pembrolizumab (Keytruda®) – Standard of Care 
Other names for the drug: Keytruda® 
Please refer to the package insert for pembrolizumab for details of storage, administration 
etc. 
Availability/ordering 
Commercially available. Standard of care. 
10.0 
CORRELATIVES/SPECIAL STUDIES 
We will archive patient tumor, plasma and serum samples for future unspecified testing including 
but not limited to PD-L1 and anti-drug antibody testing. Submission of samples for correlative 
studies is expected of all subjects at baseline and optional tumor biopsy will be performed for 
those who consent to it. 
 
10.1 
Sample Collection Guidelines 
Tumor Tissue 
An archived tissue block must be identified to submit unstained slides prior to registration. 
Unstained slides from an archived formalin-fixed paraffin embedded tissue block are to 
be submitted for each subject from prior cystectomy or biopsy of metastatic lesion 
(estimated tumor content >30% of nucleated cells in specimen) to create a tissue archive 
of these patients. 
Representative tumor specimens in paraffin blocks (preferred) or at least 15 unstained 
slides, with an associated pathology report, must be identified to submit for determination 
of sufficient viable tumor content prior to study enrollment. Tumor specimens will be 
evaluated for PD-L1 expression at a future time when funding is secured. 
Blood Collection for Banking 
Whole blood samples (20 mL)  


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Serum samples (5-10 mL)  
Serum processing: Collect whole blood in a covered test tube. If commercially available 
tubes are to be used, the researcher should use the red topped tubes. These are 
available from Becton Dickinson (BD). BD’s trade name for the blood handling tubes is 
Vacutainer. After collection of the whole blood, allow the blood to clot by leaving it 
undisturbed at room temperature. This usually takes 15-30 minutes. Remove the clot by 
centrifuging at 1,000-2,000 x g for 10 minutes in a refrigerated centrifuge. 
The resulting supernatant is designated serum. Following centrifugation, it is important to 
immediately transfer the liquid component (serum) into a clean polypropylene tube using 
a Pasteur pipette. The samples should be maintained at 2-8°C while handling. The serum 
should be apportioned into 0.5 ml aliquots, stored, and transported at –20°C or lower. It is 
important to avoid freeze-thaw cycles because this is detrimental to many serum 
components. Samples which are hemolyzed, icteric or lipemic can invalidate tests. 
Plasma samples (5-10 mL) 
Plasma Collect whole blood into commercially available anticoagulant-treated tubes e.g., 
EDTA-treated (lavender tops) or citrate-treated (light blue tops). Heparinized tubes 
(green tops) are not permitted. Cells are removed from plasma by centrifugation for 10 
minutes at 1,000-2,000 x g using a refrigerated centrifuge. Centrifugation for 15 minutes 
at 2,000 x g depletes platelets in the plasma sample. 
The resulting supernatant is designated plasma. Following centrifugation, it is important 
to immediately transfer the liquid component (plasma) into a clean polypropylene tube 
using a Pasteur pipette. The samples should be maintained at 2-8°C while handling. If 
the plasma is not analyzed immediately, the plasma should be apportioned into 0.5 ml 
aliquots, stored, and transported at –20°C or lower. It is important to avoid freeze-thaw 
cycles. 
 
10.2 
Specimen Banking 
Patient samples (plasma and serum) collected for this study will be retained at the 
University of Michigan. Specimens will be stored indefinitely or until they are used up. If 
future use is denied or withdrawn by the patient, best efforts will be made to stop any 
additional studies and to destroy the specimens. 
Specimens being stored long-term for potential use not outlined in the protocol are subject 
to University Policy Governing Tissue Sample Collection, Ownership, Usage, and 
Disposition within all UMMS Research Repositories 
 
11.0 
STATISTICAL CONSIDERATIONS 
The primary aim of this single-arm phase 2 trial is to determine the efficacy of the combination of 
pembrolizumab and abraxane in patients with advanced urothelial carcinoma. The primary 
endpoint is the ORR (Overall Response Rate = Complete Response + Partial Response per 
RECIST 1.1) proportion. 
 
11.1 
Study Design 
Historical ORR in these subjects (both platinum-refractory and cisplatin- ineligible) treated with 
anti-PD1/PDL1 is 16-23%. For study design purposes, we state that an ORR of <25% with the 
combination of pembrolizumab and abraxane would be uninteresting and an ORR of 45% or 
greater would be interesting for further investigation. We will utilize a Simon’s two-stage 
minimax design with 17 response evaluable patients in stage 1 and 19 additional response 
evaluable patients possible in stage 2 for a total sample size of 36 response evaluable 


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patients.  This design will provide 80% power with a 5% type I error.  If 4 or less responses are 
found in stage 1, then the combination will be considered uninteresting for further study.  If 5 or 
more responses are in stage 1, then stage 2 will be opened to accrual.  After accrual of 36 
response evaluable patients, if 14 or more responses are observed then the combination 
treatment will be declared interesting for further study.  This trial design has a 57% probability of 
terminating early if the true response rate is < 25% and only 6% probability of early termination if 
the true response rate is 45% or greater.  Response evaluable is defined below. 
Interim Analysis in the Simon’s two-stage mini-max design:   
After 17 response evaluable patients have been accrued in stage 1, an interim efficacy analysis 
will be done.  If 4 or fewer responses are observed, then the trial will stop and the combination 
will be deemed uninteresting for further investigation. If 5 or more responses are observed, then 
stage 2 will be opened and 19 more response evaluable patients will be accrued. 
Populations for Analysis 
Intent-to-Treat Population: All patients consented and enrolled in the trial. 
Response Evaluable Population: Only those patients who have had their disease re-evaluated by 
imaging after 2 cycles of therapy OR exhibit objective or unequivocal clinical disease progression 
prior to the end of cycle 2 will be considered evaluable for the primary endpoint. 
Safety Evaluable Population: Patients who receive any treatment on protocol will be considered 
evaluable for safety. 
 
11.2 
Sample Size and Accrual 
The planned accrual for Stage 1 of the Simon two-stage trial is 17 subjects. If the criterion 
for the interim efficacy analysis (as above) is met, the study will move on to Stage 2 for 
an additional accrual of 19 subjects more. 
Accrual for Stage 1 is expected to be over 12 months at the University of Michigan. 
Accrual for Stage 2 (if applicable) will be over an additional 12 months at the University of 
Michigan. 
 
11.3 
Data Analyses Plans 
Primary Analysis:  
The primary efficacy endpoint is best overall response rate. The primary analysis will 
include the response count and proportion with the associated exact 95% binomial 
confidence interval in the response evaluable population.  If stage 2 is initiated, then the 
efficacy analysis methods for the reported response confidence interval will be as 
described by Koyama and Chen [32]. A secondary analysis in the intent-to-treat 
population will be reported.  Patients who are unable to receive 2 cycles of treatment due 
to toxicity will be considered non-responders in the intent-to-treat analysis. 
Secondary Endpoint Analysis: 
Safety and Toxicity of pembrolizumab and abraxane will be listed and tabulated by organ 
system per CTCAE grade version 4.03. The number of cycles, dose reductions and dose 
delays will be described.  All safety and toxicity analyses will be done on the Safety 
evaluable population.   
Time-to-event endpoints including PFS (Progression-Free Survival), DOR (Duration of 
Response) and OS (Overall Survival) will be described using Kaplan-Meier methods.   
Kaplan-Meier plots and median, 12-month and 24-month product limit estimates with 
95% confidence intervals will be reported. DOT (Duration of Therapy) will be described 


UMCC 2017.077 
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using a median and inter-quartile range. CR (Complete Response) proportion will be 
reported with a count, proportion and associated 95% exact binomial confidence interval. 
Correlative analysis:  
PD-L1 expression in tumor tissue and TILs at baseline (and in optional tumor biopsy at 
progression) will be reported when such testing is performed with count and proportions 
and 95% confidence intervals, and correlated with response using chi-square tests and 
logistic models. 
Exploratory analysis:  
Development of a Therapy Response Predictor based on baseline (and separately in 
optional tumor biopsy tissue at progression when available) immune parameters in tissue 
will be explored using logistic models.  Elastic net and random forest methods will be 
used and compared to develop the predictor model. Quality of Life with patient-reported 
outcomes (EQ-5D-5L) will be described using means or medians and associated 
measures of variability. 
12.0 
Investigator Reporting Responsibilities 
The conduct of the study will comply with all FDA safety reporting requirements.   
IND Annual Reports 
If the FDA has granted an IND, it is a requirement of 21 CFR 312.33, that an annual report is 
provided to the FDA within 60-days of the IND anniversary date.  21 CRF 312.33 provides the 
data elements that are to be submitted in the report.  The Annual Report should be filed in the 
study's Regulatory Binder, and a copy provided to  
Celgene Corporation as a supporter of this study as follows: 
Celgene Corporation 
Attn: Medical Affairs Operations 
86 Morris Avenue 
Summit, NJ  07901 
Tel: (908) 673-9000 
All adverse experience reports must include the patient number, age, sex, weight, severity of 
reaction (e.g. mild, moderate, severe), relationship to drug (e.g. probably related, unknown 
relationship, definitely not related), date and time of administration of test medications and all 
concomitant medications, and medical treatment provided.   The investigator is responsible for 
evaluating all adverse events to determine whether criteria for “serious” and as defined above are 
present.  The investigator is responsible for reporting adverse events to Celgene as described 
below. 
13.0 DATA MANAGEMENT 
All information will be recorded locally and entered into Case Report Forms (CRFs) on the web 
based electronic data capture (EDC) system of the University of Michigan.  
CRFs will be reviewed and source verified during annual monitoring visits. Discrepant, unusual 
and incomplete data will be queried by the Quality Assurance Monitoring Team. The investigator 
or study coordinator will be responsible for providing resolutions to the data queries, as 
appropriate. The investigator must ensure that all data queries are dealt with promptly.  


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14.0 
DATA AND SAFETY MONITORING 
This trial will be monitored in accordance with the NCI approved University of Michigan Rogel 
Cancer Center Data and Safety Monitoring Plan. 
The study team will meet quarterly or more frequently depending on the activity of the protocol. 
The discussion will include matters related to the safety of study participants (SAE/UaP 
reporting), validity and integrity of the data, enrollment rate relative to expectations, 
characteristics of participants, retention of participants, adherence to the protocol (potential or 
real protocol deviations) and data completeness. At these regular meetings, the protocol specific 
Data and Safety Monitoring Report form will be completed and signed by the Principal 
Investigator or by one of the co-investigators. 
Data and Safety Monitoring Reports will be submitted to the University of Michigan 
Rogel Cancer Center Data and Safety Monitoring Committee (DSMC) on a quarterly basis for 
independent review.  
15.0 
QUALITY ASSURANCE AND AUDITS 
The Data and Safety Monitoring Committee can request a ‘for cause’ quality assurance audit of 
the trial if the committee identifies a need for a more rigorous evaluation of study-related issues.  
A regulatory authority (e.g., FDA) may also wish to conduct an inspection of the study, during its 
conduct or even after its completion. If an inspection has been requested by a regulatory 
authority, investigator must immediately inform the CTO that such a request has been made. 
16.0 
REFERENCES 
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into host immunity. Endocr Relat Cancer 12:1‐17, 2005  
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Emens LA, Asquith JM, Leatherman JM, et al: Timed sequential treatment with 
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immune activation. J Clin Oncol 27:5911‐8, 2009  
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Demaria S, Volm MD, Shapiro RL, et al: Development of tumor‐infiltrating lymphocytes in breast 
cancer after neoadjuvant paclitaxel chemotherapy. Clin Cancer Res 7:3025‐30, 2001  
17. 
Carson WE, 3rd, Shapiro CL, Crespin TR, et al: Cellular immunity in breast cancer patients 
completing taxane treatment. Clin Cancer Res 10:3401‐9, 2004  
18. 
Tsuda N, Chang DZ, Mine T, et al: Taxol increases the amount and T cell activating ability of self‐
immune stimulatory multimolecular complexes found in ovarian cancer cells. Cancer Res 
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Garnett CT, Schlom J, Hodge JW: Combination of docetaxel and recombinant vaccine enhances 
T‐cell responses and antitumor activity: effects of docetaxel on immune enhancement. Clin 
Cancer Res 14:3536‐44, 2008  
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9:292‐300, 2012  
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undergoing chemotherapy with taxanes. Br J Cancer 87:21‐7, 2002  
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myeloid‐derived suppressor cells and chronic inflammation in the spontaneous melanoma 
model. J Immunol 190:2464‐71, 2013  
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2000  
24. 
Mullins DW, Martins RS, Burger CJ, et al: Tumor cell‐derived TGF‐beta and IL‐10 dysregulate 
paclitaxel‐induced macrophage activation. J Leukoc Biol 69:129‐37, 2001  
25. 
Ibrahim NK, Desai N, Legha S, et al: Phase I and pharmacokinetic study of ABI‐007, a  
Cremophor‐free, protein‐stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res 
8:1038‐44, 2002  
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Sparreboom A, van Zuylen L, Brouwer E, et al: Cremophor EL‐mediated alteration of paclitaxel 
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27. 
ten Tije AJ, Verweij J, Loos WJ, et al: Pharmacological effects of formulation vehicles : 
implications for cancer chemotherapy. Clin Pharmacokinet 42:665‐85, 2003  
28. 
Nyman DW, Campbell KJ, Hersh E, et al: A phase I trial of ABI‐007, nanoparticle paclitaxel, 
administered to patients with advanced non‐hematologic malignancies. Journal of Clinical  
Oncology 22:2027‐2027, 2004  
29. 
Allwood MC, Martin H: The extraction of diethylhexylphthalate (DEHP) from polyvinyl chloride 
components of intravenous infusion containers and administration sets by paclitaxel injection.  
International Journal of Pharmaceutics 127:65‐71, 1996  
30. 
Gelderblom H, Verweij J, Nooter K, et al: Cremophor EL: the drawbacks and advantages of 
vehicle selection for drug formulation. Eur J Cancer 37:1590‐8, 2001  
31. 
Pfeifer RW, Hale KN, Cronquist SE, et al: Precipitation of paclitaxel during infusion by pump. Am J 
Hosp Pharm 50:2518, 2521, 1993  
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Song D, Hsu LF, Au JL: Binding of taxol to plastic and glass containers and protein under in vitro 
conditions. J Pharm Sci 85:29‐31, 1996  
33. 
Venkataramanan R, Burckart GJ, Ptachcinski RJ, et al: Leaching of diethylhexyl phthalate from 
polyvinyl chloride bags into intravenous cyclosporine solution. Am J Hosp Pharm 43:2800‐2, 
1986  
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Xu QA, Trissel LA, Zhang Y: Paclitaxel Compatibility with the IV Express Filter Unit. Int J Pharm 
Compd 2:243‐5, 1998  
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S. S. Sridhar CMC, S. D. Mukherjee, E. Winquist, C. Elser, A. Eisen, M. N. Reaume, A. Chung, Y. Ko: 
A phase II study of single‐agent nab‐paclitaxel as second‐line therapy in patients with metastatic 
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Camidge DR LS, Powderly J, et al. Atezolizumab (MPDL3280A) combined with platinumbased 
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Thorac Oncol. 2015;10:S176–S177. 84. :   
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Giaccone G CD, Liu SV, et al. Safety, activity and biomarker of atezolizumab (MPDL3280A) with 
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Eur J Cancer. 2015;51:S107–S108). Safety, activity and biomarker of atezolizumab (MPDL3280A) 
with platinum‐based chemotherapy (chemo) in non‐small cell lung cancer (NSCLC): a phase IB 
study. Eur J Cancer. 2015;51:S107–S108).   
38. 
Adams S DJ, Hamilton E, et al. : Phase IB trial of atezolizumab in combination with nab paclitaxel 
in patients with metastatic triple negative breast cancer (mTNBC). J Clin Oncol. 2016;34:1009  
39. 
Tolaney S SC, Aktan G, et al.: Phase 1b/2 study to evaluate eribulin mesylate in combination with 
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San Antonio Breast Cancer Symposium; December 6‐10, 2016; San Antonio, TX. Abstract P5‐
1502.  
40. 
Adams S DJ, Hamilton E, et al.: Safety and clinical activity of atezolizumab (anti‐PDL1) in  
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Abstract P2‐11‐06.  
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Nakanishi J, Wada Y, Matsumoto K, et al: Overexpression of B7‐H1 (PD‐L1) significantly  
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Immunol Immunother 56:1173‐82, 2007  
42. 
Mu CY, Huang JA, Chen Y, et al: High expression of PD‐L1 in lung cancer may contribute to poor  
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maturation. Med Oncol 28:682‐8, 2011  
 


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17.0 
APPENDICES 
APPENDIX 1 
 
Appendix 2 
 


UMCC 2017.077 
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Health Questionnaire 
English version for the USA 
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
Check the ONE box that best describes your health TODAY. 
MOBILITY 
I have no problems walking 

I have slight problems walking 

I have moderate problems walking 

I have severe problems walking 

I am unable to walk 
SELF-CARE 

I have no problems washing or dressing myself 

I have slight problems washing or dressing myself 

I have moderate problems washing or dressing myself 

I have severe problems washing or dressing myself 

I am unable to wash or dress myself 

USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
I have no problems doing my usual activities 

I have slight problems doing my usual activities 



UMCC 2017.077 
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Page 66 of 63 
I have moderate problems doing my usual activities 

I have severe problems doing my usual activities 

I am unable to do my usual activities 
PAIN / DISCOMFORT 

I have no pain or discomfort 

I have slight pain or discomfort 

I have moderate pain or discomfort 

I have severe pain or discomfort 

I have extreme pain or discomfort 
ANXIETY / DEPRESSION 

I am not anxious or depressed 

I am slightly anxious or depressed 

I am moderately anxious or depressed 

I am severely anxious or depressed 

I am extremely anxious or depressed 



UMCC 2017.077 
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Page 67 of 63 
We would like to know how good or bad your health is TODAY. 


UMCC 2017.077 
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Page 68 of 63 
This scale is numbered from 0 to 100. 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
Mark an X on the scale to indicate how your health is TODAY. 
Now, please write the number you marked on the scale in the box below. 
 
YOUR HEALTH TODAY = 
 

ICF_001.pdf: 
ID: UMCC 
2017.077 
    Abraxane With Anti-PD1/PDL1 in Patients With 
Advanced Urothelial Cancer 
    NCT03240016 
 


Study ID: HUM00135166   IRB: IRBMED   Date Approved: 2/19/2021   Expiration Date: 9/10/2021
Page 1 of 25
Consent Subtitle:  UMCC 2017.077
Consent Version: ICF v. 11.17.2020
UNIVERSITY OF MICHIGAN
CONSENT TO BE PART OF A RESEARCH STUDY
1.  KEY INFORMATION ABOUT THE RESEARCHERS AND THE STUDY
Study title:  ABLE:  Phase 2, Single Arm, Two-Stage Study of Abraxane with Anti-PD1/PDL1 in Patients with 
Advanced Urothelial Cancer
Company or agency sponsoring the study: 
The University of Michigan is the sponsor of this trial and Dr. Ajjai Alva is the lead investigator.  
The study is also supported by the Celgene Corporation, who is supplying the drug Abraxane.
Names, degrees, and affiliations of the researchers conducting the study:
Principal Investigator:
Ajjai Alva, MD
Internal Medicine/Hematology-Oncology, University of Michigan
1.1 Key Study Information
You may be eligible to take part in a research study.  This form contains important information that will help you 
decide whether to join the study.  Take the time to carefully review this information.  You should talk to the 
researchers about the study and ask them any questions you have.  You may also wish to talk to others such as 
your family, friends, or other doctors about joining this study.  If you decide to join the study, you will be asked to 
sign this form before you can start study-related activities.  Before you do, be sure you understand what the 
research study is about.
A research study is different from the regular medical care you receive from your doctor.  Research studies hope 
to make discoveries and learn new information about diseases and how to treat them.  You should consider the 
reasons why you might want to join a research study or why it is not the best decision for you at this time.  
Research studies do not always offer the possibility of treating your disease or condition.  Research studies also 
have different kinds of risks and risk levels, depending on the type of the study.  You may also need to think about 
other requirements for being in the study.  For example, some studies require you to travel to scheduled visits at 
the study site in Ann Arbor or elsewhere. This may require you to arrange travel, change work schedules, find 
childcare, or make other plans.  In your decision to participate in this study, consider all of these matters carefully. 
This is a Phase II study, which means the goal is to test the effectiveness and safety of the investigational 
combination of abraxane and the anti-PD1 immunotherapy drug called pembrolizumab.  The purpose of this study 
is to determine the effectiveness of the combination. Another purpose of the study is to determine if people with 
urothelial cancer are able to tolerate the combination. 
This research is studying a new drug in small numbers of people to learn about its safety and its effect on your 
body at certain doses as a treatment for Advanced Urothelial Cancer.  This study will test the effectiveness and 
safety of the investigational combination of abraxane and the anti-PD1 immunotherapy drug called 
pembrolizumab.  The purpose of this study is to determine the effectiveness of the combination. Another purpose 


Study ID: HUM00135166   IRB: IRBMED   Date Approved: 2/19/2021   Expiration Date: 9/10/2021
Page 2 of 25
Consent Subtitle:  UMCC 2017.077
Consent Version: ICF v. 11.17.2020
of the study is to determine if people with urothelial cancer are able to tolerate the combination.  Your health-
related information and biospecimens (blood and urine) will be collected for this research study.   
 
There can be risks associated with joining any research study.  The type of risk may impact whether you decide to 
join the study.  For this study, some of these risks may include:

Risks of Pembrolizumab: Itching of the skin, loose or watery stools, cough, joint pain, fever, back pain, 
immune –related reactions and rash

Risks of Abraxane: Decreased levels of red blood cells, the cells that carry oxygen (anemia), decreased 
levels of a type of white blood cell (neutrophils, leukocytes) that helps fight infection, decreased levels of 
platelets, the cells that help the blood clot, abdominal pain, constipation, diarrhea, nausea and vomiting

More detailed information will be provided later in this document. 
This study may not offer any benefit to you now but may benefit others in the future by creating knowledge about
how best to treat your disease in the future. More information will be provided later in this document.
We expect the amount of time you will participate in the study will be 24 months.
You can decide not to be in this study. Alternatives to joining this study include: standard treatment for this
condition, taking part in a different study, or having no treatment.
Even if you decide to join the study now, you are free to leave at any time if you change your mind.
More information about this study continues in Section 2 of this document.
2. PURPOSE OF THIS STUDY
2.1 Study purpose: 
This study is looking at the commonest type of bladder cancer called urothelial carcinoma.  A common treatment 
option for urothelial carcinoma is chemotherapy combination containing a drug called cisplatin.  You are being 
asked to take part in this study because you have advanced urothelial cancer. Advanced means that the cancer 
has spread to other parts of the body beyond where it started (metastatic) or has progressed locally and cannot 
be surgically removed.  
Immunotherapy is a type of therapy that boosts the body's natural defenses (immune system) to fight cancer.  
Pembrolizumab (Keytruda®) is a type of immunotherapy drug.  Pembrolizumab is approved by the FDA for the 
treatment of patients with metastatic urothelial carcinoma who are not eligible for cisplatin-containing 
chemotherapy or whose tumors have progressed after platinum-containing chemotherapy. Abraxane is approved 
by the U.S. Food and Drug Administration (FDA) for use in certain metastatic breast cancers, locally advanced or 
metastatic non-small cell lung cancer, and metastatic pancreatic cancer.  Abraxane is not yet approved by the FDA 
by itself for urothelial cancer. 
3. INFORMATION ABOUT STUDY PARTICIPANTS (SUBJECTS)
Taking part in this study is completely voluntary.  You do not have to participate if you do not want to.  You may 
also leave the study at any time.  If you leave the study before it is finished, there will be no penalty to you, and 
you will not lose any benefits to which you are otherwise entitled. 


Study ID: HUM00135166   IRB: IRBMED   Date Approved: 2/19/2021   Expiration Date: 9/10/2021
Page 3 of 25
Consent Subtitle:  UMCC 2017.077
Consent Version: ICF v. 11.17.2020
3.1 Who can take part in this study?
You are being asked to take part in this study because you have a type of cancer called urothelial carcinoma that 
has spread to other parts of the body (metastatic) or has progressed and cannot be surgically removed.
Every study has strict guidelines for determining which people may participate.  These are called eligibility criteria.  
You will need to meet all of these criteria before you can participate in this study.  If you agree to consider 
participating in this study, you will undergo evaluations to see if you meet the eligibility criteria for this study.  
Even though you may meet all the criteria for participation, it is possible that you may not be enrolled in this study 
for other reasons.
3.2 How many people (subjects) are expected to take part in this study?
About 36 people are expected to participate in this study, all at the University of Michigan.
4.  INFORMATION ABOUT STUDY PARTICIPATION
4.1 What will happen to me in this study?  
Study Visits:
The study team will explain the research study and answer any questions you have about the study.  If you still 
want to participate in the study the study team will request you sign the consent form prior to any activities 
pertaining to the study.  Once your consent is obtained, the study team will look through your medical chart, ask 
you questions, and begin scheduling tests and procedures to determine if you are eligible for the study.  The study 
team will inform you of the types of tests and procedures required before the study begins.  
Once it is determined you are eligible to enter the study, tests and procedures done at your study visits as part of 
your regular cancer care will continue, but some may be done more often because you are participating in this 
research study.  Also, some of the tests or procedures may have to be repeated if, for example, they were done 
too long ago or the results are not normal. 
Some tests and procedures may be done that are not part of your regular cancer care and are being done only for 
this research study.  Tests and procedures that are performed more often or are not part of your standard cancer 
care will be identified below as “for research”.  
Refer to the study calendar at the end of this consent form for information about what to expect during each 
study visit.
Before you can begin the study (Screening Period):
You will need to have certain exams, tests, or procedures to find out if you can be in the study. These will be done 
after you sign the consent but before you can start study treatment (called the screening period).  If you have had 
some of the screening procedures recently, they may not need to be repeated.  The screening tests and 
procedures do not have to be completed in one day and you are allowed to take breaks if you have multiple 
procedures in one day.  The following tests or procedures will be performed at screening:

You will be asked about your medical history, including any past treatments

You will be asked about any medications you have taking, including over the counter medicines, vitamins, 
or herbal treatments

You will be asked about any side effects you have experienced

You will be asked about how well you are able to perform daily tasks (performance status)

Physical exam, including weight, and vital signs


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
Blood for routine tests to check your health (blood counts, blood chemistry) and organ function

Blood to test for hepatitis B, hepatitis C, and HIV

Pregnancy test will be performed if you are a woman able to have children.  This may be a blood test or a 
urine test.

Computed tomography (CT) of the chest and CT or magnetic resonance imaging (MRI) of the abdomen 
and pelvis.  A CT or MRI of the brain may be performed if clinically indicated.
o
A CT scan uses special x-ray equipment to make detailed pictures of body tissues and organs.  For 
the CT scan, you may be given a “contrast material” (special dye that makes it easier for doctors 
to see different tissues in your body).  You will be asked to lie still and may be asked to hold your 
breath for a few seconds.
o
An MRI scan takes an image of your body using magnets

Correlative studies for research will be performed on some of your samples.  
o
Approximately 4 teaspoons of blood will be collected for correlative studies.
o
A part of your tumor tissue collected during a previous biopsy or surgery (archival) will be used for 
correlative studies.  You will not need to have a new biopsy for this part of the study.
o
Refer to “Research Samples Stored for Future Use” below for more information. 

You will be asked to complete questionnaires asking about your symptoms and health.  You may find 
some of the questions uncomfortable to answer.  You do not have to answer any question you do not 
want to answer.  This is for research.
While you are receiving the study intervention (Study Intervention Period):
The study intervention period consists of blocks of time called “cycles” and each cycle lasts 21 days (three weeks).  
You may continue to receive the study drugs until your disease gets worse or you choose to withdraw from the 
study, or your doctor decides it is in your best interest to stop taking the study drugs.  You will be asked to come 
to the clinic on Day 1 and Day 8 of each cycle.
You will receive abraxane intravenously on Day 1 and Day 8 of every cycle.  You will also receive pembrolizumab 
intravenously on Day 1 of every cycle.  
The following tests and procedures will be performed at one or more study visits.  Refer to the study calendar at 
the end of this consent form for information about which procedures will be performed at certain study visits.

You will be asked about your medical history, including any past treatments

You will be asked about any medications you have taking, including over the counter medicines, vitamins, 
or herbal treatments

You will be asked about any side effects you have experienced

You will be asked about how well you are able to perform daily tasks (performance status)

Physical exam, including weight, and vital signs

Blood for routine tests to check your health (blood counts, blood chemistry) and organ function

Computed tomography (CT) of the chest and CT or magnetic resonance imaging (MRI) of the abdomen 
and pelvis.  A CT or MRI of the brain may be performed if clinically indicated.
o
A CT scan uses special x-ray equipment to make detailed pictures of body tissues and organs.  For 
the CT scan, you may be given a “contrast material” (special dye that makes it easier for doctors 
to see different tissues in your body).  You will be asked to lie still and may be asked to hold your 
breath for a few seconds.
o
An MRI scan takes an image of your body using magnets


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Consent Subtitle:  UMCC 2017.077
Consent Version: ICF v. 11.17.2020

You will be asked to complete questionnaires asking about your symptoms and health.  You may find 
some of the questions uncomfortable to answer.  You do not have to answer any question you do not 
want to answer.  This is for research.
End of Treatment and Follow-up Visits:
After your last dose of study drugs, you will be asked to come back to the clinic for and End of Treatment Visit.  
If you complete 17 cycles of study drug, decide to withdraw, or your study doctor decides it is in your best interest 
to stop taking the study drug, you will be asked to come back for an End of Treatment Visit.  Afterwards, you will 
be followed every 12 weeks for 2 years via phone call or clinic visit.  Refer to the study calendar at the end of this 
consent form for information about which procedures will be performed at certain study visits.
Research Samples Stored for Future Use:
The study team will keep some of your samples to store and use in future research.  The future research may be 
similar to this study or may be completely different.  Some of these tests may include your genes or genetic 
information.  The DNA contained in your genes holds the instructions that your body uses to grow and function.  
Your genes are responsible for your physical features such as eye color, blood type, and how your body breaks 
down medications.  Genes can also be responsible for some medical conditions.  Your samples would be kept at 
the University of Michigan.  Samples will be stored indefinitely or until they are used up.
Blood, tumor tissue, and related medical information (for example, your diagnosis, disease history, prior 
treatments, blood work results, or CT scans) will be stored so that we may study them in future research.  
Approximately 4 teaspoons of blood will be collected to store for this purpose.  The tumor tissue sample will come 
from a previous biopsy (archival) and you will not need to have a new biopsy.  For information related to loss of 
confidentiality, genetic risks, and risk of blood draws, please refer to Section 5.1 of this consent form.
By taking part in this study, you are giving us permission to use your stored samples and related medical 
information for future research.  Even if you give us permission now to keep some of your samples and related 
medical information, you can change your mind later and ask us to destroy it.  Keep in mind, however, that once 
we have analyzed your samples, we may not be able to take the information out of our research.
Samples will be labeled with your subject number and the date the sample was collected.  The University of 
Michigan will retain the link to the subject number.  We may share your stored samples and related medical 
information with other researchers inside and outside of the University of Michigan so that they can use it in their 
research and evaluations with the aim of helping future patients.  Dr. Alva will be responsible for reviewing and 
approving requests for specimens from potential research collaborators outside of the University of Michigan.  No 
identifiable information that could be directly linked to you will be provided.  The use of your samples may be 
used for research similar to this study or may be completely different.  Once we have shared your samples and 
medical information with other researchers, we will not be able to get it back.
You will not find out the results of future research on your samples.  Allowing us to do future research on your 
samples will not benefit you directly.
The University of Michigan, the investigators, or a collaborating researcher may benefit financially from future 
research on your samples and related medical information.  


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Consent Subtitle:  UMCC 2017.077
Consent Version: ICF v. 11.17.2020
You will be asked to affirm in Section 12 of this consent form that you understand your required participation in 
this sub-study.
Optional – Tumor biopsy at disease progression:
You will also be able to take part in an optional tumor biopsy for research.  If you decide to participate in the 
optional tumor biopsy collection, you will have an additional tumor biopsy performed at the time of disease 
progression.  Participation in this optional tumor biopsy is completely voluntary.  You can still participate in the 
main study even if you do not want to participate in the optional tumor biopsy at progression.
You may need to have an ultrasound, x-ray, or CT scan to guide the biopsy collection.  For information related to 
risks of biopsies and imaging, please refer to Section 5.1 of this consent form.
If you agree to allow the collection of an optional tumor biopsy at the time of disease progression, the tumor 
tissue sample and related medical information (for example, your diagnosis, disease history, prior treatments, 
blood work results, or CT scans) will be stored for future research.  Optional tumor tissue will be stored and used 
in the same manner as other samples collected as part of the main study as described above in the section 
“Research Samples Stored for Future Use”.
Your decision whether or not to participate in the optional tumor biopsy at time of disease progression will be 
documented in Section 12 of this consent form.    
Optional - Photographs:
Photographs may be taken to document and monitor any skin lesions, or cancer visible on your skin.  Care will be 
taken to ensure that these photographs do not reveal your identity.  The photograph will only show the lesion and 
surrounding skin.  Every attempt will be made to avoid taking a full face photograph.  If this is not possible, the 
photograph will be ‘de-identified’ as much as possible so that we minimize the chance that someone could 
identify you from the picture.  There is a risk that a photograph may not protect your identity.  You will be asked 
to document your decision in Section 12 of this consent form.  You can take part in this study even if you decide 
not to let us take photographs.
4.2 How much of my time will be needed to take part in this study?  
The length of your study visits will vary depending on which procedures need to be done.  The screening visit may 
take approximately 4 hours.
Abraxane will be administered intravenously (through a vein; IV) over 30-40 minutes.  Pembrolizumab will be 
administered intravenously (through a vein; IV) over 60 minutes.  If the first infusion of pembrolizumab is 
administered with no major side effects or complications, subsequent infusions may be delivered over 30 
minutes.  On days when you receive study drug, these visits may take approximately 2-3 hours.  If you need to 
have CT or MRI scans, these visits will take longer.  
4.3 When will my participation in the study be over? 
The study intervention period consists of blocks of time called “cycles” and each cycle lasts 21 days (three weeks).  
You may continue to receive the study drugs until your disease gets worse, you choose to withdraw from the 
study, or your doctor decides it is in your best interest to stop taking the study drugs.  We estimate that the 
average subject will receive the study drugs for approximately 6 cycles.  Abraxane can be discontinued after 6 
cycles at your doctor’s choice, or if you have too many side-effects and pembrolizumab alone could be continued. 


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Consent Subtitle:  UMCC 2017.077
Consent Version: ICF v. 11.17.2020
Abraxane alone can be continued if pembrolizumab is stopped for pembrolizumab related toxicities, and vice 
versa.
After your last dose of study drugs, you will be asked to come back for an End of Treatment Visit.  Afterwards, you 
will be followed every 12 weeks for 2 years via phone call or clinic visit.
4.4 What will happen with my information and/or biospecimens used in this study? 
With appropriate permissions, your samples and collected information may also be shared with other researchers, 
here, around the world, and with companies. Your identifiable private information or identifiable biospecimens 
may be stripped of identifiers and used for future research studies or distributed to another researcher for future 
research studies without additional informed consent. 
5.  INFORMATION ABOUT RISKS AND BENEFITS
5.1 What risks will I face by taking part in the study?  What will the researchers do to protect me against these 
risks?
Your study doctor and study staff will monitor you closely for side effects.  Even with frequent blood tests and 
other examinations, taking the study drug involves risks, and some side effects cannot be predicted.  Side effects 
can range from mild to severe and life-threatening.  Many side effects will get better when you stop taking the 
study drug, but some may be long lasting or may never go away.  Side effects may even cause death.  You should 
tell your study doctor immediately about any side effects that you have or any change in how you feel while on 
this study.  If you have side effects, your dose may have to be reduced, or you may have to stop taking the drugs 
and wait until you feel better before you start again.  Your study team may give you medicines or lower your dose 
of drugs to help lessen side effects.  If any side effect is intolerable, you may have to permanently stop taking the 
drugs.
We will minimize the risks by monitoring you carefully.  We will provide the usual supportive care that would be 
routinely given to someone with your condition.  If you have side effects from the investigational study treatment, 
we will make appropriate adjustments as defined by the study protocol.  You may need to discontinue the 
investigational study treatment if the side effects are too serious.  If you have signs of infection, you will receive 
appropriate antibiotics.  If you have signs of bleeding you may need to receive transfusions of platelets, plasma, or 
red cells.  If you are at risk of having blood clots, you may receive an anticoagulant (blood thinner).  If your 
hemoglobin level is too low, you may receive a red cell transfusion.  If you start feeling sick to your stomach, you 
may be given medications to help reduce nausea.  If you have vomiting, you may be given fluids through an IV.
Risks of Abraxane:
Very Common (occurring in 10% or more of people):

Decreased levels of red blood cells, the cells that carry oxygen (anemia)

Decreased levels of a type of white blood cell (neutrophils, leukocytes) that helps fight infection

Decreased levels of platelets, the cells that help the blood clot

Abdominal pain

Constipation

Diarrhea

Nausea, vomiting

Inflammation of the mouth and mouth sores

Feeling weak and having no energy


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Consent Version: ICF v. 11.17.2020

Chills

Fatigue

Buildup of fluid in the body or extremities, causing swelling

Fever

Increased level of a liver enzyme (alanine aminotransferase) in the blood

Weight decreased, decreased appetite

Dehydration

Low levels of potassium in the blood

Joint pain, musculoskeletal pain

Muscle aches

Dizziness

Taste changes which may affect the way foods normally taste

Headache

Weakness, numbness, and pain from nerve damage, usually in the hands and feet (peripheral neuropathy)

Depression

Problems falling or staying asleep (insomnia)

Cough

Difficult or labored breathing

Nosebleed

Hair loss

Nail disorder including loosening or separation of the nail from the nail bed and discoloration

Itching

Rash, including generalized rash
Common (occurring in 1% or more people but less than 10% of people):

Fever with low white blood cell count

Decreased levels of a type of white blood cell (lymphocytes) that helps fight infection

Decreased levels of all components of the blood (red blood cells, white blood cells, and platelets)

Condition in which the heart does not pump blood as well as it should (congestive heart failure)

Fast heart beat or heart beats that are fast, strong, or irregular

Excessive tears

Visual impairment

Inflammation of the colon (colitis)

Dry mouth

Heartburn

Difficulty swallowing

Blockage of the intestine or bowel which can cause nausea, vomiting, and pain (intestinal blockage)

Chest pain

Infusion site reactions

Inflammation of the mucosal membranes (mucosal inflammation)

Bile duct infection

High levels of bilirubin in the blood.  Bilirubin is a bile pigment produced by the liver which is normally and 
continually excreted from the body. This may indicate that too many red blood cells are being destroyed 
or that the liver or gallbladder is not functioning properly.

Upper or lower respiratory tract infection including bronchitis


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
Candida infection, which is a type of yeast infection

Infection of follicles, which are the pockets from which hair grows

Nail infection

Pneumonia

A serious condition that occurs in response to an infection that causes widespread inflammation, resulting 
in poor blood supply to vital organs (sepsis).  Symptoms may include a fast hear rate, fever, confusion, and 
rapid breathing.

Urinary tract infection

Increased levels of liver enzymes (aspartate aminotransferase or alkaline phosphatase) in the blood

Increased levels of creatinine in the blood, a substance normally eliminated by the kidneys into the urine

Muscular weakness

Loss of muscle coordination, including awkward, unsteady walking

Anxiety

Acute kidney failure which is when both of your kidneys fail and your body holds fluid which can be 
serious or life-threatening.  Your blood pressure rises and harmful wastes build up in your body.  You may 
experience fatigue, nausea, and loss of appetite.  You may need treatment to replace the work of your 
failed kidneys, such as dialysis.

Blood in the urine

Vomiting or coughing up blood

Nasal congestion

Pain in the middle part of the throat that includes the base of the tongue, the tonsils, the soft palate, and 
the part of the throat that is behind the mouth and nasal cavity

Buildup of fluid around the lungs in the chest cavity (pleural effusion), which can cause shortness of 
breath and may require treatment

Inflammation of the lungs (pneumonitis)

Blood clot formed in the veins of the leg which may manifest as a dull ache or heaviness in the limb (deep 
vein thrombosis).  If the clot moves to other organs, it can be serious or life-threatening.

A blood clot that causes a sudden blockage in a lung blood vessel, usually due to a blood clot that traveled 
to the lung from the leg (pulmonary embolism).  A pulmonary embolism is a serious condition that can 
cause: permanent damage to part of your lung from lack of blood flow to lung tissue; low oxygen levels in 
your blood; damage to other organs in your body from not getting enough oxygen.  If a clot is large, or if 
there are many clots, a pulmonary embolism can cause death.

Dry skin, redness of the skin

Reddening, swelling, numbness, and peeling of the skin usually on the palms of your hands or the soles of 
your feet

Flushing

High or low blood pressure

Swelling in the arms or legs caused by a blockage in the lymphatic system
Uncommon (occurring in 0.1% or more people but less than 1% of people):

Decrease in the production of cells responsible for fighting infection, carrying oxygen, and clotting blood 

Clotting in small blood vessels of the body resulting in a low platelet count

Heart beats too fast, too slow, or in an abnormal or irregular rhythm

Sudden, unexpected stopping of the heart (cardiac arrest)

Decrease in the heart’s ability to pump blood.  This may be serious or life-threatening.


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
Irritation and redness of the thin membrane covering the eye (conjunctivitis)

Appearance of cyst-like areas of fluid in the macula of the eye, causing swelling to the retina

Inflammation of the cornea of the eye.  Eye pain, tearing, and sensitivity to light are common symptoms.  

Damage to the macula, the part of the eye associated with vision

Sleepiness

A vague feeling of bodily discomfort, feeling bad

Allergic reaction (hypersensitivity) that may include a rash, hives, fever, difficulty breathing, and low blood 
pressure

Injection site infection

Significant inflammatory response to an infection with or without a fever (neutropenic sepsis)

Fluid retention

Facial paralysis

A condition called hemolytic uremic syndrome which is associated with the decrease in red blood cells, 
platelets, and kidney function.  This may cause high blood pressure or swelling of the face, hands, feet, or 
the entire body.  This can progress to acute kidney failure which can be life-threatening.

Dry throat or nasal dryness

Allergic skin irritation or rash

Skin disorder with lesions that look like rings and can sometimes be painful or itchy

Skin exfoliation

Hives
Rare (occurring in 0.01% or more people but less than 0.1% of people):

A type of heart block in which the electrical conduction between the atria and the ventricles is impaired
The following events were identified post-marketing in people taking abraxane.  The frequency of these events 
are not known:

Inflammatory reaction in areas that were previously treated with radiotherapy

Weakness or paralysis of a cranial nerve

Slight or incomplete paralysis of the vocal cord

Radiation-induced lung disease following treatment with radiotherapy

Sensitivity or an immune system reaction triggered by light

A condition called Stevens-Johnson syndrome (SJS), which is a skin condition that causes painful blisters 
and sores of the skin and mucous membranes, especially in the mouth.  May cause difficulty eating and 
swallowing.  This is similar to the skin damage from a severe burn and is serious and life-threatening.

A condition called toxic epidermal necrolysis (TEN), which is a rare, life-threatening skin condition that is 
usually caused by a reaction to a drug.  The top layer of the skin detaches from the lower layers of skin all 
over the body.  This is similar to the damage from a severe burn and is serious and life-threatening.
Risks of Pembrolizumab:
Pembrolizumab is also known as KEYTRUDA® (approved in the USA and several other countries) and is available by 
prescription to treat malignant melanoma (a type of skin cancer), head and neck squamous cell carcinoma, and 
non-small cell lung cancer that has spread to other parts of the body. In clinical trials, both men and women with 
cancer were treated, some for up to approximately 2 years.  Safety was studied across several cancers treated 


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with different doses: 2mg/kg every 3 weeks, 10mg/kg every 2 or 3 weeks, and 200mg fixed dose every 3 weeks.  
The side effects seen were similar.
Pembrolizumab is being studied by its manufacturer in clinical trials to see if it is effective in treating more than 30 
types of cancer, as a single therapy or in combination with other therapies, and to see what side effects are 
associated with its use.
trials.   
Very common (side effects seen in ≥10% or more of people treated with pembrolizumab) include:

Fatigue 

Rash 

Loss of pigment from areas of skin 

Pain in joints 

Back pain 

Cough 

Difficulty breathing

Headache

Itching

Diarrhea

Fever

Asthenia

Weight loss

Musculoskeletal pain

Decreased appetite

Low levels of sodium in the blood 

Constipation

Nausea

Abdominal pain

Elevated LFTs

Vomiting 

Swelling of legs or hands 

Urinary tract infection

Anemia

Increased blood creatinine

Blood in Urine 


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Severe and Fatal Immune-Mediated Adverse Reactions (side effects seen in  <1% of people treated with 
pembrolizumab) include:

 Inflammation of lungs so you may feel short of breath and cough.  Rarely this might lead to death.

Inflammation of the inner lining of the colon

Mild elevation of liver enzymes

Inflammation of the pituitary gland (a gland in the head), which may cause headaches, sick to your 
stomach, changes in behavior, double vision, few to no menstrual cycles, weakness, vomiting, and 
dizziness or fainting

Adrenal glands (glands on top of the kidneys) may not make enough hormone, causing tiredness, weight 
loss, muscle weakness, feeling faint, joint, muscle, and abdominal aches, nausea, vomiting, loose or 
watery stools, fever, salt craving, and sometimes darkening of the skin like a suntan

Too much thyroid hormone so you may feel anxious, angry, cannot sleep, weak, tremble, increased 
sweating, weight loss, hair loss, tired, have loose and watery stools

Not enough thyroid hormone so you may feel tired, gain weight, feel cold, have infrequent or hard bowel 
movements.

Inflammation of the pancreas (a gland in your abdomen that controls sugar levels) so you may have 
severe pain in the top part of your belly that may move to the back, feel sick to your stomach, and 
vomiting that gets worse when you eat

Too much sugar in your blood (diabetes) so you may feel thirsty and are likely to need regular insulin 
shots

Inflammation of the kidney so you may pass less urine or have cloudy or bloody urine, swelling and low 
back pain. 

Inflammation of the skin so you may have peeling of the skin, itching, skin redness 
Other Immune-Mediated Adverse Reactions

Inflammation of the middle layer of your heart wall (myocarditis) that may cause your heart to have 
difficulty pumping blood throughout your body, which can cause chest pain, shortness of breath, and 
swelling of the legs.  You may experience a fast or irregular heartbeat that may cause dizziness or fainting.  
Sometimes this condition can lead to death.

Inflammation of the thin saclike membrane surrounding the heart (pericardium).

Inflammation of the blood vessel that causes blood vessel walls to thicken and narrow, cutting off vital 
blood supply to tissues and organs.

Inflammation of the brain (encephalitis) and/or spinal cord membrane (meningitis).  Inflammation of the 
spinal cord can cause the myelin and axons to be damaged (demyelination) which can cause paralysis and 
sensory loss (myelitis)

Weakness and rapid fatigue of muscles (Myasthenic syndrome/myasthenia gravis (including 
exacerbation)). 

Immune system can attack the nerves (Guillain-Barré syndrome).

Inflammation of the nerves that may cause pain, weakness or tingling in the hands and feet, and may 
spread to the legs, arms, and upper body leading to severe muscle weakness and possible temporary 
paralysis.

Nerves that control involuntary body function can be damaged. Blood pressure, temperature control, 
digestion, bladder function and sexual function can be affected. 

Inflammation of the middle layer of the eye.

Inflammation of the iris of the eye. 


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
Inflammation of the pancreas (a gland in your abdomen that controls sugar levels) so you may have 
severe pain in the top part of your belly that may move to the back, feel sick to your stomach, and 
vomiting that gets worse when you eat.

Inflammation of the lining of the stomach.

Inflammation of the small intestine which may result in abdominal pain, bleeding, and other abdominal 
symptoms.

Low levels of parathyroid hormone (hypoparathyroidism)._

Red blood cells may be destroyed faster than they can be made (hemolytic anemia). 

Not enough new blood cells being made (aplastic anemia.) 

Severe systemic inflammatory syndrome, can be fatal. 

Inflammatory state affecting the whole body (systemic inflammatory response syndrome). 

Inflammation of the lymph nodes (histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis)),

Growth of tiny collections of inflammatory cells in different parts of the body.  The growths most 
commonly occur in the lungs, lymph nodes, eyes, and skin. 

Low blood platelets.

Solid organ transplant rejection.

Severe infusion related reactions. 
Some of the symptoms listed in the sections above have been reported to occur simultaneously in patients 
treated with pembrolizumab. For example, Vogt-Koyanagi-Harada (VKH) syndrome is a grouping of symptoms 
including headache, loss of vision, eye pain, sensitivity to light, neck stiffness, hearing problems, and dizziness, 
that is caused by immune system activation against certain cells in the body. (You should report any symptoms to 
the study team.)
Additional serious side effects seen in less than 1% of people treated with pembrolizumab include dizziness or 
fainting (low blood pressure), flushing or pain at the site of infusion.
Pembrolizumab can cause severe or life-threatening infusion-related reactions, including hypersensitivity and 
anaphylaxis (allergic reaction).  Signs and symptoms of infusion-related reactions include chills and shivering, 
wheezing, itchy skin, flushing, rash, low blood pressure, low oxygen in the blood, and fever.
Risks of Procedures:
Blood Draw Risks:  Collection of blood samples may cause pain, bleeding, bruising or infection. It is also possible 
that you may feel lightheaded or faint. Please tell your study doctor or the study nurse if you do not feel well after 
having your blood drawn at any time during your study participation.
Tumor Biopsy:  Potential risks and discomforts that you may experience as a result of the procedure depend upon 
the location of the tumor.  The more common risks/discomforts include pain, bleeding, infection, damage to 
tissues, and healing complications.  Your doctor will further explain any specific risks that may apply based on the 
procedures, and you will sign a separate consent for the procedure which will provide risk information in more 
detail.  In order to make the procedure more comfortable, you will get a local anesthetic to numb the area.  A mild 
sedative may also be given to you.
CT Scans:  CT imaging uses ionizing radiation, which increases your risk of cancer.  Everyone is exposed to 
naturally occurring ionizing radiation every day.  The amount of radiation exposure from 1 CT scan is 
approximately comparable to 1-3 years of natural background radiation.  


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The contrast substance injected during the CT scan may cause pain, burning feeling, sweating, and rarely an 
allergic reaction that can be serious.  If you know you are allergic to iodine, you must inform your doctor 
immediately.  The contrast agent used in the CT scan may cause kidney damage, especially if you are diabetic, 
dehydrated, and if you’re older.  In addition, your thyroid function may be affected.
MRI Scans:  Contrast is used to improve the pictures of the inside of the body made by the MRI.  Common risks if 
MRI include:  feeling fearful of being in a small enclosed space (claustrophobia) when you are lying inside the MRI 
scanner; feeling uncomfortable because of the loud noises made by the machines; and feeling uncomfortable with 
the physical sensations you may feel during the process.  You are also exposed to some risk because of the 
injected contrast, gadolinium-DTPA, which may cause headache, nausea, and local burning sensation.
The contrast agent, gadolinium, has been linked to development of Nephrogenic Fibrosing Dermopathy (NFD), 
also known as Nephrogenic Systemic Fibrosis (NSF).  NFD is a thickening of the skin, organs, and other tissues and 
is a rare complication in subjects with kidney disease who undergo an MRI with contrast material.  To help 
prevent this, we will check how well your kidneys work before you have any MRIs.  Because of the use of contrast, 
all female subjects who are able to have children will be required to use adequate birth control.  If you have 
implanted metal objects such as a pacemaker, artificial limbs, or metal joints, you will not be able to have an MRI 
done, and may not be able to take part in this research.
Questionnaires:  As part of the study, you will be asked to complete questionnaires.  Some of the questions may 
seem very personal or embarrassing.  They may make you uncomfortable. You may refuse to answer any of the 
questions that you do not wish to answer. If the questions make you uncomfortable, we can help you to find a 
counselor.
Privacy and Confidentiality Risks:
There are also non-physical risks associated with taking part in this study, such as the risks associated with a loss 
of privacy or confidentiality.  For example, if your identity as a participant in this research or your identifiable 
genetic or health information were disclosed to unauthorized persons, there is the possible risk of discrimination 
by employers or insurance providers.  The researchers believe that the risks of such improper disclosure are very 
small because strict privacy and confidentiality procedures for this research have been adopted.
Reproductive Risks:
Women:
If there is ANY chance that you can get pregnant, you must either agree to not have vaginal intercourse or you 
must use TWO types of birth control (one from each list below) AT THE SAME TIME.  These birth control methods 
must be used for 28 days prior to starting the investigational study treatment, all during investigational study 
treatment (including during temporary breaks from therapy), and for at least 6 months after the last dose of study 
drug.  The following methods are considered acceptable birth control methods:
Primary Forms

Tubal sterilization (tubes tied)

Partner’s vasectomy

Intrauterine device

Hormonal contraceptives (includes transdermal 
patch, injectables, implantables)
Secondary Forms

Male latex condom with or without spermicide

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal sponge (contains spermicide)


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Any birth control method can fail.  The reports of birth control failing are more frequent for females who use only 
a single form of birth control.  Using two forms of birth control at the same time greatly reduces the chances of 
pregnancy.  In addition, women must not breast-feed for at least 6 months after the last dose of study drug.
Men:
Men must agree to either abstain from sexual activities that could result in pregnancy or use an acceptable form 
of birth control all during investigational study treatment (including during temporary breaks from therapy) and 
for at least 6 months after the last dose of study drug.  Acceptable forms of birth control are male latex condom 
(with or without spermicide).  Men must use a male latex condom even if they have previously had a vasectomy.  
In addition, men should not donate sperm or semen while taking part in the study and for at least 6 months after 
the last dose of study drug.
Genetic Risks:
The federal Genetic Information Nondiscrimination Act (GINA) generally makes it illegal for health insurance 
companies, group health plans, and most employers to discriminate against you based on your genetic 
information.  This law does not protect you against genetic discrimination by companies that sell life insurance, 
disability insurance, or long-term care insurance.  Under this law:

Health insurance companies and group health plans may not request your genetic information that we 
obtain from this research

Health insurance companies and group health plans may not use your genetic information when making 
decisions regarding your eligibility or premiums

Employers with 15 or more employees may not use your genetic information that we obtain from this 
research when making a decision to hire, promote, or fire you or when setting the terms of your 
employment
GINA does not apply to the following groups; however, these groups have policies in place that provide similar 
protections against discrimination:

Members of the US Military receiving care through Tricare

Veterans receiving care through the Veteran’s Administration (VA)

The Indian Health Service

Federal employees receiving care through the Federal Employees Health Benefits Plans
As with any research study, there may be additional risks that are unknown or unexpected.
5.2 What happens if I get hurt, become sick, or have other problems as a result of this research?
The researchers have taken steps to minimize the risks of this study.  Even so, you may still have problems or side 
effects, even when the researchers are careful to avoid them. Please tell the researchers listed in Section 10 about 
any injuries, side effects, or other problems that you have during this study.  You should also tell your regular 
doctors.
If you think you have an injury or illness that is related to your participation in this clinical trial, it is important that 
you tell your study doctor immediately.  If you have a clinical trial related injury or accident, the study staff will 
make sure that you get medical treatment.  
You will receive appropriate medical care for any side affects you have while participating in this study.  Your 
study doctor may also lower the drug dose or stop drug if you experience side effects.


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You must inform your study doctor immediately if there are any changes in your health/condition, or if you have 
any concerns regarding the study.  If for any reason you are seen by another healthcare provider or admitted to 
another hospital, you should make known your participation in this research study.  These healthcare providers 
may wish to contact your study doctor to discuss your condition.  Your study doctor may need to contact your 
other doctors if you develop any potentially significant, unexpected diseases or conditions that may have been 
caused by the study intervention or procedures or are discovered during the study.
5.3 If I take part in this study, can I also participate in other studies?
Being in more than one research study at the same time, or even at different times, may increase the risks to you.  
It may also affect the results of the studies.  You should not take part in more than one study without approval 
from the researchers involved in each study.  
5.4 How could I benefit if I take part in this study?  How could others benefit?  
You may or may not receive any direct personal benefits from being in this study.  There is a chance that the study 
intervention may improve your quality of life or increase the length of disease-free survival.  The researchers hope 
that the information learned from this study will help other patients with this type of cancer in the future.
5.5 Will the researchers tell me if they learn of new information that could change my willingness to stay in this 
study?
Yes, the researchers will tell you if they learn of important new information that may change your willingness to 
stay in this study. If new information is provided to you after you have joined the study, it is possible that you may 
be asked to sign a new consent form that includes the new information.
6.  OTHER OPTIONS
6.1 If I decide not to take part in this study, what other options do I have?
You do not have to participate in this trial to receive care for your cancer.  There may be other ways of treating 
your cancer.  These include:

You may receive other available standard treatments such as pembrolizumab immunotherapy alone, or 
atezolizumab, another immunotherapy drug or carboplatin and gemcitabine chemotherapy for your 
cancer

You may be eligible for other cancer research studies

You may receive treatment for pain or other symptoms only

You may choose to receive no treatment at all
Please talk to your doctor about your choices before you decide if you will take part in this study.
7.  ENDING THE STUDY
7.1 If I want to stop participating in the study, what should I do?
You are free to leave the study at any time.  If you leave the study before it is finished, there will be no penalty to 
you. You will not lose any benefits to which you may otherwise be entitled.  If you choose to tell the researchers 
why you are leaving the study, your reasons for leaving may be kept as part of the study record. If you decide to 
leave the study before it is finished, please tell one of the persons listed in Section 10 “Contact Information” 
(below).


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You are free to partially or completely end your participation in the study.  An example of partially ending your 
participation would be to discontinue receiving study intervention, while still allowing continuation of study 
follow-up procedures.
Please note that any information collected before you withdraw will be kept and used to complete the research.
Please note that even if you withdraw consent for further follow-up or contacts, if the study doctor becomes 
aware of additional safety information this will be reported to the sponsor in order to comply with legal or 
regulatory requirements.
You may participate in an optional tumor biopsy performed at the time of disease progression (see “Optional – 
Tumor biopsy at disease progression” in Section 4.1, above).  Please note that if you decide to withdraw from the 
main study and had agreed to participate in the optional tumor biopsy, you will not be automatically withdrawn 
from the optional tumor biopsy.  If you wish to also withdraw your samples from the optional tumor biopsy, you 
will need to tell your study doctor.
7.2 Could there be any harm to me if I decide to leave the study before it is finished? 
Tell the study doctor if you are thinking about stopping or decide to stop.  It is important to tell the study doctor if 
you are thinking about stopping so any risks can be evaluated by your doctor.  They will also tell you how to stop 
safely and discuss what follow-up care and testing could be most helpful for you.  If you choose to tell the 
researchers why you are leaving the study, your reasons for leaving may be kept as part of the study record.  If 
you decide to leave the study before it is finished, please tell your study doctor or one of the researchers listed in 
Section 10 “Contact Information” (below).
7.3 Could the researchers take me out of the study even if I want to continue to participate?
Yes. There are many reasons why the researchers may need to end your participation in the study.  Some 
examples are:

The researcher believes that it is not in your best interest to stay in the study.

You become ineligible to participate.

Your condition changes and you need treatment that is not allowed while you are taking part in the study.

You do not follow instructions from the researchers.

The study is suspended or canceled.
8.  FINANCIAL INFORMATION
8.1 Who will pay for the costs of the study? Will I or my health plan be billed for any costs of the study?  
The study will pay for research-related items or services that are required or provided only because you are in the 
study.  If you are not sure what these are, see Section 4.1 above or ask the researchers for a list.  If you get a bill 
you think is wrong, call the researchers’ number listed in section 10.1.
You or your health plan will pay for all the things you would have paid for even if you were not in the study, like:

Health care given during the study as part of your regular care

Items or services needed to give you study drugs or devices

Monitoring for side effects or other problems

Deductibles or co-pays for these items or services

The drug pembrolizumab


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If you do not have a health plan, or if you think your health plan may not cover these costs during the study, 
please talk to the researchers listed in Section 10 below or call your health plan’s medical reviewer.
The Celgene Corporation is supplying the drug Abraxane at no charge to you.
What if I am injured while taking part in this study?
The study team has given you instructions about this research study. It is important that you follow these 
instructions carefully. If you get sick, have a medical complication, or are injured as a result of your being in the 
study, call Dr. Alva immediately, at 734-936-0091 or 734-936-4000 (24-hour paging). The doctor will either treat 
you or send you to another doctor for treatment.
You will get free medical care at the UMHS for any hospitalization or ER visits directly caused by the study drug, 
device, or procedure. The UMHS and the study doctor are responsible for determining whether your condition 
was the result of your participation in the study.
The UMHS will pay for your treatment only if the need for treatment has been caused by the study drug, device, 
or procedure. This means that you or your health plan must pay for any treatment that is part of your usual 
medical care or that is related to a medical condition you had before participating in the study.
By signing this form, you do not give up your right to seek payment if you are harmed as a result of being in this 
study.
8.2 Will I be paid or given anything for taking part in this study?
No, you will not be paid for taking part in this study.
8.3 Who could profit or financially benefit from the study results?
The company whose product is being studied:  Celgene Corporation (supplier of Abraxane)
The University of Michigan and the researchers conducting the study have no financial interest in the outcome of 
the study.
The University of Michigan, the investigators, or a collaborating researcher may benefit financially from future 
research on your samples and related medical information as described in Section 4.1 above under “Research 
Samples Stored for Future Use”.
Research can lead to new discoveries, such as new tests, drugs, or devices. Researchers, their organizations, and 
other entities, including companies, may potentially benefit from the use of the data or discoveries. You will not 
have rights to these discoveries or any proceeds from them. 
9. CONFIDENTIALITY OF SUBJECT RECORDS AND AUTHORIZATION TO RELEASE YOUR PROTECTED HEALTH 
INFORMATION
The information below describes how your privacy and the confidentiality of your research records will be 
protected in this study.


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9.1 How will the researchers protect my privacy?
Your participation will occur at the University of Michigan medical center.  The University of Michigan study team 
will use your medical records during the course of participation to conduct the study.  Study data will include your 
medical history, physical examinations, laboratory and pathology evaluation results, imaging studies, study 
intervention, side effects reported, other medications you are taking, and other medically relevant information 
needed for the trial.
The University of Michigan has rules to protect information about you.  Federal and state laws also protect your 
privacy.  We will take measures to protect the privacy and security of your personal information, but we cannot 
guarantee complete confidentiality of study data.  Once your health information is shared with someone outside 
of the study team, it may no longer be protected.
HIV and hepatitis are reportable diseases.  If you test positive for HIV or hepatitis, the law mandates that your 
study doctor disclose your identity to the appropriate people (such as health care workers who are involved in 
your care) and appropriate authorities.
Your data will be kept confidential, to the extent permitted by applicable laws, in the following manner:

Your name will not be used in any reports about the study

You will be identified only by a study code: a subject ID number, and initials

Your identifying information will be kept secure
You will be assigned a subject code number to help ensure that your medical and personal information is kept 
confidential.  The key to this code will remain at the University of Michigan.  All data, forms, records, and samples 
related to the study will use this subject code number.  
The study team will use the study data for research purposes to support the scientific objectives of the study.  
Study data (that does not directly identify you) may be published in medical journals or shared with others as part 
of scientific discussions.
Samples banked for future research will also be coded and the key to this code will remain at the University of 
Michigan.  No identifiable information that could be directly linked to you will be provided.
9.2 What information about me could be seen by the researchers or by other people?  Why?  Who might see it?
Signing this form gives the researchers your permission to obtain, use, and share information about you for this 
study, and is required in order for you to take part in the study.  Information about you may be obtained from any 
hospital, doctor, and other health care provider involved in your care, including:

Hospital/doctor's office records, including test results (X-rays, blood tests, urine tests, etc.)

Mental health care records (except psychotherapy notes not kept with your medical records)

Alcohol/substance abuse treatment records

HIV/AIDS status

Sexually transmitted disease and/or other communicable disease status

Health plan/health insurance records

All records relating to your condition, the treatment you have received, and your response to the 
treatment

Billing information

Demographic information

Personal identifiers


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There are many reasons why information about you may be used or seen by the researchers or others during or 
after this study.  Examples include:

The researchers may need the information to make sure you can take part in the study.  

The researchers may need the information to check your test results or look for side effects.  

University, Food and Drug Administration (FDA) and/or other government officials, auditors, and/or the 
IRB may need the information to make sure that the study is done in a safe and proper manner.   

Study sponsors or funders, or safety monitors or committees, may need the information to: 
o
Make sure the study is done safely and properly
o
Learn more about side effects 
o
Analyze the results of the study 

Insurance companies or other organizations may need the information in order to pay your medical bills 
or other costs of your participation in the study.

The researchers may need to use the information to create a databank of information about your 
condition or its treatment.

Information about your study participation may be included in your regular UMHS medical record.

If you receive any payments for taking part in this study, the University of Michigan accounting 
department may need your name, address, social security number, payment amount, and related 
information for tax reporting purposes. 

Federal or State law may require the study team to give information to government agencies. For 
example, to prevent harm to you or others, or for public health reasons. 
The results of this study could be published in an article, but would not include any information that would let 
others know who you are. 
A description of this clinical trial will be available on http://www.clinicaltrials.gov/, as required by U.S. Law. This 
Web site will not include information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time.
9.3 What happens to information about me after the study is over or if I cancel my permission?
As a rule, the researchers will not continue to use or disclose information about you, but will keep it secure until it 
is destroyed.  Sometimes, it may be necessary for information about you to continue to be used or disclosed, even 
after you have canceled your permission or the study is over.  
Examples of reasons for this include:

To avoid losing study results that have already included your information 

To provide limited information for research, education, or other activities (This information would not 
include your name, social security number, or anything else that could let others know who you are.) 

To help University and government officials make sure that the study was conducted properly
As long as your information is kept within the University of Michigan Health System, it is protected by the Health 
System’s privacy policies.  For more information about these policies, ask for a copy of the University of Michigan 
“Notice of Privacy Practices”.  This information is also available on the web at 
http://www.uofmhealth.org/patient+and+visitor+guide/hipaa. Note that once your information has been shared 
with others as described under Question 9.2, it may no longer be protected by the privacy regulations of the 
federal Health Insurance Portability and Accountability Act of 1996 (HIPAA).  


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9.4 When does my permission expire?  
Your permission will not expire unless you cancel it. You may cancel your permission at any time by writing to the 
researchers listed in Section 10 "Contact Information" (below).  
10. CONTACT INFORMATION
10.1 Who can I contact about this study?
Please contact the researchers listed below to:

Obtain more information about the study

Ask a question about the study procedures or treatments

Talk about study-related costs to you or your health plan 

Report an illness, injury, or other problem (you may also need to tell your regular doctors)

Leave the study before it is finished

Express a concern about the study
Principal Investigator:
Ajjai Alva, MD
Mailing Address:
University of Michigan
1500 E. Medical Center Dr., 7316 Cancer Center
Ann Arbor, MI 48109
Telephone:
(734) 936-0091
Emergency Contact:
(734) 936-4000 (Hospital Operator - 24-hour paging)
You may also express a concern about a study by contacting the Institutional Review Board listed below.
University of Michigan Medical School Institutional Review Board (IRBMED)
2800 Plymouth Road
Building 520, Room 3214
Ann Arbor, MI 48109-2800
Telephone: 734-763-4768  (For International Studies:  US Country Code: 001)
Fax: 734-763-1234
e-mail: irbmed@umich.edu 
If you are concerned about a possible violation of your privacy or concerned about a study you may contact the 
University of Michigan Health System Compliance Help Line at 1-866-990-0111.
When you call or write about a concern, please provide as much information as possible, including the name of the 
researcher, the IRBMED number (at the top of this form), and details about the problem.  This will help University 
officials to look into your concern.  When reporting a concern, you do not have to give your name unless you want 
to.
11.  RECORD OF INFORMATION PROVIDED
11.1 What documents will be given to me?
Your signature in the next section means that you have received copies of all of the following documents:

This "Consent to be Part of a Research Study" document.  (Note: In addition to the copy you receive, 
copies of this document will be stored in a separate confidential research file and may be entered into your 
regular University of Michigan medical record.)

Other (specify):


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Study Calendar
Cycle 1
Cycle 2
Cycle 3
Subsequent 
Cycles
Assessment
Screening
Day 
1
Day 
8
Day 1
Day 
8
Day 
1
Day 8
Day 
1
Day 
8
EOT
Follow-up 
(every 12 
weeks for 24 
months) 4
Informed Consent
X
Tumor tissue specimen  
identified from a previous 
biopsy
X
Medical history, physical 
exam, medication history, 
weight, and vital signs
X
X
X
X
X
X
Performance Status
X
X
X
X
X
X
Quality of Life 
questionnaire
X
X
X
X
X
Toxicity Evaluation
X
X
X
X
X
X
Pregnancy test (blood or 
urine test)
X
Blood for HIV and 
hepatitis tests
X
Blood to check your blood 
counts and blood 
chemistry 1
X
X
X
X
X
X
X
X
X
X
Blood collected to check 
your organ function
X
X
X 2
X
Blood collected to bank 
for future research
X
Tumor response 
assessment 3
X
X
X 3
X
Optional – Tumor Biopsy
X
Pembrolizumab 
Administration
X
X
X
X
Abraxane Administration
X
X
X
X
X
X
X
X
Cycles are 21 days long.  EOT = end of investigational study treatment
1 Blood tests may be performed on Day 15 of any cycle at the discretion of the study doctor.
2 Performed every 42 calendar days.
3 Tumor assessments will be performed every 2 cycles (i.e., every 6 weeks) for the first 4 assessments after 
baseline, and then every 3 cycles (i.e., every 9 weeks).  Assessments include:  CT scans of the chest; CT or MRI 
of the abdomen/pelvis; and CT or MRI of the brain if indicated.  
4 Follow-up via phone call or clinic visit.


Study ID: HUM00135166   IRB: IRBMED   Date Approved: 2/19/2021   Expiration Date: 9/10/2021
Page 23 of 25
Consent Subtitle:  UMCC 2017.077
Consent Version: ICF v. 11.17.2020
12.  SIGNATURES
Consent/Assent to Participate in the Research Study
I understand the information printed on this form.  I have discussed this study, its risks and potential benefits, 
and my other choices with _________________________________________.  My questions so far have been 
answered.  I understand that if I have more questions or concerns about the study or my participation as a 
research subject, I may contact one of the people listed in Section 10 (above).  I understand that I will receive a 
copy of this form at the time I sign it and later upon request.  I understand that if my ability to consent or 
assent for myself changes, either I or my legal representative may be asked to re-consent prior to my 
continued participation in this study.
Legal Name: ________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
Consent/Assent for an Optional Tumor Biopsy at Disease Progression:
This project involves an optional tumor biopsy at the time of disease progression.  I understand that it is my 
choice whether or not to have the optional tumor biopsy.  I understand that if my ability to consent or assent 
for myself changes, either I or my legal representative may be asked to re-consent prior to my continued 
participation in this study.
_____ Yes, I agree to allow the collection of a tumor biopsy at disease progression.
_____ No, I do not agree to allow the collection of a tumor biopsy at disease progression.
Legal Name: ________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________


Study ID: HUM00135166   IRB: IRBMED   Date Approved: 2/19/2021   Expiration Date: 9/10/2021
Page 24 of 25
Consent Subtitle:  UMCC 2017.077
Consent Version: ICF v. 11.17.2020
Consent/Assent for Optional Photographs
I understand that the study team may want to take photographs to document and monitor any skin lesions, or 
cancer visible on my skin.  Every attempt will be made to avoid taking a full face photograph.  There is a risk 
that a photograph may not protect my identity.  You can take part in this study even if you decide not to let us 
take photographs.
_____ Yes, I agree to allow photographs to document and monitor any skin lesions.
_____ No, I do not agree to allow photographs to document and monitor any skin lesions.
Legal Name: ________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
Consent/Assent for Samples to be Stored for Future Research
I understand that by participating in this study, some of my blood and tissue samples, and medical information 
will be stored for future research.  I understand that my samples and information will be stored at the 
University of Michigan indefinitely or until they are used up.  I understand that I can withdraw my consent at 
any time and ask that the specimens be destroyed.  However, any specimens and information that have 
already been analyzed cannot be removed from the research.
Legal Name: ________________________________________________________________________
Title: ______________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________


Study ID: HUM00135166   IRB: IRBMED   Date Approved: 2/19/2021   Expiration Date: 9/10/2021
Page 25 of 25
Consent Subtitle:  UMCC 2017.077
Consent Version: ICF v. 11.17.2020
Principal Investigator or Designee
I have provided this participant and/or his/her legally authorized representative(s) with information about this 
study that I believe to be accurate and complete.  The participant and/or his/her legally authorized 
representative(s) indicated that he or she understands the nature of the study, including risks and benefits of 
participating.
Legal Name: ________________________________________________________________________
Title: ______________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________


Study ID: HUM00135166   IRB: IRBMED   Date Approved: 2/19/2021   Expiration Date: 9/10/2021
UMCC 2017.077
PERSONAL CENSUS FORM
Name _______________________________________________
Date ____________________
The National Cancer Institute requires that The University of Michigan Comprehensive Cancer Center 
report race and ethnicity information about people who participate in clinical research to ensure that all 
populations are offered the opportunity to participate. 
 Check here if you do not wish to provide some or all of the information below.
1. What race do you consider yourself to be?

American Indian/Alaska Nativea
(Please select one or more)

Asianb

Black or African Americanc

Native Hawaiian or Other
Pacific Islanderd

Whitee

More than one racef
2. Do you consider yourself to be Hispanicg?           Yes                 No
________________________________________________________________________
a American Indian or Alaska Native- A person having origins in any of the original peoples of North, Central, or South America, 
and who maintains tribal affiliation or community attachment.
b Asian- A person having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian subcontinent, 
including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand and 
Vietnam.
c Black or African American- A person having origins in any of the black racial groups of Africa.  (Terms such as “Haitian” or 
“Negro” are sometimes used in addition to “Black” or “African American.”)
d Native Hawaiian or Other Pacific Islander- A person having origins in any of the original peoples of Hawaii, Guam, Samoa, or 
other Pacific Islands.
e White- A person having origins in any of the original peoples of Europe, the Middle East, or North Africa.
f More than one race- (It is preferred that this be selected in addition to the selection of the specific races listed above, but 
this may also be solely selected.)
g Hispanic or Latino- A person of Mexican, Puerto Rican, Cuban, Central or South American, or other Spanish culture or origin, 
regardless of race.  The term “Spanish origin” is sometimes used in addition to “Hispanic” or “Latino.”