Phase II Study of Nab-Paclitaxel With Gemcitabine for Relapsed Small Cell Cancer or Those With Progression on First Line Therapy
Phase: PHASE2
Conditions: Small Cell Lung Cancer (SCLC)
Sponsor: Muhammad Furqan

1 
 
 
University of Iowa Hospitals and Clinics 
Holden Comprehensive Cancer Center 
 
Phase II Study of Nab-Paclitaxel with Gemcitabine for Relapsed Small Cell  
Cancer or Those with Progression on First Line Therapy 
 
Principal Investigator:  Muhammad Furqan, M.D. 
Division of Hematology, Oncology and Blood and 
Marrow Transplantation, Department of Internal 
Medicine 
University of Iowa Hospitals and Clinics 
200 Hawkins Drive, C32GH 
Iowa City, Iowa 52242 
Co-investigators: 
Taher Abu-Hejleh, M.B., B.S. 
 
Jun Zhang, M.D., Ph.D. 
 
 
 
Date:   10/19/2015 (Version 1) 
 
08/14/2016 (Version 2) 
 
11/07/2016 (Version 3) 
 
11/30/2016 (Version 4) 
 
05/31/2017 (Version 5) 
 
11/28/2017 (Version 6) 
 
06/23/2019 (Version 7) 
 
 
 
Protocol # AG001 
 

2 
 
 
Index 
 
Schema 
 
1.0 
Background 
 
2.0 
Goals 
 
3.0 
Patient Eligibility 
 
4.0 
Test Schedule 
 
5.0 
Stratification Factors 
 
6.0 
Registration/Randomization Procedures 
 
7.0 
Protocol Treatment 
 
8.0 
Dosage Modification Based on Adverse Events 
 
9.0 
Ancillary Treatment 
 
10.0 
Adverse Event Reporting and Monitoring 
 
11.0 
Treatment Evaluation Using RECiST Criteria 
 
12.0 
Descriptive Factors 
 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient 
 
14.0 
Drug Information 
 
15.0 
Statistical Considerations and Methodology 
 
16.0 
Records and Data Collection Procedures 
 
17.0 
References 
 
 
 
 
 
 
 
 
 
 
Appendix I 
HCCC Clinical Trial Data and Safety Monitoring Plan (DSMP) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

3 
 
 
 
Table of Contents 
 
 
Schema ............................................................................................................................................ 5 
1.0 Background ................................................................................................................................ 6 
1.1 Overview of Small Cell Lung Cancer ................................................................................................ 6 
1.2 Standard Treatment for Small Cell Lung Cancer ............................................................................. 6 
1.3 Combination Treatment for Small Cell Lung Cancer ....................................................................... 7 
1.4 Gemcitabine as Single Agent for Treatment of Small Cell Lung Cancer ......................................... 7 
1.5 Nab-Paclitaxel as Single Agent for Treatment of Small Cell Lung Cancer ....................................... 8 
1.6 Combination of Nab-Paclitaxel and Gemcitabine for Treatment of Malignancy: Efficacy and 
Toxicity .................................................................................................................................................. 9 
2.0 Goal ......................................................................................................................................... 11 
2.1 Primary Endpoint .......................................................................................................................... 11 
2.2 Secondary Endpoints .................................................................................................................... 11 
3.0 Patient Eligibility ...................................................................................................................... 12 
3.1 Eligibility criteria ............................................................................................................................ 12 
3.2 Exclusion criteria ........................................................................................................................... 13 
4.0 Test Schedule ........................................................................................................................... 15 
5.0 Stratification Factors ................................................................................................................ 16 
6.0 Screening.................................................................................................................................. 16 
7.0 Protocol Treatment .................................................................................................................. 17 
7.1 Treatment Schedule ...................................................................................................................... 17 
8.0 Dosage Modification Based on Adverse Events ......................................................................... 18 
8.1 Nab-paclitaxel/Gemcitabine based on day of treatment counts ................................................. 18 
8.2 Dose modifications based on interval adverse events (other than day 1) ................................... 19 
8.3 Dose modifications at the time of re-treatment (start of new cycle) ........................................... 21 
8.4 Modification of regimen ............................................................................................................... 21 
9.0 Ancillary Treatment .................................................................................................................. 22 
10.0 Adverse Event (AE) Reporting and Monitoring ........................................................................ 23 
10.1 Monitoring, Recording and Reporting of Adverse Events .......................................................... 23 
10.2 Evaluation of Adverse Events ...................................................................................................... 24 

4 
 
 
10.3 Pregnancies ................................................................................................................................. 27 
10.4 Overdose ..................................................................................................................................... 28 
10.5 Celgene Drug Safety Contact Information .................................................................................. 28 
10.6 Adverse events to be graded at each evaluation per CTCAE v.4.03 ........................................... 29 
11.0 Treatment Evaluation Using RECIST Criteria ............................................................................ 30 
11.1 Schedule of Evaluations .............................................................................................................. 30 
11.2 Definitions of Measurable and Non-measurable Disease .......................................................... 30 
11.3 Guidelines for Evaluation of Measurable Disease ...................................................................... 30 
11.4 Measurement of Effect ............................................................................................................... 31 
12.0 Descriptive Factors ................................................................................................................. 33 
13.0 Treatment and Follow-up Decision at Evaluation of Patient .................................................... 33 
14.0 Drug Information .................................................................................................................... 33 
14.1 nab-Paclitaxel .............................................................................................................................. 33 
    14.2 Gemcitabine (Gemzar) ......................................................................................................... 42 
15.0 Statistical Considerations and Methodology ........................................................................... 44 
16.0 Records and Data Collection Procedures ................................................................................. 49 
17.0 References .............................................................................................................................. 49 
Appendix I HCCC Clinical Trial Data & Safety Monitoring Plan (DSMP) ............................................ 52 
 
 
 
 

5 
 
 
Schema 
 
 
 
 
 
 
Generic names: albumin-bound paclitaxel; 
paclitaxel protein-bound particles for injectable 
suspension (albumin-bound); Nab-paclitaxel 
Brand name: Abraxane ® 
Availability: HCCC pharmacy 
Generic name: gemcitabine 
Brand name: Gemzar ®  
Availability: HCCC Pharmacy 
 
 
 
Enrollment
Treatment: 
Nab-paclitaxel 100 mg/m2, day 1, 8 q 21 days
Gemcitabine 1000 mg/m2, day 1, 8 q 21 days
Progression
Adverse Events
Patient Refusal
Event Monitoring

6 
 
 
1.0 Background 
 
1.1 
Overview of Small Cell Lung Cancer  
 
Small cell lung cancer (SCLC) comprises approximately 14% of bronchogenic carcinomas of 
the lungs. For all lung cancers overall in 2014, it is estimated that there will be 224,210 
new cases and 159,260 deaths, accounting for highest age-adjusted cancer death rates in 
the United States1. The incidence of SCLC is mostly related to smoking.    The incidence of 
small cell lung cancer has decreased in the past 20 years2.  SCLC is a chemosensitive 
cancer; however, most patients develop relapse within 2 years after initial treatment and 
die of systemic metastases. Relapsed SCLC is relatively resistant to chemotherapy with 
only 10-25% response rate to subsequent therapy. Median survival of limited stage SCLC 
is 15-20 months and 9.4-12.8 months in extensive-stage disease3. National 
Comprehensive Cancer Network (NCCN) guidelines list single-agent topotecan, oral or 
intravenous, as the only category 1 treatment for sensitive relapsed SCLC4. Other agents 
including paclitaxel, docetaxel, irinotecan, vinorelbine, gemcitabine, ifosfamide, 
temozolomide, bendamustine, amrubicin and oral etoposide are also active in phase II 
trials. Only topotecan and etoposide are approved for this indication along with 
methotrexate and mechlorethamine5. 
  
Several combinations of chemotherapeutic agents and targeted therapies for second line 
treatment of SCLC have been investigated. Most of the studied combinations can be 
divided into platinum-based and irinotecan-based therapy..  
 
Nab-paclitaxel and gemcitabine in combination have been well studied in patients with 
metastatic pancreatic cancer where the combination has an improved response rate and 
increased survival compared to gemcitabine alone6 with an acceptable toxicity profile. 
Paclitaxel and gemcitabine, as single agents, were shown to have efficacy in SCLC7-10and a 
phase I study of the combination showed responses in 3 of 6 patients   
1.2 
Standard Treatment for Small Cell Lung Cancer 
 
Patients who do not respond to initial therapy or who develop relapse within 90 days 
after completion of their initial therapy are considered to have resistant or refractory 
disease and are likely to respond poorly to subsequent chemotherapy (14.8% response 
rate). Patient who developed relapse after 90 days from the initial treatment have a 
better prognosis with a longer median overall survival (7.7 months vs. 5.4 months, 
p=0.0035)11. Patients who relapse after 6 months after initial treatment should be treated 
with the same regimen used for initial therapy.  
 
Topotecan was first shown to be equivalent to a cyclophosphamide-doxorubicin-
vincristine (CAV) regimen in a multi-centered phase III study12 with response rate of 24.3% 
vs. 18.3% in topotecan and CAV arms, respectively in relapse sensitive disease. Median 
survival in the topotecan group was 25.0 weeks vs 24.7 weeks in CAV. No statistical 
difference was found in either response rate or median survival. However, topotecan had 
less grade 4 neutropenia (37.8% vs. 51.4%). Grade 4 thrombocytopenia and grade 3/4 
anemia were more common in the topotecan group (9.8% and 17.7% vs. 1.4 and 7.2%). 
Other toxicities were similar. In this study topotecan 1.5 mg/m2 was given intravenously 
as a 30-minute infusion daily for 5 days of 21-day cycle for 6 cycles or until disease 

7 
 
 
progression or unacceptable toxicity occurred. Since then topotecan has become 
standard of care for sensitive relapsed SCLC. Later, oral topotecan was demonstrated to 
have benefit over best supportive care13 when it is given 2.3 mg/m2/day in the same 
fashion as intravenous route.  The response rate was 7% partial and 44% stable disease 
and median survival was 25.9 weeks (vs. 13.9 in best supportive care group). A 
subsequent trial suggested equivalency of oral and intravenous topotecan in this setting14. 
NCCN list oral or intravenous topotecan as the only category 1 treatment for sensitive 
relapsed SCLC.  However, a more recent report from SWOG emphasized that other 
prognostic factors are more important than “platinum sensitivity” and that platinum 
sensitivity is not associated with PFS or overall survival15.  
 
There are several single-agents that have been shown efficacy in the treatment of 
relapsed SCLC. Etoposide16 and irinotecan17 were tested in randomized controlled studies 
while other agents including paclitaxel9,10, docetaxel18, gemcitabine7,8, bendamustine19, 
picoplatin20 (not available in the United States), vinorelbine21, oral etoposide22, and 
temozolomide23 were tested in non-comparative or phase II studies. We had previously 
reported trials of intravenous and subcutaneous IL-2 in relapsed small cell lung cancer.  
With intravenous therapy, 4 of 24 patients achieved a complete remission for a response 
rate of 21% The remission durations were 8, 9 and ongoing at 11 months.  One patient 
had not relapsed at 8 months but had developed acute leukemia24,25. 
 
These agents (except bendamustine, IL2, and picoplatin) are currently in category 2A in 
the NCCN guideline.  
1.3 
Combination Treatment for Small Cell Lung Cancer 
 
Combinations of two to four chemotherapeutic agents have been investigated in relapsed 
SCLC3. Most of the studies were platinum-based or irinotecan-based regimens. The 
observed response rates ranged from 10% (liposomal doxorubicin-cyclophosphamide-
vincristine) to 88% (cisplatin-vincristine-doxorubicin-etoposide) and median survival time 
from 4.4 months (vincristine-ifosfamide-mesna-carboplatin) to 11.8 months (cisplatin-
etoposide-irinotecan). However, these studies may have enrolled different study 
population and should not be compared directly.  
 
The only combination therapy in the NCCN guideline (category 2A) is CAV regimen that 
was studied in the topotecan trial mentioned above.  
 
An intensive regimen of irinotecan/etoposide for previously treated extensive small call 
had a 71% response rate. Growth factor support was used26. 
 
A phase II trial of irinotecan/paclitaxel in recurrent or refractory small cell enrolled 51 
patients who had at least one dose of therapy. The overall response rate was 21% and 
there was substantial hematologic toxicity. A trial of paclitaxel and bevacizumab in 
chemosensitive relapsed small cell had an overall response rate of 18%27. 
1.4 
Gemcitabine as Single Agent for Treatment of Small Cell Lung Cancer 
 
Gemcitabine is a nucleoside (deoxycytidine) analog acting as a pyrimidine antimetabolite 
in its triphosphate form28 by competing with natural deoxycytidine 5-triphosphate in DNA 
replication. Its diphosphate metabolite also inhibits ribonucleotide reductase (RNR) 

8 
 
 
needed for deoxyribonucleotides synthesis and DNA repair. Gemcitabine is used for 
treatment in variety of cancers such as non-small cell lung cancer, pancreatic cancer, 
bladder cancer, breast cancer.  
 
The activity in SCLC was first evaluated by van der Lee et al in a single-center study in the 
Netherlands8 in 41 patients with resistant disease (progression during or within 3 months 
of finishing the primary regimen). Gemcitabine 1000 mg/m2 was given intravenously on 
day 1, 8, and 15 of four-week cycle for maximum of five cycles. Response rate was 13% 
(95% confidence interval (CI) 6-27%) with median survival of 17 weeks. Related toxicity 
included grade 3 thrombocytopenia (29%) and grade 3 leukopenia (18%) and it was 
otherwise well tolerated.  
 
Subsequently, gemcitabine efficacy was investigated in a phase II study7 that also included 
26 patients with relapsed sensitive disease and 20 patients with primary resistant disease. 
Only one patient in primary resistant group had partial response; however, 4 patients 
(16.7%) in the sensitive relapse group had partial response. Median survival was 7.3 
months in relapsed sensitive disease group. There were 47.7% of patients who 
experienced worst toxicity as grade 3. 18.2% had worst toxicity as grade 4 including 
thrombocytopenia (9.1%), neutropenia (6.8%), leukopenia (2.3%), anemia (2.3%), 
vomiting (2.3%) and liver toxicity (2.3%). The author concluded that gemcitabine was well-
tolerated with an observed response rate and survival similar to a previous study of CAV. 
  
Another trial was published in the2003 by Hoang et al29 in the same setting as the 
previous study and recruited 27 patients (15 patients were sensitive disease.) Three 
patients achieved stable disease after six cycles but none achieved response. Median time 
to progression was 6 weeks in sensitive group and 5.6 weeks in resistant group and the 
median survival was 8.8 months in sensitive group and 4.2 months in resistant group. 
Hematologic adverse effects included grade 3/4 neutropenia and grade 3 
thrombocytopenia, both of which occurred in 5 patients (30%). 
 
According to 2 phase-II trials7,8 mentioned above, NCCN guideline has adopted 
gemcitabine as a subsequent chemotherapy in both relapsed resistant and sensitive SCLC.  
1.5 
Nab-Paclitaxel as Single Agent for Treatment of Small Cell Lung Cancer 
 
Taxanes work through the inhibition of microtubule depolymerization, resulting in a 
stagnation of cells in G2 and M phases and leading to cell death. Paclitaxel and docetaxel 
are known to have high insolubility in water. The current formulation used Kolliphor EL 
(also called Cremophor EL, a polyethoxylated castor oil) and dehydrated ethanol to 
stabilize the emulsion of non-polar paclitaxel in aqueous system to allow intravenous 
administration. This solvent-based paclitaxel is associated with varieties of adverse 
reactions, for example, hypersensitivity reactions, peripheral neuropathy, and 
neutropenia. Nab-paclitaxel (Abraxane®) was developed to avoid these toxicities which 
are potentially related to the non-ionic surfactant used in the formulation30. When nab-
paclitaxel enters the blood stream, the non-covalently bound albumin-paclitaxel complex 
is dissolved and some paclitaxel molecules are released and bound with albumin or other 
biomolecules in the blood stream.  The albumin molecule was found to help nab-
paclitaxel reach the tumor by receptor-mediated transcytosis (via albumin-specific 

9 
 
 
receptors: glycoprotein 60 and caveolae) and by enhanced permeation and retention 
effect (via secreted protein acidic and rich in cysteine, SPARC). Kolliphor EL was also found 
to be inhibitory in paclitaxel transcytosis through endothelial cells31. 
 
As noted above, paclitaxel has been incorporated in the NCCN guideline for treatment of 
SCLC based on the results of two following phase-II studies: 
 
Smit et al.9 conducted a phase II study of paclitaxel in previously treated primary resistant 
SCLC patients (last cytotoxic treatment less than 3 months). Intravenous paclitaxel 175 
mg/m2 was administered every 21 days. 7 of 24 patients (29%) had a partial response with 
median time to progression of 65 days and median survival of 100 days. Toxicities 
included grade 3/4 leukopenia in 10 out of 63 evaluable cycles and grade 3/4 
thrombocytopenia in 5 of 63 evaluable cycles. 
 
After reports of activity and tolerability of weekly paclitaxel compared to every 3 weeks, 
Yamamoto et al10 conducted a study of weekly paclitaxel in SCLC. Paclitaxel 80 mg/m2 was 
administered weekly for 6 weeks of the 8-week cycle; 21 patients were included (11 
patients with sensitive disease). Three out of 11 (27.3%) with sensitive disease patients 
and 2 out of 10 (20.0%) with resistant disease achieved a partial response and the median 
survival was 5.8 months. The most frequent toxicity was neutropenia and 6 patients 
(28.6%) developed grade 4 neutropenia.  
 
 A clinical study of nab-paclitaxel in SCLC was done as part of a phase I trial in which nab-
paclitaxel was combined with gemcitabine and will be discussed in the next section. 
 
There is a case report published on a patient with complete remission of SCLC after 
administration of nab-paclitaxel 100 mg/m2 for 2 cycles32. Unfortunately, the patient 
developed severe interstitial pneumonitis and died of respiratory failure after a week of 
diagnosis. The tumor was found to be positive for caveolin-1 but negative for SPARC by 
immunohistochemistry.  
1.6 
Combination of Nab-Paclitaxel and Gemcitabine for Treatment of Malignancy: 
Efficacy and Toxicity 
 
Both paclitaxel and gemcitabine have demonstrated activity in SCLC. Both agents have 
different mechanisms of action and also non-overlapping toxicities. Nab-paclitaxel has 
been designed to improve its pharmacokinetics and has fewer adverse events compared 
to its solvent-based formula. Nab-paclitaxel and gemcitabine in combination is a very 
attractive option for investigation for activity and safety in clinical trial. There was a trial 
of gemcitabine and paclitaxel as second line therapy for small cell with a response rate of 
22% but the dose of paclitaxel weekly x 2 was 135 mg/m2 and there was unacceptable 
toxicity33. 
  
There is only one clinical trial of the combination of nab-paclitaxel and gemcitabine in 
treatment of SCLC to date, a phase-I trial of nab-paclitaxel combined with gemcitabine in 
patients with thoracic malignancy34, which included 6 patients with SCLC. Three out of 5 
evaluable SCLC patients achieved partial response. The chemotherapeutic agents 
administered were nab-paclitaxel at 3 different doses (260 mg/m2, 300 mg/m2, and 340 

10 
 
 
mg/m2) on day 1 and gemcitabine 1000 mg/m2 on day 1 and day 8 of 21-day cycle. This 
regimen was relatively well-tolerated with only one episode of grade 4 neutropenia and 
one grade 3 febrile neutropenia. Efficacy of this combination in SCLC is obviously limited 
by its phase-I design and small sample size.  
 
A phase-II study sponsored by National Cancer Center, Korea has investigated the efficacy 
and toxicity of combination of weekly paclitaxel plus gemcitabine as second-line in SCLC. 
The study was completed in March 2010 but there is no result available through 
clinicaltrials.gov (NCT00453167)35 or searchable publication.  
 
A recent phase III study6 of combination of nab-paclitaxel and gemcitabine showed an 
increase in survival in advanced pancreatic adenocarcinoma compared to gemcitabine 
alone. The most common non-hematologic adverse reaction was fatigue (54%), alopecia 
(50%), and nausea (49%). Nab-paclitaxel-gemcitabine group had more grade 3/4 
hematologic adverse events than in the gemcitabine-alone group (neutropenia 38% vs. 
27%, thrombocytopenia 13% vs. 9%, febrile neutropenia 3% vs. 1% in nab-paclitaxel-
gemcitabine and gemcitabine-alone groups, respectively.  The result of this study has put 
nab-paclitaxel in combination with gemcitabine into category 1 treatment of metastatic 
pancreatic adenocarcinoma. 
 
Comparing the toxicity of Topotecan as second line therapy for small cell lung cancer and 
the toxicity of nab/paclitaxel in pancreatic cancer, the combination appears to be 
associated with less neutropenic fever and less transfusion requirement.  
 
 
 

11 
 
 
2.0 Goal 
 
2.1 
Primary Endpoint 
 
To evaluate the response rate per RECIST 1.1 of nab-paclitaxel plus gemcitabine  
(with clinically meaningful response rate defined as 35%  of patients responding ) 
2.2 
Secondary Endpoints 
 
2.2.1   To estimate the time to progression  
(defined as the first day of treatment to the date that disease progression is reported) 
 
2.2.2   To estimate the overall survival  
(defined as the first day of treatment to the date of death) 
 
2.2.3   To examine the toxicity related to the therapy 
(defined as predefined toxicity occurred from the first day of treatment to 28 days after 
administration of the last dose of the studied drugs)  
 
 
 
 
 

12 
 
 
3.0 Patient Eligibility 
 
3.1 
 Eligibility criteria  
 
3.11 
Age ≥18 years old, both male and female 
 
3.12 
Histologically or cytologically confirmed SCLC or small cell cancer from other 
organs or poorly differentiated neuroendocrine tumors that are treated like small 
cell cancer. This study is for patients with metastatic or recurrent disease.  
 
3.13 
ECOG performance status 0-2 
 
3.14 
Patients must have at least one measurable lesion as  defined per RECIST 1.1 
 
3.15 
Progression during or after first-line chemotherapy. .  Prior maintenance therapy, 
targeted therapy, and immunotherapy are allowed. Prior use of Rovalpituzumab 
or other ADC agent is allowed. Immunotherapy or targeted therapy if used as 2nd 
line therapy will not be considered as second line therapy as these are not true 
chemotherapeutic agents.  Patients treated with definitive chemo-radiation will 
be eligible if they progressed within a year of definitive therapy (as definitive 
therapy will be considered 1st line therapy for these patients).  
 
3.16 
Before study therapy, a minimum of 21 days must have elapsed since any prior 
chemotherapy and 2 weeks from the last dose of prior targeted or 
immunotherapy.   
 
3.17 
Prior definitive XRT is allowed if it has been 2 weeks since the end of definitive 
XRT.  For palliative XRT, protocol-specified treatment can begin at minimum 48 
hours after completion of radiation.  .  Lesions within the XRT field can only be 
used as target lesions if definite progression has been demonstrated since the 
completion of radiation.    
 
3.18 
Adequate major organ function including the following:  
Hematologic function: Absolute neutrophil count (ANC) ≥ 1800 /mm3, platelet 
count ≥ 100,000/mm3, and Hgb ≥ 9.0 gm/dl  
 
Hepatic function: bilirubin ≤ 1.5 x ULN, AST and ALT levels ≤ 2.5 x ULN. If liver 
metastases are present, then AST and ALT < 5 x ULN. 
 
Renal function: serum creatinine ≤ 1.5 x ULN. 
 
3.19 
Patients must be willing and able to sign informed consent for themselves 
 
3.19a 
If female: childbearing potential either terminated by surgery, radiation, or 
menopause, or attenuated by use of an approved contraceptive method 
(intrauterine device [IUD], birth control pills, or barrier device) during and for 6 
months after trial. If male, use of an approved contraceptive method during the 
study and 6 months afterwards. Females with childbearing potential must have a 
urine negative hCG test within 7 days prior to the study therapy. 
 
Females of child-bearing potential (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 

13 
 
 
postmenopausal for at least 24 consecutive months [i.e., has had menses at any 
time during the preceding 24 consecutive months]) must: 
• 
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 IP therapy (including dose interruptions), and while on study 
medication or for a longer period if required by local regulations  
following the last dose of IP; and 
• 
Have a negative serum pregnancy test (β -hCG) result at screening and 
agree to ongoing pregnancy testing during the course of the study, as per 
clinical judgement of the investigator, and after the end of study therapy.  
This applies even if the subject practices true abstinence* from 
heterosexual contact. 
 
3.19b 
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 IP 
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 (eg, calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception]. 
 
 
 
3.2 
 Exclusion criteria  
 
3.21 
Any of the following because this study involves an agent that has known 
genotoxic, mutagenic, and teratogenic effects: 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential, who are unwilling to employ 
adequate contraception as determined by treating physician, while on 
this study and for 6 months after the end of treatment with the study 
drugs. 
 
3.22 
History of the following within the prior 6 months: a myocardial infarction, 
severe/unstable angina pectoris, coronary/peripheral artery bypass graft, 
New York Heart Association (NYHA) Class III-IV heart failure, uncontrolled 
hypertension, clinically significant cardiac dysrhythmia or clinically 
significant ECG abnormality, cerebrovascular accident, transient ischemic 
attack, or seizure disorder. 
 
3.23 
Serious concurrent infection or nonmalignant illness that is uncontrolled or whose 
control may be jeopardized by complication of study therapy 
 
3.24 
History of other invasive malignancy that is currently active and/or has been 
treated within 12 months prior to enrollment  (notable exceptions include; basal 
cell carcinoma, squamous cell carcinoma of the skin, localized prostate cancer, in 

14 
 
 
situ carcinomas of the cervix and breast, and superficial bladder cancers [non-
muscle invasive]). 
 
3.25 
Psychiatric disorder which, per treating physician discretion, may  preclude 
compliance 
 
3.26 
Major surgery in the last two weeks of starting study therapy. This does not 
include procedures like biopsy (needle or excisional) or port placement as these 
are not considered as major surgery.  
 
3.27 
Individuals with the presence of symptomatic CNS metastasis requiring radiation, 
surgery, or ongoing use of corticosteroids. Untreated or brain metastasis causing 
any symptoms. Treated brain metastasis must be stable for 4 weeks prior to first 
dose of study drug and not requiring steroids for at least 7 days prior to study 
treatment. 
 
3.28 
Pre-existing peripheral neuropathy > Grade 1 (using CTCAE v 4.3 criteria) 
 
3.29a 
Received any prior treatment with any taxane (docetaxel or paclitaxel) for small 
cell lung cancer.   
 
3.29b 
History of allergy or hypersensitivity to albumin-bound paclitaxel, or gemcitabine.  
 
 
 

15 
 
 
4.0 Test Schedule 
 
Test and Procedures 
Within 30 
days prior 
to therapy 
Within 15 
days prior 
to study 
therapy 
(screening 
visit) 
Within 3 
days prior 
to or day of 
each 
subsequent 
cycle of 
treatment 
Active monitoring Phase 
Post 
treatment8 
Weekly 
for first 
two 
cycles 
Every 
two 
cycles  
End of 
treatment7 
History and physical 
examination 
(including weight, 
performance status, 
concurrent 
medications) 
 
X 
X 
 
 
X 
X 
Height and weight4  
X 
 
X 
 
 
X 
 
Pregnancy test 
(serum) 
 
1 
 
 
 
 
 
Complete blood count 
with differential 
counts 
 
X 
X 
X9 
 
X 
X 
Complete metabolic 
profile5 
 
X 
X 
 
 
X 
X 
Adverse Event 
Assessment 
 
X 
2 
 
 
2 
 
Uric acid, LDH, CEA6  
 
X 
 
 
 
 
 
Tumor measurement 
3 
 
 
 
3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. For women of childbearing age only. Must be done within 7 days prior to therapy. 
2. Adverse events form. Any grade 4 toxicity or unanticipated grade 3 or 4 toxicity must be reported within 24 
hours (MON-FRI) to the data safety monitoring board, and Celgene, the sponsor of the study.  Event must be 
reported to the IRB within 10 days. 
3. Measure every other cycle if done by CT, CXR, or MRI depending on the study used for the initial tumor 
measurement (i.e. prior to cycles 1, 3, 5, …). 2-3 days window is allowed for the scans if needed.. Same 
method must be used for baseline and throughout study. Patients with stable disease or response after 6 
cycles of treatment may have CT scans scheduled less frequently than every 2 cycles as clinically indicated. 
4. Height only needs to be collected at baseline. 
5. TESTS in the CMP to include Na, K, Cl, CO2, BUN, creatinine, AST, ALT, ALK Phos, albumin, calcium, TP, glucose. 
6. LDH, CEA and uric acid are to be determined at baseline but will only need to be repeated as clinically 
indicated for care of the patient. 
7. End of Treatment visit:  Every effort will be made to follow the patient off study (regardless of the reason) at 
approximately 28 days (+/- 7 days to accommodate scheduling).  Followup visit will include physical, vitals, 
weight, ECOG status, assessment of toxicities and labs including CBC and CMP.  Other clinic visit can be utilized 
for this purpose if all of the assessments are made.   

16 
 
 
8. Every effort will be made to follow all patients after the completion of therapy every 2 months ± 3 weeks for 
progression, whether or not they ended the therapy as it was completed or if they came off study therapy for 
any other reason.  Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subjects will be contacted by telephone every 12 ± 4 weeks to assess for survival status until 
death, withdrawal of consent, or 3 years from screening date or till the end of study, whichever occurs first.  
9. Weekly CBC/diff may be obtained locally (Day 15 CBC is not required after 2 cycles). 
 
5.0 Stratification Factors 
 
There will not be stratification for platinum sensitivity or any other factors   
 
6.0 Screening 
 
 
 
6.1 
Treatment cannot begin prior to screening and must begin within 14 days after 
screening, if patient is eligible and completed all required testing.  
6.2 
Pretreatment tests/procedures must be completed within the guidelines specified 
on the test schedule. 
6.3 
All required baseline symptoms must be documented   
6.4 
 
6.5 
 
 
Study drug availability checked.    
 
Rescreening is allowed.   
 
 
 
 
 
 
 

17 
 
 
7.0 Protocol Treatment 
 
7.1 
Treatment Schedule 
 
Actual weight will be used to calculate body surface area unless the subject has 
significant edema.  In that case, ideal body weight will be used as far as it is less than 
actual body weight.  Height needs to be recorded only once at screening (within 30 
days of therapy).  Weight needs to be monitored on Day 1 of each cycle.  The body 
surface area and drug dose should be recalculated only if the subject’s weight 
changes by > 10% during the course of the study from Cycle 1 day 1.   
 
Treatment may be given as inpatient or outpatient at discretion of treating physician.  
 
Treatment visits and chemotherapy infusions may be performed +/- 3 days of the 
“scheduled day” for reasons such as observed holidays, inclement weather, 
scheduling conflicts, etc.   This needs to be documented in the subject’s chart and/or 
research documents. 
 
Drug will be assigned to subjects by the Investigational Drug Service (IDS) at 
University of Iowa Hospitals and Clinics per their SOPs.  Drug accountability will also 
be the responsibility of the IDS.   
 
Agent 
Sequence 
Dose 
Level 0 
(mg/m2) 
Dose  
Level 
-1 
(mg/m2) 
Dose 
level -2 
(mg/m2) 
 
Route 
Day 
Cycle 
Frequency 
Nab-
Paclitaxel 
First 
100 
mg/m2 
80 
60 
IV (30 
min) 
1, 8 
q 21 days 
Gemcitabine 
Second 
1,000 
mg/m2 
800 
600 
IV (30 
min) 
1, 8 
q 21 days 
 
 
 
 
 

18 
 
 
8.0 Dosage Modification Based on Adverse Events 
 
Following  tables serve as a guide for dose modifications of chemotherapy during study period.. If 
multiple adverse events are observed, the one with greatest dose reduction should be followed. Dose 
delay due to toxicities, febrile neutropenia and due to other illnesses (except hematologic toxicities) for 
up to 3 weeks is allowed. If period of more than 3 weeks is required, then approval of principal 
investigator is needed. Dose modifications or clinical situations not covered in the section below need to 
be discussed with PI.   
 
8.1 
Nab-paclitaxel/Gemcitabine based on day of treatment counts  
 
8.11 
Dose Level modification Table 
 
Day of 
cycle 
ANC 
(cell/µL) 
Platelets ( 
µL) 
Dose 
level 
Nab-
paclitaxel 
(mg/m2) 
Gemcitabine 
(mg/m2) 
Day 1 
>1800 
>100,000 
0 
100  
1000 
Day 1 
>1500-
1800  
>100,000 
-1 
80 
800 
Day 1 
≤1500 
≤ 100,000 
 
Hold 
treatment 
until counts 
improve * 
Hold treatment 
until counts 
improve*  
Day 8 
> 1500  
 >100,000   
0 
100 
1000 
Day 8  
> 1000-
1500 
> 75-
100,000  
-1 
80 
800 
Day 8  
500- 
1000 
50,000-
75,000  
-2 
60 
600- 
Day 8  
≤ 499  
≤49,999  
Hold 
Hold 
treatment 
until counts 
improve ** 
Hold treatment 
until counts 
improve** 
ANC: Absolute neutrophil count  
* Modification for day 1:  
1. If patient had delay in chemotherapy in the previous cycle due to 
treatment related toxicities the next cycle will start at  1 dose level below 
the prior dosing level and dose  will not be re-escalated. If dose reduction 
was required during the previous cycle, new cycle will start at the new 
reduced dose level. In the event that a patient was dose reduced directly 
from level 0 to level -2, the investigator may choose to re-challenge the 
patient at dose level -1 to assess the tolerability at this dose level.   
2. New cycle will begin after a week of chemotherapy break (no 
chemotherapy in the prior week).   

19 
 
 
** Modifications for Day 8:  
1. Follow dose levels as per table 8.11 and 8.2.   
2. If ANC or Platelet counts are ≤ 499 or 49,999/ul respectively, hold 
chemotherapy by 1 week. Administer at 1 dose  level below the previous 
dosing level on day 15 if counts recovered to or above that dose level.   
3. If ANC or Platelet counts are ≤ 499 or 49,999/ul respectively on day 8 and 
day 15,  then day 8 chemotherapy will not be administered and on day 21 
patient will receive next cycle Day 1 at 1 dose level below the previous 
dosing level  if counts recovered to or above that dose level for Day 1. I If 
Day 8 therapy can’t be administered on day 8 or 15 while patient received 
Day 1 at dose level -2 for more than once then  patient  will be taken off the 
study and will be monitored for events.   
 
 
8.12 
Please note that there are two different dose adjustment schedules: 
1) Adjustment at the beginning of the new course of therapy, based 
upon labs on the scheduled day of treatment and upon the worst 
adverse event encountered in the previous course; 
2) Adjustment or actions based on adverse events observed since the 
start of the course or during the interval until the start of the next 
cycle. 
 
8.13 
Noted that all dose modification should be based on the worst preceding 
adverse event and are relative to the starting dose.  
If several adverse events with different grades or severity occur at the same 
time, the dose reductions should be based on the greatest reduction 
applicable. 
 
 
 
 
 
8.2 
Dose modifications based on interval adverse events (other than day 1) 
 
Please refer to Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03 unless otherwise specified. 
 
 
 
CTCAE v.4.03 
category 
Adverse Events 
Agents 
Action 
Blood and 
lymphatic 
system 
disorders 
 
 
Hematologic  
Nab-paclitaxel 
Gemcitabine 
 
Any time during cycle or on Day 15: (when 
noticed during first 2 cycles or beyond) 
ANC < 100/ul and/or  
PLT  <-10,000/ul 
 
Consider decrease to 1 dose level below 
the prior dosing level with the next 
scheduled dose. 
Consider growth factor support  

20 
 
 
 
 
 
 
 
Nervous System 
disorders 
 
Respiratory, 
thoracic and 
mediastinal 
disorders 
 
 
 
 
Thrombotic microangiopathy (thrombotic 
thrombocytopenic purpura, hemolytic 
uremic syndrome) 
Gemcitabine 
Discontinue patient from trial  
Neuropathy (paresthesia, peripheral 
motor neuropathy, peripheral sensory 
neuropathy) ≥ grade 3 
Nab-paclitaxel 
Omit Nab-paclitaxel until ≤ grade 1. .  
Pneumonitis ≥ grade 2 
Gemcitabine 
Nab-paclitaxel  
Discontinue therapy of both Gemcitabine 
and Abraxane and discontinue patient 
from trial. Initiate steroid therapy if due 
to drug therapy  
Other non-
hematologic 
adverse events 
 
Intolerable Grade 3 
Nab-paclitaxel 
Gemcitabine 
Hold gemcitabine and  Abraxane until 
resolution to ≤ grade 1. Then resume 
therapy at next lower dose as scheduled.  
If occurs recurrently while patient is at 
dose level -2  then consider taking 
patient off study and monitor for events.  
Grade 4 (except pulmonary embolism) 
Nab-paclitaxel 
Gemcitabine 
Discontinue appropriate drug(s). Patients 
must be followed on study until adverse 
event is resolved or stable. 
  
 
 
 
 
 

21 
 
 
8.3 
Dose modifications at the time of re-treatment (start of new cycle) 
 
Adjustment should be based on worst adverse event encountered during the 
previous cycle. 
 
 
 
CTCAE v.4.03 
category 
Adverse Events 
Agents 
Action 
Blood and 
lymphatic 
system 
disorders 
ANC < 1500 or  
PLT < 100,000 
Nab-paclitaxel 
Gemcitabine 
Hold all study drugs until ANC and PLT 
above these values (reevaluate every 
week until recovery). 
See above 8.11    
Renal 
dysfunction  
Creatinine  1.5 -3.0 x ULN  
Gemcitabine 
Consider 1 dose level below the prior 
dosing level.  
Creatinine > 3 x ULN  
 
Discontinue on study therapy  
Hepatobiliary 
disorders 
 
 
Nervous system 
disorders 
Bilirubin > 1.5 x ULN and/or AST or ALT > 5 
x ULN  
Nab-paclitaxel 
Hold nab-paclitaxel until these 
chemistries get within parameters of 
administration. Perform appropriate 
work up. Continue Gemcitabine.  
Neuropathy (paresthesia, peripheral 
motor neuropathy, peripheral sensory 
neuropathy) ≥ grade 3 
Nab-paclitaxel 
Omit Nab-paclitaxel until ≤ grade 1.. 
Continue with Gemcitabine 
Neuropathy grade 4 
Patients with grade 4 toxicity should be 
removed from study 
 
 
Respiratory, 
thoracic and 
mediastinal 
disorders 
Pneumonitis ≥ grade 2 
Gemcitabine 
Nab-paclitaxel 
Discontinue study drugs and begin 
supportive care.  
Other non-
hematologic 
adverse events 
Intolerable grade 3 
Nab-paclitaxel 
Gemcitabine 
Omit appropriate drug(s) until ≤ grade 1, 
and decrease 1 dose level below the 
prior dosing level.  If recurrent grade 3 
toxicity at dose level -2, then discontinue 
patient from study therapy 
Grade 4 
 
Discontinue study therapy. Patients must 
be followed on study until adverse event 
is resolved or stable. 
(If all study drugs are discontinued, 
patient goes to Event Monitoring.) 
 
8.4 
 
Modification of regimen 
 
If the doublet proves intolerable based on the AEs observed in the first 6 patients, 
the trial would continue using only single agent nab-paclitaxel. If greater than 3 
patients experience grade 3-4 non-hematologic toxicities or grade 4 hematologic 
toxicities with the first 6 patients treated during the first 2 cycles, it will be concluded 
the doublet is not tolerable in this patient population and the study would continue 
with single agent nab-paclitaxel. The grade 4 toxicity of neutropenic fever would be 
grade 4 at any time in the cycle.  
9.0 Ancillary Treatment 
 

22 
 
 
9.1 
Patient should receive full supportive care while they are on the study including blood 
product transfusion support, antibiotics, and treatment of other new of underlying 
medical conditions.  
All blood products and other supportive medications (antiemetics, antidiarrheals, 
analgesics, etc.) that the patient receives from the start of study drugs until 30 days 
after final dose are to be recorded in the medical record and on the treatment form. 
9.2 
Use of hematopoietic growth factors such as G-CSF, GM-CSF, are allowed at discretion 
of treating physician. Erythropoietin is not allowed on this study  Oncologists are 
encouraged to follow ASCO or NCCN guidelines and to discontinue growth factor use 96  
hours prior to initiation of the next cycle of chemotherapy. Any use of growth factors 
must be documented in the patient’s record and on treatment form. 
 
9.21 
Use of colony-stimulating factors is allowed at physician discretion for patients 
with neutropenia necessitating dose reduction or delay as guided by dose 
modification table. 
 
9.22 
Therapeutic use in patients with serious neutropenic complications such as 
tissue infection, sepsis syndrome, fungal infection, etc., may be considered at 
physician discretion. 
9.3 
Both nab-paclitaxel and gemcitabine have low emetic risk (10-30% frequency of 
emesis). Antiemetics must be given and may include ondansetron or granisetron or 
palonosetron with or without aprepitant or other agents as clinically indicated. 
9.4  
For management of myalgia and/or arthralgia from nab-paclitaxel, treating physician 
may consider non-steroidal anti-inflammatory drug (NSAID), anti-histamines, or for 
severe cases, a narcotic analgesic agent. 
9.5  
The use of bisphosphonates (i.e., pamidronate, zoledronic acid) or denosumab will be 
allowed for palliation of pain or lytic lesions from bone metastasis. 
9.6 
Patient will not be allowed to enroll in a different clinical study in which investigational 
therapies are administered while receiving treatment in this study. However, exception 
may be granted for trials related to symptom management (Cancer Control) which do 
not interfere with the study drugs. Treating physician must consult the Study Chair 
regarding specific trial participation. 
 
 
 
 
 

23 
 
 
10.0 Adverse Event (AE) Reporting and Monitoring 
 
Toxicity will be scored using CTCAE Version 4.03 for toxicity and adverse event reporting.  A copy 
of the CTCAE Version 4.03 can be downloaded from the CTEP homepage 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). All 
appropriate treatment areas should have access to a copy of the CTCAE Version 4.03.  All adverse 
clinical experiences, whether observed by the investigator or reported by the patient, must be 
recorded, with details about the duration and intensity of each episode, the action taken with 
respect to the test drug, and the patient’s outcome.  The investigator must evaluate each adverse 
experience for its relationship to the test drug and for its seriousness. 
The investigator must appraise all abnormal laboratory results for their clinical significance.  If any 
abnormal laboratory result is considered clinically significant, the investigator must provide details 
about the action taken with respect to the test drug and about the patient’s outcome. 
10.1 
Monitoring, Recording and Reporting of Adverse Events 
 
10.11 
An adverse event (AE) is any noxious, unintended, or untoward medical 
occurrence that may appear or worsen in a subject during the course of a study. 
It may be a new intercurrent illness, a worsening concomitant illness, an injury, 
or any concomitant impairment of the subject’s health, including laboratory test 
values, regardless of etiology.  Any worsening (i.e., any clinically significant 
adverse change in the frequency or intensity of a pre-existing condition) should 
be considered an AE. A diagnosis or syndrome should be recorded on the AE 
page of the CRF rather than the individual signs or symptoms of the diagnosis or 
syndrome.   
 
10.12 
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be 
reported as an AE.  An overdose, accidental or intentional, whether or not it is 
associated with an AE, should be reported. Any sequela of an accidental or 
intentional overdose of an investigational product should be reported as an AE.  
If the sequela of an overdose is an SAE, then the sequela must be reported on an 
SAE report form and as an AE.  The overdose resulting in the SAE should be 
identified as the cause of the event on the SAE report form and CRF but should 
not be reported as an SAE itself. 
 
10.13 
In the event of overdose, the subject should be monitored as appropriate and 
should receive supportive measures as necessary. There is no known specific 
antidote for ABRAXANE® overdose. Actual treatment should depend on the 
severity of the clinical situation and the judgment and experience of the treating 
physician. 
 
10.14 
All subjects will be monitored for AEs during the study. Assessments may include 
monitoring of any or all of the following parameters: the subject’s clinical 
symptoms, laboratory, pathological, radiological or surgical findings, physical 
examination findings, or findings from other tests and/or procedures. 
 
10.15 
All AEs will be recorded by the Investigator from the time the subject signs 
informed consent until 28 days after the last dose of IP and those SAEs made 

24 
 
 
known to the investigator at any time thereafter that are suspected of being 
related to IP.  AEs and serious adverse events (SAEs) will be recorded on the AE 
page of the CRF and in the subject’s source documents.  All SAEs must be 
reported to Celgene Drug Safety within 24 hours of the Investigator’s knowledge 
of the event by facsimile, or other appropriate method, using the SAE Report 
Form, or approved equivalent form. 
10.2 
Evaluation of Adverse Events 
 
10.21 
Seriousness 
 
 
A serious adverse event (SAE) is any AE occurring at any dose that: 
• 
Results in death; 
• 
Is life-threatening (i.e., in the opinion of the Investigator, the subject is 
at immediate risk of death from the AE); 
• 
Requires inpatient hospitalization or prolongation of existing 
hospitalization (hospitalization is defined as an inpatient admission, 
regardless of length of stay); 
• 
Results in persistent or significant disability/incapacity (a substantial 
disruption of the subject’s ability to conduct normal life functions); 
• 
Is a congenital anomaly/birth defect; 
• 
Constitutes an important medical event 
 
 
Important medical events are defined as those occurrences that may not be 
immediately life threatening or result in death, hospitalization, or disability, but 
may jeopardize the subject or require medical or surgical intervention to prevent 
one of the other outcomes listed above.  Medical and scientific judgment should 
be exercised in deciding whether such an AE should be considered serious. 
 
 
Events not considered to be SAEs are hospitalizations for: 
• 
A standard procedure for protocol therapy administration. However, 
hospitalization or prolonged hospitalization for a complication of 
therapy administration will be reported as an SAE. 
• 
Routine treatment or monitoring of the studied indication not 
associated with any deterioration in condition. 
• 
The administration of blood or platelet transfusion as routine treatment 
of studied Indication.  However, hospitalization or prolonged 
hospitalization for a complication of such transfusion remains a 
reportable SAE. 
• 
A procedure for protocol/disease-related investigations (e.g., surgery, 
scans, endoscopy, sampling for laboratory tests, bone marrow 
sampling).  However, hospitalization or prolonged hospitalization for a 
complication of such procedures remains a reportable SAE. 
• 
Hospitalization or prolongation of hospitalization for technical, practical, 
or social reasons, in absence of an AE. 
• 
A procedure that is planned (i.e., planned prior to starting of treatment 
on study); must be documented in the source document and the CRF.  
Hospitalization or prolonged hospitalization for a complication remains a 
reportable SAE. 
• 
An elective treatment of or an elective procedure for a pre-existing 

25 
 
 
condition unrelated to the studied indication. 
• 
Emergency outpatient treatment or observation that does not result in 
admission, unless fulfilling other seriousness criteria above. 
 
 
If an AE is considered serious, both the AE page/screen of the CRF and the SAE 
Report Form must be completed.  For each SAE, the Investigator will provide 
information on severity, start and stop dates, relationship to IP, action taken 
regarding IP, and outcome. 
 
10.22 
Severity / Intensity 
 
 
For both AEs and SAEs, the Investigator must assess the severity / intensity of 
the event. 
 
 
The severity/intensity of AEs will be graded based upon the subject’s symptoms 
according to the current active minor version of the Common Terminology 
Criteria for Adverse Events (CTCAE, Version 4.03); 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#c
tc_40 
 
 
AEs that are not defined in the CTCAE should be evaluated for severity/intensity 
according to the following scale: 
• 
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; 
no medical intervention/therapy required 
• 
Grade 2 = Moderate – mild to moderate limitation in activity, some 
assistance may be needed; no or minimal medical intervention/therapy 
required 
• 
Grade 3 = Severe – marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, hospitalization is 
possible 
• 
Grade 4 = Life-threatening – extreme limitation in activity, significant 
assistance required; significant medical intervention/therapy required, 
hospitalization or hospice care probable 
• 
Grade 5 = Death - the event results in death 
 
 
The term “severe” is often used to describe the intensity of a specific event (as in 
mild, moderate or severe myocardial infarction); the event itself, however, may 
be of relatively minor medical significance (such as severe headache).  This 
criterion is not the same as “serious” which is based on subject/event outcome 
or action criteria associated with events that pose a threat to a subject’s life or 
functioning. 
 
 
Seriousness, not severity, serves as a guide for defining regulatory obligations. 
 
10.23 
Causality 
 
 
The Investigator must determine the relationship between the administration of 
IP and the occurrence of an AE/SAE as Not Suspected or Suspected as defined 
below: 
• 
Not suspected: Means a causal relationship of the adverse event to IP 
administration is unlikely or remote, or other medications, therapeutic 
interventions, or underlying conditions provide a sufficient explanation 

26 
 
 
for the observed event. 
• 
Suspected: Means there is a reasonable possibility that the 
administration of IP caused the adverse event. ‘Reasonable possibility’ 
means there is evidence to suggest a causal relationship between the IP 
and the adverse event. 
 
 
Causality should be assessed and provided for every AE/SAE based on currently 
available information. Causality is to be reassessed and provided as additional 
information becomes available. 
 
 
If an event is assessed as suspected of being related to a comparator, ancillary or 
additional IP that has not been manufactured or provided by Celgene, please 
provide the name of the manufacturer when reporting the event. 
 
10.24 
Duration 
 
 
For both AEs and SAEs, the Investigator will provide a record of the start and 
stop dates of the event. 
 
10.25 
Action Taken 
 
 
The Investigator will report the action taken with IP as a result of an AE or SAE, 
as applicable (e.g., discontinuation, interruption, or dose reduction of IP, as 
appropriate) and report if concomitant and/or additional treatments were given 
for the event. 
 
10.26 
Outcome 
 
 
The Investigator will report the outcome of the event for both AEs and SAEs.  All 
SAEs that have not resolved upon discontinuation of the subject’s participation 
in the study must be followed until recovered (returned to baseline), recovered 
with sequelae, not recovered or death (due to the SAE). 
 
10.27 
Abnormal Laboratory Values 
 
 
An abnormal laboratory value is considered to be an AE if the abnormality: 
• 
results in discontinuation from the study; 
• 
requires treatment, modification/ interruption of IP dose, or any 
other therapeutic intervention;  
• 
or is judged to be of significant clinical importance, e.g., one that 
indicates a new disease process and/or organ toxicity, or is an 
exacerbation or worsening of an existing condition. 
 
 
Regardless of severity grade, only laboratory abnormalities that fulfill a 
seriousness criterion need to be documented as a serious adverse event.  If a 
laboratory abnormality is one component of a diagnosis or syndrome, then only 
the diagnosis or syndrome should be recorded on the AE page/screen of the 
CRF.  If the abnormality was not a part of a diagnosis or syndrome, then the 
laboratory abnormality should be recorded as the AE.  If possible, the laboratory 
abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (e.g., record thrombocytopenia rather than 
decreased platelets). 

27 
 
 
10.3 
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 6 
months  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 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. 
 
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 OTHERAPPROPRIATE METHOD, WITHIN 24 HOURS OF THE 
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 Investigator’s knowledge of the event using the SAE Report Form, or approved 
equivalent form. 
 
Male Subjects 
 
If a female partner of a male subject taking investigational product becomes pregnant, 
the male subject taking IP should notify the Investigator, and the pregnant female 
partner should be advised to call their healthcare provider immediately. Male patients 
treated with nab-paclitaxel are advised not to father a child during and up to 6 months 
after treatment. 

28 
 
 
10.4  
Overdose 
 
10.41 
Overdose, as defined for this protocol, refers to Abraxane or Gemcitabine 
dosing only.   
 
10.42 
On a per dose basis, an overdose is defined as the following amount over the 
protocol-specified dose of Abraxane or Gemcitabine assigned to a given patient, 
regardless of any associated adverse events or sequelae. 
 
> 
10% over the protocol-specified dose 
 
10.43 
On a schedule or frequency basis, an overdose is defined as anything more 
frequent than the protocol required schedule or frequency.   
 
10.44 
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. 
 
10.45 
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.    
10.5 
Celgene Drug Safety Contact Information 
 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
 
 
 
 
 
 

29 
 
 
 
10.6 Adverse events to be graded at each evaluation per CTCAE v.4.03 
 
Category (CTCAE v 
4.03) 
Adverse Events/Symptoms 
Baseline 
Each 
evaluation 
Blood and lymphatic 
Anemia 
x 
x 
Febrile neutropenia (ANC < 1000/mcL and a single temperature 
of > 38.3 degrees C (101 degrees F) or a sustained temperature 
≥ 38 degrees C (100.4 degrees F) for more than 1 hour 
 
x 
Cardiac 
Chest pain (substernal discomfort due to insufficient myocardial 
oxygenation) or Acute coronary syndrome 
 
x 
Gastrointestinal 
Stool count/day 
x 
 
Diarrhea 
 
x 
Mucositis (oral) 
x 
x 
Nausea 
x 
x 
Vomiting 
x 
x 
General disorder 
and administration 
site conditions 
Edema (limbs) 
x 
x 
Fatigue/Malaise 
x 
x 
Fever (without neutropenia) 
 
x 
Infusion related reaction/infusion site extravasation 
 
x 
Pain 
x 
x 
Immune system 
Allergic reaction/serum sickness 
 
x 
Investigations 
AST, ALT, alkaline phosphatase increased 
x 
x 
Blood bilirubin increased 
x 
x 
Neutrophil count decreased 
x 
x 
Platelet count decreased 
x 
x 
Nervous system 
Peripheral sensory neuropathy 
x 
x 
Renal and urinary 
Acute kidney injury 
x 
x 
Respiratory, 
thoracic and 
mediastinal  
Dyspnea 
x 
x 
Pharyngeal mucositis 
x 
x 
Skin and 
subcutaneous tissue 
Rash (acneiform/maculo-papular) 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

30 
 
 
11.0 Treatment Evaluation Using RECIST 1.1 Criteria 
11.1 Schedule of Evaluations 
 
For the purposes of this study, patients should be reevaluated every 6 weeks. 
11.2 Definitions of Measurable and Non-measurable Disease 
 
11.21 
Measurable disease is defined as at least one lesion  which can be measured 
accurately at least in on dimension with a minimum size of:  
10 mm by CT Scan or MRI (slice thickness ≤ 5 mm)  
10 mm by caliper measurement by clinical exam  
20 mm by chest x-ray. However, CT is preferable. 
If it is malignant lymph-node then it must be ≥15 mm in short axis 
  
 
11.22 
Non-measurable disease: that do not fit the above criteria or leptomeningeal 
disease, effusions, ascites, blastic lesions in bones, simple cysts or lesion that 
have received prior local therapies unless developed progression afterwards.   
11.3 Guidelines for Evaluation of Measurable Disease 
 
11.31 
Measurement Methods: 
• 
All measurements should be recorded in metric notation using a ruler or 
calipers. 
• 
The same method of assessment and the same technique must be used 
to characterize each identified and reported lesion at baseline and 
during follow up. Imaging-based evaluation is preferred to evaluation by 
clinical examination when both methods have been used at the same 
evaluation to assess the antitumor effect of a treatment. 
 
11.32 
Acceptable imaging modalities for measurable disease: CT scan (conventional 
and spiral), MRI, chest x-ray, and physical examination. 
• 
Conventional CT and MRI must be performed with slice thickness of ≤ 5 
mm. 
 
 
11.33 
Measurement at Follow-up Evaluation: 
• 
A subsequent scan will be obtained in  6 weeks (after 2 more 
chemotherapy cycles as scheduled) following initial documentation of an 
objective status of either complete response (CR) or partial response 
(PR). 
• 
In the case of stable disease (SD), follow-up measurements must have 
met the SD criteria at least once after study entry at a minimum interval 
of 6 weeks (see Section 11.44). 
• 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has 
met criteria for response or stable disease will be considered if possible  
to differentiate between response or stable disease (an effusion may be 
a side effect of the treatment) and progressive disease. 

31 
 
 
11.4 Measurement of Effect 
 
11.41 
Target Lesions 
 
 
All measurable lesions (as defined in Section 11.21) up to a maximum of 5 lesions 
representative of all involved organs should be identified as target lesions and 
recorded and measured at baseline. If the protocol specified studies are 
performed, and there are fewer than 5 lesions identified (as there often will be), 
there is no reason to perform additional studies beyond those specified in the 
protocol to discover new lesions. To meet study criteria, 1 lesion is enough.   
 
For any one organ, no more than 2 lesions need to be measured. Target lesions 
should be selected on the basis of their size (lesions with the longest diameter) 
and their suitability for accurate repetitive measurements (either by imaging 
techniques or clinically). 
 
A sum of the longest diameter (LD) for all target lesions (short axis for lymph 
nodes) will be calculated and reported as the baseline sum LD. The baseline sum 
LD will be used as reference to further characterize the objective tumor response 
of the measurable dimension of the disease. 
 
11.42 
Non-Target Lesions 
 
 
All other lesions (or sites of disease) should be identified as non-target lesions 
and should also be recorded at baseline as present or absent. Measurements are 
not required. . 
 
11.43 
Response Criteria 
 
 
11.431 
All identified sites of disease must be followed on re-evaluation. 
Specifically, a change in objective status to either a PR or CR cannot be 
done without rechecking all identified sites (i.e., target and non-target 
lesions) of pre-existing disease. 
 
 

32 
 
 
 
 
11.432 
Evaluation of Target Lesions 
 
 
 
Complete Response 
(CR) 
Disappearance of all target lesions 
Partial Response 
(PR) 
At least a ≥30% decrease in the sum of the 
LD of target lesions taking as reference the 
baseline sum LD. 
Progression of 
disease (PD) 
At least a ≥20% increase in the sum of 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 and as defined by 
RECIST 1.1 guidelines. 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD 
taking as references the smallest sum LD. 
 
 
11.433 
Evaluation of Non-Target Lesions 
 
 
 
Complete Response 
(CR) 
Disappearance of all non-target lesions 
Progression of 
disease (PD) 
Appearance of one or more new lesions. 
Unequivocal progression of existing non-
target lesions. 
Stable disease (SD) 
Persistence of one or more non-target 
lesions. 
 
11.44 
Overall Objective Status 
 
 
The overall objective status for an evaluation is determined by combining the 
patient’s status on target lesions, non-target lesions, and new disease as defined 
in the following table. 
 
 
Target lesions 
Non-target 
lesions 
New lesions 
Overall objective 
status 
CR 
CR 
None 
CR 
CR 
SD 
None 
PR 
PR 
Non-PD 
None 
PR 
SD 
Non-PD 
None 
SD 
PD 
Non-PD 
None 
SD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
11.45 
Residual Disease: In some circumstances it may be difficult to distinguish 
residual disease from normal tissue. When the evaluation of complete response 
depends upon this determination, it is recommended that the residual lesion be 
investigated (fine needle aspirate/biopsy) before confirming the complete 
response status. 
 
11.46 
Symptomatic Deterioration: Patients with global deterioration of health status 
requiring discontinuation of treatment without objective evidence of disease 

33 
 
 
progression at that time, and not either related to study treatment or other 
medical conditions, should be reported as PD due to “symptomatic 
deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment due to symptomatic 
deterioration: 
 
• 
Clear worsening of tumor-related symptoms convincing enough to call 
clinical progression of the tumor as determined by the treating physician 
or investigator.   
• 
Significant decline in performance status due to increasing tumor burden 
as determined by the treating physician or investigator.  
11.5 
Formal statistical definitions of analysis variables involving response and disease 
progression are contained in Section 15.0. 
 
12.0 Descriptive Factors  
12.1 
Prior chemotherapy: Cisplatin and etoposide, Carboplatin and etoposide or others.   
 
 
13.0 Treatment and Follow-up Decision at Evaluation of Patient 
13.1 
Patients who are CR, PR, or SD will continue treatment per protocol. 
13.2 
Patients who develop PD while receiving therapy will go to the event-monitoring phase. 
13.3 
Patients who go off protocol treatment for reasons other than PD will go to the event 
monitoring phase per Section 16.0. 
13.4 
The criteria for discontinuation of study therapy are: 
• 
Tumor progression 
• 
Patient refusal 
• 
Unacceptable adverse events 
• 
Intercurrent illness which would affect assessments of clinical status to a 
significant degree or require discontinuation of study treatment 
• 
Administration of non-protocol anti-tumor therapy 
• 
Treatment delay >3 weeks, or need for recurrent dose modifications that clearly 
indicates intolerability of the regimen as judged by the treating physician or 
investigator.  
• 
Pregnancy 
• 
Loss to follow up 
• 
Symptomatic deterioration as defined in Section 11.46 
13.5 
10. If a patient has discontinued study therapy for any reason, the patient enters the 
event monitoring phase of the trial, in which, every effort will be made to follow all 
patients every 2 months ± 3 weeks for progression. Once a subject experiences 
confirmed disease progression or starts a new anti-cancer therapy, they will be 
contacted by telephone every 12 ± 4 weeks to assess for survival status until death, 
withdrawal of consent, or 3 years from registration or the end of the study, whichever 
occurs first.   

34 
 
 
 
13.6 
Once a patient enters the event-monitoring phase, the next treatment used for the 
patient’s small cell lung cancer (chemotherapy, radiation, etc.) will be attempted to be be 
documented on the Event Monitoring Form. 
13.7 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Event monitoring will be required per Section 16.0 
of the protocol. 
• 
 
 
 
13.8 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 
 
 

35 
 
 
14.0 Drug Information 
14.1 
nab-Paclitaxel 
 
14.11 
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 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 (Ibrahim, 2002; Sparreboom, 
1999; ten Tije, 2003). nab-Paclitaxel 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). 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 (Gelderblom, 2001; Venkataramanan, 1986; Pfeifer, 1993; Allwood, 
1996; Song, 1996; Xu, 1998).  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; non-PVC-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 (Ibrahim, 2002; Nyman, 2004). 
 
 
As of October 2014, nab-paclitaxel is approved under the trade name of 
ABRAXANE® in 51 countries worldwide for the treatment of patients with 
metastatic breast cancer. ABRAXANE® is also approved in 8 countries worldwide for 
the first-line treatment of locally advanced or metastatic non-small cell lung cancer 
(NSCLC), and in 40 countries for the first-line treatment of metastatic 
adenocarcinoma of the pancreas, and it is approved in Japan for treatment of 
advanced gastric cancer. 

36 
 
 
 
14.12 
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. 
 
14.13 
Adverse Events 
 
 
As of 06 Oct 2014, approximately 11,867 subjects have been treated with nab-
paclitaxel in clinical studies, with 3,905 in the Celgene development program 
worldwide and an estimated 7,962 in non-Celgene-sponsored studies globally.  It is 
estimated that cumulative exposure to nab-paclitaxel during marketing experience 
is approximately 296,427 patients.  Therefore, overall estimated cumulative 
exposure to nab-paclitaxel during clinical trials and commercial experience is 
approximately 308,294 patients. Clinically significant adverse drug reactions 
identified during clinical trials or post-marketing surveillance, considered by 
Celgene to be at least possibly associated with nab-paclitaxel, are provided below.  
 
 
Very common (≥ 10%): 
 
 
• 
anemia, red blood cell count decreased 
• 
febrile neutropenia, leukopenia, lymphopenia, neutropenia, 
thrombocytopenia  
• 
constipation   
• 
diarrhea  
• 
nausea   
• 
vomiting  
• 
abdominal pain, abdominal pain upper 
• 
stomatitis, mucosal inflammation  
• 
SMQ peripheral neuropathy  
• 
dizziness   
• 
headache  
• 
asthenia, fatigue  
• 
arthralgia, back pain, bone pain, chest pain, musculoskeletal pain, myalgia, 
pain in  extremity  
• 
edema, edema peripheral  
• 
pyrexia  
• 
chills   
• 
decreased appetite   
• 
dysgeusia  
• 
weight decreased   
• 
insomnia  

37 
 
 
• 
depression  
• 
cough  
• 
dyspnea  
• 
alopecia  
• 
rash, generalized rash, maculopapular rash   
• 
pruritus  
• 
nail disorder, nail discoloration, onycholysis   
• 
alanine aminotransferase increased, aspartate aminotransferase increased  
• 
dehydration  
• 
epistaxis 
• 
hypokalemia  
 
 
Common (≥ 1% to < 10% ): 
 
 
• 
bone marrow depression (failure), pancytopenia   
• 
candidiasis, cholangitis, folliculitis, lower respiratory infection, nail 
infection, oral candidiasis, pneumonia, upper respiratory tract infection, 
urinary tract infection  
• 
neutropenic sepsis, sepsis  
• 
bronchitis  
• 
pneumonitis 
• 
colitis, intestinal obstruction, small intestinal obstruction 
• 
dysphagia  
• 
dyspepsia 
• 
hyperbilirubinemia, blood alkaline phosphatase increased, blood bilirubin 
increased, blood creatinine increased  
• 
acute renal failure  
• 
hematuria  
• 
ataxia  
• 
muscle weakness  
• 
anxiety   
• 
nasal congestion   
• 
oropharyngeal pain  
• 
dry mouth, dry throat, nasal dryness  
• 
hemoptysis 
• 
pulmonary embolism, deep vein thrombosis  
• 
pleural effusion  
• 
flushing, erythema  
• 
dry skin   
• 
palmar-plantar erythrodysesthesia syndrome 
• 
hypertension  
• 
hypotension  
• 
tachycardia, cardiac failure congestive, palpitations  
• 
increased lacrimation 
• 
visual disturbance, visual Impairment vision blurred  
• 
infusion site extravasation, infusion site inflammation, infusion site rash, 
infusion site reaction, injection site reactions, injection site infection, 
extravasation  

38 
 
 
• 
lymphedema 
 
 
Uncommon (0.1% < 1.0%): 
 
 
• 
left ventricular dysfunction  
• 
arrhythmia, sinus bradycardia, atrioventricular block, supraventricular 
tachycardia   
• 
cardiac arrest  
• 
drug hypersensitivity, hypersensitivity, dermatitis allergic  
• 
thrombotic thrombocytopenic purpura, hemolytic uremic syndrome  
• 
cystoid macular edema, maculopathy  
• 
conjunctivitis  
• 
keratitis  
• 
fluid retention  
• 
malaise  
• 
lethargy  
• 
skin exfoliation  
• 
urticaria 
• 
erythema multiforme 
• 
facial palsy, VIIth nerve paralysis 
 
 
Elderly 
 
 
In subjects ≥ 65 years old with metastatic breast cancer who received nab-
paclitaxel monotherapy, a higher incidence of epistaxis, diarrhea, dehydration, 
fatigue and peripheral edema has been reported. 
 
 
nab-Paclitaxel in combination with gemcitabine  
 
 
In subjects with metastatic pancreatic cancer, who received the combination of 
nab-paclitaxel and gemcitabine, there may be an increase of sepsis.  Pneumonitis 
appears to occur more often (4%) when the two drugs are given together.  This 
requires early detection and treatment as it may be life-threatening or even fatal.  
In addition, acute renal or kidney failure and hemolytic uremic syndrome have 
been reported commonly and uncommonly, respectively, in combination of nab-
paclitaxel with gemcitabine. 
 
A very rare condition known as Posterior Reversible Encephalopathy Syndrome has 
occurred when gemcitabine is given alone or in combination with other 
chemotherapy medications. 
 
A very rare condition known as Capillary Leak Syndrome that causes leaking of fluid 
outside of blood vessels has occurred when gemcitabine is given alone or in 
combination with other chemotherapy medications. 
 
Additional side effects observed during post-marketing surveillance of 
gemcitabine, not otherwise noted above include: 
• 
vasculitis  
• 
gangrene 
 

39 
 
 
Additional side effects observed during post-marketing surveillance of nab-
paclitaxel, not otherwise noted above include:  
• 
cranial nerve palsies and vocal cord paresis  
• 
palmar-plantar erythrodysesthesia syndrome 
• 
photosensitivity reaction  
• 
Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema 
multiforme  radiation pneumonitis, radiation recall phenomenon 
 
 
Elderly 
 
 
In subjects ≥ 65 years old, who received nab-paclitaxel and gemcitabine, a higher 
incidence of diarrhea, decreased appetite, dehydration, and epistaxis has been 
reported compared to subjects < 65 years old.  In subjects ≥ 75 years old, a higher 
incidence of serious adverse reactions and adverse reactions leading to treatment 
discontinuation has been reported.  
  
Adverse drug reactions reported from post-marketing experience, even though 
their frequency is unknown, have been similar in type and severity to those 
reported in nab-paclitaxel clinical trials. 
 
14.14 
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 30-minute 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. 
 
 
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 

40 
 
 
proteins, using paclitaxel concentrations ranging from 0.1 to 50 μg/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-hydroxypaclitaxel.  Fecal excretion was approximately 20% of the total 
dose administered. 
 
 
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/pharmacodynamic 
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 

41 
 
 
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. 
 
14.15 
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 (AG001), 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, sites must fax a completed Drug Request 
Form to Celgene Corporation.  Allow at least 5 working days for drug shipment.  
There are no shipments on Fridays or holidays.  For re-supply of drug, please 
complete and fax the Drug Request Form as well as the Drug Accountability Log to 
Celgene Corporation at 908-673-2779. 
 
14.16 
Dosage form 
 
 
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.  
 
14.17 
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 

42 
 
 
information on the form, sign and date it, retain a copy in the study file, and return 
a copy to Celgene or its representative.   
 
14.18 
Storage and Stability 
 
 
Please see local prescribing information for ABRAXANE® for detailed instructions on 
the reconstitution, storage conditions and IV administration of ABRAXANE®. 
 
14.19 
Study Medication Administration 
 
 
ABRAXANE® is injected into a vein [intravenous (I.V.) infusion] over 30 minutes.  
The use of an in-line liter is not recommended.  Following administration, the 
intravenous line should be flushed with sodium chloride 9 mg/ml (0.9%) solution 
for injection to ensure complete administration of the complete dose, according to 
local practice. 
 
14.19a 
Reconstitution and use of ABRAXANE® 
 
 
Please see local prescribing information for ABRAXANE® for detailed instructions on 
the reconstitution and administration. 
 
14.19b 
Special Handling Instructions 
 
 
nab-Paclitaxel is a cytotoxic anticancer drug and, as with other potentially toxic 
paclitaxel compounds, caution should be exercised in handling nab-paclitaxel.  The 
use of gloves is recommended.  If nab-paclitaxel (lyophilized cake or reconstituted 
suspension) contacts the skin, wash the skin immediately and thoroughly with soap 
and water.  Following topical exposure to nab-paclitaxel, events may include 
tingling, burning and redness.  If nab-paclitaxel contacts mucous membranes, the 
membranes should be flushed thoroughly with water. 
 
14.19c 
Unused Study Drug Supplies 
 
 
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.  
 
14.19d 
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 (section 2.5) and Section 8.0 of this protocol. 
 
14.19e 
Administration of Study Drug to Patients with Hepatic Impairment 
For patients with mild hepatic impairment (total bilirubin greater than ULN and 
less than or equal to 1.5 x ULN and aspartate aminotransferase [AST] less than or 
equal to 10 x ULN), no dose adjustments are required, regardless of indication. 
Do not administer ABRAXANE® to patients with metastatic adenocarcinoma of the 
pancreas who have moderate to severe hepatic impairment. 
Do not administer ABRAXANE® to patients with total bilirubin greater than 5 x ULN 
or AST greater than 10 x ULN regardless of indication as these patients have not 
been studied. 

43 
 
 
 
14.19f 
Warnings and Precautions 
 
 
All warnings and precautions can be found in Section 5 of the Prescribing 
information.  Please note the following: 
 
 
Sensory Neuropathy 
Sensory neuropathy is dose- and schedule-dependent. The occurrence of Grade 1 
or 2 sensory neuropathy does not generally require dose modification.  If ≥ Grade 3 
sensory neuropathy develops, withhold ABRAXANE® treatment until resolution to 
Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC 
and pancreatic cancer followed by a dose reduction for all subsequent courses of 
ABRAXANE®.  
 
 
Hypersensitivity Reactions 
Hypersensitivity reactions rarely occur, but severe and sometimes fatal 
hypersensitivity reactions, including anaphylactic reactions, have been reported.  
If they do occur, minor symptoms such as flushing, skin reactions, dyspnea, lower 
back pain, hypotension, or tachycardia may require temporary interruption of the 
infusion.  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 experience a severe hypersensitivity reactions 
to ABRAXANE® should not be re-challenged.  The use of ABRAXANE® in patients 
previously exhibiting hypersensitivity to paclitaxel injection or human albumin has 
not been studied.  
 
 
Sepsis  
Sepsis occurred in 5% of patients with or without neutropenia who received 
ABRAXANE® in combination with gemcitabine. Biliary obstruction or presence of 
biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile 
(regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile 
neutropenia, interrupt ABRAXANE® and gemcitabine until fever resolves and ANC ≥ 
1500, then resume treatment at reduced dose levels per Section 2.5 of Prescribing 
Information. 
 
 
Pneumonitis  
Pneumonitis, including some cases that were fatal, occurred in 4% of patients 
receiving ABRAXANE® in combination with gemcitabine.  Monitor patients for signs 
and symptoms of pneumonitis and interrupt ABRAXANE® and gemcitabine during 
evaluation of suspected pneumonitis.  After ruling out infectious etiology and upon 
making a diagnosis of pneumonitis, permanently discontinue treatment with 
ABRAXANE® and gemcitabine. 
 
14.19g 
Albumin (Human) 
 
 
ABRAXANE® contains albumin (human), a derivative of human blood.  Based on 
effective donor screening and product manufacturing processes, it carries a 
remote risk for transmission of viral diseases.  A theoretical risk for transmission of 
Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of 
transmission of viral diseases or CJD have ever been identified for albumin. 
For adverse event reporting, please see section 10.0. 

44 
 
 
 
14.19h 
References 
 
 
• 
Allwood MC, Martin H. The extraction of diethylhexylphthalate (DEHP) 
from polyvinyl chloride components of intravenous infusion containers and 
administration sets by paclitaxel injection. Int J Pharm. 1996;127:65-71. 
• 
Gelderblom H, Verweij J, Nooter K, et al. Cremophor EL: The drawbacks 
and advantages of vehicle selection for drug formulation.  
• 
Eur J Cancer. 2001;37:1590−1598. 
• 
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.2002;8:1038−1044. 
• 
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. J Clin Oncol. 2004;22(14S):2027. 
• 
Pfeifer RW, Hale KN, Cronquist SE, Daniels M. Precipitation of paclitaxel 
during infusion by pump. Am J Hosp Pharm. 1993;50(12):2518-2521. 
• 
Song D, Hsu LF, Au JL. Binding of Taxol to plastic and glass containers and 
protein under in vitro conditions. J Pharm Sci. 1996;85(1):29-31. 
• 
Sparreboom A, van Zuylen L, Brouwer E, et al. Cremophor EL-mediated 
alteration        of  paclitaxel distribution in human blood: Clinical 
pharmacokinetic implications. Cancer Res. 1999;59:1454−1457. 
• 
Taxol US prescribing information. Princeton, New Jersey (USA): Bristol-
Myers Squibb Co.; March 2003. 
• 
ten Tije AJ, Verweij J, Loos WJ, et al. Pharmacological effects of formulation 
vehicles:  Implications for cancer chemotherapy.  
• 
Clin Pharmacokinet. 2003;42:665−685. 
• 
Venkataramanan R, Burckart GJ, Ptachcinski RJ, et al. Leaching of 
diethylhexylphthalate from polyvinyl chloride bags into intravenous 
cyclosporine solution. Am J Hosp Pharm. 1986;43(11):2800-2802. 
• 
Xu QA, Trissel LA, Zhang Y. Paclitaxel Compatibility with IV Express Filter 
Unit. Int J Pharm Compounding. 1998;2:243-245. 
 
 
 
14.2 
Gemcitabine (Gemzar®) 
 
14.21 
Preparation and storage 
 
 
Gemcitabine is supplied as a lyophilized powder in 200 mg and 1000 mg vials. 
Store intact vials at room temperature, do not refrigerate. Reconstitute the 200 
mg vials with 5 mL normal saline and the 1000 mg vials with 25 mL of normal 
saline (NS) to yield a concentration of 38 mg/mL. The reconstituted solution 
contains no preservatives and should be used within 24 hours. IV solutions in 250 
mL NS are stable for 24 hours. IV infusion in 250 mL NS over 30 (up to 60) minutes. 
(The maximum final concentration should not exceed 40 mg/mL - may dilute up to 
400 mL NS if needed). Do not use other diluents. The pH of the final solution is 
around 3. There may be some local irritation due to the low pH (pain at injection 
site). Gemcitabine is not a vesicant. 
 
14.22 
Known potential adverse events 

45 
 
 
 
 
 
 
 
• 
Hematologic: Myelosuppression (neutropenia, anemia, 
thrombocytopenia). 
• 
Dermatologic: Alopecia, transient mild erythematous pruritic rash, 
desquamation, Stevens Johnson Syndrome. 
• 
Gastrointestinal: Nausea, vomiting, anorexia, diarrhea. 
• 
CNS: Somnolence, agitation, insomnia, dizziness, paresthesia, confusion, 
convulsion, coma. 
• 
Renal: Renal dysfunction (increased BUN and creatinine values, 
proteinuria, hematuria, anuria), kidney damage. 
• 
Other: Headache, shortness of breath, mild chills and fever, arthralgias, 
tachycardia, flu-like symptoms, asthenia, malaise, and fatigue, weakness 
with or without myalgia, cardiac insufficiency, irregular heartbeat, 
elevated bilirubin, capillary leak syndrome. 
 
14.23 
Drug procurement 
 
 
HCCC Pharmacy 
 
14.24 
Nursing guidelines 
 
 
• 
Monitor CBC, differential, PLT prior to each dose. Myelosuppression is the 
principal dose-limiting factor. Modification may be considered by 
physician when bone marrow suppression is suspected. 
• 
Evaluate hepatic and renal function prior to initiation of therapy and 
periodically thereafter. Closely observe those patients with a history of 
preexisting mild renal impairment or hepatic insufficiency. Encourage 
hydration. 
• 
Gemcitabine clearance is affected by age and gender. Grade ¾ 
thrombocytopenia has been more common in elderly women. 
• 
Antiemetics may be required for probable mild to moderate nausea and 
vomiting. 
• 
Instruct patient in management of possible mild diarrhea and stomatitis. 
• 
Gemcitabine may cause fever in the absence of clinical infection. Fever 
can be accompanied by other flu-like symptoms. Instruct patient to report 
fever or flu-like symptoms to healthcare team. Treat symptoms as they 
occur. 
• 
Macular or finely granular maculopapular eruptions were experienced by 
30% of patients tested. Instruct patients to report any skin changes. 
• 
Instruct patient to report any respiratory changes. 

46 
 
 
15.0 Statistical Considerations and Methodology 
15.1 
Overview 
 
This protocol will assess the efficacy of nab-paclitaxel plus gemcitabine in patients with 
relapsed small cell lung cancer who progressed on first line therapy using a single stage 
phase II study design. 
 
15.11 
Primary Endpoint 
 
 
The primary endpoint of this trial is the response rate, defined as the sum of 
complete response rate and partial response rate, of greater than or equal to 
35% to be considered clinically meaningful.  
15.2 
Statistical Design 
 
15.21 
This study will assess the efficacy of nab-paclitaxel (Abraxane) plus gemcitabine 
in patients with relapsed small cell lung cancer whose cancer has progressed on 
first line therapy. This will confirm our pilot assessment and set hypotheses for a 
larger study. We’ve designed a single-stage phase II study in which the primary 
endpoint is the response rate to treatment. Response rate is defined as the sum 
of complete response rate and partial response rate. Current standard of care is 
topotecan which is estimated to have a response rate around 15%,  In addition, 
topotecan has a higher rate of serious adverse events when compared with 
Abraxane/Gemcitabine — These include  anemia (31%) for Topotecan vs 13% for 
Abraxane/gemcitabine), febrile neutropenia (10% for Topotecan vs 3% for 
Abraxane/gemcitabine, neutropenia (54% for Topotecan vs 38% for 
Abraxane/gemcitabine), thrombopenia (54% for Topotecan vs 13% 
Abraxane/gemcitabine) . Based on the phase I data, it is reasonable to expect a 
response rate closer to 35% for Abraxane plus Gemcitabine   
Within two-and-half years, we expect approximately 35 patients seen in our 
institution will meet our treatment criteria. 
A sample of size 28 achieves 82% power to detect a difference of 20% using a 
one-sided binomial exact test. The target significance level is 0.05 and the 
achieved level is 0.04. The results assume that the current standard of care has a 
response rate of 15%. 
There will be 28 evaluable patients (for the primary endpoint of response)  
accrued onto this study unless undue adverse events are encountered. We 
anticipated accruing an additional 4 patients to account for ineligibility, 
cancellation, major treatment violation, or other reasons. Having set our 
attrition rate to 12.5%, a total of 32 patients will be accrued onto this study in 
order to reach 28 evaluable patients.  
We will report the actual response rate among the evaluable subjects as well as 
an exact confidence interval around the observed response rate. In addition, the 
study will keep track of the proportion of adverse events (AE) and serious 
adverse events (SAE) so that SAE profiles can be compared between nab-
paclitaxel plus gemcitabine and current standard of care Topotecan. This report 
of toxicity profile is necessary so that the full benefit of nab-paclitaxel and 

47 
 
 
gemcitabine can be documented.  
Sample size needed: 32 patients to reach 28 evaluable 
 
15.22 
Accrual Time and Study Duration 
 
 
The number of patients anticipated to be accrued is 1.5 patients per month.  
Therefore, the accrual period for this Phase II study is expected to be 24 months. 
The final analysis can begin approximately 24 months after the trial begins, i.e. as 
soon as the last patient has been observed for 3 months. 
 
15.23 
Other Considerations 
 
 
Adverse events, quality/duration of response, and patterns of treatment failure 
observed in this study, as well as scientific discoveries or changes in standard 
care will be taken into account in any decision to terminate the study. 
15.3 
Analysis Plan 
 
The analysis for this trial will commence at planned time points (see 16.23) and at the time 
the patients have become evaluable for the primary endpoint. Such a decision will be 
made by the Statistician and Study Chair, in accordance with availability of data for 
secondary endpoints (e.g., laboratory correlates) and the level of data maturity. 
 
15.31 
Primary Endpoint 
 
 
• 
Response rate is defined to be either a CR or PR noted as the objective 
status on 2 consecutive evaluations at least 6 weeks apart. The 
confirmed response rate will be estimated by the number of confirmed 
responses in evaluable patients divided by the total number of evaluable 
patients. The appropriate confidence interval will be calculated based on 
the binomial distribution. 
 
15.32 
Secondary Endpoints 
 
 
• 
Survival time is defined as the time from Screening to death due to any 
cause. The distribution of survival time will be estimated using the 
method of Kaplan-Meier (1958). 
• 
Time to progression: Defined as the time from screening until tumor 
progression. Time to progression does not include deaths. Death will be 
censored.  
• 
 
• 
Progression-free survival time is defined as the time from registration to 
the earliest date of documentation of disease progression. If a patient 
dies without a documentation of disease progression the patient will be 
considered to have had disease progression at the time of their death. If 
the patient is declared to be a major treatment violation, the patient will 
be censored on the date the treatment violation was declared to have 
occurred. In the case of a patient starting treatment and then never 
returning for any evaluations, the patient will be censored for 
progression 1 day post-screening. The distribution of time to progression 
will be estimated using the method of Kaplan-Meier (1958). 

48 
 
 
• 
Adverse Events: All eligible patients that have initiated treatment will be 
considered evaluable for assessing adverse event rate(s). The maximum 
grade for each type of adverse event will be recorded for each patient, 
and frequency tables will be reviewed to determine patterns. 
Additionally, the relationship of the adverse event(s) to the study 
treatment will be taken into consideration. Adverse event monitoring 
will be done until 30 days after the last dose of nab-paclitaxel or 
Gemcitabine 
 
 
 
15.33 
Data & Safety Monitoring 
 
 
The principal investigator and the study statistician will review the study at least 
twice a year to identify accrual, adverse event, and any endpoint problems that 
might be developing. 
 
 
Adverse Event Stopping Rule 
 
 
The stopping rule specified below is based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in 
the event of either (1) the study re-opening to accrual or (2) at any time during 
the conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under investigation. The 
study team may choose to suspend accrual because of unexpected adverse 
event profiles that have not crossed the specified rule below. CTCAE v4.03 will 
be used to determine grading for these stopping rules. 
 
Accrual will be temporarily suspended to this study if at any time we observe 
events considered at least possibly related to study treatment (i.e., an adverse 
event with attribute specified as “possible”, “probable”, or “definite”) that 
satisfy the following: 
• 
If 3 or more patients in the first 15 treated patients (or 10% after 20 
patients have been accrued) experience a Grade 4 or higher non-
hematologic adverse event. 
 
We note that we will review Grade 4 and 5 adverse events deemed “unrelated” 
or “unlikely to be related”, to verify their attribution and to monitor the 
emergence of a previously unrecognized treatment-related adverse event. 
15.4 
Inclusion of Women and Minorities 
 
15.41 
This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
 
15.42 
There is no information currently available regarding differential effects of this 
treatment regimen in subsets defined by race, gender, or ethnicity, and there is 
no reason to expect such differences to exist. Therefore, although the planned 
analysis will, as always, look for differences in treatment effect based on racial 
and gender groupings, the sample size is not increased in order to provide 
additional power for subset analyses. 

49 
 
 
 
15.43 
According to the Surveillance, Epidemiologic, and End Results (SEER) database2, 
we expect 50% of patients will be women.  
 
 
 
 
 
 
 
 
 
16.0 Records and Data Collection Procedures  
 
All required clinical data will be entered into the Clinical Trials Management System, OnCore. Electronic 
case report forms (eCRF) will be designed and developed to capture study specific data. All corrections 
or revisions to the eCRFs must be made by authorized personnel and an audit trail will be maintained.  
 
All finalized data will be reviewed by the Investigator.  Data recorded in the eCRFs will be retained by the 
site in accordance with FDA regulations. 
 
17.0 References 
 
1. 
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: a cancer journal for clinicians 2014;64:9-
29. 
2. 
Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the 
United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results 
database. J Clin Oncol 2006;24:4539-44. 
3. 
Asai N, Ohkuni Y, Kaneko N, Yamaguchi E, Kubo A. Relapsed small cell lung cancer: treatment 
options and latest developments. Therapeutic advances in medical oncology 2014;6:69-82. 
4. 
Kalemkerian GP, Akerley W, Bogner P, et al. Small cell lung cancer. Journal of the National 
Comprehensive Cancer Network : JNCCN 2013;11:78-98. 
5. 
Drugs approved for lung cancer. 2014. (Accessed 9/16/2014, 2014, at 
http://www.cancer.gov/cancertopics/druginfo/lungcancer.) 
6. 
Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel 
plus gemcitabine. The New England journal of medicine 2013;369:1691-703. 
7. 
Masters GA, Declerck L, Blanke C, et al. Phase II trial of gemcitabine in refractory or relapsed small-
cell lung cancer: Eastern Cooperative Oncology Group Trial 1597. J Clin Oncol 2003;21:1550-5. 
8. 
van der Lee I, Smit EF, van Putten JW, et al. Single-agent gemcitabine in patients with resistant 
small-cell lung cancer. Annals of oncology : official journal of the European Society for Medical 
Oncology / ESMO 2001;12:557-61. 
9. 
Smit EF, Fokkema E, Biesma B, Groen HJ, Snoek W, Postmus PE. A phase II study of paclitaxel in 
heavily pretreated patients with small-cell lung cancer. British journal of cancer 1998;77:347-51. 
10. 
Yamamoto N, Tsurutani J, Yoshimura N, et al. Phase II study of weekly paclitaxel for relapsed and 
refractory small cell lung cancer. Anticancer research 2006;26:777-81. 
11. 
Pillai RN, Owonikoko TK. Small cell lung cancer: therapies and targets. Seminars in oncology 
2014;41:133-42. 
12. 
von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and 
vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999;17:658-67. 

50 
 
 
13. 
O'Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care alone with 
supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol 
2006;24:5441-7. 
14. 
Eckardt JR, von Pawel J, Pujol JL, et al. Phase III study of oral compared with intravenous 
topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol 2007;25:2086-92. 
15. 
Lara PN, Jr., Moon J, Redman MW, et al. Relevance of Platinum-Sensitivity Status in 
Relapsed/Refractory Extensive-Stage Small-Cell Lung Cancer in the Modern Era: A Patient-Level 
Analysis of Southwest Oncology Group Trials. Journal of thoracic oncology : official publication of 
the International Association for the Study of Lung Cancer 2014. 
16. 
Wolff SN, Birch R, Sarma P, Greco FA. Randomized dose-response evaluation of etoposide in small 
cell carcinoma of the lung: a Southeastern Cancer Study Group Trial. Cancer treatment reports 
1986;70:583-7. 
17. 
Pallis AG, Agelidou A, Agelaki S, et al. A multicenter randomized phase II study of the 
irinotecan/gemcitabine doublet versus irinotecan monotherapy in previously treated patients with 
extensive stage small-cell lung cancer. Lung cancer 2009;65:187-91. 
18. 
Smyth JF, Smith IE, Sessa C, et al. Activity of docetaxel (Taxotere) in small cell lung cancer. The 
Early Clinical Trials Group of the EORTC. European journal of cancer 1994;30A:1058-60. 
19. 
Schmittel A, Knodler M, Hortig P, Schulze K, Thiel E, Keilholz U. Phase II trial of second-line 
bendamustine chemotherapy in relapsed small cell lung cancer patients. Lung cancer 
2007;55:109-13. 
20. 
Eckardt JR, Bentsion DL, Lipatov ON, et al. Phase II study of picoplatin as second-line therapy for 
patients with small-cell lung cancer. J Clin Oncol 2009;27:2046-51. 
21. 
Jassem J, Karnicka-Mlodkowska H, van Pottelsberghe C, et al. Phase II study of vinorelbine 
(Navelbine) in previously treated small cell lung cancer patients. EORTC Lung Cancer Cooperative 
Group. European journal of cancer 1993;29A:1720-2. 
22. 
Johnson DH, Greco FA, Strupp J, Hande KR, Hainsworth JD. Prolonged administration of oral 
etoposide in patients with relapsed or refractory small-cell lung cancer: a phase II trial. J Clin Oncol 
1990;8:1613-7. 
23. 
Pietanza MC, Kadota K, Huberman K, et al. Phase II trial of temozolomide in patients with relapsed 
sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA 
methyltransferase as a potential biomarker. Clinical cancer research : an official journal of the 
American Association for Cancer Research 2012;18:1138-45. 
24. 
Clamon G, Herndon J, Akerley W, Green M. Subcutaneous interleukin-2 as initial therapy for 
patients with extensive small cell lung cancer: a phase II trial of Cancer and Leukemia Group B. 
Lung cancer 1998;19:25-9. 
25. 
Clamon G, Herndon J, Perry MC, et al. Interleukin-2 activity in patients with extensive small-cell 
lung cancer: a phase II trial of Cancer and Leukemia Group B. Journal of the National Cancer 
Institute 1993;85:316-20. 
26. 
Masuda N, Matsui K, Negoro S, et al. Combination of irinotecan and etoposide for treatment of 
refractory or relapsed small-cell lung cancer. J Clin Oncol 1998;16:3329-34. 
27. 
Ramalingam SS, Foster J, Gooding W, Evans T, Sulecki M, Belani CP. Phase 2 study of irinotecan 
and paclitaxel in patients with recurrent or refractory small cell lung cancer. Cancer 
2010;116:1344-9. 
28. 
Cerqueira NM, Fernandes PA, Ramos MJ. Understanding ribonucleotide reductase inactivation by 
gemcitabine. Chemistry 2007;13:8507-15. 
29. 
Hoang T, Kim K, Jaslowski A, et al. Phase II study of second-line gemcitabine in sensitive or 
refractory small cell lung cancer. Lung cancer 2003;42:97-102. 

51 
 
 
30. 
Yardley DA, Hart L, Bosserman L, et al. Phase II study evaluating lapatinib in combination with nab-
paclitaxel in HER2-overexpressing metastatic breast cancer patients who have received no more 
than one prior chemotherapeutic regimen. Breast cancer research and treatment 2013;137:457-
64. 
31. 
Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel concentrations, 
and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared 
with cremophor-based paclitaxel. Clinical cancer research : an official journal of the American 
Association for Cancer Research 2006;12:1317-24. 
32. 
Wang B, Yang J, Luo D, et al. Complete remission and fatal interstitial pneumonitis related to nab-
paclitaxel in refractory small cell lung cancer: A case report and review of the literature. Thoracic 
Cancer 2012;3:84-7. 
33. 
Dazzi C, Cariello A, Casanova C, et al. Gemcitabine and paclitaxel combination as second-line 
chemotherapy in patients with small-cell lung cancer: a phase II study. Clinical lung cancer 
2013;14:28-33. 
34. 
Stinchcombe TE, Socinski MA, Lee CB, et al. Phase I trial of nanoparticle albumin-bound paclitaxel 
in combination with gemcitabine in patients with thoracic malignancies. Journal of thoracic 
oncology : official publication of the International Association for the Study of Lung Cancer 
2008;3:521-6. 
35. 
Weekly Paclitaxel Plus Gemcitabine as Second-line in Small Cell Lung Cancer. 2014. (Accessed 
9/21/2014, 2014, at http://clinicaltrials.gov/show/NCT00453167.) 
 
  
 
 

52 
 
 
Appendix I 
HCCC Clinical Trial Data and Safety Monitoring Plan (DSMP) 
 
Type of Clinical Trial: 
   Investigator-initiated (UI/HCCC) 
 Investigator-initiated, participating site 
 Pilot study 
 Phase I 
 Phase I/II 
   Phase II 
 Phase III 
 Compassionate-use drug protocol 
   Interventional Treatment 
 Interventional Non-Treatment 
 Non-Interventional 
 
 
Study risk-level:  
 Level 1—low risk of morbidity or death, * <1% of death or any adverse event  
 Level 2—risk of death* <1% or any adverse event 1% – 5%  
   Level 3—risk of death* 1% – 5% or grade 4 – 5 SAE 1% – 5%  
 Level 4—risk of death* >5% or grade 4 – 5 SAE >15%  
 Drugs being used on a “compassionate” basis  
 
* Risk of death” refers specifically to 100-day treatment-related mortality 
___________________________ 
 
Reporting and Monitoring Requirements:  
All institutional investigator initiated trials (IITs), regardless of assigned risk level are subject to routine 
DSMC monitoring activities which may include but are not limited to review of signed consent 
documents, eligibility and adverse event reporting.  
 
All institutional IITs have the following reporting requirements as part of their DSMP: 
• 
Provide an annual progress report to the DSMC and PRMC 
• 
Register subjects in HCCC’s Clinical Trial Management System, OnCore 
• 
Document Adverse Events  
• 
Document protocol deviations  
 
 
 
 

53 
 
 
Selected monitoring strategy based on risk-level:  
Risk Level 3  
Interventional treatment and non-treatment trials with a risk of death* (1% – 5% or grade 4 – 5 SAE 1% 
– 5%), e.g. moderate risk procedures Phase I or II clinical trials with available safety data in humans, 
studies treating subjects with placebo for a recognized disease, and trials with risk of radiation exposure.  
 
Study Safety Review 
An independent study monitor and/or the DSMC Chair (or designee), will review study data (provided by 
the PI/available in OnCore) and communicate with the PI at least annually.  A copy of this 
communication will be forwarded to the DSMC and PRMC Chairs.   
 
Additional Reporting Requirements 
- A scanned copy of the completed eligibility checklist, with screening information and PI signature, 
will be attached in OnCore for ongoing review by DSMC staff. 
- Serious adverse events will be entered directly into an OnCore SAE report by the research team.  
OnCore will send an automatic notification to DSMC Chair/acting Chair and staff for review.   
- The DSMC utilizes a risk-based monitoring approach. The trial's research records will be monitored 
at minimum once per year. Monitoring may be done more frequently depending on the protocol, 
risks to subjects, reported serious/adverse events, patient population and accrual rate.   A minimum 
of 25% of subject records will be monitored for the entire study.   
Monitoring will involve the following: 
• 
review eligibility of patients accrued to the study, 
• 
check for the presence of a signed informed consent, 
• 
determine compliance with protocol’s study plan, 
• 
determine whether SAEs are being appropriately reported to internal and external 
regulatory agencies,  
• 
compare accuracy of data in the research record with the primary source documents, 
• 
review investigational drug processing and documentation, 
• 
assess cumulative AE/SAE reports for trends and compare to study stopping rules. 
 
 
Routine Adverse Event Reporting 
 
For non-serious Adverse Events, documentation must begin from the first day of study treatment and 
typically continue through 30 days after the last dose of IP.  
 
Collected information should be recorded in the electronic/Case Report Forms (eCRF/CRF) for that 
subject. A description of the event, its severity or toxicity grade (according to NCI’s Common Toxicity 
Criteria (CTCAE)), onset and resolved dates (if applicable), and the relationship to the study drug should 
be included. Documentation should occur in real time. The principal investigator has final responsibility 
for determining the attribution of the event as it is related to the study drug. 
 

54 
 
 
Serious Adverse Event Reporting 
 
For any experience or condition that meets the definition of a serious adverse event (SAE), recording of 
the event must begin after signing of the informed consent and continue through the 30 day follow-up 
period after treatment is discontinued.  
Investigators must report to the DSMC any serious adverse events (SAE), whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64). SAEs must be reported 
via an OnCore SAE Report within 24 hours of learning of the event.  
 
An adverse event is considered serious if it results in ANY of the following outcomes:   
 
1. Death 
2. A life-threatening adverse event  
3. An adverse event that results in inpatient hospitalization OR prolongation of existing 
hospitalization for ≥ 24 hours  
4. A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
5. A congenital anomaly/birth defect.  
6. 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. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
 
Data Monitoring and Management  
All studies that undergo PRMC review and/or utilize HCCC Clinical Research Services (CRS) resources are 
required to register subjects in OnCore. Subject registration includes the following: 
• 
Consent date and the IRB approved consent used  
• 
Date of eligibility and eligibility status (eligible, not eligible) 
• 
On study date and subject’s disease site (and histology if applicable) 
• 
On treatment date (if applicable)  
 
 
Subject Data 
 
In addition to the subject registration and subject status data entered in OnCore for all HCCC trials, 
research staff also enters the subject study data into electronic case report forms (eCRFs) for HCCC 
investigator initiated studies. eCRFs are approved by the PI and statistician prior to study activation to 
ensure the most effective data acquisition. All information on eCRFs will be traceable to the source 
documents which are generally maintained in the subject’s file. eCRF data are expected to be entered 
into OnCore within 30 calendar days after a subject’s study visit. 
 
Forms Monitoring 
 
OnCore eCRF data are monitored on a routine basis (dependent on accrual) to ensure all mandatory 
fields are entered completely, accurately and within time requirements. The assigned DSMC monitor 
manages the logistics associated with the data monitoring review. Once the clinical trial is identified for 

55 
 
 
monitoring, the monitor arranges for a selection of cases to review from among the subjects registered 
in OnCore.  As part of the forms monitoring process, the assigned monitor will issue queries within the 
eCRF to resolve missing, incomplete and/or incorrect information. A member of the research team is 
expected to respond to monitoring queries within 14 business days.  
 
This process can often identify a misunderstanding or deficiency in protocol requirements early in the 
study and can improve data quality.  
 
Final Reports 
 
A summary of each subject’s data record is continually available to the PI, research staff, and DSMC from 
OnCore’s Biostat Console. The availability of this information is a valuable tool for the preparation of 
final reports and manuscripts as well as ongoing deficiency reports.