Clinical trial NCT03655080
Conditions: Cord Compression
Sponsor: Washington University School of Medicine
Start date: 2019-01-09; Completion date: 2021-06-15
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this research study is to look at a combination treatment of radiation therapy and a drug called Abraxane to treat epidural spinal cord compression.

Detailed description:

Arms: arm 1: * 10 fractions of 3Gy radiation therapy will be delivered.
* A total of 4 chemoradiation blocks should be delivered ideally in consecutive days
* On day 1 of the chemoradiation block, nab-paclitaxel is delivered in the morning followed by radiotherapy the latest possible and ideally at least 6 hours later (no earlier than 4 hours after the start of nab-paclitaxel)
* On day 2, radiotherapy is delivered in the morning, ideally within 24 hours from the start of nab-Paclitaxel infusion the previous day
* There will be 2 radiation fractions that won't be part of any chemoradiation block and can be placed anywhere before, after, or between blocks
Interventions: intervention 1: Radiation therapy intervention 2: nab-Paclitaxel
Intervention descriptions: intervention 1: Using the View Ray System intervention 2: * Dose 15 mg/m\^2
* Should be administered by IV over 30 minutes

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Version: 11/20/18 
 
Page 1 of 39 
 
 
NOVEL APPROACH OF PULSED ABRAXANE AND RADIOTHERAPY FOR 
IMPROVING AND MAINTAINING AMBULATION AFTER CANCER-RELATED 
CORD COMPRESSION 
 
Washington University School of Medicine 
Department of Radiation Oncology 
660 South Euclid Avenue, Campus Box 8224 
St. Louis, MO  63110 
 
Protocol #: 201809175 
Version Date: 11/20/18 
 
 
Principal Investigator: 
Hiram A. Gay, M.D. 
Phone: (314) 362-8516 
E-mail: hiramgay@wustl.edu  
 
Sub-Investigators 
 
 
Modality 
Peter Oppelt, M.D. 
 
 
Medical Oncology 
Esther Lu, Ph.D. 
 
 
Biostatistics 
 
 
Study Drug(s): 
 
nab-Paclitaxel (Abraxane)  
 
IND #: 
141137 
ClinicalTrials.gov #: 
NCT03655080 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 
 


Protocol Version: 11/20/18 
 
Page 2 of 39 
NOVEL APPROACH OF PULSED ABRAXANE AND RADIOTHERAPY FOR 
IMPROVING AND MAINTAINING AMBULATION AFTER CANCER-RELATED 
CORD COMPRESSION 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
07/30/2018 
Amendment #1 Version 
 
 
 
 
 
 
11/20/2018 
 
 
 


Protocol Version: 11/20/18 
 
Page 3 of 39 
NOVEL APPROACH OF PULSED ABRAXANE AND RADIOTHERAPY FOR 
IMPROVING AND MAINTAINING AMBULATION AFTER CANCER-RELATED 
CORD COMPRESSION 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Plan 
 
4 blocks of nab-paclitaxel and RT and 2 blocks of RT alone for a total of 10 
fractions of RT and 4 doses of nab-paclitaxel 
 
Blocks of nab-Paclitaxel and RT 
 
Day 1 
Day 2 
AM 
 
nab-Paclitaxel 
15 mg/m2 
3 Gy** 
PM 
 
3 Gy* 
 
 
*latest possible, ideally at least 6 hours later after the start of the nab-Paclitaxel infusion 
**earliest possible, ideally within 24 hours from the start of the nab-Paclitaxel infusion the previous 
day 
Avoid splitting Day 1 and Day 2 over a weekend. 
 
Blocks of RTDay 1 
3 Gy 
 
Blocks can be delivered in any order. For example, treatment can start with 1 or 2 RT blocks while 
chemotherapy is arranged, or an RT block can be strategically placed to avoid splitting a block of 
pulsed nab-Paclitaxel and RT over the weekend. 
Eligible Patients 
Patients with metastatic epidural spinal cord compression on MRI.   
 
Patients selected will be in Group I and II with ≤37 points. See Table 
1 for the scoring scale. 


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Table of Contents 
SCHEMA ........................................................................................................................................ 3 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 6 
1.1 
Epidural Spinal Cord Compression (ESCC) .................................................................... 6 
1.2 
nab-Paclitaxel (Abraxane)................................................................................................ 8 
1.3 
Rationale for Concurrent pulsed Paclitaxel with Radiotherapy ....................................... 9 
2.0 
OBJECTIVES .................................................................................................................... 11 
2.1 
Primary Objective .......................................................................................................... 11 
2.2 
Secondary Objectives ..................................................................................................... 11 
3.0 
PATIENT SELECTION .................................................................................................... 12 
3.1 
Inclusion Criteria ............................................................................................................ 12 
3.2 
Exclusion Criteria ........................................................................................................... 13 
3.3 
Inclusion of Women and Minorities............................................................................... 14 
4.0 
REGISTRATION PROCEDURES ................................................................................... 15 
4.1 
Confirmation of Patient Eligibility ................................................................................. 15 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 15 
4.3 
Assignment of UPN ....................................................................................................... 15 
5.0 
TREATMENT PLAN ........................................................................................................ 16 
5.1 
Chemoradiotherapy ........................................................................................................ 16 
5.2 
nab-Paclitaxel Premedication Administration ............................................................... 16 
5.3 
nab-Paclitaxel Agent Administration ............................................................................. 16 
5.4 
Dexamethasone .............................................................................................................. 16 
5.5 
Radiotherapy .................................................................................................................. 17 
5.6 
Evaluability .................................................................................................................... 17 
5.7 
Women of Childbearing Potential .................................................................................. 18 
5.8 
Duration of Therapy ....................................................................................................... 18 
5.9 
Duration of Follow-up .................................................................................................... 19 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 20 
6.1 
nab-Paclitaxel ................................................................................................................. 20 
6.2 
Radiotherapy .................................................................................................................. 21 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 22 
7.1 
Definitions ...................................................................................................................... 22 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
24 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University .............................................................................................................. 24 
7.4 
Reporting to Celgene Corporation ................................................................................. 24 
7.5 
Reporting to the FDA ..................................................................................................... 27 
7.6 
Timeframe for Reporting Required Events .................................................................... 27 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 28 
8.1 
nab-Paclitaxel Description ............................................................................................. 28 
9.0 
STUDY CALENDAR ....................................................................................................... 32 
10.0 DATA SUBMISSION SCHEDULE ................................................................................. 33 
11.0 DATA AND SAFETY MONITORING ............................................................................ 34 
12.0 STATISTICAL CONSIDERATIONS............................................................................... 35 


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12.1 Study design ................................................................................................................... 35 
12.2 Study endpoints .............................................................................................................. 35 
12.3 Sample size calculation .................................................................................................. 36 
12.4 Accrual ........................................................................................................................... 37 
12.5 Statistical analysis .......................................................................................................... 37 
13.0 REFERENCES .................................................................................................................. 38 
 
 


Protocol Version: 11/20/18 
 
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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Epidural Spinal Cord Compression (ESCC) 
 
 
Many cancer patients have asymptomatic or unrecognized epidural spinal cord 
 
compression (ESCC), while others present with ESCC, develop it during the course of 
 
illness, or it is detected during diagnostic imaging. For these reasons, the incidence of 
 
ESCC can only be estimated. One population-based study of spinal cord compression 
 
reported that the likelihood of a patient with cancer suffering cord compression in the five 
 
years before death was 2.5%, ranging from 0.2% in pancreatic cancer to 7.9% in 
 
myeloma (1). A study of malignant spinal cord compression in hospitalized patients with 
 
cancer identified an annual incidence of 3.4% (2). 
 
Autopsy studies suggested that 5% of patients dying with cancer have ESCC (3). Similar 
findings were noted in a Danish study based upon referrals to a regional treatment center, 
in which the incidence of ESCC in cancer patients rose from 4.4% to 6% between 1979 
and 1985 (4). 
 
 
In a population-based series of over 15,000 hospitalizations for ESCC, the three most 
common underlying cancer diagnoses were lung cancer, breast cancer, and multiple 
myeloma; the highest incidence rates were seen in patients with multiple myeloma (15%), 
Hodgkin and non-Hodgkin lymphomas (13.9%) and prostate cancer (5.5%) (2). 
Approximately 20% of cases of ESCC are the initial manifestation of malignancy (5). 
ESCC most commonly arises in the thoracic spine. Approximately 60% of cases occur in 
the thoracic spine, 30% in the lumbosacral spine, and 10% in the cervical spine (6). 
 
 
ESCC can have a number of symptoms including pain, motor findings, sensory findings, 
 
bladder and bowel dysfunction, and/or ataxia. Pain is usually the first symptom of ESCC, 
 
present in 83% to 95% of patients at the time of diagnosis (4,7). Weakness is present 
 
in 60% to 85% of patients with ESCC at the time of diagnosis (7,8). 
 
Conventional fractionation is routinely used to palliate the symptoms of ESCC. Most of 
the data on conventional radiotherapy for ESCC is retrospective in nature. Summarizing 
the retrospective data, 5125 patient ambulatory outcomes were described, although it is 
possible that in some cases, patient outcomes were described in different reports by the 
same authors at different time intervals. Based on the reported data, 4155 patients remained 
ambulatory after radiation (81%; range, 58%–100%). In the same group of papers, an 
average of 32% (range, 6%–67%) of patients who were nonambulatory before radiation 
became ambulatory after radiotherapy alone (9). 
 
Level 1 evidence shows that 60% to 74% of patients remain ambulatory after conventional 
radiation in the setting of cord compression, whereas 19% to 33% of nonambulatory 
patients are able to walk after radiation. Prospective series and retrospective data report 
rates of ambulation are somewhat more optimistic than the data from randomized trials, 
but there is no doubt that conventional radiation is able to provide ambulatory benefit to 
patients who undergo treatment. Ambulation status is correlated with survival. 


Protocol Version: 11/20/18 
 
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However, ambulation status may have less to do with radiation therapy than with the ability 
of the patient to walk before treatment, or the timing between radiation and the onset of 
symptoms, as only a minority of patients who are nonambulatory before treatment are able 
to walk after radiation. Pain is palliated in about 50% to 70% of patients treated with 
conventional radiotherapy (9). For multiple myeloma, 30 Gy in 10 fractions resulted in 
better functional outcome than short-course radiotherapy (10). 
 
A scoring system for predicting post-radiotherapy ambulatory rates was proposed taking 
into consideration the variables in Table 1 (11). Figure 1 illustrates the original five total 
score groups versus the ambulatory rate. These 5 groups were subsequently validated 
prospectively and simplified into 3 groups: I, II, and III which we will use in this clinical 
trial. (12) 
 
 
Table 1. Significant Prognostic Factors and Corresponding Scores. (11) 
 
 
 
 
 


Protocol Version: 11/20/18 
 
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Figure 1. Original scoring system. Post-radiotherapy ambulatory rates of the five patient 
groups formed according to the total score (A: ≤28 points; B: 29–31 points; C: 32–34 
points; D: 35–37 points; E: ≥38 points) (11) 
 
 
 
Figure 2. Simplified scoring system. Postradiotherapy ambulatory rates for patients of 
Group I (21–28 points), Group II (29–37 points), and Group III (38–44 points).This 
scoring system will be used in the trial (12) 
 
 
 
1.2 
nab-Paclitaxel (Abraxane) 
 
nab-Paclitaxel is a novel biologically interactive albumin-bound paclitaxel combining a 
protein with a chemotherapeutic agent in the particle form. nab-Paclitaxel for Injectable 
Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 
is currently indicated for the treatment of breast cancer after failure of combination 
chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy; 
for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in 
combination with carboplatin, in patients who are not candidates for curative surgery or 
radiation therapy; and for the first-line treatment of patients with metastatic 


Protocol Version: 11/20/18 
 
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adenocarcinoma of the pancreas, in combination with gemcitabine. 
 
Paclitaxel at the proposed dose and schedule has been studied in multiple lung cancer trials 
(Phase I, Phase I/II, Phase II, and Phase III) and deemed safe and effective (13-16). 
Compared to paclitaxel, nab-paclitaxel causes less neutropenia, hypersensitivity reactions, 
diarrhea and nausea than standard paclitaxel. 
 
1.3 
Rationale for Concurrent pulsed Paclitaxel with Radiotherapy 
 
 
The most radiosensitive phase of the cell cycle is G2/M. The radiosensitivity difference 
between G2/M and the most radioresistant phase can be an order of magnitude. 
Unfortunately mammalian tumor cells spend consistently around 1 hour in G2/M, while 
the rest of the phases in the cell cycle have high variability in length.  
 
One strategy to exploit the radiosensitivity of G2/M is pulsed paclitaxel. This strategy was 
based on preclinical translational research suggesting that a low dose of paclitaxel would 
maximally block most tumor cells in the G2/M cell cycle phase, the most radiosensitive 
phase, in 24 hours. Therefore, by administering paclitaxel three times a week and using an 
alternating schedule of radiotherapy, the radiation treatments would be optimally 
radiosensitized (17).  
 
This strategy has been studied clinically in lung cancer at the University of Rochester, and 
its safety and tolerability are well documented (see Table 2 and Table 3) (13-15,18). Much 
higher doses of radiotherapy were delivered in these studies (60 to 70 Gy in 30 to 35 
fractions) than the 30 Gy proposed in this trial, and with more cycles of chemotherapy. In 
addition, higher cumulative doses of paclitaxel were delivered (3 paclitaxel doses of 15 
mg/m2 per week, for 6 weeks), versus the proposed 4 doses of nab-paclitaxel of 15 mg/m2. 
In the phase III trial, patients had also received 2 to 4 cycles of induction chemotherapy, 
including cisplatin containing doublets: vinorelbine/cisplatin, gemcitabine/cisplatin, 
paclitaxel/cisplatin, docetaxel/cisplatin, or pemetrexed/cisplatin (15).  
 
Another trial designed by Dr. Gay treated lung cancer patients with 55 Gy, with the last 
week utilizing 3 Gy fractions. The same pulsed paclitaxel strategy was used, and 4 cycles 
of adjuvant gemcitabine and carboplatin were delivered (16). Spinal cord toxicity has not 
been observed in any of these clinical trials. Therefore, we anticipate that the proposed 
lower dose of 30 Gy in 10 fractions and only 4 doses of nab-paclitaxel of 15 mg/m2 will 
be safe and well tolerated, even in patients who may have received previous chemotherapy. 
 
 
 


Protocol Version: 11/20/18 
 
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Table 2. Arm 1 [paclitaxel at 15 mg/ m2, three times per week (Monday, Wednesday, and 
Friday) for 6 weeks] and Arm 2 (weekly paclitaxel at 45 mg/m2 for 6 weeks). (15) 
 
 
Table 3. Hematological toxicities: ≥ Grade 3. Arm 1 and 2 as in Table 2. (15) 
 
A particularly useful advantage of this strategy is the rapid tumor shrinkage (average tumor 
volume reduction at 1 month post-therapy was 69.9 ± 22.6% [standard deviation]) (18). A 
rapid reduction in tumor volume of a few millimeters may have a dramatic impact in a 
patient experiencing motor deficits, sensory deficits, and/or pain from ESCC. 
 
 
 
 


Protocol Version: 11/20/18 
 
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2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
 
To assess ambulatory status at 1 month in patients with ESCC treated with pulsed nab-
paclitaxel and radiotherapy. 
 
2.2 
Secondary Objectives 
 
1. To assess ambulatory status at 3 months, 6 months, 9 months, and 12 months in patients 
with ESCC treated with pulsed nab-paclitaxel and radiotherapy. 
2. To assess strength of lower extremities at 1 month in patients with ESCC treated with 
pulsed nab-paclitaxel and radiotherapy. 
3. To assess pain in the irradiated area in patients with ESCC treated with pulsed nab-
paclitaxel and radiotherapy at 1 month, 3 months, 6 months, 9 months, and 12 months. 
 
2.3 
Exploratory Objectives 
 
1. To determine the retreatment rate of patients with ESCC treated with pulsed nab-
paclitaxel and radiotherapy. 
2. To determine quality of life in patients with ESCC treated with pulsed nab-paclitaxel 
and radiotherapy at 1 month, 3 months, 6 months, 9 months, and 12 months. 
3. To determine the walking index in patients with ESCC using the walking index for 
spinal cord injury scale (WISCI II) in patients with ESCC treated with pulsed nab-
paclitaxel and radiotherapy at 1 month, 3 months, 6 months, 9 months, and 12 months. 
 
 
 
 


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3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Patients with ≤ 37 points per the scoring system in the table below. 
 
 
 
2. Histologically or cytologically confirmed diagnosis of cancer not of CNS or spinal 
column origin.  
 
3. MRI or CT evidence of metastatic epidural spinal cord compression. 
 
4. Patients who have started 30 Gy in 10 fractions are not excluded as long as 4 doses of 
chemotherapy could potentially be given. This means the latest nab-paclitaxel can start 
is the morning of the third fraction of radiotherapy. Radiotherapy should ideally be 
delivered at least 6 hours after the nab-paclitaxel infusion started. 
 
5. At least 18 years of age. 


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6. Normal bone marrow and organ function as defined below: 
a. Absolute neutrophil count ≥ 1,500 cells/mm3 
b. Platelets ≥ 100,000 cells/mm3 (transfusion independent, defined as not receiving 
platelet transfusions within 7 days prior to blood draw) 
c. Hemoglobin > 9.0 g/dL 
d. Total bilirubin ≤ 1.5 mg/dL 
e. AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN 
f. Alkaline phosphatase ≤ 2.5 x IULN (unless bone metastasis is present (< 5 x IULN) 
in the absence of liver metastasis) 
g. Creatinine ≤ 1.5 mg/dL 
 
7. Women of childbearing potential (defined as a sexually mature woman who (1) has not 
undergone hysterectomy or bilateral oophorectomy or (2) has not been naturally 
postmenopausal for at least 24 consecutive months) must: 
a. 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 treatment with nab-
paclitaxel and while on study; and 
b. Have a negative serum pregnancy test result at screening and agree to ongoing 
pregnancy testing during the course of the study and after the end of study therapy.  
This applies even if the subject practices true abstinence from heterosexual contact. 
 
8. 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 nab-paclitaxel 
discontinuation, even if he has undergone a successful vasectomy. 
 
9. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
3.2 
Exclusion Criteria 
 
1. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac 
arrhythmia. 
 
2. Pregnant and/or breastfeeding.  Women of childbearing potential must have a negative 
serum pregnancy test prior to study entry. 
 
3. Known HIV-positivity on combination antiretroviral therapy because of the potential 
for pharmacokinetic interactions with nab-paclitaxel.  In addition, these patients are at 
increased risk of lethal infections when treated with marrow-suppressive therapy.  
Appropriate studies will be undertaken in patients receiving combination antiretroviral 
therapy when indicated. 
 


Protocol Version: 11/20/18 
 
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4. Previous spinal cord radiotherapy that would overlap with the proposed treatment field. 
 
5. Spinal instability or bony retropulsion causing the cord compression. That is, 
mechanical, not tumor, cord compression. In these cases surgery may be indicated. 
 
6. Patients eligible for surgical decompression like laminectomy. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.  
 
 
 


Protocol Version: 11/20/18 
 
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4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
 
 


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5.0 
TREATMENT PLAN 
 
5.1 
Chemoradiotherapy 
 
 
 
A total of 10 fractions of 3 Gy each are delivered. A total of four chemoradiation blocks as 
described in the table below should be delivered ideally in consecutive days (Day 1 and 2 
ideally not separated by a weekend). On Day 1 of the chemoradiation block, nab-paclitaxel 
(15 mg/m2) is delivered in the morning followed by radiotherapy the latest possible and 
ideally at least 6 hours later (no earlier than 4 hours after the start of nab-paclitaxel). On 
Day 2, radiotherapy is delivered in the morning, ideally within 24 hours from the start of 
the nab-Paclitaxel infusion the previous day. There is flexibility in how these blocks are 
arranged. There will be 2 radiation fractions that won’t be part of any chemoradiation block 
and can be placed anywhere before, after, or between blocks. 
 
Chemoradiation block x 4 
 
 
Day 1*** 
Day 2*** 
AM 
 
nab-Paclitaxel 
15 mg/m2 
3 Gy** 
PM 
 
3 Gy* 
 
*latest possible, ideally at least 6 hours later after the start of the nab-Paclitaxel infusion 
**earliest possible, ideally within 24 hours from the start of the nab-Paclitaxel infusion the 
previous day 
***Avoid splitting Day 1 and Day 2 over a weekend. 
 
5.2 
nab-Paclitaxel Premedication Administration 
 
Patients do not require premedication prior to nab-paclitaxel administration, as 
hypersensitivity reactions are rare. In the unlikely event of a mild hypersensitivity reaction, 
premedication may be administered using the premedication regimen the institution 
typically uses for solvent based paclitaxel. In the rare event of a severe hypersensitivity 
reaction, discontinue nab-paclitaxel (but continue RT). However, it is recommended that 
patients receive granisetron 1mg prior to receiving nab-paclitaxel.  
 
5.3 
nab-Paclitaxel Agent Administration 
 
Albumin-bound paclitaxel should be administered by IV over 30 minutes. The drug can be 
administered either inpatient or outpatient depending on the condition of the patient. 
 
NOTE: It is not a requirement to use filter needles in the preparation of, or in-line filters 
during the administration of nab-paclitaxel. In any event, filters of pore-size less than 15 
micrometers must not be used.  
 
5.4 
Dexamethasone 
 
At the discretion of the physician, patients without neurologic deficits or with only 


Protocol Version: 11/20/18 
 
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radiculopathy and no massive invasion of the spine do not need to receive dexamethasone. 
(20) The rest of the patients with cord compression should receive a loading IV dose of 
dexamethasone (suggested dose 10 mg IV), followed by dexamethasone 4 to 6 mg every 6  
to 8 hours unless the physician thinks the potential for harm outweighs the benefits (i.e. 
diabetes, peptic ulcer disease, etc.). 
 
5.5 
Radiotherapy 
 
A total dose of 30 Gy in 10 consecutive daily fractions (Monday to Friday) will be delivered 
to the vertebral body(ies) causing the cord compression. Treatments can start during the 
weekend if necessary.  An additional 1-2 vertebral bodies above and below the target lesion 
may be treated at the discretion of the radiation oncologist. Other vertebral bodies with 
radiologic evidence of metastatic disease may be treated if the patient is experiencing pain, 
neurologic symptoms, or if the radiation oncologist anticipates tumor progression may 
result in future symptoms that may require palliation. Treatment technique could be 2D, 
3D conformal, or IMRT at the discretion of the radiation oncologist as long as treatment 
starts within 36 hours of the cord compression referral. Choose a beam arrangement to 
avoid or minimize radiation to the esophagus, head and neck mucosal surfaces and 
salivary glands, and small bowel. AP-PA beams may be preferred ONLY in the 
thorax if there is tumor in the lung, sternum, or mediastinum anterior to the vertebral 
bodies to be treated since this approach has been used to treat lung tumors and is well 
understood.  Avoid AP-PA arrangements encompassing the gastrointestinal tract and 
to a lesser degree the head and neck as feasible to minimize unnecessary toxicity. 
 
5.5.1 CT Simulation  
 
As per routine practice, computed tomography (CT) will be the primary image 
platform for targeting and treatment planning. 
 
5.5.2 Virtual Simulation and Contouring 
 
The CT scan will be exported to a commercially available virtual simulation 
software package. 
 
5.6 
Evaluability 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 28-day follow up after the conclusion 
of treatment or death. 
 
Response will be evaluated at 1 month and every 3 months for one year. A positive 
response to treatment will be scored for patients who were nonambulatory or paraplegic 
and then became ambulatory without an aid or ambulatory with an aid. A positive response 
to treatment will be scored for patients who were ambulatory with an aid and then became 
ambulatory without an aid. (11)  
 


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5.7 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as a sexually mature woman who (1) has not 
undergone hysterectomy or bilateral oophorectomy or (2) has not been naturally 
postmenopausal for at least 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 treatment with nab-paclitaxel and while on study; and have a negative serum 
pregnancy test result at screening and agree to ongoing pregnancy testing during the course 
of the study and after the end of study therapy.  This applies even if the subject practices 
true abstinence from heterosexual contact. 
 
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 nab-paclitaxel 
discontinuation, even if he has undergone a successful vasectomy. 
 
If a patient is suspected to be pregnant, treatment should be immediately discontinued.  In 
addition a positive urine test must be confirmed by a serum pregnancy test.  If it is 
confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 28 days after the last dose of nab-paclitaxel, the investigator must be notified in 
order to facilitate outcome follow-up. 
 
5.8 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue for 10 
fractions of RT (including 4 blocks of chemoradiation) or until one of the following criteria 
applies: 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious noncompliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 


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• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
5.9 
Duration of Follow-up 
 
Patients will be followed for one year after the completion of treatment. A phone 
evaluation, review of medical record, or physical follow-up visit ensues every 3 months 
for a year or until death, whichever occurs first.  Patients removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event.  
 
 
 


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6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
6.1 
nab-Paclitaxel 
 
Dose reductions or discontinuation may be needed based on severe hematologic, 
neurologic, cutaneous, or gastrointestinal toxicities. Use the table below as a guideline for 
dose modifications.  
 
Dose Level  
nab-Paclitaxel (mg/m
2)  
Starting Dose  
15 
-1  
10 
-2 
omit 
 
Sensory Neuropathy 
If ≥ Grade 3 sensory neuropathy develops, withhold nab-paclitaxel until resolution to 
Grade 1 or 2 followed by a dose reduction for all subsequent courses of nab-paclitaxel. 
  
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 nab-paclitaxel  should not be re-challenged.  The use 
of nab-paclitaxel in patients previously exhibiting hypersensitivity to paclitaxel injection 
or human albumin has not been studied.  
 
Administration of Study Drug to Patients with Abnormal Hematologic Function 
nab-Paclitaxel dosing should not be administered unless the patient’s ANC > 0.5 x 109 
cells/L and platelets > 50 x 109 cells/L.  If the ANC or platelets are not adequate on the day 
of administration, the dose for that day will be omitted. 
 
Hepatic Impairment 
For patients with mild hepatic impairment (total bilirubin > ULN and ≤ 1.5 x ULN and 
AST ≤ 10 x ULN), no dose adjustments are required regardless of indication. For patients 
with moderate hepatic impairment (total bilirubin between 1.5 x ULN and 5 x ULN), 
reduce nab-paclitaxel by one dose level. Do not administer nab-paclitaxel to patients with 
total bilirubin > 5 x ULN or AST > 10 x ULN regardless of indication as these patients 
have not been studied. 
 
Other Toxicities 
If toxicities are > grade 3, except for anemia and lymphopenia, treatment should be 
withheld until resolution to < grade 1 or baseline if baseline was greater than grade 1, then 


Protocol Version: 11/20/18 
 
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reinstituted, if medically appropriate, at the next lower dose level. 
 
6.2 
Radiotherapy 
 
No dose adjustments are permitted for radiotherapy. 
 
 


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Page 22 of 39 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outline below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as outlined 
in Section 7.2. 
 
The FDA requires that all serious and unexpected adverse events be reported as outlined in Section 
7.5.  In addition, any fatal or life-threatening adverse experiences where there is a reasonable 
possibility of relationship to study intervention must be reported. 
 
Celgene Corporation requires that all events being reported to the FDA be reported as outlined in 
Section 7.4. 
 
7.1 
Definitions 
 
7.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for 
all toxicity reporting.  A copy of the CTCAE version 5.0 can be downloaded from 
the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 
terms listed that should be used are those provided by the Department of Health 
and Human Services’ Office for Human Research Protections (OHRP).  A copy of 
this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
7.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention 


Protocol Version: 11/20/18 
 
Page 23 of 39 
to prevent one of the outcomes listed above 
 
All unexpected SAEs must be reported to the FDA. 
 
7.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
 
Events that are both serious AND unexpected must be reported to the FDA.  
 
7.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 
Life-threatening adverse experiences must be reported to the FDA. 
 
7.1.5 Unanticipated Problems 
 
Definition: 
 
• unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) 
the characteristics of the subject population being studied; 
• related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
and 
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
7.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
 


Protocol Version: 11/20/18 
 
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7.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial 
harm to subjects or others, or that materially compromises the rights or welfare of 
participants. 
 
7.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event.   
 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
• Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 
• Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
• Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies 
as a reportable event should be reported within 1 working day of the occurrence of the 
event or notification to the PI of the event. 
 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or 
any BJH or SLCH institution that has been reported to and acknowledged by HRPO as 
reportable.  (Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
a QASMC auditor. 
 
7.4 
Reporting to Celgene Corporation 
 
All SAEs must be reported to Celgene Drug Safety within 24 hours of the investigator’s 


Protocol Version: 11/20/18 
 
Page 25 of 39 
knowledge of the event by facsimile or other appropriate method using the SAE report 
form or approved equivalent form. 
 
For the purpose of regulatory reporting, Celgene Drug Safety will determine the 
expectedness of events of being related to nab-paclitaxel based on the Investigator 
Brochure.  In the United States, all suspected unexpected serious adverse reactions 
(SUSARs) will be reported in an expedited manner in accordance with 21 CFR 312.32. 
 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene in 
writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 
hours of being aware of the event.  The written report must be completed and supplied to 
Celgene by facsimile within 24 hours.  The initial report must be as complete as possible, 
including an assessment of the causal relationship between the event and the investigational 
product(s).  Information not available at the time of the initial report (e.g., an end date for 
the adverse event or laboratory values received after the report) must be documented on a 
follow-up report.  A final report to document resolution of the SAE is required.  The 
Celgene tracking number (AX-CL-OTHER-PI-13261) and the institutional protocol 
number should be included on SAE reports (or on the fax cover letter) sent to Celgene.  A 
copy of the fax transmission confirmation of the SAE report to Celgene should be attached 
to the SAE and retained with the patient records. 
 
7.4.1 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 28 days of the subject’s last dose of IP, 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 


Protocol Version: 11/20/18 
 
Page 26 of 39 
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. 
 
7.4.2 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. 
 
7.4.3 Overdose 
 
Overdose, as defined for this protocol, refers to nab-paclitaxel dosing only.   
 
On a per dose basis, an overdose is defined as the following amount over the 
protocol-specified dose of nab-paclitaxel assigned to a given patient, regardless of 
any associated adverse events or sequelae. 
PO 
any amount over the protocol-specified dose 
IV 
10% over the protocol-specified dose  
 
SC 
10% over the protocol-specified dose 
 
On a schedule or frequency basis, an overdose is defined as anything more frequent 
than the protocol required schedule or frequency.   
 
On an infusion rate basis, an overdose is defined as any rate faster than the protocol-
specified rate.  For nab-paclitaxel, an infusion completed in less than 25 minutes 
may increase Cmax by approximately 20%, therefore a nab-paclitaxel infusion 
completed in less than 25 minutes will meet the infusion rate criterion for an 
overdose. 
 
Complete data about drug administration, including any overdose, regardless of 
whether the overdose was accidental or intentional, should be reported in the case 
report form.    
 
7.4.4 Drug Safety Contact Information 
 
Celgene Corporation      
Global Drug Safety and Risk Management    
86 Morris Avenue 


Protocol Version: 11/20/18 
 
Page 27 of 39 
Summit, New Jersey 07901 
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 
Telephone: 1-908-673-9667 
Toll Free:    1-800-640-7854 
 
7.5 
Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER 
FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It is the 
responsibility of the investigator to report any unanticipated problem to the FDA as 
follows: 
 
• Report any unexpected fatal or life-threatening adverse experiences (Section 7.1.4) 
associated with use of the drug (i.e., there is a reasonable possibility that the 
experience may have been caused by the drug) by telephone or fax no later than 7 
calendar days after initial receipt of the information.   
• Report any serious, unexpected adverse experiences (Section 7.1.2), as well as 
results from animal studies that suggest significant clinical risk within 15 calendar 
days after initial receipt of this information.  
 
All MedWatch forms will be sent by the investigator or investigator’s team to the FDA at 
the following address or by fax: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Oncology Drug Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 1-800-FDA-0178 
 
7.6 
Timeframe for Reporting Required Events  
 
Adverse events will be tracked for 28 days after the last dose of nab-paclitaxel.  Late 
toxicities for RT will be collected for 1 year after the end of RT.  
 
 
 


Protocol Version: 11/20/18 
 
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8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
nab-Paclitaxel Description 
 
8.1.1 nab-Paclitaxel Description 
 
nab-Paclitaxel is a novel biologically interactive albumin-bound paclitaxel 
combining a protein with a chemotherapeutic agent in the particle form. nab-
Paclitaxel for Injectable Suspension (paclitaxel protein-bound particles for 
injectable suspension) (albumin-bound) is currently indicated for the treatment of 
breast cancer after failure of combination chemotherapy for metastatic disease or 
relapse within 6 months of adjuvant chemotherapy.  
 
Molecular formula: C47H51N014  
Chemical name: 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 
4,10-diacetate 2-benzoate 13 
Molecular weight: 853.91. 
 
8.1.2 Clinical Pharmacology 
 
nab-Paclitaxel is an antimicrotubule agent that promotes the assembly of 
microtubules from tubulin dimers and stabilizes microtubules by preventing 
depolymerization. This stability results in the inhibition of the normal dynamic 
reorganization of the microtubule network that is essential for vital interphase and 
mitotic cellular functions. Paclitaxel induces abnormal arrays or “bundles” of 
microtubules throughout the cell cycle and multiple asters of microtubules during 
mitosis. 
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
Absorption  
The pharmacokinetics of total paclitaxel following 30 and 180-minute infusions of 
nab-Paclitaxel 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 nab-Paclitaxel. Following 
intravenous administration of nab-Paclitaxel, 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 nab-Paclitaxel were independent 
of the duration of intravenous administration. The pharmacokinetic data of 260 
mg/m2 nab-Paclitaxel 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 
nab-Paclitaxel than for paclitaxel injection. There were no differences in terminal 
half-lives.  
 


Protocol Version: 11/20/18 
 
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Distribution  
Following nab-Paclitaxel 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 nab-Paclitaxel (6.2%) than with 
solvent-based paclitaxel (2.3%). This contributes to significantly higher exposure 
to unbound paclitaxel with nab-Paclitaxel compared with solvent-based paclitaxel, 
when the total exposure is comparable. In vitro studies of binding to human serum 
proteins, using paclitaxel concentrations ranging from 0.1 to 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. 
 
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 


Protocol Version: 11/20/18 
 
Page 30 of 39 
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 
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. 
 
The effect of pre-existing mild (creatinine clearance ≥60 to The metabolism of 
paclitaxel is catalyzed by CYP2C8 and CYP3A4. Caution should be exercised 
when administering ABRAXANE concomitantly with medicines known to inhibit 
(e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, 
gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce 
(e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either 
CYP2C8 or CYP3A4. 
 
8.1.4 Supplier(s) 
 
nab-Paclitaxel will be distributed by Celgene Corporation and labeled 
appropriately as investigational material for this study. Labels will bear Celgene’s 
name and address, the protocol number, product name, dosage form and strength, 
medication identification/kit number, lot number, expiry date, dosing instructions, 
storage conditions, the quantity of IP contained, and require education 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 nab-Paclitaxel upon identification and screening of a potential trial subject.  
 
Upon identification of a potential subject, sites must fax a completed Drug Request 


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Page 31 of 39 
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 to Celgene Corporation at 908-673-2779. 
 
8.1.5 Dosage Form and Preparation 
 
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.  
 
Please see local prescribing information for nab-paclitaxel for detailed instructions 
on the reconstitution and administration. 
 
8.1.6 Storage and Stability 
 
Please see local prescribing information for nab-paclitaxel for detailed instructions 
on the reconstitution, storage conditions, and IV administration of nab-paclitaxel. 
 
8.1.7 Administration 
 
nab-Paclitaxel is injected into a vein [intravenous (I.V.) infusion] over 30 minutes.  
The use of an in-line filter 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.  
 
8.1.8 Special Handling Instructions 
 
nab-Paclitaxel is a cytotoxic 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 paclitaxel, events may include tingling, 
burning and redness. If nab-Paclitaxel contacts mucous membranes, the 
membranes should be flushed thoroughly with water. 
 
 


Protocol Version: 11/20/18 
 
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9.0 
STUDY CALENDAR 
 
Scans and x-rays must be done no more than 8 weeks prior to SIM date. 
 
 
 
Screeninge 
Baseline 
Treatment 1 month 
+/- 1 
week 
Every 3 
months for 
1 year 
Informed consent 
X 
 
 
 
 
Physical exam, weight 
X 
 
 
 
 
CBC 
X 
 
Xd 
X 
 
CMP 
X 
 
Xd 
X 
 
Pregnancy testc 
X 
 
 
 
 
MRI or CT of cervical, 
thoracic, and/or lumbar 
spine 
X 
 
 
 
 
ECOG 
X 
 
 
X* 
X* 
Radiation 
 
 
Xa 
 
 
nab-Paclitaxel 
 
 
Xb 
 
 
Lower extremity strength 
 
X 
 
X 
X 
Ambulatory Status 
 
X 
 
X* 
X* 
Pain 
 
X 
 
X* 
X* 
WISCI II scale 
 
X 
 
X 
X 
SF-12 
 
X 
 
X* 
X* 
Adverse event 
assessment 
 
X ------------------------------------- X 
 
a. 10 daily fractions of 3 Gy 
b. 4 doses; refer to Section 5.1 for schedule 
c. Women of childbearing potential only 
d. Prior to the 3rd dose of nab-paclitaxel only 
e. +/- 2 days after start of RT 
 
*Office visit preferred. Phone call allowed if patient is unable to come to clinic. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Prior to starting treatment 
Treatment Summary Form 
End of treatment 
Toxicity Form 
Continuous 
Follow Up Form 
1 month, 3 months, 6 months, 9 months, 12 months 
Ambulatory Status Form 
Lower Extremity Strength Form 
Pain Form 
QOL Form 
Baseline, 1 month, 3 months, 6 months, 9 months, 12 
months 
MedWatch Form 
See Section 7.0 for reporting requirements 
 
 
 
 


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11.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least five patients have been enrolled) or one 
year after accrual has opened (if fewer than five patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, 
regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date 
of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date 
• Objectives of protocol with supporting data and list the number of participants who have 
met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have met 
the early stopping rules 
• Summary of toxicities 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
 
 
 


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12.0 
STATISTICAL CONSIDERATIONS 
 
12.1 
Study design 
 
This is a single arm phase II study. All enrolled patients will receive both radiation therapy 
and chemotherapy when the trial starts. A score using a scoring system in the table below 
will be calculated for every patient at the beginning of the trial. The patients with ≤ 37 
points per the scoring system are included in this study. Groups I and II include the patients 
with scores of 21-28 and 29-37, respectively.   
 
 
 
12.2 
Study Endpoints 
 
12.2.1 Primary Endpoint 
 
The primary endpoint includes ambulatory status at 1 month.  Ambulatory status is 
categorized as paraplegic, not ambulatory, ambulatory with aid (for example, with 
assistive device like walker or crutches), and ambulatory without aid. Ambulatory 
rate is defined as the proportion of number of patients who are either ambulatory 


Protocol Version: 11/20/18 
 
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with aid or ambulatory without aid among the enrolled patients.  
 
12.2.2 Secondary Endpoints 
 
The secondary endpoints include ambulatory status and pain in irradiated area every 
3 months until 1 year, strength assessment of lower extremities at 1 month. 
Ambulatory status at 3 months and every 3 months for 1 year, may be though phone 
interview.  Strength assessment is categorized as follows 
 
Strength assessment of lower extremities 
0/5 
no contraction 
1/5 
muscle flicker, but no movement 
2/5 
movement possible, but not against gravity (test the joint in its horizontal 
plane) 
3/5 
movement possible against gravity, but not against resistance by the 
examiner 
4/5 
movement possible against some resistance by the examiner 
5/5 
normal strength. 
 
Pain in irradiated area from 0-10 at 3 months and every 3 months for 1 year, may 
be though phone interview, medical record review, or office visit. 
 
12.2.3 Exploratory Endpoints 
 
The exploratory endpoints include retreatment rate, quality of score and walking 
index at 1 month and every 3 months until 1 year.  Retreatment rate is defined as 
the proportion of number of patients who are retreated during the study among the 
enrolled patients. Quality of life score and walking index are calculated using the 
12-Item Short Form Health Survey (SF-12) questionnaire and WISCI II, 
respectively. 
 
12.3 
Sample size calculation 
 
The sample size calculations are based on the primary endpoint – ambulatory status only.  
Patients with cord compression have a number of clinical characteristics listed in Table 1 
including type of primary tumor, interval from tumor diagnosis, visceral metastases, motor 
function before RT, and time of developing motor deficits. Each one is associated with a 
score and although these scores were simplified into groups I, II, and III (Figure 2) with 
ambulatory rates of  10.6 %, 70.9 %, and 98.5 % respectively, there is continuum of 
ambulatory rates seen in the clinic (Figure 3). We will focus this study on the worst two 
groups, group I and II. The reason is that these two groups are the ones that will gain the 
most from the proposed treatment. Focusing on these two groups will also reduce the 
number of patients needed to show a positive trial, and will accelerate the accrual rate. In 
the Rades et al. study, 21.6 % of patients were in group I, and 48.4% and in Group II. (12) 
Therefore, approximately 70 % of the cord compression patients referred for radiotherapy 
may be eligible for the trial, thus accelerating the accrual rate. 


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Figure 3. The total score, which ranged between 21 and 44 points in relation to the post 
radiotherapy ambulatory rate, given as a percentage. 
 
Using a one-sided Exact test, with a type I error of 0.05 and 80% power, a sample size of 
15 for group I is needed to detect the difference if the post-RT/Chemo ambulatory rate at 
one month is increased by 24% (34.6%) and a sample size of 16 for group I is needed to 
detect the difference if the post-RT/Chemo ambulatory rate at one month is increased by 
24% (94.9%). Powers were calculated using Power Analysis and Sample Size (PASS 15) 
software. 
   
12.4 
Accrual 
 
We estimate around 30 patients/year may be eligible for this trial at Washington University. 
We expect approximately 30% of the eligible patients for this trial to fall in Group I, and 
70 % in Group II based on the Rades et al. study (12). Approximately two years to enroll 
15 patients in Group I and one year to enroll 16 patients in Group II are anticipated. 
 
12.5 
Statistical analysis 
 
One-group proportion test using binomial distribution will be used for ambulatory rate at 
1 month, strength assessment of lower extremities at 1 month, and retreatment rate per 
group. The proportion and 95% CI will be calculated. The descriptive statistics will be used 
to summarize pain in irradiated area at 1 month. The generalized estimating equation 
(GEE) model with logit link function will be used to analyze the longitudinal data, in which 
the correlation among the repeated measures from the same patient need be considered. 
The autoregressive of first order as working correlation structure will be used. The GEE 
model includes time points only. The p-value will be estimated to assess whether the 
percentages across all time points are different. Least square means for ambulatory status 
at each time point will be estimated and the standard errors will be calculated within the 
use of GEE sandwich method when accounting for within-patient correlation. All analyses 
will be conducted using SAS (SAS Institute, Cary, NC) at the two-sided 5% significance 
level. 


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13.0 
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