Conditions: Lung Cancer Untreated Stage IV or Recurrent Squamous Cell Lung Cancers
Keywords: Albumin-Bound Paclitaxel Gemcitabine 15-054
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 40
Healthy volunteers: no

Brief summary:
The purpose of this study is to test the safety and effectiveness of albumin-bound paclitaxel plus gemcitabine in patients with advanced squamous cell lung cancers. The investigators would like to determine the percentage of patients with squamous cell lung cancers who experience shrinkage of their tumors following treatment with this regimen. This combination of drugs is not a standard therapy for patients with squamous cell lung cancers. However, each of these drugs, when given alone or with other chemotherapies, is FDA-approved for the treatment of this disease.

Detailed description:

Arms:
arm 1: During each 21-day cycle, albumin-bound paclitaxel at 100mg/mg2 over 120 minutes and gemcitabine at 1000mg/m2 over 30 minutes will be given intravenously on days 1 and 8 of each 21 day cycle. Treatment will continue until disease progression or intolerable side effects. After the 4th cycle of treatment, patients will have the option of discontinuing gemcitabine and proceeding with weekly albumin-bound paclitaxel as maintenance therapy.

Interventions: intervention 1: albumin-bound paclitaxel intervention 2: gemcitabine
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
 
A Phase II Trial of Albumin-Bound Paclitaxe l and Ge mcitabine in Patie nts with Untre ate d 
Stage IV Squamous Ce ll Lung Cance rs 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator/Department: 
Paul K. Paik, MD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Kenneth N g, MD 
Medicine 
Investigator(s)/Department: 
Piro Lito, MD, P hD 
Mark G. Kris, MD 
Gregory J. Riely, MD, P hD 
Helena Yu, MD 
Alexander Drilon, MD 
Jamie C haft, MD 
Marjorie G. Zauderer, MD 
Matthew Hellmann, MD 
Charles Rudin, MD, P hD 
Stephen Veach, MD 
Robert Daly, MD 
Bob Li, MD 
Victoria Lai, MD 
Kathryn Arbour, ND 
Michael O ffin, MD 
Michelle S. Ginsberg, MD 
Andrew J. P lodkowski, MD 
Leslie Tyson, RN, NP 
Linda Ahn, NP 
Elizabeth Panora, NP 
Alison Massey, NP 
Michelle Lyn, NP 
Christina Larsen, NP 
Diana Velez, NP 
Afsheen Iqbal, MD 
Sree B, C halasani, MD 
Han Xiao, MD 
Leticia S mith, APN 
Janet Cogswell, C RN 
Jahan Aghalar, MD 
Juliana Eng, MD 
Avni Desai, MD 
John F iore, MD 
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Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
Stuart Lichtman, MD 
Jia Li, MD 
Wanqing Iris Zhi, MD P hD 
Arlyn Apollo, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Kenneth N g, MD 
Tiffany Troso-Sandoval, MD 
Erin Scansarole, CRN 
Daniel McFarland, DO 
Parisa Momtaz, MD 
Alice Zervoudakis, MD 
Gloria Wasilewski, CRN 
Jason Konner, MD 
Serena Wong, MD 
Loren Michel, MD 
Azadeh Namakydoust, MD 
Colette Owens, MD 
Jacqueline Bromberg, MD P hD 
Marina S hcherba, DO 
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Consenting Professional(s)/Department: Paul K. Paik, MD 
Mark G. Kris, MD 
Gregory J. Riely, MD, P h.D. 
Helena Yu, MD 
Alexander Drilon, MD 
Jamie C haft, MD 
Marjorie G. Zauderer, MD 
Matthew Hellmann, MD 
Charles Rudin, MD, P hD 
Stephen Veach, MD 
Robert Daly, MD 
Bob Li, MD Victoria 
Lai, MD Kathryn 
Arbour, ND Michael 
O ffin, MD 
Afsheen Iqbal, MD 
Sree B, C halasani, MD 
Han Xiao, MD 
Jahan Aghalar, MD 
Juliana Eng, MD 
Avni Desai, MD 
John F iore, MD 
Stuart Lichtman, MD 
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Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
Jia Li, MD 
Wanqing Iris Zhi, MD P hD 
 
Arlyn Apollo, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Kenneth N g, MD 
Tiffany Troso-Sandoval, MD 
 
Daniel McFarland, DO 
Parisa Momtaz, MD 
Alice Zervoudakis, MD 
 
Jason Konner, MD 
Serena Wong, MD 
Azadeh Namakydoust, MD 
Colette Owens, MD 
Loren Michel, MD 
Jacqueline Bromberg, MD P hD 
Marina S hcherba, DO 
Medicine 
Medicine 
 
Medicine 
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Ple ase Note: A Consenting Professional must have completed the mandatory Human 
Subje cts Education and Ce rtification Program. 
 
 
 
 
OneMSK Sites 
Manhattan 
Basking Ridge 
Commack 
Monmouth 
Rockville Centre 
Westchester 
 
 
 
Bapsti st Alliance MCI Clinical Trials 
Sites 
PI's Name 
Site's Role 
Miami Cancer Institute 
Miguel Villalona-Calero, MD 
Data Collection 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA............................................................................ 5 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ..................................................................................... 7 
 
3.0 
BACKGROUND AND RATIONALE ........................................................................................... 7 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................ 11 
 
4.1 
Design................................................................................................................................ 11 
4.2 
Intervention ........................................................................................................................12 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS................................................................................. 12 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY................................................................................. 14 
 
6.1 
Subject Inclusion Criteria ...................................................................................................14 
6.2 
Subject Exclusion Criteria..................................................................................................15 
7.0 
RECRUITMENT PLAN ............................................................................................................. 15 
 
8.0 
PRETREATMENT EVALU ATION ............................................................................................ 15 
 
9.0 
TREATMENT/INTERVENTION  PLAN ..................................................................................... 16 
 
10.0 EVALU ATION DURING TREATMENT/INTERVENTION........................................................ 16 
 
11.0 TOXICITIES/SIDE EFFECTS ................................................................................................... 18 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT .......................... 24 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ............................................................................ 26 
 
14.0 BIOSTATISTICS ....................................................................................................................... 27 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ... 28 
 
15.1 Research Participant Registration .....................................................................................28 
15.2 Randomization...................................................................................................................28 
16.0 DAT A M AN AGEMENT ISSUES............................................................................................... 28 
 
16.1 Quality Assurance..............................................................................................................29 
16.2 Data and Safety Monitoring ............................................................................................... 29 
17.0 PROTECTION OF HUMAN SUBJECTS.................................................................................. 29 
 
17.1 Privacy ............................................................................................................................... 30 
17.2 Serious Adverse Event (SAE) Reporting ..........................................................................31 
Pregnancies ..................................................................................................................................... 33 
 
18.0 INFORMED CONSENT PROCEDURES.................................................................................. 34 
 
19.0 REFERENCES .......................................................................................................................... 34 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Study Title : 
A Phase II Trial of Albumin- Bound Paclitaxel and Gemcitabine in 
Patients with Untreated  S tage IV or Recurrent Squamous Cell Lung 
Cancers 
Study Obje ctives: 
Prima ry Obje ctive : To determine the  best objective response (partial 
response and complete response at any time) of albumin-bound paclitaxel 
and gemcitabine in patients with untreated stage IV or recurrent 
squamous cell lung cancers 
Se conda ry Obje ctive s: 
• 
To evaluate the safety and tolerability of the combination of 
albumin bound paclitaxel and gemcitabine in this population 
• 
To estimate 1 year, 2 year, and median PFS and OS 
• 
To correlate genotype with response to therapy 
Patie nt population: 
Untreated stage IV or recurrent squamo us cell lung cancer 
Numbe r of 
patie nts: 
17-41 patients 
Inclusion Crite ria: 
All patients must have: 
1.   Histologically confirmed squamous cell lung cancer 
2.   Newly diagnosed untreated Stage IV and/or recurrent after adjuvant 
therapy with metastatic disease 
3.   Patients previous ly treated with immune checkpoint inhibitor therapy 
are eligible. 
4.   Measurable disease as per RECIS T 1.1 
5.   Greater than 6 months since receiving neo-adjuvant or adjuvant 
chemotherapy. 
6.   Age ≥  18 years 
7.   Eastern Cooperative O ncology Group (ECOG) performance 
status of 0-1 
8.   Women of childbearing potential and sexually active men 
enrolled in the study must agree to practice effective 
contraception  method during treatment and for three months 
after completing treatment 
9.   Negative serum or urine β- hCG pregnancy test at screening for 
patients of childbearing potential 
10. < Grade 2 pre-existing peripheral neuropathy (per C TCAE) 
11. Marrow and organ function as follows: 
a.   ANC ≥  1500 cells/mm3 
b.   Platelets >  100,000 cells/mm3 
c.   Hemoglobin>9g/dL 
d.   Creatinine clearance ≥ 40mL/min 
e.   Bilirubin ≤  1.5 mg/dL 
f. AST/ALT≤2.5 x upper limit of normal range (ULN), 
alkaline phosphatase ≤ 2.5 X upper limit of normal, 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
unless bone metastasis in present in the absence of liver 
metastasis 
Exclusion Crite ria: 
Patients are to be excluded from the study if they meet any of the 
following criteria: 
1. Prior treatment with albumin-bound paclitaxel or gemcitabine 
2. Prior systemic anticancer therapy for metastatic squamous cell 
lung cancer 
3. Untreated brain metastasis. Patients with treated brain metastases who 
are off steroids are eligible 
4. Peripheral neuropathy greater than grade 1 
5. Malignancies within the past 5 years other than non- melanoma 
skin cancer or insitu cervical cancer status post treatment 
6. Patients with other serious medical illnesses including, ongoing or 
active infection, unstable angina pectoris, or psychiatric 
illness/social situations that would limit compliance with study 
requirements 
7. Class III or IV congestive heart failure by New York Heart 
Association 
Study D rug: 
Albumin-bound paclitaxel and gemcitabine 
Study De sign: 
This protocol is a phase II, single institution study of albumin-bound 
paclitaxel and gemcitabine in patients with stage IV or recurrent 
squamous cell lung cancer who have not rece ived prior therapy. 
The study incoporates a S imon-two stage design. The null and desired 
response rate are selected as 25% and 45%. In stage 1, 17 patients will 
enter the study. If there are fewer than 6 responses, the study will be 
terminated early. If 6 or more patients respond, enrollment will be 
extended to 41 patients. At the end of the study, if 15 or more of the 41 
evaluable patients responds, the treatment regimen will be declared 
worthy of further testing. 
Patients will be treated as follows: albumin-bound paclitaxel 100mg/m2 
and gemcitabine 1000mg/m2 on days 1 and 8. Each cycle consists of 21 
days.  Treatment will continue until disease progression or intolerable 
side effects.  After the 4th cycle of therapy, patients will ha ve the option of 
stopping gemcitabine and proceeding with weekly albumin-bound 
paclitaxel as maintenance therapy. 
Toxicity will be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), 
version 4.0. Response to therapy will be assessed by interval imaging 
with C T scan of the chest after every 2 cycles with response evaluated per 
RECIS T 1.1. 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
Corre lative Studie s Molecular testing through the Integrated Mutation P rofiling of Actionable 
Cancer Targets (IMP ACT) will be performed at the time of diagnosis or 
when tissue is available in order to characterize tumor genotype and 
explore its correlation with response to treatment. These include 
assessment of FGFR1 amplification status, PI3K axis aberrations 
(PIK3CA mutations, PTEN mutations, and P TEN loss), DDR2 mutations, 
and exon-capture/next generation sequencing for somatic variations and 
copy number changes in 279 oncogenes and tumor suppressors. 
 
 
 
 
2.0     OBJECTIVES AND SCIENTIFIC AIMS 
 
Hypo the sis:  Albumin-bound  paclitaxel  will  potentiate  gemcitabine  activity  and  will  lead  to  a 
synergistic increase in response rate and progression free survival. 
 
Prima ry Obje ctive : To determine the best objective response (complete response + partial response 
at any time before progression, by RECIS T) of the combination of albumin-bound paclitaxel and 
gemcitabine in patie nts with stage IV or recurrent squamous cell lung cancer 
 
Se conda ry Obje ctive s: 
• To evaluate the safety and tolerability of the combination of albumin-bound paclitaxel and 
gemcitabine in patients with Stage IV squamous cell lung cancers 
• To estimate 1 year, 2 year, and median PFS and OS 
• To explore the correlation between tumor genotype and response 
 
3.0     BACKGROUND AND RATIONALE 
 
3.1 SQUAMOUS CELL LUNG CANCER (SQCLC) 
 
Unme t The rape utic Ne eds 
 
Non-small cell lung cancer remains the leading cause of cancer related  mortality in the US and 
worldwide. Squamous cell lung cancer accounts for approximately 25% of all non-small cell lung 
cancer cases. In the United States, 55,000 patients are diagnosed with squamous cell lung cancer per 
year, with approximately half of these patients  harboring metastatic disease at diagnosis. Patients 
with advanced squamous cell lung cancers generally have a poor prognosis with a median survival of 
12  months.  F urthermore,  these  patients  have  fewer  therapeutic  options  than  those  with  other 
histologies. Pemetrexed, which has greater efficacy in non-squamous NSCLC, is not FDA approved 
for patients with squamous cell lung cancers.1 Because of rare cases of life threatening hemoptysis in 
early phase clinical trials, bevacizumab is similarly not F DA approved for patients with squamous 
cell lung cancers. Most pressing of all is the current absence of druggable molecular targets in 
squamous cell lung cancers. For instance, activating mutations in EGFR that render lung tumors 
sensitive to erlotinib and afatinib and ALK rearrangements that sensitize to treatment with crizotinib 
do  not occur  in  SQCLCs.2   Taken together,  there  remains a  high  unmet  medical need  for  new 
treatment for squamous cell lung cancer. 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
Curre nt First Line Tre atme nt fo r S qua mo us Ce ll Lung Ca nce r 
 
Platinum based doublet chemotherapy with a third generation therapeutic,  most commonly with a 
taxane or gemcitabine, remains the first line treatment for patients with newly diagnosed Stage IV 
squamous cell lung cancers. These therapies have similar response rates and median overall survivals. 
Unfortunately, a large portion of the population cannot tolerate platinum based therapies based on 
poor  performance  status  and/or  history  of  baseline  hearing  loss,  renal  insufficiency,  or  other 
comorbid medical conditions such as diabetes and heart failure which precludes them from platinum- 
based therapy. Although carboplatin is often substituted for cisplatin, it is associated with increased 
myelosuppression. Development of an effective non-platinum containing chemotherapy regimen with 
improved  response rates are desperately  needed  for patients  with advanced  squamous cell  lung 
cancer.  Beyond  toxicity  concerns,   no  first-line  regimen  has  surmounted  the  modest  activity 
associated with first-line platinum doublet chemotherapy, which has an overall response rate of only 
35% and a median PFS of just 4-6 months.  Within this context, existing data suggest that there are 
chemotherapy agents that exhibit greater efficacy against squamous cell lung cancer tumors as 
compared to other histologies.  C hief among these is albumin-bound paclitaxel and gemcitabine. 
 
3.2 ALBUM IN-BOUND PACLITAXEL 
 
Pre clinica l Studie s : 
 
Albumin  bound  paclitaxel was  initially  developed  to  avoid  toxicities  associated  with  oil-based 
solvents required to solubilize paclitaxel, such as cremophor EL. Albumin-bound paclitaxel combines 
non- modified  human serum albumin and  paclitaxel in  a 130nm particle  formulation.  Preclinical 
studies  suggest  that  albumin-bound  paclitaxel  may  reach  the  tumor  micro-environment  more 
efficiently than solvent based-paclitaxel and  may be preferentially taken up by cancer cells. 3  It is 
believed that this process occurs via an albumin specific receptor mediated transport process in which 
albumin binds to  gp60  on the endothelial cell wall.3   This activates caveolin 1  and  leads to  the 
formation of caveolae which allow for the transport of the albumin-bound chemotherapeutic complex 
to the underlying tumor interstitium. SPARC (secreted protein acidic and rich in cysteine) is a 
matricellular protein up-regulated in several cancers, which binds and entraps albumin, allowing 
release of the hydrophobic drug to the tumor.4 Therefore, albumin-bound paclitaxel exploits this gp- 
60/caveolin-1/caveolae/SPARC pathway to increase intra-tumoral concentration of the drug and 
reduce toxic drug in normal tissue. 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2.1 Mechanis ms for the trans port and accumulation of 
albumin-bound paclita xe l in tu mo rs . 
Des ai, Neil et a l. Trans Oncol. 2009 May; 2(2):59 -64. 
 
Clinical S tudie s : 
 
The efficacy and safety of albumin-bound paclitaxel has been tested in several clinical trials in non- 
small cell lung cancer. In one phase II study, albumin-bound paclitaxel was administered to forty- 
three  patients   with   untreated   non-small  cell   lung   cancer   without   steroid   or  antihistamine 
premedication at a dose of 260mg/m2  every three weeks.5  A median of six cycles were administered 
and 95% of patients were treated without a dose reduction.  No severe hypersensitivity reactions were 
reported. The overall response rate was 16% and median survival was 11 months. 
 
In our P hase I/II study, led and reported by Dr. Naiyer Rizvi (IRB protocol #03-111), patients were 
treated with a lbumin-bound paclitaxel on days 1, 8 and 15 of a 28 day cycle.6    During the P hase I 
portion, 100 mg/m2 was determined to be the maximum tolerated dose.  The obje ctive re sponse rate  
was 30% in this untre ate d population,  with a  me dian ove rall survival of 11  months. This is 
comparable to the efficacy of platinum doublet therapy in the first- line setting.  It was determined that 
an infusion rate of two hours as compared to 30 minutes caused less peripheral neuropat hy.7  The 
median number of cycles administered wa s four (range, 1 to 14).  No hypersensitivity reactions were 
observed.  Notably, 58% were aged ≥ 70, accurately reflecting the percent of elderly patients in the 
United States with this illness. 
 
A randomized phase III trial of carboplatin plus albumin-bound paclitaxel versus carboplatin plus 
paclitaxel in untreated stage IV SQCLC patients was associated with a near doubling of the overall 
response  rate  from  24%  to  41%  (p<0.001)  in  patients  with  squamous  versus  non-squamous 
histology.8  Furthermore, although the median cumulative taxane dose and average dose intensity 
were higher for albumin-bound paclitaxel, in general albumin-bound paclitaxel was better tolerated, 
with lower rates of grade 3 and 4 neuropathy, neutropenia, arthralgia, and myalgia. 
 
The PK of nab-paclitaxel in pediatric patients with solid tumors was examined from the ABI-007- 
PST-001 study. After a single 30- minute IV infusion of nab-paclitaxel, dose-normalized peak drug 
exposure values (C max) were comparable across the dose range studied; ho wever, dose-normalized 
total drug exposure values (AUC) were only comparable across 120 to 240 mg/m2 with lower dose- 
normalized AUC24 and AUC ∞ at the 270 mg/m2 dose level. These results suggest a less than dose 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
proportional increased extent of exposure at the highest dose level tested in pediatrics. Mean whole 
blood CL and volume of distribution at the steady state (Vss) increased from the younger to the older 
pediatric age groups. In summary, PK in pediatrics is consistent with saturable elimination at higher 
doses, as well as the deep distribution of paclitaxel that was previously observed in adult patients 
with advanced or metastatic solid tumors. 
 
3.3 GEM CITABINE 
 
Gemcitabine is an active therapy in squamous cell lung cancer.   In a phase III trial of first line 
therapy in NSCLC randomizing patients to cisplatin plus either gemcitabine or pemetrexed , cisplatin 
plus gemcitabine was associated with a significantly higher median OS compared to cisplatin plus 
pemetrexed in patients with squamous cell lung cancer (10.8 v 9.4 months, respectively).1  It is 
hypothesized that the short half life of gemcitabine may be a barrier to its antitumor activity in vivo. 
As such, methods that increase gemcitabine delivery or stability have been proposed to circumvent 
this problem, specifically with the addition of albumin-bound paclitaxel. 
 
3.4    RATION ALE    FOR    COM BINING    ALBUM IN -BOUND    PACLITAXEL    WITH 
GEM CITABINE 
 
Pre clinica l studie s: 
 
There is compelling evidence that antitumor synergy exists between gemcitabine and albumin-bound 
paclitaxel. F rese et al. showed that albumin-bound paclitaxel downregulates cytidine deaminase, the 
primary enzyme that metabolically inactivates gemcitabine, leading to an increase in gemcitabine 
concentration in a mouse model of pancreatic adenocarcinoma.9 These data are consistent with mouse 
xenografts of pancreatic adenocarcinoma where the intra-tumoral gemcitabine concentration was 2.8 
times higher when alb umin bound paclitaxel was given concurrently. 
 
Clinical studie s: 
 
Based on these data, a series of clinical trials assessing the safety and efficacy of albumin-bound 
paclitaxel plus gemcitabine were performed.   A phase I/II trial of albumin-bound  paclitaxel and 
gemcitabine in patients with previously untreated advanced pancreatic cancer showed that the 
maximum  tolerated  dose  was  1,000mg/m2   of  gemcitabine  plus  125mg/m2   of  albumin-bound 
paclitaxel given once weekly for 3 weeks every 28 days with a response rate of 48%.10 A randomized 
phase III trial of albumin bound paclitaxel plus gemcitabine versus gemcitabine alone in patients with 
untreated pancreatic adenocarcinomas saw a tripling of the ORR from 7% to 23%  in favor of the 
combination, and a marked increase in progression free survival and overall survival (HR 0.69, 
p<0.001 and  HR 0.72, p<0.001 respectively).11     This study quickly  led to  the F DA approval of 
albumin-bound paclitaxel plus gemcitabine as first- line therapy in patients with untreated stage IV 
pancreatic cancer in late 2013. 
 
In non-small cell lung cancer, several phase II trials of weekly paclitaxel plus gemcitabine as first line 
treatment showed that this drug combination is an active and well tolerated regimen for the treatment 
of advanced NSCLC, with an overall response rate of 23%-55%, median survival of 4.9-11.9 months 
and 1 year survival rate of 26-53%.12-19 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
 
 
 
 
 
 
 
Firs t author (ref.) No. of 
patients 
Regimen and s chedule 
Res pons e rate 
(% ) 
S urvi val 
me di an 
One-year 
(% ) 
Be lani et a l. [12] 
50 
Arm 
A 
2 
P 200 mg/ m  day 1 q 3w 
28.2 
7.5 
34 
G 1 g/ m2 days 1, 8 q3w 
50 
Arm 
B 
2 
P 100 mg/ m  days 1, 8 q 3w 
26.8 
9.6 
42 
G 1 g/ m2 days 1, 8 q3w 
Bhatia et a l. [ 13] 
39 
2 
P 110 mg/ m  days 1, 8, 15 q 4w 
38.2 
4.9 
26 
G 1 g/ m2 days 1, 8, 15 q4w 
De Pas et al. [14] 
54 
P 100 mg/ m2 days 1, 8, 15, 22 q 
4w 
46 
9.6 
53 
G 1 g/ m2 days 1, 8, 15, 22 q4w 
Akerley et a l. [15] 39 
P 85 mg/ m2 days 1, 8, 15, 22, 
29, 36 q 8w 
23.1 
7.5 
32 
G 1 g/ m2 days 1, 8, 15, 22, 29, 
36 q8w 
Gillenwater et a l. 
[16] 
39 
P 100 mg/ m2 days 1, 8, 15, 21 q 
4w 
35 
4.9 
35 
G 1 g/ m2 days 1, 8, 15, 21 q4w 
Kos midis et al. 
[17] 
225 
P 200 mg/ m2 day 1 q 3w 
31 
9.3 
42 
G 1 g/ m2 days 1, 8, q3w 
Treat et al. [18] 
312 
P 200 mg/ m2 day 1 q 3w 
43.6 
8.4 
33 
G 1 g/ m2 days 1, 8, q3w 
Mori, et a l. [19] 
40 
P 100 mg/ m2 days 1, 8, q 3w 
55 
11.9 
47.5 
G 1 g/ m2 days 1, 8 q3w 
 
3.5 GOAL OF S TUD Y: 
 
In light of the  greater single-agent activities of both albumin-bound paclitaxel and gemcitabine in 
squamous cell lung cancer versus non-squamous NSCLCs, we hypothesize that the same synergistic 
increase  in efficacy  seen  with  albumin-bound  paclitaxel and  gemcitabine  in pancreatic 
adenocarcinoma will also be seen in squamous cell lung cancer, opening a new avenue of therapy to 
those who are, at a minimum, ineligible for treatment with platinum chemotherapy and which, at 
most, may supplant platinum chemotherapy as a new standard of care for these patients. 
 
 
 
4.0    OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
This is an open label, single institution phase II trial of albumin-bound paclitaxel and 
gemcitabine  in patients with untreated stage IV or recurrent squamous cell lung cancer. A 
Simon two-stage design will be applied. The primary endpoint is best objective response. 
 
A maximum of 17 patients will be enrolled in the first stage of the study.  If there are fewer 
than 6 responses, the study will be terminated early.  If 6 or more patients respond, enrollment 
will be extended to 41 patients.  At the end o f stage 2, if 15 or more patients respond, the 
treatment regimen will be declared worthy of further testing. 
 
4.2     Intervention 
 
Patients with stage IV or recurrent squamous cell lung cancer who  have received  no prior 
treatment for metastatic disease will be enrolled in this trial. During each 21-day cycle, 
albumin-bound paclitaxel at 100 mg/mg2  over 120  minutes and  gemcitabine at 1000mg/m2 
over 30 minutes will be given intravenously on days 1 and 8 of each 21 day cycle.   Treatment 
will continue until disease progression or intolerable side effects.   After the 4th  cycle of 
treatment, patients will have the option of discontinuing  gemcitabine and proceeding with 
weekly albumin-bound paclitaxel as maintenance therapy. 
 
Patients will be evaluated before each treatment on day 1 and  8. Safety evaluations will 
consist of medical history, physical examination, vital signs, and blood work during each day 
of treatment. Patients will be evaluated for adverse events (all grades), serious adverse eve nts, 
and adverse events requiring study drug interruption or discontinuation at each study visit for 
the duration of their participation in the study. This treatment regimen will be continued until 
documentation of disease progression, unacceptable toxicity, or patient refusal. 
 
To assess response, patients will have a C T scan of the chest and other sites of disease after 
every 2 cycles. 
 
4.3       Corre lative Studie s 
 
Molecular  testing  through  Dr.  Paik’s  Squamous  Cell  Lung  Cancer  Mutation  Analysis 
Program will be performed at the time of diagnosis or when tissue is available in order to 
molecularly characterize patients for associations with response. These include assessment of 
FGFR1 amplification status, PI3K axis aberrations (PIK3CA mutations, PTEN mutations, and 
PTEN loss), DDR2 mutations, and exon-capture/next generation sequencing for somatic 
variations and copy number changes in 279 oncogenes and tumor suppressors. 
 
5.0     THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1.     Albumin-bound paclitaxel (ABI-007, Abraxane ®): 
 
Albumin-bound paclitaxel is a Cremophor EL- free form of paclitaxel with a mean particle 
size of approximately 130 nanometers.   Each 50-mL single-use vial contains 100 mg of 
paclitaxel, and approximately 900 mg of human albumin.   Albumin-bound paclitaxel is 
supplied as a white to  yellow sterile lyophilized powder for reconstitution with 20 mL of 
0.9% Sodium C hloride Injection USP. 
 
5.1.1.  Dosing and Administration: 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
Albumin-bound paclitaxel will be administered intravenously at 100 mg/m2 on days 1 and 8 of 
a 21-day cycle together with ge mictabine.  After the 4th cycle of therapy, patients will have to 
option to receive albumin-bound paclitaxel alone as maintenance therapy at 100mg/ m2 on 
days 1 and 8 of a 21-day cycle.  The drug will be given over 120 minutes 6, 7.  NOTE: It is not 
a requirement to use filter needles in the preparation of, or in- line filters during the 
administration of albumin-bound paclitaxel.  In any event, filters of pore-size less than 15 
micrometers must not be used. 
 
 
 
5.1.2.  Supply and Packaging: 
 
Albumin-bound paclitaxel will be supplied by Celgene, in single-use vials.  Each single-use 
50 mL vial will contain paclitaxel (100 mg) and approximately 900 mg of human albumin 
(HA) as a stabilizer.  Each vial will be labeled accord ing to regulatory requirements for 
labeling of investigational products.  The study medication will be dispensed by the MSKCC 
pharmacy. 
 
5.1.3.   Storage and S tability: 
 
Unreconstituted albumin-bound paclitaxel should be stored at controlled room temperature 
(20° to 25°C or 68° to 77°F) in its carton and retained in the original package to protect from 
bright light. Unopened vials of albumin-bound paclitaxel are stable until the date indicated on 
the package when stored at the above temperatures in the original package. Reconstituted 
albumin-bound paclitaxel should be used immediately.   If not used immediately, the vial of 
reconstituted albumin-bound  paclitaxel must be  protected  from bright  light,  placed  in  its 
carton and refrigerated at 2° to 8°C (38° to 46°F) for a maximum of 24 hours. Any unused 
portion of the reconstituted suspension should be discarded.  Both forms should be stored in 
an area free of environmental extremes and must be accessible only to study personnel. 
 
5.1.4.   Re constitution and Use of Albumin-bound paclitaxe l 
 
Albumin-bound   paclitaxel  will  be  reconstituted   by  appropriate  study  personnel  and 
administered to the patient in the study site setting per institutional pharmacy guidelines. 
 
 
 
 
5.1.5.   Drug Distribution, Re turn and De struction 
 
Drug Distribution 
 
Albumin-bound paclitaxel will be distributed by Celgene.  No supplies will be shipped until 
regulatory approval has been obtained.  Investigational sites will be supplied with albumin- 
bound paclitaxel upon identification and screening of a potent ial trial subject. 
 
Upon identification of a potential subject, the Drug Request Form must be completed and 
faxed to Celgene.  At least 5 working days should be allowed for drug shipment.  There are no 
shipments on Fridays or holidays. 
 
For re-supply of drug, please complete and fax the Drug Request Form to Celgene 
Corporation at 908-673-2779. 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
Drug Return/Destruction 
 
Partially used and completely used vials should be discarded according to institutional 
guidelines, and their disposition should be recorded on an investigational drug accountability 
form. Drug can be destroyed on site if proper accountability of the destruction is maintained 
(number of vials, expiration date, lot number, etc.) as well as documentation that the drug was 
destroyed according to the institution’s SOP. Celgene will need to obtain copies of the 
destruction and a memo stating what was destroyed (lot number and quantity) as well as a 
copy of the institution’s destruction SOP. 
 
 
The MSKCC pharmacy will keep accountability of the lot and quantity of drug returned. This 
will be reconciled once the study is fully closed. 
 
5.2.      Ge mcitabine (Ge mzar®, Eli Lilly) 
 
Gemcitabine (Gemzar®,  Eli Lilly) is a commercially available medication with a complete 
description of the drug,  its clinical pharmacology, contraindications,  warnings, precautions 
and  adverse reactions available in  the package insert.   Gemcitabine  will be administered 
intravenously at 1000mg/m2  on days 1 and 8 of a 21-day cycle.  The drug will be given per 
standard institutional procedures. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1     Subject Inclusion Criteria 
 
• Histologically confirmed squamous cell lung cancer 
• 
Newly diagnosed untreated Stage IV and/or recurrent after adjuvant therapy 
with metastatic disease 
• 
Patients previous ly treated with immune checkpoint inhibitor therapy are 
eligible 
• Measurable disease as per RECIS T 1.1 
• Greater than 6 months since receiving neo-adjuvant or adjuvant 
chemotherapy. 
• Age ≥  18 years 
• Eastern Cooperative O ncology Group (ECOG) performance status of 0- 
1 
• Women of childbearing potential and sexually active men enrolled in 
the study must agree to practice effective contraception  method during 
treatment and for three months after completing treatment 
• Negative serum or urine β- hCG pregnancy test at screening for patients 
of childbearing potential 
• < Grade 2 pre-existing peripheral neuropathy (per C TCAE) 
• Marrow and organ function as follows: 
ANC ≥  1500 cells/mm3 
Platelets >  100,000 cells/mm3 
Hemoglobin>9g/dL 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
Creatinine clearance ≥ 40mL/min 
Bilirubin ≤  1.5 mg/dL 
AST/ALT≤2.5 x upper limit of normal range (ULN), alkaline 
phosphatase ≤ 2.5 X upper limit of normal, unless bone metastasis in 
present in the absence of liver metastasis 
 
 
 
 
 
6.2 
Subject Exclusion Criteria 
 
• Prior treatment with albumin-bound paclitaxel or gemcitabine 
• Prior systemic anticancer therapy for metastatic squamous cell lung 
cancer 
• 
Untreated brain metastasis. Patients with treated brain metastases who are off 
steroids are eligible 
• Peripheral neuropathy greater than grade 1 
• Malignancies within the past 5 years other than non- melanoma skin 
cancer or insitu cervical cancer status post treatment 
• Patients with other serious medical illnesses including, ongoing or 
active infection, unstable angina pectoris, or psychiatric illness/social 
situations that would limit compliance with study requirements 
• Class III or IV congestive heart failure by New York Heart Association 
 
 
7.0       RECRUITMENT PLAN 
 
All patients recruited will be under the care of attending medical oncologists on the Thoracic 
Oncology Service and Regional Networks at MSKCC.  Patients will be accrued to this study without 
regard for gender or minority status. 
 
8.0     PRETREATMENT EVALUATION 
 
The following te st must be orde re d be fore patie nt e nrollme nt: 
• 
Integrated Mutation Profiling of Actionable Cancer Ta rgets (IMP ACT) 
 
The following te sts must be comple ted within 28 days of patie nt e nrollme nt: 
• 
Complete medical history 
• 
Complete physical examination 
• 
Determination of performance status on the Karnofsky scale 
• 
CT scan of the chest and other relevant disease sites 
• 
MRI brain with gadolinium or CT head with contrast 
 
The following te sts must be comple ted within 14 days of patie nt e nrollme nt: 
• 
CBC with differential 
• 
Comprehensive metabolic panel 
 
The following te st must be comple ted within 7 days of patie nt e nrollme nt: 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
• Women of childbearing potential must have a negative pregnancy test 
 
 
 
 
 
 
 
 
 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
 
 
Patients will be treated with albumin-bound paclitaxel and gemcitabine as follows in an every 21-day 
cycle until disease progression or the decision is made to begin maintenance therapy: 
 
Days 1 and 8 : 
Albumin-bound  paclitaxel  (100  mg/m2   over  120  minutes)  +  Gemcitabine 
(1000 mg/m2 over 30 minutes) 
 
After the 4th cycle of therapy, patients will have the option to begin maintenance therapy in an every 
21-day cycle as follows: 
 
Days 1 and 8 : 
Albumin-bound paclitaxel (100 mg/m2 over 120 minutes) 
 
Dose reductions and omissions will be allowed  for toxicities according to  guidelines specified  in 
Section 11.0. 
 
Alb umin-bo und pac lita xe l p re- med ica tio n 
Patients do not require premedication prior to albumin-bound paclitaxel administration, as 
hypersensitivity reactions are not expected. Initial antiemetic prophylaxis is recommended due to 
administration of gemcitabine following albumin-bound paclitaxel treatment.  If a hypersensitivity 
reaction occurs, the infusion should be stopped and  not restarted. At the investigator’s discretion, 
treatment  may  continue  on  subsequent  cycles  using  the  premedication  regimen  the  institution 
typically uses for Taxo l if felt to be in the patient’s best interest. 
 
Ge mc itab ine pre- med icatio n 
Initial antiemetic prophylaxis is recommended with dexamethasone 8 IV prior to administration of 
gemcitabine.  If  a  patient  experiences  nausea  and/  or  vomiting  following  the  first  dose,  the n 
institutional guidelines should be followed for breakthrough antiemetic management. 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
Patients enrolled in this study will require an office visit prior to each dose of chemotherapy.  They 
will be evaluated clinically and with standard laboratory tests on days 1 and 8 of each 21-day cycle. 
Safety evaluations will consist of medical interviews, recording of adverse events, physical 
examinations, and laboratory measurements during each day of treatment (see Table 10.1). 
 
Patients will be evaluated for adverse events (all grades), serious adverse events, and adverse events 
requiring study drug interruption or discontinuation at each study visit for the duration of their 
participation in the study. 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
 
A CBC and co mprehensive metabolic panel will be drawn and checked at each visit with dose 
adjustments made according to Section 11.0 of the protocol.  Tests should be performed within 7 
days prior to dosing. The results of the comprehensive metabolic panel must be reviewed prior to 
chemotherapy administration, and appropriate dose adjustments made according to Section 11.0 of 
the protocol 
 
 
 
To assess response, patients will have a CT scan of the chest and other clinically relevant sites after 
every 2 cycles. 
 
Table 10.1  Study Flow Chart 
Cycle 1 
Cycle 2+ 
Mainte nance 
the rapy 
End of 
Study 
Assessment 
Base line Day 
1 
Day 
8 
We e k 
3 
Day 
1 
Day 
8 
We e k 
3 
Day 
1 
Day 
8 
Within 30 
days of 
last 
tre atme nt 
Medical 
History 
Xc 
X 
X 
X 
X 
X 
X 
X 
Physical 
Exam 
Xc 
X 
X 
X 
X 
X 
X 
X 
Performance 
status 
Xc 
X 
X 
X 
X 
X 
X 
X 
CBCa 
Xd 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
X 
CMPb 
Xd 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
X 
Pregnancy 
test for 
women of 
childbearing 
potential 
Xe 
CT chest and 
other 
relevant 
disease sites 
Xc 
Xg 
Xg 
Brain MRI 
gadolinium 
or CT 
contrast 
Xc 
Integrated 
Mutation 
Profiling of 
Actionable 
Cancer 
Targets 
(IMPAC T) 
Xh 
Tre atme nt: 
Albumin 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
bound 
paclitaxel 
 
Gemcitabine 
Xi 
Xi 
Xi 
Xi 
 
 
 
 
 
a Comp lete blood count, with platelet count and differentia l. 
b Co mprehens ive metabolic panel. 
c Within 28 days prior to s tarting treatment. 
d Within 14 days prior to s tarting treatment. 
e Pregnancy tes ting is mandatory for all wo men of childbearing potential.  Mus t be done within 7 days prior to s tarting 
treat ment. 
f May be obtained within 7 days if s ame-day blood work not available. 
g CT s can of ches t and other relevant dis ease s ites wil l be performed during week 3 a fter every 2 cycles . (+/- 7 day 
window) 
hMolecular tes ting through MSK-IMPA CT will be performed prior to s tudy initiation 
i There mus t be at leas t 7 days inbetween treatments . The treatment window is (+/- 7 days ) 
 
11.0   TOXICITIES/SIDE EFFECTS 
 
Toxicity grading will be performed in accordance with NCI CTCAE, version 4.0. 
 
11.1     Known Pote ntial S ide Effe cts 
 
Albumin-bound paclitaxel (Abraxane® ) 
 
Albumin-bound paclitaxel is not formulated in cremophor and thus the risk of hypersensitivity 
reactions is much less than that of Taxol.   The major risks of albumin-bound paclitaxel have been 
assessed in clinical trials in patients with a variety of malignances. The most common toxicities 
reported following albumin-bound paclitaxel administration are: 
• 
Hematologic :  Grade 4 neutropenia was reported and typically resolved in <7 
days and did  not require colony stimulating  factor support. Anemia,  febrile 
neutropenia,  leukopenia,  lymphopenia,  pancytopenia  and  thrombocytopenia 
were common occurrences. Thrombotic thrombocytopenic purpura occurred 
infrequently. 
• 
Nervous S ystem Disorders :  Grade 3 peripheral neuropathy  was  reported and 
typically improved to Grade 1 or 2 within 21 days of  interrupting the albumin- 
bound paclitaxel dose.   Following resolution of the peripheral neuropathy to 
acceptable  levels,  clinicians  were  able  to  restart  albumin-bound  paclitaxel 
dosing at a lower dose level. Ataxia, dizziness, dysgeusia and headache were 
commonly observed occurrences. Facial paralysis was an uncommon 
occurrence. 
• 
Gastrointestinal: 
Nausea, 
vomiting, 
mucositis, 
anorexia, 
weight 
loss, 
constipation, hepatotoxicity, and diarrhea were seen, typically at Grade 1 or 2 
levels.   This AE responded well to standard anti -emetic regimens. Mucositis 
was reported typically Grade 1 or 2.  It was not dose- limiting. Abdominal pain, 
Colitis, dry mouth, dyspepsia, dysphagia, intestinal obstruct ion and stomatitis 
were also common occurrences. 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
• 
Musculoskeletal and Connective Tissue Disorders :   Myalgia, arthralgia, and 
fluid overload were reported and typically were Grade 1 or 2; these were 
responsive to standard acetaminophen-containing medication. Muscular pain 
and weakness were commonly observed occurrences. 
• 
Alopecia: Alopecia was reported by  most patients and was similar to that seen 
with Taxol. 
• 
Infection: Albumin bound paclitaxel contains albumin  derived  from human 
blood,  which has a theoretical risk of viral transmission.  Lower respiratory 
tract   infection   including   bronchitis,   candida   infection,   folliculitis,   nail 
infection, pneumonia, sepsis, upper respiratory tract infection, and urinary tract 
infection were common occurrences. Injection site infection and neutropenic 
sepsis were infrequent occurrences. 
• 
Fetal harm:  fetal harm may occur when administered  to  pregnant women. 
Women of childbearing potential need to avoid becoming pregnant while on 
study. Men should be advised to not father a c hild while on study. 
• 
Respiratory, Thoracic and Mediastinal Disorders : Cough, dyspnea, epistaxis, 
hemoptysis,  nasal  congestion,  oropharyngeal  pain,  pleural  effusion, 
pneumonitis and pulmonary embolism were commonly observed occurrences. 
Dry throat and nasal dryness were uncommonly observed occurrences. 
• 
Cardiac: cardiac failure congestive, palpitations and tachycardia were common 
occurrences.  Arrhythmia,  cardiac  arrest,  left  ventricular  dysfunction,  sinus 
bradycardia  and  supraventricular  tachycardia  are  unco mmon  occurrences. 
Atrioventricular block occurred at rare frequencies. 
• 
Eye: increased lacrimation and visual impairment were common occurrences. 
Conjunctivitis,  cystoid   macular  edema,  keratitis,  and   maculopathy  were 
uncommon occurrences. 
• 
General Disorders and Administration S ite Conditions: Asthenia, chest pain, 
chills,  fatigue,  infusion  site  reactions,  mucosal  inflammation,  edema  and 
pyrexia were common occurrences.  Lethargy and  malaise were occasional, 
uncommon occurrences. 
• 
Hepatobiliary  Disorders: cho langitis  and  hyperbilirubinemia  were  common 
occurrences. 
• 
Investigations: Alanine aminotransferase increased, aspartate aminotransferase 
increased, blood alkaline phosphatase increased and blood creatinine increased 
were commonly observed occurrences. 
• 
Metabolism   and   N utrition   Disorders:   Decreased   appetite,   dehydration, 
hypokalemia  were  commonly  observed   occurrences.   F luid   rention   was 
uncommonly observed. 
• 
Psychiatric  Disorders:  anxiety,  depression  and  insomnia  were  commonly 
observed occurrences. 
• 
Skin and S ubcutaneous Tissue Disorders: alopecia, dry skin, erythema,  nail 
disorder 
including 
onycholysis 
and 
discoloration, 
palmar-plantar 
erythrodysesthesia syndrome, pruritis and rash including generalized are 
commonly observed occurrences. Dermatitis allergic and erythema multiforme 
were uncommonly observed occurrences. 
• 
Vascular Disorders: deep vein thrombosis, flushing, hypertension, hypotension 
and lymphedema were commonly observed occurrences. 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
 
Gemcitabine (Gemzar® ) 
The most common toxicities reported for ge mcitabine are: 
• Hematologic: Myelosuppression is the dose- limiting toxicity with gemcitabine, 
but <1% of patients discontinued therapy for either anemia,  leukopenia,  or 
thrombocytopenia.  Patients should be monitored for myelosuppression during 
gemcitabine  therapy  and  dosage  modified  or  suspended  according  to  the 
degree of hematologic toxicity 
• Gastrointestinal: Nausea and vomiting are commonly reported but were usually 
of mild to moderate severity.  Diarrhea and stomatitis can also be seen 
• Hepatic: In clinical trials, gemcitabine was associated with transient elevations 
of one or both serum transaminases in approximately 70% of patients, but there 
was no evidence of increasing hepatic toxicity with either longer duration of 
exposure to gemcitabine or with greater total cumulative dose.   Serious 
hepatotoxicity, including liver failure and death, has been reported ve ry rarely 
in patients receiving gemcitabine. 
• Renal:  In  clinical  trials,  mild  prote inuria  and  hematuria  were  commo nly 
reported.   Hemolytic  Uremic  S yndrome  (HUS)  has  been  reported  rarely 
(0.25%) with the use of gemcitabine.  Renal failure may not be reversible even 
with discontinuation of therapy and dialysis may be required. 
• Fever: The overall incidence of fever was 41%.   This is in contrast to  the 
incidence of infection (16%) and indicates that gemcitabine may cause fever in 
the absence of clinical infection.   Fever was frequently associated with other 
flu- like symptoms and was usually mild and clinically manageable. 
• Rash: Rash was reported in 30% of patients.  The rash was typically a macular 
or finely granular maculopapular pruritic eruption of mild to moderate severity 
involving the trunk and extremities.  Pruritus was reported for 13% of patients. 
• Pulmonary: In clinical trials,  dyspnea,  unrelated  to  underlying  disease,  has 
been reported in association with gemcitabine therapy.    Dyspnea was 
occasionally accompanied by bronchospasm.   Pulmonary toxicity has been 
reported  with  the  use  of  gemcitabine.    The  etiology  of  these  effects  is 
unknown.  If such effects develop, gemcitabine should be discontinued.  Early 
use of supportive care measures may help ameliorate these conditions. 
• Edema: Edema (13%), peripheral edema (20%), and generalized edema (<1%) 
were reported.  Less than 1% of patients discontinued due to edema. 
• Flu- like  S ymptoms:  “F lu  syndrome”  was  reported   for  19%  of  patients. 
Individual symptoms of fever, asthenia, anorexia, headache, cough, chills, and 
myalgia were commonly reported.   Fever and asthenia were also reported 
frequently as iso lated   symptoms.   Insomnia, rhinitis, sweating, and malaise 
were reported infrequently. Less than 1% of patients discontinued due to flu- 
like symptoms. 
• Infection: Infections were reported  for 16% of patients.   Sepsis was rare ly 
reported. 
• Alopecia: Hair loss, usually minimal, was reported by 15% of patients. 
• Neurotoxicity: There was a 10% incidence of   mild paresthesias and a <1% 
rate of severe paresthesias. 
 
11.2 
Dose Modification Sche dule 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
 
Toxicities will be graded using the NCI CTCAE Version 4.0 and dose modifications of the study 
drugs will be made for hematologic and other toxicities. Dose adjustments are to be made according 
to  the system showing  the  greatest degree of toxicity.  Patients experiencing  stud y drug related 
toxicities that require a delay in scheduled albumin-bound paclitaxel and gemcitabine dosing for >21 
days will be discontinued from further participation in this study. 
 
Table 11.1  Dose Modification for Albumin-bound Paclitaxe l 
Dose Le vel 
Albumin-bound Paclitaxe l (Abraxane ®) 
0 
100 mg/m2 
-1 
75 mg/m2 
-2 
50 mg/m2 
If additional dose reduction required 
Discontinue 
 
Table 11.2  Dose Modification for Ge mcitabine 
Dose Le vel 
Ge mcitabine (Ge mzar®) 
0 
1000 mg/m2 
-1 
800 mg/m2 
-2 
600 mg/m2 
If additional dose reduction required 
Discontinue 
 
 
 
 
11.2.1 HEM ATOLOGIC TOXICITY: 
 
A CBC will be obtained prior to each treatment.  The following parameters should be observed: 
 
Albumin-bound paclitaxel and  gemcitabine dosing should not be administered at the start of each 
cycle until the absolute neutrophil count returns to ≥ 1.5 x 109 cells/L and the platelet count returns to 
> 100 x 109 cells/L. 
 
For each subsequent dose of albumin-bound paclitaxel and gemcitabine within a cycle, patients must 
have an ANC ≥ 1.0 x 109  cells/L and platelets > 75 x 109  cells/L. If the ANC and platelets are not 
adequate for treatment, the following dose adjustments will be made (See Table 11.3). 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.3: Dose Modifications for Ne utrope nia and/or Thrombocytope nia at the Start of a 
Cycle or within a Cycle 
Cycle Day 
ANC (ce lls/mm3) 
Plate le t count 
(ce lls/mm3) 
Albumin-bound 
paclitaxe l / 
Ge mcitabine 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
Day 1 
<1500 
OR 
<100,000 
Delay dose for 1 week 
intervals 
Day 8 
<1000 
OR 
<75,000 
Reduce 1 dose level + G- 
CSF (treat on time) or 
delay dose for 1 week +/- 
G-CSF (i.e. Day 8 retry) 
or withhold Day 8 dose 
+/- G-CSF and re- 
evaluate for Day 15 
treatment. 
Fe brile Neutropenia 
Any Day 
Hold doses. Upon 
resuming dosing, 
decrease to next lower 
level and do not re- 
escalate throught the rest 
of treatment. 
 
 
 
 
 
A:G-CSF  is  optional if patient  on ly  with  thrombocytopenia.  If patient  does  not  experience  res olution  of neutropenia 
within 21 days , des pite uninterrupted G-CSF treat ment, s tudy treatment will be dis continued. G-CSF s hould  be given 24 
hours after chemotherapy and held 48 hours prior to th e ne xt dos e 
 
11.2.2 NON-HEM ATOLOGIC TOXICITY: 
 
Table 11.4: Dose Modifications for Non-He matologic Toxicities 
Adve rse Drug Re action 
Albumin-bound paclitaxe l 
Ge mcitabine 
Pe riphe ral Ne uropathy: 
Grade 3 or 4 
Withhold until neuropathy 
improved to <=Grade 1; 
resume at next lower dose 
level 
Continue. No Dose Reduction 
Cutane ous Toxicity: 
Grade 2 or 3 
Reduce to next lower dose level for both drugs 
Gastrointe stinal Toxicity: 
Grade 3 mucositis or diarrhea 
Withhold both drugs until improves to <= Grade 1, then resume 
both drugs at next lower dose level 
Othe r Non-He matologic 
Toxicities: 
Grade ≥ 3 
Withold both drugs until improves to <= Grade 1.  Consider 
dose reduction at resumption of one or both drugs per 
investigator judgment. 
Othe r Non-He matologic 
Toxicities: 
Grade < 3 
If considering dose modification for non- hematologic toxicities 
grade < 3, must discuss with P I for approval. 
 
 
The decision regarding which drug to modify will depend upon the type of non-hematologic toxicity 
seen and which course is medically most sound in the judgment of the physician/investigator. 
 
PERIPHERAL NEUROPATHY 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
Treatment with albumin bound paclitaxel should be withheld in patients who experience ≥Grade 3 
peripheral neuropathy. Gemcitabine administration can continue during this period. Albumin bound 
paclitaxel may be resumed at the next lower dose level in subsequent cycles after the peripheral 
neuropathy improves to ≤Grade 1. The time to resolution to Grade ≤1 should be the adverse event 
duration used for adverse event reporting. Patients experiencing peripheral neruoapthy that requires a 
delay  in  scheduled  albumin  bound  paclitaxel  dosing  for  over  21  days  will  discontinue  study 
treatment. 
 
CUTANEOUS TOXICITY 
Patients who develop Grade 2 or 3 cutaneous toxicity should have their dose reduc ed to the next 
lower dose level for both drugs. If the patient continues to experience these reactions, despite dose 
reduction, treatment should be discontinued. Patients who develop Grade 4 cutaneous toxicity should 
have treatment discontinued. 
 
GAS TROIN TES TIN AL TOXICITY 
If Grade 3 mucositis or diarrhea occurs, study drugs should be withheld until resolution to ≤Grade 1, 
then reinstituted at the next lower dose levels. Patients who develop Grade 4 mucositis or diarrhea 
should have treatment discontinued. 
. 
 
COLONY STIMULATING F ACTOR ADMINISTRATION 
Table 11.3 provides a guideline for the use of G-CSF or pegfilgrastim and for implementing dose 
reductions for treatment-related hematologic toxicity. Colony stimulating factors should be given 
according to institutional guidelines for treatment of neutropenic fever or infections associated with 
neutropenia and for the prevention of febrile neutropenia in patients with an ANC <1000cells/uL. 
 
HYP ERS ENSITIVITY REAC TIONS : 
Hypersensitivity reactions are not expected with either albumin bound paclitaxel or gemcitabine. If 
they do occur, minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia 
may require temporary interruption of the infusion. P remedication may be needed in patients who 
have had prior hypersensitivity reactions to albumin bound paclitaxel. However, severe reactions, 
such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or 
generalized urticaria require immediate discontinuation of study drug administration and aggressive 
symptomatic therapy. Patients who develop a severe hypersensitivity reaction to albumin bound 
paclitaxel should not be re-challenged. 
 
ADMINISTRATION   OF   STUDY   DRUG   TO   P ATIEN TS   WITH  ABNORMAL   HEPATIC 
FUNCTION: 
Albumin-bound paclitaxel and gemcitabine should only be administered if hepatic function is within 
the parameters established  in the eligibility criteria.   S ignificant hepatic toxicity from taxanes or 
gemcitabine may occur but is not common. For this reason, hepatic dysfunction that occurs while the 
patient is on study should prompt evaluation to determine the cause, including the possibility of 
progressive metastatic disease and hepatotoxicity from concurrent medications. 
 
INTERS TITIAL PNEUMONITIS : 
Pneumonitis has been reported to occur in 4% of patients who  have received the combination of 
albumin-bound paclitaxel and gemcitabine. Monitor patients for signs and symptoms of pneumonitis 
and interrupt albumin bound paclitaxel and gemcitabine during evaluation of suspected pneumonitis. 
After  ruling  out  infectious  etiology  and  making  the  diagnosis  of pneumonitis,  treatment  with 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
gemcitabine should be permanently discontinued and corticostero ids with appropriate ventilation and 
oxygen support when required should be promptly initiated.  If the pneumonitis resolves to grade ≤1 
within 28 days and was grade ≤ 3, the investigator can consider resuming albumin bound paclitaxel 
as a single agent at a -1 dose level.  If pneumonitis recurs, albumin bound paclitaxel should be 
permanently discontinued. 
 
DISCONTINUATION FROM S TUDY : 
After the doses of both albumin-bound paclitaxel and gemcitabine have been reduced twice for an 
adverse event, the patient will be discontinued from the study. 
 
 
 
 
11.3     RULES FOR DOSE OM ISSIONS AND M ODIFIED SCHED ULES: 
 
Day 1 dose he ld: If the dose held or missed was to be given on Da y 1 of the next cycle, that next 
cycle will not be considered to start until the day the first dose is actually administered to the patient. 
 
Day 8 dose he ld: Patients who have therapy held on Day 8 can have a re-attempt at treatment 1 week 
later.  If trea tment is held again, the next treatment will be considered Day 1 of a new cycle. 
 
 
 
11.4  CONCOM ITANT M EDICATIONS: 
 
Supportive care,  including but not limited to anti-emetic medications, may be administered at the 
discretion of the Investigator. Administration of other chemotherapy, immunotherapy, or anti-tumor 
hormonal therapy during the study is not allowed. Irradiation is not allowed during the study except 
for symptomatic non-target lesions. All concomitant treatments, including blood and blood products, 
must be reported on the case report form. 
 
Since albumin-bound paclitaxel is a formulation containing paclitaxel, the potential drug-drug 
interactions precautions contained  in the Taxol®  package insert will be applied to  this study (see 
Taxol®  package  inse rt).  Specifically,  the  metabolism of Taxol is catalyzed  by cytochrome P450 
isozymes CYP2C8  and  CYP3A4.  Caution  is recommended  when administering  Taxol® 
concomitantly with inducers (e.g. : rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) 
or inhibitors (ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, 
cimetidine, and protease inhibitors including ritonavir, saquinavir, indinavir, and nelfinavir) of the 
cytochrome P450  isozymes CYP2C8 and CYP3A4. S imilarly,  herbal preparations, and/or dietary 
supplements known to influence the expression of CYP3A (e.g., St. John’s wort, garlic supplements, 
grapefruit juice) and/or CYP2C8 should be used with caution (see www.drug-interactions.com for a 
regularly updated list of drug interactions with cytochrome P450 isozymes). 
 
 
 
 
 
 
 
 
12.0   CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
The Response Evaluation Criteria in Solid Tumors Group 1.1 (RECIST 1.1) will be used to evaluate 
the response to treatment. The same method and the same technique (i.e. with or without contrast) 
should be used to characterize each identified and reported lesion at baseline and after every 6 weeks 
+/-  1  week  while on study.  If an appropriate  imaging study  is done early  for any reason  (i.e. 
hospitalization), it can be used for disease assessment and the subsequent set of imaging scans may 
be completed 6 weeks (+/- 1 week) from the date of that assessment. A designated 
radiologist/physician will be responsible for interpretation of the study imaging according to RECIS T 
v1.1. 
 
A CT scan of the chest or CT chest (+/- abdomen/pelvis depending on sites of disease) with or 
without contrast  will be performed  to  demonstrate all known areas of measurable disease.  The 
baseline study will occur no more than 4 weeks prior to first study drug administration. An alternative 
imaging test, including MRI, can be used in patients with contraindications to radiographic contrast 
media used in CT scans. All patients must have at least one measurable disease lesion by CT or MRI. 
 
Confirmation of an objective response will occur with repeat imaging ≥4  weeks after the initial 
response scan. 
 
 
 
12.1     DISEAS E PARAMETERS 
Measurab le d isea se : Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques (CT, 
MRI,  x-ray) or as >10 mm with spiral C T scan.   All tumor measurements must be recorded  in 
millimeters (or decimal fractions of centimeters). 
 
Non-me asurab le d isea se : All other  lesions (or sites of disease),  including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm using spiral C T scan), are considered 
non- measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis, inflammatory breast disease, abdominal masses (not followed by C T or MRI), 
and cystic lesions are all non- measurable. 
 
Targe t le sio ns: All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, 
representative  of all  involved  organs,  should  be  identified  as  target  lesions  and  recorded  and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be calculated 
and reported as the baseline sum LD. The baseline sum LD will be used as reference by which to 
characterize the objective tumor response 
 
Non-target lesio ns: All other lesions (or sites of disease) including any measurable lesions over and 
above the 10 target lesions should be identified as non-target lesions and should also be recorded at 
baseline. Measurements of these lesions are not required, but the presence or absence of each should 
be noted throughout follow-up. 
 
Eva lua tio n o f best overa ll respo nse : The best overall response is the best response recorded from the 
start of treatment until disease progression, as defined in Table 12.1 (See below). 
 
Eva luab le fo r objec tive respo nse : 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
Patients evaluable for response are defined as those who complete at least the first planned C T scan 
after the 2nd cycle of therapy. 
 
 
 
Progressio n free surviva l (PFS): is defined as the duration of time from first treatment to time of 
progression or death, whichever occurs first. 
Overa ll surviva l (OS): is defined as the duration of time from first treatment to time of death. 
Definitions of response in target and non-target lesions are described in Table 12.1 and Table 12.2 
below. Table 12.3 provides overall responses for all possible combinations of tumor responses in 
target and non-target lesions. 
 
 
 
 
Table 12.1: Evaluation of targe t le sions 
Complete Response (CR target lesions): 
Disappearance of all 
Partial response (P R): 
At least a 30% decrease in the sum of the diameters 
of the target lesions 
Progressive disease (P D): 
At least a 20% increase in the sum of the diameter of 
the target lesions or the appearance of one or more 
new lesions 
Stable disease (SD): 
Neither  sufficient shrinkage  to  qualify  for P R  nor 
sufficient increase to qualify for P D 
 
 
 
Table 12.2: Evaluation of non-targe t le sions 
Complete Response (CR): 
Disappearance of all non-target lesions 
Incomplete response/S table disease (S D): 
Persistence of one or more non-target lesions 
Progressive disease (P D): 
Appearance of one or more new lesion and/or 
unequivocal progression of existing non-target lesion 
 
 
 
Table 12.3: Combination of Re sponses 
Targe t Le sions 
Non-targe t le sions 
Ne w Le sions 
Ove rall Response 
CR 
CR 
No 
CR 
CR 
Incomplete/S D 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or NO 
PD 
Any 
PD 
Yes or NO 
PD 
Any 
Any 
Yes 
PD 
  
 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
Patients may withdraw from the study at any time. Patients who discontinue early should return 
within 30 days of the last dose for a follow up evaluation. Patients who withdraw from the study for 
reasons other than disease progression without completing a full treatment cycle will be replaced. 
 
Patients will be withd rawn from the study should they experience any of the following: 
 
• 
Grade  4  adverse  event  recurs  after  the  dose  of both  albumin-bound  paclitaxel and 
gemcitabine have been reduced twice 
• 
Disease progression (as defined by RECIST 1.1 ) 
• 
Change in patient eligibility for the protocol, as designed in the section on Criteria for 
Patient/S ubject Eligibility (i.e: change in diagnosis) 
• 
Investigator’s decision based on patient’s best interest 
• 
Withdrawal of consent 
• 
Lost to follow up 
• 
Severe, unexpected toxicities/side effec ts 
• 
Non-compliance with the defined treatment plan 
• 
Death 
 
14.0    BIOSTATISTICS 
 
14.1.    Primary Obje ctives 
 
14.1.1.  Obje ctive Overall Re sponse Rate s 
 
The primary efficacy endpoint of the study is the best objective response (BOR) rate, 
defined as the proportion of patients with complete or partial responses based on 
RECIS T 1.1, at any time prior to disease progression, out of all evaluable patients. A 
response needs to be confirmed 28 days after it was initially observed. 
 
The trial is designed using a S imon opt imal two-stage design. A BOR rate less than 
25% is considered not promising (null hypothesis), a BO R rate >45 % is promising 
(alternative hypothesis), and the probabilities of a one-sided Type I error (falsely 
accepting a non-promising therapy) and Type II error (falsely rejecting a promising 
therapy) are set to 0.05 and 0.2, respectively.   In the first stage of this design,  17 
patients will be treated.  If fewer than 6 patients have a response, then the study will be 
terminated and declared negative.   If 6 or more patients have a response, then an 
additional 24 patients will be accrued to the second stage. At the end of the study, the 
regimen will be considered worthy of further investigation if 15 or more responses are 
observed among the  41 patients treated.  With this design,  the probability of early 
termination under the null hypothesis is 77%, and the expected sample size is 23. 
 
We expect to  accrue  2  patients/month to  this study,  therefore completing accrual 
within 9 mo (if one stage) or 21 months (if both stages of the trial are completed). 
 
 
 
14.2.    Se condary Obje ctives 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
14.2.1.  Safe ty and Tole rability 
 
Toxicity data (AEs,  laboratory data and vital sign data) will be collected, tabulated 
according to C TCAE version 4.0 and summarized using descriptive statistics. Adverse 
events will be listed individually per patient. Safety and tolerability will be assessed 
after 6 patients are treated.  A decision will be made, based on this, as to whether to 
proceed at the current dose/frequency schedule.  Patients eva luable for this will have 
needed to have received at least 1 dose of the treatment regimen. 
 
14.2.2  Progre ssion-Fre e Survival and Ove rall Survival 
 
Progression-free survival (PFS) and  overall survival (OS) will be estimated  using 
Kaplan Meier method. For PFS, patients will be followed up from the date of the first 
dose  of the  treatment  regimen  until  disease  progression  (by  RECIS T)  or  death, 
whichever comes first. For OS, patients will be followed up from the date of the first 
dose of the treatment regimen until death. Patients who do not experience the event of 
interest during study time will be censored at the time of the last available follow- up. 
Median PFS/OS, as well as 1-year and 2-year PFS and OS will be reported, with the 
corresponding exact 95% co nfidence intervals. 
 
14.2.3  Corre lative studies 
 
The association between BOR and molecular aberrations (FGFR1 amplification status, 
PIK3CA mutations, PTEN mutations, P TEN loss, DDR2 mutations) will be examined 
using F isher’s exact test. This analysis will be exploratory and hypothesis generating. 
  
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1    Re search Participant Re gistration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures.  During  the  registration  process  registering  individuals  will  be  required  to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility 
Checklist is confirming whether or not the participant is eligible to enroll in the study. Study 
staff are responsible for ensuring that all institutional requirements necessary to enroll a 
participant  to  the study  have  been completed.  See  related  C linical  Research Policy and 
Procedure #401 (Protocol Participant Registration). 
 
15.2    Randomization 
 
There will be no randomization in this phase II study. 
 
16.0 
DAT A M AN AGEMENT ISSUES 
 
A Research S tudy Assistant (RSA) will be assigned to the study.  The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team.  The data collected  for this  study  will be entered  into  a secure 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
database (C linical Research Database CRDB).   Source documentation will be available to 
support the computerized patient record. The principle investigator will maintain ultimate 
responsibility for the clinical trial. 
 
16.1    Quality Assurance 
 
Weekly meetings will occur to monitor patient accrual and completeness of registration data. 
Routine data quality reports will be generated to assess missing data and inconsistencies. 
Accrual rates  and  extent  and  accuracy of evaluatio ns  and  follow  up  will  be  monitored 
periodically throughout the study period and potential problem will be brought to the attention 
of the study team for discussion and action. Random sample data quality and protocol 
compliance audits will be conducted by t he study team, at a minimum of two times a year, 
and more frequently if indicated. 
 
 
16.2    Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) P lans at Memorial S loan-Kettering Cancer Center 
were approved by the National Cancer Institute in Septe mber 2001.   The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute  for  Data  and  Safety  Monitoring  of  C linical  Trials”  which  can  be  found  at: 
http ://ca ncertria ls. nc i. nih. go v/resea rc hers/dsm/inde x. html.   The DSM P lans at MSKCC were 
established and are monitored by the C linical Research Administration. The MSKCC Data 
and    Safety    Monitoring    P lans    can    be    found    on    the    MSKCC    Intranet    a t: 
http://msk web2.msk cc.org/irb/index .htm 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality.   There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff e ducation 
on clinical research QA) and departmental procedures for quality control,  plus there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 
programs.  The committees: Data and Safety Monitoring Committee (DSMC) for P hase I a nd 
II clinical trials, and the Data and Safety Monitoring Board (DSMB) for P hase III clinic a l 
trials,  report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required.  Every type of protocol (e.g., NIH sponsored, 
in- house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and 
the monitoring procedures will be established at the time of protocol activation. 
 
 
 
 
 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to enrollment of each patient, the risks, benefits, and objectives of the study will be 
reviewed with the participant, including a discussion of the possible toxicities, side effects, 
and   alternative,   non-protocol  treatment  options.  The  patients  will  be  reminded   that 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
participation in this clinical trial is voluntary and the patient may withdraw consent at any 
time. 
 
Risk s:   The standard  front- line treatment for patients diagnosed with advanced squamous 
NSCLC (unresectable or metastatic disease) and an adequate performance status is 
chemotherapy with a platinum-based regimen.  It is possible that non-platinum chemotherapy 
in the front- line setting is less effective than standard platinum-based chemotherapy. 
 
Be ne fits:  It  is  hoped  that  this  regimen  will  allow  delivery  of a  highly-active  cytotoxic 
chemotherapy combination which will prove at least as effective as a platinum-based 
combination chemotherapy in a group of patients who might otherwise be unable to receive 
standard platinum-based therapies.  This study uses albumin-bound paclitaxel, which does not 
require  steroid-premedication  and   thus,  circumvents  many  of  the   infusion  difficulties 
associated with the standard solvent-based taxanes, paclitaxel and docetaxel.   Patients who 
progress on this treatment can still receive standard, second line chemotherapy and or 
participate in an alternative clinical trial. 
 
Conse nt p rocess: Participation in this trial is voluntary. All patients will be required to sign a 
statement of informed consent which must conform to MSKCC IRB guidelines. 
 
Costs: Patients will be charged for physician visits, routine laboratory and radiologic studies 
required for monitoring their condition. Patients will not be billed for the study drug, albumin- 
bound paclitaxel.     CLIA-certified mutation testing (i.e. fragment analysis, Sequenom or 
standard sequencing) will be billed to the patient/patient’s insurance. 
 
Alternatives : Alternative treatment options include standard chemotherapy, best supportive 
care, or participation in other investigational studies. 
 
Confid e ntia lity: Every effort will be made to maintain patient confidentiality. Research and 
hospital records are confidential.   Patient's names or any other personally identifying 
information will not be used in reports or publications resulting from this study.   Qualified 
monitors from MSKCC, Celgene (the manufacturer of albumin-bound paclitaxel), and the 
FDA may review patient records as required. 
 
Patie nt  sa fe ty: Patients  are  monitored  by  physicians  and  oncology  nurses  who  are  very 
familiar with clinical trials. In the case of an adverse reaction, immediate medical attention is 
available.  In  the  evenings  and  weekends,  we  have  a  24  hour  urgent  care  facility  for 
outpatients.  The PI or co-PIs will also be available at all times to organize any necessary 
intervention. 
 
Monitoring o f da ta to e nsure sa fe t y: this study is to be monitored by institutional IRB. This 
incorporates an  independent data and safety  monitoring committee established by 
arrangement  with  the  National Cancer  Institute.  The  analysis  of safety  will  include  all 
patients. Adverse events, including all toxic effects of treatment, will be tabulated individually 
and summarized by severity and causality. 
 
 
17.1    Priv acy 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
MSKCC’s Privacy O ffice may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected  health  information will be  lim ited  to  the  individuals described  in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/P B). 
 
17.2 
Se rious Adverse Event (SAE) Re porting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
 
SAE reporting is required as soon as the participant signs consent.  SAE reporting is 
required for 30-days after the participant’s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting of Serious 
Adverse Events’, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org.  All other reports should be sent to saemskind@mskcc.org. 
 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org.  All other reports should be sent to sae@mskcc.org. 
 
 
 
 
 
 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject’s initials 
• 
Medical record number 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
The PI’s signature and the date it was signed are required on the completed report. 
 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions.  If appropriate, t he 
report will be forwarded to the FD A by the SAE staff through the IND Office 
  
 
17.1  Proce dure for Re porting Se rious Adve rse Eve nts to Ce lgene 
 
Celgene is required to evaluate and expedite reporting of serious adverse events to 
worldwide regulatory authorities; therefore, the appropriate parties, as specified in this 
section, must be notified immediately (within 24 hours of awareness) regarding the 
occurrence of any serious adverse event. 
 
The procedure for reporting serious adverse events, regardless of causal relationship, is 
as follows: 
• 
The investigator must inform Celgene in writing  using the CRDB S AE report 
form o f a ny SAE within 24 ho urs o f be ing a ware o f the e ve nt.  The written 
report must be completed and supplied to Celgene by facsimile within 24 
ho urs/1 b usiness da y. 
• 
The initial report must be as complete as possible, including an assessment of 
the causal relationship between the event and the investigational product(s), if 
available.  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 Ce lge ne 
track ing number (AX-CL-NSCLC-PI-003548) and the institutio na l pro toco l 
numb er sho uld be inc luded o n SAE reports (or o n the fa x co ve r le tte r) se nt to 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
Celge ne.  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. 
 
Ce lge ne Drug Safe ty Contact Information 
 
C elge ne C orpo rat io n 
G loba l Dr ug S a fet y a nd R isk Ma na ge me nt 
C onne ll C orpora te P ark 
300 C onne ll D r.  S uit e 6000 
Berke le y He ight s, N J  07922 
F ax: 
(908) 673 - 9115 
E- mail:drugsa fe ty@ce lge ne.co m 
 
 
Pre gnancie s 
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 albumin bound 
paclitaxel and gemcitabine, or within 3 months of the subject’s last dose of albumin bound 
paclitaxel and gemcitabine, are considered immediately reportable events. The study drugs are 
to be discontinued immediately. The pregnancy, suspected pregnancy, or positive pregnancy 
test must be reported to Celgene Drug Safety immediately by facsimile, or other approp riate 
method, using the P regnancy 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 professiona l for further evaluation. 
 
The 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 P regnancy Follow- up Report Form, or approved equivalent 
form. 
 
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 
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 Investigator’s knowledge of 
the event using the S AE Report Form, or approved equivalent form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as S AEs. 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 Investigator’s 
knowledge of the event using the S AE Report Form, or approved equivalent form. 
 
Male Subje cts 
 
If a female partner of a male subject taking investigational product become s pregnant, the 
male subject taking albumin bound paclitaxel and gemcitabine should notify the Investigator, 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
and the pregnant female partner should be advised to call their healthcare provider 
immediately. 
 
18.0    INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they a re free to 
withdraw from the study at any time. All participants must sign an IRB/P B-approved consent 
form indicating their consent to participate. O nly those individuals designated on the protocol 
title page as consenting professionals may obtain informed consent. This consent form meets 
the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
 
1.   The nature and objectives, potential risks and benefits of the intended study. 
2.   The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.   The name of the investigator(s) responsible for the protocol. 
5.   The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.   In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. The Research Authorization requires 
a separate set of signatures from the patient. 
 
Three copies of the Informed Consent will be signed and dated by both patient (or his or her 
guardian) and physician. O ne copy will be returned to the patient, one copy will be placed in 
the patient’s medical record, and the third will be stored in the research file. 
 
19.0 
REFERENCES 
  
1.   Scagliotti GV, Parikh P, von Pawel J, et al.  P hase III study co mparing cisplatin plus 
gemcitabine with cisplatin plus pemetrexed in chemotherapy- naive patients with 
advanced-stage non-small-cell lung cancer. J C lin O ncol. 2008 Jul 20;26(21):3543-51. 
2.   Paz-Ares L, Soulieres D, Melezinek I et al. C linical outcomes in non-small- cell lung cancer 
patients with EGFR mutations: pooled analysis. J Cell Mol Med 2010; 14(1-2):51-69. 
3.   Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel 
concentrations, and endothelial cell transport of cremophor- free, albumin-bound 
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Memorial Sloan Kettering Cancer Center
IRB Number: 15-054 A(12) 
Approval date: 12-Mar-2019 
 
 
 
 
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