Phase II Study of The Efficacy And Safety of Chloroquine (C) in CombinAtion With Taxane or Taxane-like (T) Chemo Agents in The Treatment of Patients With Advanced or Metastatic Breast Cancer Who Have Failed Anthracycline Chemo Base Therapy
Phase: PHASE2
Conditions: Breast Neoplasms, Breast Cancer
Sponsor: The Methodist Hospital Research Institute

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TMHRI IRB# 0811-0147 
 
 
 
CAT Trial 
PHASE II STUDY OF THE EFFICACY AND SAFETY OF CHLOROQUINE (C) IN 
COMBINATION WITH TAXANE OR TAXANE-LIKE (T) CHEMO AGENTS IN THE 
TREATMENT OF PATIENTS WITH ADVANCED OR METASTATIC BREAST CANCER WHO 
HAVE FAILED ANTHRACYCLINE BASED CHEMOTHERAPY. 
 
 
 
 
 
AMENDMENT: 7 
VERSION: 6 
DATE: 07/10/2013 
PHASE: II 
 
 
 
 
 
Jenny Chang, MD. 
Director, Methodist Cancer Center 
The Methodist Hospital/Weill Cornell University 
6445 Main Street, OPC 21 Houston Texas, 77030 
Phone: 713-441-0681 
Fax: 713-793-1642 
jcchang@tmhs.org 

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STUDY SUMMARY 
Title: 
Phase II Study of The Efficacy And Safety of Chloroquine (C) in CombinAtion 
With Taxane or Taxane-like (T) Chemo Agents in The Treatment of Patients With 
Advanced or Metastatic Breast Cancer Who Have Failed Anthracycline Chemo 
Base Therapy. 
Objectives: 
The primary objective: 
To determine the anti-tumor activity of the combination of Chloroquine + Taxane 
or Taxane-like chemo agents (Paclitaxel, Docetaxel, Abraxane, Ixabepilone) 
(C/T) measured by Overall Response Rate (ORR). 
The secondary objective(s): 
• To assess the safety and tolerability of the combination of C/T 
• To assess the response rate and tumor control rate (TCR) of patients receiving 
C/T 
• To assess the Time to Progression (TTP) of patients receiving C/T. 
• To assess the duration of response (DOR) of patients receiving C/T. 
Exploratory Objective(s): 
• To evaluate biomarkers for response and toxicity of the combination of C/T. 
Study 
Population: 
Patients with advanced or metastatic breast cancer, who have failed 
anthracycline based chemotherapy. 
Sample 
Size: 
47 patients 
Number of 
Centers: 
Single Institution: The Methodist Hospital Research Institute. Weill Cornell 
Medical College 
Treatment 
Plan: 
This is a phase II trial; 47 patients with diagnosis of advanced or metastatic 
breast cancer, who have failed anthracycline based therapy, will be enrolled in 
the study. Patients will receive Chloroquine (C) together with Taxane or Taxane-
like (Paclitaxel, Docetaxel, Abraxane, Ixabepilone) (T) Chemo Agents. 
The study population will include subjects ≥ 18 years of age with 
histologically/pathologically confirmed advanced or metastatic breast carcinoma. 
Subjects will have a medical history and physical assessment to include 
concomitant medication, standard of care breast cancer staging including 
mammogram, ultrasound, bone scan, chest x-ray or chest CT as well as blood 
tests for Complete Blood Count (CBC) with differentials, Complete Metabolic 
Panel (CMP). 
Prior to starting treatment, subjects will have a research blood draw and research 

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biopsy. The study doctor will determine if the subject qualified to be enrolled in 
this study. 
Study treatment may continue as determined by the investigator until disease 
progression, intolerable AEs, death, voluntary withdrawal from the study by the 
patient, or discontinuation of the study by the sponsor. 
Treatment * 
Patients will receive Chloroquine 250mg daily together with Taxane or Taxane 
like chemo agents (Paclitaxel, Docetaxel, Abraxane, Ixabepilone) (C/T) 
Recommended prophylaxis for fluid retention/hypersensitivity reactions for 
Taxanes will be dexamethasone 8 mg Q12 hours for 3 doses starting the night 
prior to Taxanes or premedication per institution standards. 
* See section 2.2.3 for full drug use and premedications. 
Inclusion 
Criteria: 
1.  Females with pathologically determined advanced or metastatic breast 
cancer. 
2. Advanced breast cancer patients must have progressed or have residual 
disease after treatment with regimen that included at least 2 cycles of an 
anthracycline containing regimen. 
3. Metastatic breast cancer patients must have had at least 4 cycles of an 
anthracycline containing regimen. 
4. Patients must have measurable disease by Response Evaluation Criteria in 
Solid Tumors. 
5. ≥18 years of age. 
6. At least one measurable disease site, defined as lesion of ≥ 1 cm 
7. No known underlying ocular/retinal pathology. 
8. No medically documented preexisting auditory damage. 
9. No cardiac conduction disturbances or medication potentially causing them: 
10. QTc interval prolongation with other medications that required discontinuation 
of the treatment 
11. Medication that might cause QT-prolongation or Torsades de pointes 
tachycardia is not allowed. (See appendix E) 
12. ECOG PS of 0, 1, or 2. 
13. Laboratory values within the following ranges: 
• 
Hemoglobin ≥9.0gm/dL (≥1.5μmol/L); transfusions permitted. 
• 
Absolute neutrophil count ≥1500/mm3 (1.5 x 109/L) 
• 
Platelet count ≥100,000/mm3 (100 x 109/L) 
• 
Creatinine (Cr) <2 X the upper limit of normal (ULN), Cr clearance 
(CrCl) ≥30 by 
Cockcroft and Gault 
• 
Alanine aminotransferase and aspartate aminotransferase <2 X the 
ULN; if liver metastases are present then must be <5 X the ULN, 
Bilirubin <2 X the ULN, for patients receiving Ixabepilone Potassium 
and Magnesium must be within normal limits. 
14. Negative serum pregnancy test at the time of first dose for women of 
childbearing potential (WOCBP). For WOCBP, adequate contraception must be 
used throughout the study. For this study, acceptable methods of contraception 
include a reliable intrauterine device or a spermicide in combination with a barrier 
method. Women who are already on hormonal forms of birth control may 
continue that treatment but must also use a barrier method. 
15. Ability to understand the requirements of the study, provide written informed 

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consent and authorization of use and disclosure of protected health information, 
and agree to abide by the study restrictions and return for the required 
assessments. 
16. Patient must be willing to undergo breast biopsies as required by the study 
protocol. 
Exclusion 
Criteria: 
1. Radiation therapy within 2 weeks; or chemotherapy or non-cytotoxic 
investigational agents within 2 weeks of initiating study treatment. 
2. Evidence of New York Heart Association class III or greater cardiac disease. 
3. History 
of 
myocardial 
infarction, 
stroke, 
ventricular 
arrhythmia, 
or 
symptomatic conduction abnormality within 12 months. 
4. History of congenital QT prolongation. 
5. QT >500. 
6. Concurrent severe or uncontrolled medical disease (i.e., active systemic 
infection, diabetes, hypertension, coronary artery disease, congestive heart 
Failure or major surgery) that, in the opinion of the Investigator, would 
compromise the safety of the patient or compromise the ability of the patient 
to complete the study. 
7. Symptomatic central nervous system metastases. 
8. The patient must be stable after radiotherapy for ≥2 weeks and off 
corticosteroids for ≥1 week. 
9. Pregnant or nursing women. 
10. Hypersensitivity or intolerance to Quinolones, Chloroquine, Paclitaxel, 
Docetaxel, Abraxane, Ixabepilone or other Taxane like drugs. 
11. Active diagnosis of psoriasis or currently receiving treatment for psoriasis. 
12. Alcoholism or hepatic disease. 
13. History of epilepsy or seizures in the past 20 years. 
14. Receiving concurrent treatment with prohibited medications (See appendix E) 
Examples include: ampicillin, antacids, cimetidine, cyclosporine, kaolin, 
magnesium trisilicate, coumarin-type anticoagulants, macrolide antibiotics 
(e.g., clarithromycin, isoniazid, and erythromycin), anti-HIV agents (e.g., 
ritonavir and delavirdine), antidepressants (e.g. fluoxetine and fluvoxamine), 
calcium channel blockers (e.g. verapamil and diltiazem), steroids and their 
modulators (e.g., gestodene, raloxifene, and mifepristone), and several herbal 
and dietary components (e.g. bergamottin and glabridin). 
15. Severe renal insufficiency (CrCl <30mL/min [Cockcroft and Gault]). 
16. History of gastrointestinal bleeding, ulceration, or perforation. 
17. Concurrent use of potent CYP3A4 inhibitors, such as ketoconazole, 
itraconazole, clarithromycin, atanazir, indinavir, nefazodone, neflinavir, 
ritonavir, saquinavir, telithromycin, and voriconazole. 
18. Concurrent use of potent CYP3A4 inducers, such as dexamethasone, 
phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbitol, and 
St. John’s wort. 
19. Used an investigational drug within 14 days preceding the first dose of study 
medication. 
Statistical 
Design: 
A sample size of 47 patients achieves 80% power to detect the difference 
between the null median overall response rate (ORR) of 30% and the alternative 
hypothesis median ORR 50% at a 0.05 significance level (alpha) using a two- 
sided binomial test. 

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CAT Trial 
PHASE II STUDY OF THE EFFICACY AND SAFETY OF CHLOROQUINE (C) IN COMBINATION WITH TAXANE OR 
TAXANE-LIKE (T) CHEMO AGENTS IN THE TREATMENT OF PATIENTS WITH ADVANCED OR METASTATIC BREAST 
CANCER WHO HAVE FAILED ANTHRACYCLINE CHEMO BASE THERAPY. 
ADVANCED 
OR    
METASTATIC 
BREAST 
CARCINOMA 
(MBC) 
CHLOROQUINE 250mg Daily 
+ 
TAXANE OR TAXANE-LIKE 
CHEMO AGENTS 
Study treatment may 
continue as determined 
by the investigator until 
disease progression, 
intolerable AEs, death, 
voluntary withdrawal 
from the study by the 
patient, or 
discontinuation of the 
study by the sponsor. 
O 
R 
R 
E 
V 
A 
L 
U 
A 
T 
I 
O 
N 
Figure 1 
STUDY DESIGN AND TREATMENT 

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Phase II Study of The Efficacy And Safety of Chloroquine (C) in CombinAtion With 
Taxane or Taxane-like (T) Chemo Agents in The Treatment of Patients With Advanced or 
Metastatic Breast Cancer Who Have Failed Anthracycline Chemo Base Therapy. 
0.0 STUDY SUMMARY ........................................................................................... 2 
0.0 Schema ............................................................................................................. 5 
1.0 Synopsis ............................................................................................................ 9 
2.0 Introduction ....................................................................................................... 9 
3.0 Background and Rationale… ........................................................................... 9 
3.0.1 Clinical Experience with Chloroquine .............................................................. 9 
3.0.2 Summary Experience with Chloroquine ........................................................ 14 
3.0.3 Cytokines Background and Rationale ........................................................... 14 
4.0 OBJECTIVES ...................................................................................................15 
4.1 Primary Objective(s) ...................................................................................... 15 
4.2 Secondary Objective(s) .................................................................................. 15 
4.3 Exploratory Objective (s) ................................................................................15 
5.0 Study Flow chart or Schedule of Events… ..................................................... 16 
5.1 Study Procedures by Visit and Treatment Cycle… .......................................... 18 
5.2 Screening/Baseline visit ................................................................................. 18 
5.2.1 Radiological Evaluation Visit ..................................................................... 18 
5.2.2 Pre-Infusion Clinic Visits… ........................................................................ 18 
5.2.3 Infusion Visits ........................................................................................... 19 
5.2.4 End-of-Treatment/Early Termination Visit .................................................. 19 
5.2.5 End of Study Assessments/ Follow-up....................................................... 20 
5.3 Details of Procedure… .................................................................................. 20 
5.3.1 Safety Assessments ................................................................................ 20 
5.3.2 Efficacy Assessments… ..........................................................................21 
5.3.3 Tissue Specimen Acquisition ............................................................... 21 
6.0 Time Line and Milestones… ............................................................................ 23 
7.0 Study Design… ................................................................................................. 24 
8.0 Study Population ............................................................................................. 24 
8.1 Inclusion Criteria ............................................................................................ 24 
8.2 Exclusion Criteria ........................................................................................... 25 
9.0 Treatment Plan/Methods ................................................................................. 26 
9.0.1 Treatment (Physician Choice) .................................................................. 26 
9.1 DRUG INFORMATION AND MODIFICATIONS .............................................. 26 
9.1.1 Chloroquine .......................................................................................... 26 
9.1.2 Paclitaxel.................................................................................................31 
9.1.3 Docetaxel ............................................................................................... 36 
9.1.4 Abraxane ................................................................................................ 42 
9.1.5 Ixabepilone ............................................................................................. 45 
9.2 Discontinuation of Subjects from Treatment .................................................... 47 
10.0 Criteria for Response… ................................................................................. 47 
10.1. Definition of Target and Non-target Lesions According to RECIST 1.1…47 
10.1.1. Target lesions….................................................................................. 47 
10.1.2. Non-target lesions… .......................................................................... 47 
11. Study Materials… ............................................................................................. 48 

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11.1 Chloroquine ................................................................................................. 48 
11.2 Paclitaxel… .................................................................................................. 48 
11.3 Taxotere… ................................................................................................... 49 
11.4 Abraxane… .................................................................................................. 50 
11.5. Ixabepilone .................................................................................................. 50 
12. Investigational Product Records at Investigational site… ..............................51 
13. Destruction of Investigational Product ............................................................ 51 
14. Study Discontinuation ..................................................................................... 51 
14.1 Withdraw Procedures .................................................................................. 52 
14.2 Lack of Efficacy ............................................................................................ 52 
15. Adverse Events….............................................................................................52 
15.1 Definition of an Adverse Event (AE) ............................................................... 52 
15.1.1 Reporting of SAEs… ............................................................................ 53 
15.1.2 Reporting of SAEs “Pregnancy” ............................................................ 54 
15.1.3 Follow-up Adverse events… .................................................................. 54 
15.2 Reporting of Results to Subjects and Their Physicians… ................................ 55 
16. Data Management ............................................................................................ 55 
17. Statistical Design and Analyses… ...................................................................55 
18. Responsibilities................................................................................................ 55 
18.1 Investigator Responsibilities… ....................................................................... 55 
18.1.1 Good Clinical Practice ..............................................................................55 
18.1.2 Institutional Review Board or Independent ethics committee ..................... 56 
18.1.3 Subject Information and Informed Consent............................................... 56 
18.1.4 Confidentiality… ....................................................................................... 57 
18.1.5 Study Files Retention of Records… .......................................................... 57 
19. Consent Procedures .......................................................................................... 58 
19.1. Confidentiality Procedures… .........................................................................58 
19.2. Subject Costs ................................................................................................ 58 
19.3 Payments to Subjects… ................................................................................. 58 
20. Reference/Bibliography ................................................................................... 59 
21. Appendices… ..................................................................................................... 63 
 
List of Tables 
Table 1: Study Flow chart or Schedule of Events ....................................................... 16 
Table 2: Timeline and Milestones. ............................................................................... 23 
Table 3: Paclitaxel Pharmacokinetics .......................................................................... 31 
Table 4: Paclitaxel Side Effects .................................................................................. 33 
Table 5: Paclitaxel Summary of Hypersensitivity Reactions ..................................... 34 
Table 6: Paclitaxel Drug Interactions .......................................................................... 35 
Table 7: Paclitaxel Dosage Guidelines ....................................................................... 36 
Table 8: Paclitaxel Dosage in Hepatic Failure ........................................................... 36 
Table 9: Taxotere Pharmacokinetics…..................................................................... 37 
Table 10: Taxotere Side Effects… ............................................................................39 
Table 11: Taxotere Drug interactions ....................................................................... 41 
Table 12: Taxotere Dosage Guidelines… ................................................................. 41 
Table 13: Taxotere Dosage in Hepatic Failure ..........................................................42 
Table 14: Taxotere Dosage in Severe Peripheral Neuropathy ................................... 42 
Table 15: Abraxane Pharmacokinetics… ................................................................. 42 

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Table 16: Abraxane Side Effects ............................................................................. 44 
Table 17: Abraxane Dosage Guidelines… ................................................................45 
Table 18: Ixabepilone Side Effects .............................................................................. 46 
Table 19: Ixabepilone Dosage Guidelines… .............................................................46 
Table 20: Target Lesion Response Criteria… ............................................................ 48 
Table 21: Non-target Lesion Response Criteria… ..................................................... 48 
Table 22: Paclitaxel Parental Administration… .......................................................... 49 
Table 23: Taxotere Parental Administration… ............................................................50 
 
List of Figures 
Figure 1: Study Design and treatment ......................................................................... 5 
Figure 2: Identification of genes for Cancer Stem Cells. ............................................ 10 
Figure 3: Gene Networks and Signaling Pathways up-regulated in Cancer Stem Cells…10 
Figure 4: Screened Drug Candidates ..........................................................................11 
Figure 5: Chloroquine inhibits the mammosphere formation of cell lines ................... 11 
Figure 6: Chloroquine triggers autophagosome accumulation… ................................ 12 
Figure 7: Combination treatment of chloroquine and mPTX enhanced cell death ....... 12 
Figure 8: Chloroquin induce apoptosis in CD44h/CD24- stem cell population ............. 12 
Figure 9: Chloroquine reduced the cancer stem cell poluation within MDA-MB-231 .. 13 
Figure 10: Chloroquine follows different signaling routs to cell death ........................... 13 
Figure 11: Stereotactic needle biopsies images .......................................................... 22 
Figure 12: chloroquine structural formula .................................................................. 27 
List of Appendices 
Appendix A: ECOG Performance Status Criteria ........................................................ 63 
Appendix B: New York Heart Association (NYHA) Classifications ...............................64 
Appendix C: CTCAE V. 4.0… ...................................................................................65 
Appendix D: Determination of Menopausal Status .................................................... 66 
Appendix E: Chloroquine Drug interactions…............................................................ 67 
Appendix F: List of Abbreviations… ........................................................................... 68 

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1.0 Synopsis: 
The tumor-initiating cell (TIC) or cancer stem cell hypothesis has fundamental clinical 
implications.1-3 There is increasing evidence that human breast TICs are resistant to 
conventional treatment, including chemotherapy hormonal therapy, and radiation therapy. 4, 5  
We have recently completed a neoadjuvant breast cancer trial, that provides strong clinical 
evidence for the resistance of breast TICs to conventional chemotherapy. 6 We demonstrated a 
three-fold increase in the proportion of TICs as marked by CD44+/CD24-/low following 
chemotherapy in women with locally advanced breast cancer. Interestingly, in patients with 
HER2-amplified tumors, the EGFR/HER2 tyrosine kinase inhibitor lapatinib produced tumor 
shrinkage that was accompanied by a decrease in the proportion of TICs. 6 Our findings indicate 
that this subset of tumor cells, not affected by standard therapies, may be responsible for tumor 
initiation and self-renewal, thereby forming the basis of our hypothesis that these residual cells 
bearing stem cell-like properties may be responsible for treatment resistance, leading to relapse 
and metastases. From biopsies obtained from women with primary breast cancer, we have 
identified a “tumorigenic signature,” Preliminary in silico mathematical analysis mapping Food 
and Drug Administration (FDA) approved drugs against these key regulatory pathways in our 
tumorigenic signature has yield several drug targets that may be re-purposed or re-positioned 
as therapies against TICs., and therefore may be effective treatment to prevent resistance and 
relapse. We have in vitro data that two of these drugs (chloroquine and auranofin) have activity 
in decreasing mammosphere formation efficiency (MSFE), an in vitro assay for self-renewal. 7-11 
This is a phase II trial; 47 patients with diagnosis of advanced or metastatic breast cancer, who 
have failed anthracycline chemo base therapy, will be enrolled in the study. 
Patients will 
receive between 1) Chloroquine (C) together with Taxane or Taxane-like (Paclitaxel, Docetaxel, 
Abraxane, Ixabepilone) (T) Chemo Agents. 
The study population will include subjects ≥ 18 years of age with histologically/pathologically 
confirmed advanced or metastatic breast carcinoma. Subjects will have a history and physical 
assessment to include concomitant medication, standard of care breast cancer staging including 
mammogram, ultrasound, bone scan, chest x-ray or chest CT as well as blood tests for 
Complete Blood Count (CBC) with differentials, Complete Metabolic Panel (CMP). Prior to 
starting treatment, subjects will have a research blood draw and research biopsy. The study 
doctor will determine if the subject qualified to be enrolled in this study. Study treatment may 
continue as determined by the investigator until disease progression, intolerable AEs, death, 
voluntary withdrawal from the study by the patient. 
 
2.0 Introduction 
Breast cancer is the most common cancer in women in the US with about 192,000 new cases in 
2009. In 2010, an estimated 207,090 new cases of invasive breast cancer were expected to be 
diagnosed in women in the U.S., along with 54,010 new cases of non-invasive (in situ) breast 
cancer. Despite all of the significant advances in breast cancer biology, there has been limited 
progress in the treatment of advanced breast cancer, with little change in the overall survival for 
women with metastatic breast cancer over the last several decades. 
 
3.0 Background and Rationale 
3.0.1 Clinical Experience with Chloroquine 
Our laboratories have developed robust preclinical models utilizing both in vitro systems such as 
the mammosphere (MS) culture and in vivo systems such as human breast cancer xenografts 6, 
allowing us to identify agents which selectively target TICs, as single agents or in combination. 
These models are critical since tumor initiating cells (TICs) comprise only a small percentage of 

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the tumor bulk, so that clinical tumor regression may not be observed with inhibitors that 
selectively target TIC self-renewal alone. Nonetheless, these agents in combination with 
conventional therapy may effectively kill both actively cycling or fully differentiated cells and the 
TIC subpopulation, leading to long term remission and eradication of cancer cells. 
In addition, we have established a clinical trials network to conduct trials with selected TIC 
inhibitors, with a strong focus on correlative end-points. We propose to study the effects of 
combining repositioned or repurposed drugs with chemotherapy in women with metastatic 
breast cancers who are refractory to conventional chemotherapy. In our proposed clinical trial, 
we intend to begin with chloroquine in combination with taxanes in advanced breast cancer 
patients. 
 
Preliminary Studies 
Cancer stem cells are subpopulation in a total cancer 
cells with capacity of reconstructing the tumor from a 
single cell 15, 16 This has been a theory for two decades, 
and remains controversial. Regardless, cancer stem 
cells have been identified in numerous cancers 
including adrenal cancer, brain, ovary, leukemia, 
myeloma, breast, lung, and prostate cancers[6-8]. 
Importantly, 
pharmaceutical 
companies 
launched 
clinical studies specifically targeting cancer stem cells in 
recent years, as this subpopulation is closely correlated 
with cancer metastasis, drug resistance, and systemic 
recurrence. In breast cancer, the cancer stem cells 
have been characterized by the expression CD44, 
CD24, and aldehyde dehydrogenase 
12, 19 In our 
laboratory, we identified these cells not only in in-vitro 
conditions but also in clinical cancer biopsies obtained from patients. We utilized mammosphere 
assay to enrich the cancer stem cells and identified cancer stem cell specific gene expression 
(Figure 2) and signaling pathways (Figure 3). Moreover, through bioinformatic drug screening of 
available drug databases, we identified chloroquine as a putative re-positioned drug targeting 
cancer stem cells. 
 
Chloroquine (CQ) is an anti- 
malaria drug used for 50 years 
and used widely to treat other 
diseases such as rheumatoid 
arthritis 
and 
lupus 
erythematosus. Intriguingly, in 
an attempt to control malaria in a 
county in Tanzania, CQ was 
administered for 5 years, and 
during this time the incidence of 
a hematologic cancer, Burkitt 
lymphoma which is endemic in 
that region, declined by 75%20, 21 
The tumor incidence returned to 
the old baseline 2 years after 
Figure 3. Gene Networks and Signaling Pathways up-regulated in Cancer Stem Cells 
Figure 2. Identification of genes for Cancer Stem 
Cells 

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Figure 4. Screened Drug Candidates 
 
completion of the CQ trial. Recently, chloroquine has been been tested as an anti-cancer 
treatment in glioblastoma multiforme, a lethal form of brain cancer, and in earlier stages of in 
situ breast cancer. Even though the mechanism is not well understood, most of reports suggest 
that it works through inhibition of autophagy (self-eating survival mechanism) under p53- 
dependent pathway 22. However, our preliminary data suggest chloroquine may function 
independent of p53, and further evaluation of this mechanism may have significant impact on 
selection of appropriate therapy. We expect that chloroquine will enhance cancer cytotoxic 
effects of conventional chemotherapies by inducing cell death within the cancer stem cells and 
thus, may decrease the cancer recurrence and death. More importantly, the long history of 
chloroquine use makes combination with chemotherapy a safe approach in carefully designed 
clinical trials. 
Autophagy in normal cells can suppress tumorigenesis by removing toxic materials in the cell 
through p62 protein 23. However, in the cancer cells, autophagy works as a survival mechanism 
by providing the cancer cell to cope with detachment stress (related with metastasis), frequent 
DNA damage, metabolic and oxidative stress, and chemotherapeutics 
23. Moreover, 
overexpression of LC-3 (a gene involved in autophagy) is frequently observed in more 
advanced cancers 23. In addition to ensuring “survival” of cancer cells, autophagy is critical in 
carcinogenesis through its tumor microenvironment. Autophagy in cancer associated 
mesenchymal stem cells or fibroblasts supports the cancer stem cell survival through provision 
of nutrients or growth factors and triggers cancer metastasis 23-25. 
 
Chloroquine induces p53-independent cell death accompanying incomplete autophagy 
and DNA damage. Previously, through 
bioinformatic analysis, we identified gene 
signatures specific for tumor initiating 
cancer stem cells (Figure 1 and 2) and 
screened several drug  candidates  (Figure 
4) for a drug-reposition. We performed 
drug repositioning of FDA-approved drugs 
for any medical indication, as potential 
targets against cancer, in particular cancer 
stem cells. We discovered that chloroquine 
was the most effective in inhibiting 
mammosphere formation (Figure 5). In 
addition, 
we 
observed 
CQ 
induced 
apoptosis correlated with accumulation of 
autophagosome, DNA damage by western 
blot assay (Figure 6). The concentration of 
cytotoxic effect of CQ was seen as low as 
1µM, 30-50 times lower than the reported 
concentrations. 
Interestingly, 
in 
the contrary 
to the 
previously reported results in the literature, 
our study showed that CQ induced DNA 
damage, and that these effects of  CQ 
were p53-independent because the five 
TNBC cell lines examined had p53 gene 
mutations or deletions. Therefore, we hypothesize that the effects of CQ may in part involve 
Figure 5. Chloroquine inhibits the mammosphere formation of TNBC 
cell lines 

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Figure 7. Combination treatment of chloroquine and mPTX 
enhanced cell death in comparison to the single treatment of each. 
 
other members of the p53 family, like p63 
and 
p73. 
Various 
publications 
that 
suggested that p73 can induce DNA 
damage 26, 27 while p63 is correlated in 
cancer metastasis and drug resistance28 
Also, p63 has been implicated in stem cell 
survival and differentiation 29, 30 Supporting 
this, breast cancer cells have been 
identified to express isoforms of p63 or 
p7331, 32 However, their biological functions 
are not well described. Both N-terminal 
deleted isoforms lack DNA binding motifs 
and acts as a negative regulator of DNA 
binding isoforms of p63 or p73 33, 36 
 
Chloroquine induces apoptosis within the CD44high/CD24 neg cancer stem cell 
population in TNBC cell lines. 
First, we compared how CQ will enhance a 
nano-micelle   formulated  
conventional 
paclitaxel (mPTX). As seen in Figure 7, the 
combination  treatment 
enhances  the 
activation of caspase 3 and cleavage LC3. 
Interestingly, we observed the substantially 
decreased 
pStat3 
after 
 combination 
treatment which is important to maintain 
breast cancer  stem cells. This is  an 
imperative finding suggesting we can target 
cancer stem cells using CQ. Supporting this 
notion, we observed decrease in the viable 
cancer stem cells after CQ alone or the 
combination  treatment 
through  flow 
cytometric analysis (Figure 8). While  we 
first confirmed the enhanced cytotoxic 
effects of mPTX by CQ on TNBC cell line 
(SUM159), further analysis of the  results 
led us to the direct evidence that CQ have 
the ability to control the viability of cancer 
stem cells (Figure 8 and 9). Similar results 
were observed with a different TNBC cell 
line MDA-MB-231, well characterized for its 
metastatic propensity and chemoresistance 
(Figure 9). Here, CQ reduced dramatically 
the cancer stem cell enriched populations 
by 30 % in CD44high /CD24neg, or 80% in 
Figure 6. Chloroquine triggers autophagosome accumulation, DNA 
damage, and apoptosis in TNBC cell lines 
Figure 8. Chloroquin induce apoptosis in CD44h/CD24- stem cell 
population. AnnexinV-/PI- : Viable cells. AnnexinV+ or PI+ : 
apoptotic or dead cells. 

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Figure 9. Chloroquine reduced the cancer stem cell poluation within 
MDA-MB-231 TNBC cell line. 
 
ALDH1 positive subpopulations. Thus, we hypothesize that CQ can reduce the cancer stem 
cells in cell lines by p53 independent mechanisms, perhaps by involving other members of the 
p53 family. 
 
The pathways of cytotoxic effect of chloroquine differ by p53 status in Breast Cancers. 
Because of the promising effects of CQ on cancer stem cells, we investigated the mechanism of 
action of CQ, focusing on autophagy and the cell death-related pathways, PI3K-mTOR and p73 
expression in SUM159 and MDA-MB-231 cells. 
SUM159 cells lack p53 while MDA-MB-231 cells 
express both wild type and mutant p53. Despite 
of the similar results in reducing cancer stem cell 
populations and pStat3 in combination treatment 
with mPTX, contrary to our expectations, the 
signaling propagation was very different in both 
cell lines. In SUM159 cells, the PI3K-mTOR 
pathways were unaffected, as confirmed by p- 
mTORs and pAkt expression. The rapamycin 
sensitive 
mTOR 
complex 
protein, 
Raptor 
expression increased with increasing doses of 
chloroquine (Figure 10). The level of pStat3 
showed no change with CQ alone. However, in 
MDA-MB-231 cells, the mTOR pathway was 
severely affected by CQ and the rapamycin 
insensitive 
mTOR 
complex 
protein, 
Rictor 
decreased as the dose of CQ increased. This 
dramatic change was then followed by rapid 
reduction of pStat3. In addition, we also 
observed 
contradicting 
regulation 
of 
p73 
expression by CQ. In SUM159 cells, the 
expression  p73  isoforms  decreased  after   CQ 
treatment while p73α expression increased in MDA-MB-231 cells. In addition, the dominant 
negative regulator of p73, the expression of ΔNp73α decreased as CQ dose increased in 
SUM159 but not in MDA-MB-231. Despite the differences in mechanism, autophagy was 
Figure 10. Chloroquine follows different signaling routs to cell 
death depending on p53 genetic status in TNBC. 

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induced in both cells lines, and we confirmed increased LC-3 cleavage in both cell lines as the 
dose of CQ was increased. 
 
3.0.2 Summary of Experience with Chloroquine. 
Chloroquine has been extensively used as an antimalarial for many decades. It is safe, well 
tolerated, and with very few side effects. More recently, it has been studied in cancer patients, 
mainly as an agent that affects survival pathways like autophagy. 
Briceno et al. evaluated the addition of chloroquine to conventional chemotherapy and surgery 
for those patients with Glioblastoma Multiforme (GBM), 41 patients with GBM received 
chloroquine as an optional adjuvant administered concurrently with conventional chemotherapy, 
and compared with patients with GBM who did not receive chloroquine were included in this 
analysis as control subjects. The end point observed was time of survival after surgery. They 
found the survival time in patients treated with chloroquine as 25 ± 3.4 months, as compared 
with the 11.4 ± 1.3 months in control subjects ( P = .000; OR = 0.4; 95% CI = 0.26-0.6); the 
difference remained significant after regression analysis for possible clinical confounders. In 
agreement with this report, chloroquine exerts a strong adjuvant effect when added to the 
conventional treatment of GBM. In this large cohort of unselected patients with GBM who were 
treated with chloroquine, the median survival time doubled as compared with that of control 
subjects. 37 More important, chloroquine when administrated with a variety of chemotherapeutic 
agents did not increase adverse events, and thus can be safely given with taxanes in patients 
with advanced breast cancer who have limited prognosis. 
The American Academy of Ophthalmology recommendations for screening of chloroquine (CQ) 
and hydroxychloroquine (HCQ) retinopathy were published in 2002, but improved screening 
tools and new knowledge about the prevalence of toxicity have appeared in the ensuing years. 
New data have shown that the risk of toxicity increases sharply toward 1% after 5 to 7 years of 
use, or a cumulative dose of 1000 g, of HCQ or 460g of CQ. The risk increases further with 
continued use of the drug. The prior recommendation emphasized dosing by weight. However, 
most patients are routinely given 400 mg of HCQ daily (or 250 mg CQ). This dose is now 
considered acceptable, except for individuals of short stature, for whom the dose should be 
determined on the basis of ideal body weight to avoid overdosage. A baseline examination is 
advised for patients starting these drugs to serve as a reference point and to rule out 
maculopathy, which might be a contraindication to their use. Annual screening should begin 
after 5 years (or sooner if there are unusual risk factors). Newer objective tests, such as 
multifocal electroretinogram (mfERG), spectral domain optical coherence tomography (SD- 
OCT), and fundus autofluorescence (FAF), can be more sensitive than visual fields. Fundus 
examinations are advised for documentation, but visible bull's-eye maculopathy is a late 
change, and the goal of screening is to recognize toxicity at an earlier stage. 38 
 
3.0.3 Cytokine Background and Rationale. 
The measurement of soluble cytokines in serum and plasma is becoming increasingly important 
in the study and management of many diseases. As a result, there is a growing demand for 
rapid, precise, and cost-effective measurement of such analytes in both clinical and research 
laboratories. Multiplex bead array assays (MBAA) provide quantitative measurement of large 
numbers of analytes using an automated 96-well plate format. Wide assortments of tests have 
been devised for MBAA using both immunological and molecular ligands. The potential 
advantages of these assays are apparent, such as the ability to independently and quantitatively 
assay multiple analytes simultaneously in small volumes of material and the collection of data 
from numerous beads for each ligand to provide statistical rigor. The potential cost- and time- 

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savings that could be accrued by use of MBAA in comparison to other methods provides a 
strong impetus for the routine use of these in both the research and clinical laboratories. This 
new technology allows for (1) evaluation of multiple analytes in a single sample; (2) utilization of 
minimal sample volumes to glean data; (3) reproducibility and results comparative with previous 
experiments; (4) direct comparison with existing assays; and (5) a more rapid evaluation of 
multiple samples in a single platform. The cytometric bead array (CBA) system enables 
simultaneous measurement of multiple analytes in sample volumes too small for traditional 
immunoassays.39-46 
 
4.0  OBJECTIVES 
4.1  The primary objective: 
To determine the anti-tumor activity of the combination of Chloroquine + Taxane or Taxane-like 
chemo agents (Paclitaxel, Docetaxel, Abraxane, Ixabepilone) (C/T) measured by overall 
Response Rate (ORR). 
 
4.2  The secondary objective(s): 
• To assess the safety and tolerability of the combination of C/T. 
• To assess the response rate and tumor control rate (TCR) of patients receiving C/T. 
• To assess the Time to Progression (TTP) of patients receiving C/T. 
• To assess the duration of response (DOR) of patients receiving C/T. 
 
4.3  Exploratory Objective(s): 
• To evaluate biomarkers for response and toxicity of the combination of C/T. 
In patients with accessible tumor, biopsies will be conducted at baseline, prior to the second 
cycle of treatment, and at the end of the treatment. If the patient progresses while in treatment 
a new biopsy will be taken before the patient start the new treatment. (Please see section 5.3.3) 

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5.0 Study Flow chart or Schedule of Events 
 
Procedure 
Screening/Baseline Visit 
Prior to Each Cycle 
End-of- Treatment Visit a 
End of Study Assessments/ 
Follow-up q 
Eligibility Assessments 
Obtain Informed Consent 
X 
Confirm Inclusion/Exclusion Criteria Met b 
X 
Obtain Medical History 
X 
Safety Assessments 
Physical Exam 
X 
X 
X 
X 
ECOG performance scale b 
X 
X 
X 
X 
Record Weight, Height and Vital Signs 
X 
X 
X 
X 
Eye Examr 
X 
Assess Signs and Symptoms and Adverse Events c 
X 
X 
X 
X 
Perform Pregnancy Test in WOCBP d 
X 
Perform mammogram e * 
X 
X 
Perform ultrasound of breast and nodal region e * 
X 
X 
Perform CT scan Chest and Abdomen or CXR f 
X 
Perform Bone scan 
X 
Perform Laboratory Tests gh 
X 
X 
X 
Biopsies i** 
X 
** 
X 
Whole Blood/ serum j *** 
X 
*** 
X 
Perform Electrocardiogram k 
X 
Perform 2D Echocardiogram or MUGA 
X 
Efficacy Assessments 
Evaluate Tumor Response RECIST Criteria m 
X 
X 
Clinical Drug Supplies 
Chloroquine administration n 
X 
Infusion visitp / Premed Before Infusion o 
X 
Table 1 

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a. Evaluate subjects who discontinue the protocol for reasons other than disease progression (AEs) every 4 weeks until progression or until they receive additional anti- 
cancer therapy. 
b. ECOG Performance Status of 0-1and 2 is required for study entry. ECOG performance status will be recorded at baseline, prior to each cycle, at the end of treatment and 
at the end of the study assessment. 
c. Document signs and symptoms and adverse events at least every 4 weeks until all study drug-related toxicities resolve, stabilize, return to baseline, or are deemed 
irreversible. Adverse events will be collected at baseline with the medical history and will be recorded as an adverse event only if they increase in severity or toxicity. 
d. Pregnancy tests (serum or urine) should be performed within 72 hours of study start, or whenever pregnancy is suspected. 
e. Unilateral mammogram and ultrasound should have been performed any time within 4 weeks prior to beginning of the study treatment in patients with locally advanced 
cancer who have failed anthracycline chemotherapy. *MRI (magnetic resonance imaging) should be performed only if requested by the physician. 
f. Perform Bone Scan, CT scans chest& abdomen as an initial workup Patients with metastatic disease must repeat tests every eight weeks (+/- 2 weeks) or as a clinically 
indicated. Repeat testing for patients with advanced breast cancer is at the discretion of the investigator. A Chest XRay (PA & Lateral) can be substituted for a CT scan for 
patients with advanced breast cancer. 
g. Comprehensive Metabolic Panel to include sodium, , chloride, calcium, glucose, BUN, creatinine, AST, ALT, alkaline phosphatase, total bilirubin, and albumin. Complete 
blood count must include Hemoglobin, Hematocrit, RBC, WBC, Platelets with differential Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils. CrCL “CrCl = [(140 
- age) x IBW] / (Scr x 72) (x 0.85 for females)” before every cycle for patients with an abnormal creatinine. Potassium and Magnesium must be collected at baseline and 
prior to each infusion on patients receiving Ixabepilone. 
h. Perform laboratory tests within 72 hours of beginning each cycle. Perform baseline laboratory tests within four (4) weeks before administration of study drug. 
i. Biopsies will be obtained from accessible sites at baseline, **prior to the second cycle of chemotherapy and at completion of study. 
j. Whole blood/serum collection for cytokine arrays, ***prior to the second cycle of chemotherapy and at completion of study. 
k. A 12-lead EKG at baseline; QRS measurement is required. Electrocardiogram (EKG) with QRS measurement will be repeated whenever clinically indicated. 
m. Evaluate tumor response using RECIST criteria before chemotherapy and every 8 weeks (+/- 2 weeks) from Day 1 to disease progression. 
n. Subjects who are to receive Chloroquine will receive 250mg po daily. Chloroquine will be self-administered daily with water within 30 minutes after a meal. The site must 
perform all appropriate drug accountability. 
o. Subjects will be premedicated approximately 1 hour before a taxane or taxane-like infusion (see section 2.2.3 for doses and premedication). Standard anti-emetics for 
moderately emetogenic regimen, together with standard premedication will be prescribed with chemotherapy. Recommended prophylaxis for fluid retention/hypersensitivity 
reactions for taxane or taxane-like chemotherapy will be dexamethasone 8 mg Q12 hours for 3 doses starting the night prior to the infusion or premedication per institution 
standards. 
p. Monitor the subject for hypersensitivity reactions during and after all infusions. 
q. End of study visit will occur due to disease progression, as determined by the investigator until intolerable AEs, death, voluntary withdrawal from the study by the patient, or 
discontinuation of the study by the sponsor. Vital signs including blood pressure, heart rate and temperature will be performed during this visit. Toxicity assessment will be continuous 
throughout the study. CTC Version 4.0 will be used to grade toxicities (See Appendix C). 

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r. A baseline ophthalmologic examination will be used as a reference point and to rule out maculopathy, Baseline exam for patient with no significant medical history can 
have a baseline exam within one year of starting treatment. Patients with a history of diabetes, HTN, ocular abnormalities or any other significant medical history will have 
an eye exam within 30 days of starting treatment. 

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5.1 Study Procedures by Visit and Treatment Cycle 
Laboratory analyses and clinical examinations are to be repeated for total treatment duration. 
Radiologic examinations are to be performed before chemotherapy every eight weeks or as 
clinically indicated. (From randomization to disease progression). Study treatment  may  
continue as determined by the investigator until disease progression, intolerable AEs, death, 
voluntary withdrawal from the study by the patient, or discontinuation of the study by the 
sponsor. The maximum number of treatment cycles allowed is 6. 
Treatment * Patients will receive Chloroquine 250mg daily together with Taxane or Taxane like 
chemo agents (Paclitaxel, Docetaxel, Abraxane, Ixabepilone) (C/T) Recommended prophylaxis 
for fluid retention/hypersensitivity reactions for taxanes will be dexamethasone 8 mg Q12 hours 
for 3 doses starting the night prior to taxanes or premedication per institution standards. 
 
* See section 2.2.3 for full drug use and premedications. 
 
5.2 Screening/Baseline visit 
Informed consent must be obtained before performing any study-related procedures. Screening 
procedures may be done up to 4 weeks prior to the start the treatment for metastatic breast 
carcinoma. 
The following will be obtained at screening, prior to beginning study medication: 
-General history and physical exam, to include height, weight, blood pressure, heart rate, 
temperature, a clinical breast exam, and palpation of lymph nodes. 
-General ophthalmologic exam at baseline, and during treatment if clinically indicated. 
-Medical history should include relevant underlying conditions and concomitant medications. 
-Baseline signs and symptoms are to be recorded and followed throughout the trial. 
 
Laboratory assessments (see below). 
 
Breast imaging in patients with advanced primary cancers who have failed 
anthracyclines (see below). 
 
Bone scan 
 
CT chest and abdomen 
 
EKG and 2D ECHO or MUGA 
 
5.2.1 Radiological Evaluation Visit 
Perform radiological workup as per institutional guidelines to determine baseline metastatic 
disease. This radiological evaluation should be completed within 6 weeks before study drug 
administration. If more than 6 weeks have elapsed since the baseline radiological evaluation, a 
second radiological workup must be repeated before the initial treatment with the study drug. If, 
at any time, progressive disease is suspected, a complete radiological evaluation must be 
performed. MRI (magnetic resonance imaging) should be performed only if requested by the 
physician. 
Radiologic examinations are to be performed before chemotherapy every eight weeks or as 
clinically indicated. Use RECIST criteria to evaluate response. (See section 9.0) 
 
5.2.2 Pre-Infusion Clinic Visits 
The following assessments should be performed at each pre-infusion clinic visit. To allow for 
weekends, holidays, etc., study procedures may be completed within a ± 4 day window. 
Laboratory tests need to be completed within 72 hours of infusion. 
-Physical exam with a clinical breast exam and ECOG status. 
-Biopsies of accessible sites (mainly skin and breast) are to be performed at baseline, prior to 
the second cycle of chemotherapy, at the end of the study or prior to switching therapy. 
-Laboratory assessments to include a CBC/differential and serum chemistry panel, as defined in 
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-Record all concomitant medications added and/or changed. 
-Assess compliance to study medications and infusion schedule. 
-Non-serious and serious adverse events should be recorded and graded appropriately as 
discussed in Section 14. 
-Dispense supply of the study drug chloroquine plus either one of the next list of drugs: 
(Paclitaxel, Taxotere, Abraxane, Ixabepilone) every 3 weeks. 
 
5.2.3. Infusion Visits 
Subjects eligible for treatment will receive treatments per NCCN guidelines: 
A: Chloroquine 250mg po daily together with Paclitaxel 175 mg/m2 three hours infusion every 
two or three weeks or Paclitaxel 80 mg/m2 weekly. Or 
B: Chloroquine 250mg po daily together with Taxotere 75 mg/m2 (or 100mg/m2 in advanced 
breast cancer patients) administered intravenously over one hour every three weeks. Or 
C: Chloroquine 250mg po daily together with Abraxane 260 mg/m2 administered intravenously 
over 30 minutes every three weeks or 100mg/m2 administered weekly. Or 
D: Chloroquine 250mg po daily together with Ixabepilone is 40 mg/m2 administered 
intravenously over three hours every three weeks. Doses for patients with body surface area 
(BSA) greater than 2.2 m2 should be calculated based on 2.2 m2. 
Infusion times for chemotherapy are approximate and can vary slightly. Infusion time can be 
slowed for the safety of the patient. 
Dose reductions are allowed at the discretion of the investigator for patient safety. 
 
Subjects will be premedicated approximately 1 hour before the infusion. Standard anti-emetics 
for moderately emetogenic regimen, together with standard premedication will be prescribed 
with chemotherapy. Recommended prophylaxis for the taxane and taxane-like chemo agent 
includes: 
 
Paclitaxel premedication may consist of dexamethasone 20 mg po administered 
approximately 12 and 6 hours before Paclitaxel, diphenhydramine (or its equivalent) 50 
mg IV 30 to 60 minutes prior to Paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) 
IV 30 to 60 minutes before Paclitaxel or use premedication per institutional standards.
 
Docetaxel premedicated may consist of oral corticosteroids such as dexamethasone 16 
mg per day (e.g., 8 mg BID) for 3 days starting 1 day prior to Taxotere administration or 
use premedication per institutional standards.
 
Abraxane, no premedication is needed.
 
Ixabepilone premedication may consist of H1 antagonist (e.g., diphenhydramine 50 mg 
orally or equivalent) and a H2 antagonist (e.g., ranitidine 150 - 300 mg orally or 
equivalent). Or use premedication per institutional standards.
 
5.2.4. End-of-Treatment/Early Termination Visit 
After confirmation of progression disease or one (1) week after the patient has withdrawn from 
the study for any reason other than “completed” treatment: 
 
Physical exam with a clinical breast exam and ECOG status.
 
Biopsy is to be performed (prior to initiation of new therapy) if the patient has 
progressed, or at the end of six cycles. If the patient has locally advanced cancer, a 
surgical specimen will be obtained instead of a core biopsy after 4 – 6 cycles.
 
Laboratory assessments to include a CBC/differential and serum chemistry panel, as 
defined in see Section 2.0. Record all concomitant medications added and/or changed.
 
Assess compliance to study medications and infusion schedule.

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 
Non-serious and serious adverse events should be recorded and graded appropriately 
as discussed in section 14.
 
Perform radiological evaluation to determine the tumor status using RECIST criteria (see 
Section 9.0).
5.2.5. End of Study Assessments/ Follow-up 
End of study visit will occur when progression disease is confirmed. Vital signs including blood 
pressure, heart rate and temperature will be performed during this visit. Toxicity assessment will 
be continuous throughout the study. CTC Version 4.0 will be used to grade toxicities (See 
Appendix C web link). 
Upon completion of the investigational therapeutic regimen, subjects will be followed for adverse 
events for a period of 30 days after the last dose of investigational product. Patients with 
abnormal laboratory or clinical findings that are believed to be treatment related will be followed 
until the condition resolves or stabilizes, or until the laboratory values are no longer considered 
clinically significant as judged by the investigator. New adverse events that occur during the 30 
day follow-up period will only be recorded if the investigator believes there is a possibility that 
the adverse event is drug-related. Adverse events that are clearly not drug-related will not be 
recorded. Ophthalmologic evaluation at any time during the treatment only if clinically indicated. 
A follow-up for patients that have not progressed after 6 months of treatment completion is 
required. 
 
5.3 Details of Procedure 
Compliance 
Compliance with Chloroquine will be evaluated by a physical pill count at the scheduled clinic 
visits. Subjects will be instructed to bring their used blisters of Chloroquine to each return visit, 
along with any unused tablets. The investigator/designee will count the number of remaining 
tablets at each visit to assess compliance. In the event that the subject forgets to bring their 
used study meds to their clinic visit, compliance will be assessed by direct questioning of the 
subject. In this case, subjects should be counseled to bring their used drug bottles to their next 
scheduled infusion appointment so that compliance may be confirmed by pill count. Subjects 
should be instructed to report any missed doses of Chloroquine to the study coordinator. 
Compliance with Chloroquine will be calculated by the ratio of number of pills actually taken to 
the number of pills that should have been taken. Compliance will be defined as a ratio ≥ 0.75. 
Subjects with ratios between 1.00 and 0.75 will be allowed to continue on study. Study staff 
should ensure subject understanding of dosing instructions for subjects whose compliance is 
less than 100%. In addition, the importance of compliance with anticancer therapy should be 
reinforced. Subjects found to be in less than 75% compliance on more than one occasion will be 
taken off study for non-compliance. Patients who fail to keep more than 75% of their scheduled 
standard of care (SOC) infusions will be taken off study for non-compliance. 
 
5.3.1 Safety Assessments 
All participants will be assessed by a physician for pre-existing medical conditions and baseline 
physical abnormalities prior to the initiation of investigational therapy. Patients presenting with 
any medical history, physical exam, or laboratory abnormality that, in the opinion of the treating 
physician, would put the subject’s safety at risk will be excluded. Baseline signs and symptoms 
are to be recorded and followed throughout the trial. These will be monitored throughout the 
study and recorded if they increase in severity or frequency during treatment or within the follow 
up period. Participants will be assessed for adverse events by a physician or designated 
midlevel provider prior to each chemotherapy infusion while the patient is on study. Vital signs 
including blood pressure, heart rate and temperature should be performed at each physical 
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hematology and serum chemistry profiles will be drawn prior to the initiation of treatment and 
prior to every infusion to determine whether the study drug combination affects hematologic 
values, electrolytes or liver function tests. Laboratory assessments will be performed more 
frequently if clinically indicated. This clinical and laboratory data will be used to determine 
whether these women taking Chloroquine have any symptoms or side effects associated with 
the study medication. Subjects will be followed for adverse events for a period of 30 days after 
the completion of investigational therapy. Patients with abnormal laboratory or clinical findings 
that are believed to be treatment related will be followed every four weeks until the condition 
resolves or stabilizes, or until the laboratory values are no longer considered clinically 
significant. CTC Version 4.0 will be used to grade toxicities. 
Laboratory tests may be done more frequently if medically indicated. If CTC Grade 4 
hematologic toxicity is seen; CBC + differential + platelets should be repeated every 3 - 4 days 
until recovery. 
Patients who are on chloroquine for more than 24 weeks will be referred to the Ophthalmology 
service for retinal examination. Patients may require electroretinogram (ERG), as recommended 
by the ophthalmologist. The cost of the ERG will be paid for by the study. 
 
5.3.2 Efficacy Assessments 
A clinical assessment as well the radiological work up will be performed to assess disease 
status at baseline. Clinical tumor and metastatic site response will be assessed every eight 
weeks for patients with metastatic disease. Disease progression suspected from clinical tumor 
response assessments during any cycle should be confirmed by radiological work-up that would 
include bone scan, CT scan of chest and abdomen. If progression disease is confirmed a biopsy 
will be take prior to any treatment. An electrocardiogram (EKG) will be performed prior to the 
initiation of investigational therapy in order to ensure that the subject has adequate cardiac 
function; QRS measurement is required. The electrocardiogram (EKG) with QRS measurement 
will be repeated whenever clinically indicated. 
 
5.3.3 Tissue Specimen Acquisition 
Biopsies will be obtained from patients at baseline prior to the second cycle of chemotherapy, 
and at the end of treatment. If the patient progresses while in treatment a new biopsy will be 
taken before the patient start the new treatment. In order to maximize the likelihood of obtaining 
sufficient tissue, approximately four to six biopsies using a Bard Vacora Biopsy Instrument (or 
equipment that provides a sample of comparable quality) are taken. Biopsies are performed 
under local anesthesia, using the same entry point but reorienting the needle. The biopsies are 
done in the clinic or doctor's office by the participating oncologist or surgeon. The investigators 
in this unit have considerable experience with this technique. The outside needle is 14-gauge 
(2.1 mm), with a smaller inside cutting needle to obtain the biopsy. The length of the needle 
penetration is 22 mm and the length of the needle is 10 cm. Multiple biopsies of approximately 
2mm x 10-20mm will be obtained from each time point. Potential complications from core 
biopsies include bleeding, pain or infection. We have conducted several neoadjuvant studies 
over the past decade, involving several thousand biopsies, and the complications to date have 
been few and mild. A portion of the core biopsies will be snap frozen on dry ice and stored at - 
800C for cDNA array analysis. The remaining specimens will be fixed in formalin for 
immunohistochemical analysis. 
cDNA expression arrays on biopsies Half of the biopsy specimens will be immediately snap- 
frozen at -800C for cDNA array analysis. The remaining specimens will be fixed in formalin for 
diagnostic and immunohistochemical analysis. As human breast cancers consist of many 
different cell types, including not just carcinoma cells but also additional epithelial cell types, 
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A 
B 
epithelial cores by hematoxylin-eosin (H&E) and pan-cytokeratin stains before analysis (Fig. 
11). 
 
Figure 11. Stereotactic needle biopsies are large enough to sample breast cancers with adequate cellularity and tumor 
cells. This example shows a core fragment containing tumor cellularity of 75% on H&E (Fig. 11A), and on pan- 
cytokeratin marker (Fig. 4B). 
 
RNA isolation, cDNA synthesis, and combined in vitro transcription and biotin labeling (IVT) on 
the frozen samples will be carried out according to protocols recommended by Affymetrix 
GeneChipTM (Santa Clara, CA). Briefly, total RNA is isolated, and double-stranded cDNA is 
synthesized from total RNA using a chimeric oligo-dT/T7 RNA polymerase. Core biopsies 
typically yield 3-6 micrograms of total RNA. The IVT products will then be passed over a mini- 
RNA isolation column, and the cRNA target population will be chemically fragmented to 100-200 
bases. The fragmented cRNAs (~20 μg) will then be hybridized to the Affymetrix HG-U1332 
GeneChipsTM, which contain ~30,000 gene probes. The microarrays were pre-hybridized, 
hybridized, washed, and stained with streptavidin-phycoerythrin. 
Timing of biopsies 
Study patients will be consented for core biopsies at baseline prior to the second cycle of 
chemotherapy and at the end of treatment. If the patient progresses while in treatment a new 
biopsy will be taken before the patient start the new treatment. If the patient has locally 
advanced cancer, a surgical specimen will be obtained instead of a core biopsy 
Pre-treatment / Baseline:  Tumor biopsy specimens will be obtained prior to initiating therapy. 
A baseline research biopsy will be performed in accessible sites, like breast, skin, soft tissue 
and nodes. Four to six biopsies will be obtained for gene expression , immunohistochemistry, 
stem cell and other analyses. 
Before Cycle 2: Core biopsies will be obtained before cycle 2 of treatment, in accessible sites, 
as above. 
End of treatment: Core biopsies will be obtained at end of treatment, in accessible sites, as 
above. A surgical specimen may be obtained in lieu of a biopsy in patients who undergo 
surgery. 
 
Cytokine arrays 
Blood specimens will be collected for multi-analyte analysis with Luminex xMAP Technology. 
Luminex xMAP technology allows for the detection of multiple analytes simultaneously in a 
single assay. Luminex offer the broadest selection of analytes across a wide range of disease 
states, including inflammation, cancer and more. 
Timing of blood: 
Whole blood/serum collection for cytokine arrays at baseline, prior to the second cycle of 
chemotherapy, and at completion of study or if the patient progress while on treatment a blood 
draw will be done before the patient start the new treatment. One venous blood sample of 10 
mLs will be collected. 

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6.0 TIMELINE and MILESTONES 
Specific Aims 
Year 1 
Year 2 
Year 3 
Specific Aim 1: To determine the anti-tumor activity of the combination of Chloroquine + Taxane 
or Taxane-like chemo agents (Paclitaxel, Docetaxel, Abraxane, Ixabepilone) (C/T) measured by 
overall Response Rate (ORR). 
a. Planning and protocol writing 
--
b. Clinical recruitment 
------------------------------------------------
c. Overall Response Rate Analysis 
--------
Specific Aim 2: To Assess Safety, Tolerability and Responses Rates. 
a. Safety and Tolerability of the Combination 
---------------------------------------------------
b. Response rate and tumor control rate 
--------
c. Time to Progression (TTP) 
--------
d. Duration of response (DOR) 
--------
Specific Aim 3: Biomarkers Evaluation 
a. To evaluate biomarkers for response and toxicity of the 
chloroquine in combination with taxane or taxane-like chemo 
agents 
--------------------------------------
Table 2 

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7.0 Study Design 
 
 
CAT Trial 
PHASE II STUDY OF THE EFFICACY AND SAFETY OF CHLOROQUINE (C) IN COMBINATION WITH TAXANE OR 
TAXANE-LIKE (T) CHEMO AGENTS IN THE TREATMENT OF PATIENTS WITH ADVANCED OR METASTATIC BREAST 
CANCER WHO HAVE FAILED ANTHRACYCLINE CHEMO BASE THERAPY. 
ADVANCED 
OR    
METASTATIC 
BREAST 
CARCINOMA 
(MBC) 
CHLOROQUINE 250mg Daily 
+ 
TAXANE OR TAXANE-LIKE 
CHEMO AGENTS 
Study treatment may 
continue as determined 
by the investigator until 
disease progression, 
intolerable AEs, death, 
voluntary withdrawal 
from the study by the 
patient, or 
discontinuation of the 
study by the sponsor. 
O 
R 
R 
E 
V 
A 
L 
U 
A 
T 
I 
O 
N 
 
 
8.0 Study Population 
The study population will include subjects ≥ 18 years of age with histologically confirmed 
metastatic breast carcinoma. 
 
8.1 Inclusion Criteria: 
11. Females with pathologically determined advanced or metastatic breast cancer. 
12. Advanced breast cancer patients must have progressed or have residual disease after 
treatment with regimen that included at least 2 cycles of an anthracycline containing 
regimen. 
13. Metastatic breast cancer patients must have had at least 4 cycles of an anthracycline 
containing regimen. 
14. Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors. 
15. ≥18 years of age. 
16. At least one measurable disease site, defined as lesion of ≥ 1 cm 
17. No known underlying ocular/retinal pathology. 
18. No medically documented preexisting auditory damage. 
19. No cardiac conduction disturbances or medication potentially causing them: 
20. QTc interval prolongation with other medications that required discontinuation of the 
treatment 
11. Medication that might cause QT-prolongation or Torsades de pointes tachycardia is not 
allowed. (See appendix E) 
12. ECOG PS of 0, 1, or 2. 
STUDY DESIGN AND TREATMENT 

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13. Laboratory values within the following ranges: 
• 
Hemoglobin ≥9.0gm/dL (≥1.5μmol/L); transfusions permitted. 
• 
Absolute neutrophil count ≥1500/mm3 (1.5 x 109/L) 
• 
Platelet count ≥100,000/mm3 (100 x 109/L) 
• 
Creatinine (Cr) <2 X the upper limit of normal (ULN), Cr clearance (CrCl) ≥30 by 
Cockcroft and Gault 
• 
Alanine aminotransferase and aspartate aminotransferase <2 X the ULN; if liver 
metastases are present then must be <5 X the ULN, Bilirubin <2 X the ULN, for 
patients receiving Ixabepilone Potassium and Magnesium must bewithin normal 
limits. 
14. Negative serum pregnancy test at the time of first dose for women of childbearing potential 
(WOCBP). For WOCBP, adequate contraception must be used throughout the study. For this 
study, acceptable methods of contraception include a reliable intrauterine device or a 
spermicide in combination with a barrier method. Women who are already on hormonal forms of 
birth control may continue that treatment but must also use a barrier method. 
15. Ability to understand the requirements of the study, provide written informed consent and 
authorization of use and disclosure of protected health information, and agree to abide by the 
study restrictions and return for the required assessments. 
16. Patient must be willing to undergo breast biopsies as required by the study protocol. 
 
8.2 Exclusion Criteria: 
1. Radiation therapy within 2 weeks; or chemotherapy or non-cytotoxic investigational agents 
within 2 weeks of initiating study treatment. 
2. Evidence of New York Heart Association class III or greater cardiac disease. 
3. History of myocardial infarction, stroke, ventricular arrhythmia, or symptomatic conduction 
abnormality within 12 months. 
4. History of congenital QT prolongation. 
5. QT >500. 
6. Concurrent severe or uncontrolled medical disease (i.e., active systemic infection, diabetes, 
hypertension, coronary artery disease, congestive heart Failure or major surgery) that, in the 
opinion of the Investigator, would compromise the safety of the patient or compromise the 
ability of the patient to complete the study. 
7. Symptomatic central nervous system metastases. 
8. The patient must be stable after radiotherapy for ≥2 weeks and off corticosteroids for ≥1 
week. 
9. Pregnant or nursing women. 
10. Hypersensitivity or intolerance to Quinolones, Chloroquine, Paclitaxel, Docetaxel, Abraxane, 
Ixabepilone or other Taxane like drugs. 
11. Active diagnosis of psoriasis or currently receiving treatment for psoriasis. 
12. Alcoholism or hepatic disease. 
13. History of epilepsy or seizures in the past 20 years. 
14. Receiving concurrent treatment with prohibited medications (See appendix E) Examples 
include: ampicillin, antacids, cimetidine, cyclosporine, kaolin, magnesium trisilicate, 
coumarin-type anticoagulants, macrolide antibiotics (e.g., clarithromycin, isoniazid, and 
erythromycin), anti-HIV agents (e.g., ritonavir and delavirdine), antidepressants (e.g. 
fluoxetine and fluvoxamine), calcium channel blockers (e.g. verapamil and diltiazem), 
steroids and their modulators (e.g., gestodene, raloxifene, and mifepristone), and several 
herbal and dietary components (e.g. bergamottin and glabridin). 
15. Severe renal insufficiency (CrCl <30mL/min [Cockcroft and Gault]). 
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17. Concurrent use of potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, 
clarithromycin, atanazir, indinavir, nefazodone, neflinavir, ritonavir, saquinavir, telithromycin, 
and voriconazole. 
18. Concurrent use of potent CYP3A4 inducers, such as dexamethasone, phenytoin, 
carbamazepine, rifampin, rifabutin, rifapentin, phenobarbitol, and St. John’s wort. 
19. Used an investigational drug within 14 days preceding the first dose of study medication. 
 
9.0 Treatment Plan/Methods 
This is a phase II trial; 47 patients with diagnosis of with metastatic breast cancer, who have 
failed anthracycline chemo base therapy, will be enrolled in the study. Patients will receive 
Chloroquine (C) together with Taxane or Taxane-like (Paclitaxel, Docetaxel, Abraxane, 
Ixabepilone) (T) Chemo Agents. 
 
The study population will include subjects ≥ 18 years of age with histologically confirmed 
metastatic breast carcinoma. Subjects will have a medical history and physical assessment to 
include concomitant medication, standard of care breast cancer staging including mammogram, 
ultrasound, bone scan, chest x-ray or chest CT as well as blood tests for Complete Blood Count 
(CBC) with differentials, Complete Metabolic Panel (CMP).  Prior  to  starting  treatment, 
subjects will have a research biopsy of accessible sites. The study doctor will determine if the 
subject qualified to be enrolled in this study. Study treatment may continue as determined by the 
investigator until disease progression, intolerable AEs, death, voluntary withdrawal from the 
study by the patient, or discontinuation of the study by the sponsor. 
 
9.0.1 Treatment (Physician Choice) 
Subjects eligible for treatment will receive treatments per NCCN guidelines: 
A: Chloroquine 250mg po daily together with Paclitaxel 175 mg/m2 three hours infusion every 
two or three weeks or Paclitaxel 80 mg/m2 weekly. Or 
B: Chloroquine 250mg po daily together with Taxotere 75 mg/m2 (or 100mg/m2 in advanced 
breast cancer patients) administered intravenously over one hour every three weeks. Or 
C: Chloroquine 250mg po daily together with Abraxane 260 mg/m2 administered intravenously 
over 30 minutes every three weeks or 100mg/m2 administered weekly. Or 
D: Chloroquine 250mg po daily together with Ixabepilone is 40 mg/m2 administered 
intravenously over three hours every three weeks. Doses for patients with body surface area 
(BSA) greater than 2.2 m2 should be calculated based on 2.2 m2. 
 
Infusion times for chemotherapy are approximate and can vary slightly. Infusion time can be 
slowed for the safety of the patient. Dose reductions are allowed at the discretion of the 
investigator for patient safety. 
 
Subjects will be premedicated approximately 1 hour before the infusion. Standard anti-emetics 
for moderately emetogenic regimen, together with standard premedication will be prescribed 
with chemotherapy. Recommended prophylaxis for the taxane and taxane-like chemo agent 
includes: 
 
Paclitaxel premedication may consist of dexamethasone 20 mg PO administered 
approximately 12 and 6 hours before Paclitaxel, diphenhydramine (or its equivalent) 50 
mg IV 30 to 60 minutes prior to Paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) 
IV 30 to 60 minutes before Paclitaxel or use premedication per institutional standards.
 
Taxotere premedicated may consist of oral corticosteroids such as dexamethasone 16 
mg per day (e.g., 8 mg BID) for 3 days starting 1 day prior to Taxotere administration or 
use premedication per institutional standards.

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 
Abraxane, no premedication is needed.
 
Ixabepilone premedication may consist of H1 antagonist (e.g., diphenhydramine 50 mg 
orally or equivalent) and a H2 antagonist (e.g., ranitidine 150 - 300 mg orally or 
equivalent). Or use premedication per institutional standards.
 
9.1 DRUG INFORMATION AND MODIFICATIONS: 
9.1.1 CHLOROQUINE 
ARALEN, chloroquine phosphate, USP, is a 4-aminoquinoline compound for oral 
administration. It is a white, odorless, bitter tasting, crystalline substance, freely soluble in water. 
ARALEN is an antimalarial and amebicidal drug. 
Chemically, it is 7-chloro-4-[[4-(diethylamino)-1-methylbutyl]amino]quinoline phosphate (1:2) 
and has the following structural formula: 
 
Each tablet contains 250 mg of chloroquine phosphate USP, equivalent to 150 mg chloroquine 
base. 
Inactive Ingredients: Carnauba Wax, Colloidal Silicon Dioxide, Dibasic Calcium Phosphate, 
Hydroxypropyl Methylcellulose, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene 
Glycol, Polysorbate 80, Pregelatinized Starch, Sodium Starch Glycolate, Stearic Acid, Titanium 
Dioxide. 
CLINICAL PHARMACOLOGY 
Chloroquine is rapidly and almost completely absorbed from the gastrointestinal tract, and only 
a small proportion of the administered dose is found in the stools. Approximately 55% of the 
drug in the plasma is bound to nondiffusible plasma constituents. Excretion of chloroquine is 
quite slow, but is increased by acidification of the urine. Chloroquine is deposited in the tissues 
in considerable amounts. In animals, from 200 to 700 times the plasma concentration may be 
found in the liver, spleen, kidney, and lung; leukocytes also concentrate the drug. The brain and 
spinal cord, in contrast, contain only 10 to 30 times the amount present in plasma. Chloroquine 
undergoes appreciable degradation in the body. The main metabolite is desethylchloroquine, 
which 
accounts 
for 
one 
fourth 
of 
the 
total 
material 
appearing 
in 
the 
urine; 
bisdesethylchloroquine, a carboxylic acid derivative, and other metabolic products as yet 
uncharacterized are found in small amounts. Slightly more than half of the urinary drug products 
can be accounted for as unchanged chloroquine.47 
Microbiology 
Mechanism of Action 
Chloroquine is an antimalarial agent. While the drug can inhibit certain enzymes, its effect is 
believed to result, at least in part, from its interaction with DNA. However, the mechanism of 
plasmodicidal action of chloroquine is not completely certain. 
Activity in vitro and in vivo 
Chloroquine is active against the erythrocytic forms of Plasmodium vivax. Plasmodium malariae, 
and susceptible strains of Plasmodium falciparum (but not the gametocytes of P. falciparum). It 
is not effective against exoerythrocytic forms of the parasite. In vitro studies with trophozoites of 
Entamoeba histolytica have demonstrated that chloroquine also possesses amebicidal activity 
comparable to that of emetine. 
Figure 12 

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Drug Resistance 
Resistance of Plasmodium falciparum to chloroquine is widespread and cases of Plasmodium 
vivax resistance have been reported. 
INDICATIONS AND USAGE 
ARALEN is indicated for the suppressive treatment and for acute attacks of malaria due to P. 
vivax, P.malariae, P. ovale, and susceptible strains of P. falciparum. The drug is also indicated 
for the treatment of extraintestinal amebiasis. 
ARALEN does not prevent relapses in patients with vivax or malariae malaria because it is not 
effective against exoerythrocytic forms of the parasite, nor will it prevent vivax or malariae 
infection when administered as a prophylactic. It is highly effective as a suppressive agent in 
patients with vivax or malariae malaria, in terminating acute attacks, and significantly 
lengthening the interval between treatment and relapse. In patients with falciparum malaria it 
abolishes the acute attack and effects complete cure of the infection, unless due to a resistant 
strain of P. falciparum. 47 
CONTRAINDICATIONS 
Use of this drug is contraindicated in the presence of retinal or visual field changes either 
attributable to 4-aminoquinoline compounds or to any other etiology, and in patients with known 
hypersensitivity to 4-aminoquinoline compounds. However, in the treatment of acute attacks of 
malaria caused by susceptible strains of plasmodia, the physician may elect to use this drug 
after carefully weighing the possible benefits and risks to the patient. 
WARNINGS 
It has been found that certain strains of P. falciparum have become resistant to 4- 
aminoquinoline compounds (including chloroquine and hydroxychloroquine). Chloroquine 
resistance is widespread and, at present, is particularly prominent in various parts of the world 
including sub-Saharan Africa, Southeast Asia, the Indian subcontinent, and over large portions 
of South America, including the Amazon basin. Before using chloroquine for prophylaxis, it 
should be ascertained whether chloroquine is appropriate for use in the region to be visited by 
the traveler. Chloroquine should not be used for treatment of P. falciparum infections acquired in 
areas of chloroquine resistance or malaria occurring in patients where chloroquine prophylaxis 
has failed. Patients infected with a resistant strain of plasmodia as shown by the fact that 
normally adequate doses have failed to prevent or cure clinical malaria or parasitemia should be 
treated with another form of antimalarial therapy. Irreversible retinal damage has been observed 
in some patients who had received long-term or high-dosage 4-aminoquinoline therapy. 
Retinopathy has been reported to be dose related. When prolonged therapy with any 
antimalarial compound is contemplated, initial (base line) and periodic ophthalmologic 
examinations (including visual acuity, expert slit-lamp, funduscopic, and visual field tests) should 
be performed. If there is any indication (past or present) of abnormality in the visual acuity, 
visual field, or retinal macular areas (such as pigmentary changes, loss of foveal reflex), or any 
visual symptoms (such as light flashes and streaks) which are not fully explainable by difficulties 
of accommodation or corneal opacities, the drug should be discontinued immediately and the 
patient closely observed for possible progression. Retinal changes (and visual disturbances) 
may progress even after cessation of therapy. All patients on long-term therapy with this 
preparation should be questioned and examined periodically, including testing knee and ankle 
reflexes, to detect any evidence of muscular weakness. If weakness occurs, discontinue the 
drug. A number of fatalities have been reported following the accidental ingestion of 
chloroquine, sometimes in relatively small doses (0.75 g or 1 g chloroquine phosphate in one 3- 
year-old child). Patients should be strongly warned to keep this drug out of the reach of children 
because they are especially sensitive to the 4-aminoquinoline compounds. 
Use of ARALEN in patients with psoriasis may precipitate a severe attack of psoriasis. When 
used in patients with porphyria the condition may be exacerbated. The drug should not be used 

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in these conditions unless in the judgment of the physician the benefit to the patient outweighs 
the potential risks. 47 
Usage in Pregnancy 
Radioactively tagged chloroquine administered intravenously to pregnant pigmented CBA mice 
passed rapidly across the placenta and accumulated selectively in the melanin structures of the 
fetal eyes. It was retained in the ocular tissues for five months after the drug had been 
eliminated from the rest of the body. There are no adequate and well-controlled studies 
evaluating the safety and efficacy of chloroquine in pregnant women. Usage of chloroquine 
during pregnancy should be avoided except in the suppression or treatment of malaria when in 
the judgment of the physician the benefit outweighs the potential risk to the fetus. 
 
 
Hematological Effects/Laboratory Tests 
Complete blood cell counts should be made periodically if patients are given prolonged therapy. 
If any severe blood disorder appears which is not attributable to the disease under treatment, 
discontinuance of the drug should be considered. 
The drug should be administered with caution to patients having G-6-PD (glucose-6 phosphate 
dehydrogenase) deficiency. 
Auditory Effects 
In patients with preexisting auditory damage, chloroquine should be administered with caution. 
In case of any defects in hearing, chloroquine should be immediately discontinued, and the 
patient closely observed. 
Hepatic Effects 
Since this drug is known to concentrate in the liver, it should be used with caution in patients 
with hepatic disease or alcoholism or in conjunction with known hepatotoxic drugs. 
Central Nervous System Effects 
Patients with history of epilepsy should be advised about the risk of chloroquine provoking 
seizures. 
Drug Interactions 
Antacids and kaolin: Antacids and kaolin can reduce absorption of chloroquine; an interval of at 
least 4 hours between intake of these agents and chloroquine should be observed. 
Cimetidine: Cimetidine can inhibit the metabolism of chloroquine, increasing its plasma level. 
Concomitant use of cimetidine should be avoided. 
Ampicillin: In a study of healthy volunteers, chloroquine significantly reduced the bioavailability 
of ampicillin. An interval of at least two hours between intake of this agent and chloroquine 
should be observed. 
Cyclosporine: After introduction of chloroquine (oral form), a sudden increase in serum 
cyclosporine level has been reported. Therefore, close monitoring of serum cyclosporine level is 
recommended and, if necessary, chloroquine should be discontinued. 
Mefloquine: Co-administration of chloroquine and mefloquine may increase the risk of 
convulsions. 
The blood concentrations of chloroquine and desethylchloroquine (the major metabolite of 
chloroquine, which also has antimalarial properties) were negatively associated with log 
antibody titers. Chloroquine taken in the dose recommended for malaria prophylaxis can reduce 
the antibody response to primary immunization with intradermal human diploid-cell rabies 
vaccine. 47 
Nursing Mothers 
Because of the potential for serious adverse reactions in nursing infants from chloroquine, a 
decision should be made whether to discontinue nursing or to discontinue the drug, taking into 
account the potential clinical benefit of the drug to the mother. The excretion of chloroquine and 

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the major metabolite, desethylchloroquine, in breast milk was investigated in eleven lactating 
mothers following a single oral dose of chloroquine (600 mg base). The maximum daily dose of 
the drug that the infant can receive from breastfeeding was about 0.7% of the maternal start 
dose of the drug in malaria chemotherapy. Separate chemoprophylaxis for the infant is required. 
Geriatric Use 
Clinical studies of chloroquine did not include sufficient numbers of subjects aged 65 and over 
to determine whether they respond differently from younger subjects. However, this drug is 
known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may 
be greater in patients with impaired renal function. Because elderly patients are more likely to 
have decreased renal function, care should be taken in dose selection and it may be useful to 
monitor renal function. 
ADVERSE REACTIONS 
Special Senses: Ocular: Irreversible retinal damage in patients receiving long-term or high- 
dosage 4-aminoquinoline therapy; visual disturbances (blurring of vision and difficulty of 
focusing or accommodation); nyctalopia; scotomatous vision with field defects of paracentral, 
pericentral ring types, and typically temporal scotomas, e.g., difficulty in reading with words 
tending to disappear, seeing half an object, misty vision, and fog before the eyes. Reversible 
corneal opacities have also been reported. 
Auditory: Nerve type deafness; tinnitus, reduced hearing in patients with preexisting auditory 
damage. 47 
Musculoskeletal system: Skeletal muscle myopathy or neuromyopathy leading to progressive 
weakness and atrophy of proximal muscle groups, which may be associated with mild sensory 
changes, depression of tendon reflexes and abnormal nerve conduction, have been noted. 
Gastrointestinal system: Hepatitis, increased liver enzymes, anorexia, nausea, vomiting, 
diarrhea, abdominal cramps. 
Skin and appendages: Rare reports of erythema multiforme, Stevens-Johnson syndrome, toxic 
epidermal necrolysis, exfoliative dermatitis and similar desquamation-type events. Pleomorphic 
skin eruptions, skin and mucosal pigmentary changes; lichen planus-like eruptions, pruritus, 
urticaria, anaphylactic/anaphylactoid reaction including angioedema, photosensitivity and hair 
loss and bleaching of hair pigment. 
Hematologic system: Rarely, pancytopenia, aplastic anemia, reversible agranulocytosis, 
thrombocytopenia and neutropenia. 
Nervous 
system: 
Convulsive seizures, mild and transient headache, polyneuritis. 
Neuropsychiatric changes including psychosis, delirium, anxiety, agitation, insomnia, confusion, 
hallucinations, personality changes, and depression. 
Cardiovascular system: Rarely, hypotension, electrocardiographic change (particularly, 
inversion or depression of the T-wave with widening of the QRS complex), and cardiomyopathy. 
OVERDOSAGE 
Symptoms 
Chloroquine is very rapidly and completely absorbed after ingestion. Toxic doses of chloroquine 
can be fatal. Toxic symptoms can occur within minutes. These consist of headache, drowsiness, 
visual disturbances, nausea and vomiting, cardiovascular collapse, shock and convulsions 
followed by sudden and early respiratory and cardiac arrest. Hypokalemia has been observed 
with arrhythmias in cases of intoxication. The electrocardiogram may reveal atrial standstill, 
nodal rhythm, prolonged intraventricular conduction time, and progressive bradycardia leading 
to ventricular fibrillation and/or arrest. 
Treatment 
Treatment is symptomatic and must be prompt with immediate evacuation of the stomach by 
emesis (at home, before transportation to the hospital) or gastric lavage until the stomach is 
completely emptied. If finely powdered, activated charcoal is introduced by stomach tube, after 
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absorption of the drug. To be effective, the dose of activated charcoal should be at least five 
times the estimated dose of chloroquine ingested. Convulsions, if present, should be controlled 
before attempting gastric lavage. If due to cerebral stimulation, cautious administration of an 
ultra short-acting barbiturate may be tried but, if due to anoxia, it should be corrected by oxygen 
administration and artificial respiration. Monitor ECG. In shock with hypotension, a potent 
vasopressor should be administered. Replace fluids and electrolytes as needed. Cardiac 
compressing or pacing may be indicated to sustain the circulation. Because of the importance of 
supporting respiration, tracheal intubation or tracheostomy, followed by gastric lavage, may also 
be necessary. Peritoneal dialysis and exchange transfusions have also been suggested to 
reduce the level of the drug in the blood. Intervention options can involve: diazepam for life- 
threatening symptoms, seizures and sedation, epinephrine for treatment of vasodilation and 
myocardial depression, potassium replacement with close monitoring of serum potassium 
levels. A patient who survives the acute phase and is asymptomatic should be closely observed 
for at least six hours. Fluids may be forced, and sufficient ammonium chloride (8 g daily in 
divided doses for adults) may be administered for a few days to acidify the urine to help promote 
urinary excretion in cases of both overdosage or sensitivity. 22 
Dosage in Renal Failure 
In patients with severe renal failure (GFR less than 10 milliliters/minute) 50% of the normal dose 
should be administered. If prolonged treatment is necessary, the dosage should be further 
reduced to 50 to 100 milligrams/day. 
Dosage in Hepatic Insufficiency 
Thirty percent to 50% of the administered dose is modified by the liver, and appropriate dosage 
adjustment is necessary. Serum drug monitoring may be useful. 22 
 
9.1.2 Paclitaxel 
SYNONYM(S): NSC-125973 
COMMON TRADE NAMES: generic available, ONXOL® (USA), TAXOL® 
CLASSIFICATION: antimicrotubule agent, cytotoxic 
MECHANISM OF ACTION: Paclitaxel is an antimicrotubule agent that promotes the assembly 
and stabilization of microtubules from tubulin dimers. Late G2 mitotic phase is inhibited and thus 
cell replication is inhibited. Paclitaxel also can distort mitotic spindles resulting in chromosomal 
damage. 48 
 
PHARMACOKINETICS: 
Distribution 
biphasic; initial rapid distribution to the peripheral compartment, then a slow efflux of 
paclitaxel from the peripheral compartment; widely distributed into body fluids and tissues; 
affected by dose and duration of infusion 
Metabolism 
volume of distribution 
no 
plasma protein binding 
198-688 L/m2; varies with dose and infusion time 
hepatic via the cytochrome 
P450 isozymes CYP2C8/9 and 
CYP3A4 
89-98% 
Excretion 
active metabolite(s) 
inactive metabolite(s) 
primarily 6α-hydroxypaclitaxel 
elimination follows non-linear 
(saturable) 
pharmacokinetics; 
high concentrations found in 
bile 
yes 
Gender 
urine 
feces 
14% (1.3-12.6% as unchanged drug) 

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terminal half life 
71% (5% as unchanged drug) 
clearance 
3.0-52.7 h; varies with dose and infusion time 
(e.g., 3 h infusion of 175 mg/m2: 9.9 h) 
no information found 
11.6-24.0 L/h/m2; varies with dose and infusion time 
(e.g., 3 h infusion of 175 mg/m2: 12.4 L/h/m2) 
Elderly 
clearance 
Table 3 
Children 
terminal half life 
11.4-16.2 L/h/m2 
 
 
 
 
SPECIAL PRECAUTIONS: 
Hypersensitivity reactions (HSR): Paclitaxel infusions may be associated with acute 
hypersensitivity reactions; incidence is significantly reduced by premedication and increased 
infusion times 
Carcinogenicity: Not yet studied. 
Elderly patients are at an increased risk for developing toxicities (e.g., arthralgia, myalgia, 
neutropenia, neuropathy). 
Mutagenicity: Paclitaxel was not mutagenic in the Ames test. Paclitaxel was clastogenic in the 
mammalian in vitro and in vivo chromosome tests. 
Fertility: The effects of paclitaxel on fertility have not been established. Women of childbearing 
potential should be counseled to avoid pregnancy. 
Pregnancy: FDA Pregnancy Category D. There is positive evidence of human fetal risk, but the 
benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is 
needed in a life-threatening situation or for a serious disease for which safer drugs cannot be 
used or are ineffective). 
Breastfeeding is not recommended due to the potential secretion into breast milk. 48 
SIDE EFFECTS: 
ORGAN SITE 
SIDE EFFECT 
ONSET 
I 
= 
immediate 
(onset 
in 
hours 
to 
days); 
E 
= 
early 
(days 
to 
weeks); 
D = delayed (weeks to months); L = late (months to years) 
allergy/immunology 
hypersensitivity reactions (severe 1%) 
I 
blood/bone 
marrow/ 
febrile neutropenia 
anemia (62%, severe 6%) 
E 
neutropenia (severe 6-21%); nadir 8-11 days, recovery 15-21 
days 
I 
thrombocytopenia (6%) 
I 
cardiovascular 
(arrhythmia) 
arrhythmias (1%) (e.g., asymptomatic ventricular tachycardia, atrial 
fibrillation, supraventricular tachycardia, junctional tachycardia) 
I 
bradycardia (25%); during infusion, transient 
I 
cardiovascular (general) 
electrocardiogram abnormalities (23%) 
I 
edema (21%) 
E 
hypertension (1%) 
I 
hypotension (24%); during infusion, transient 
I 
myocardial infarction (rare) 
D 
constitutional symptoms 
dermatology/skin 
extravasation hazard: irritant 

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ORGAN SITE 
SIDE EFFECT 
ONSET 
I 
= 
immediate 
(onset 
in 
hours 
to 
days); 
E 
= 
early 
(days 
to 
weeks); 
D = delayed (weeks to months); L = late (months to years) 
alopecia (87%); usually complete, generally occurs 14-21 days 
after administration of paclitaxel with a sudden onset, often 
occurring in a single day9 
E 
flushing (28%) 
I 
nail and skin changes (2%); mild, transient 
E 
radiation recall reaction (rare) 
E 
rash (12%) 
I 
gastrointestinal 
emetogenic potential: low 
anorexia (25%) 
E 
constipation (18%) 
E 
diarrhea (38%) 
I 
intestinal obstruction (4%) 
E 
mucositis (31%); more common with 24 h infusion 
E 
nausea (52%); mild to moderate 
I 
stomatitis (15%); most common at doses >390 mg/m2 
E 
taste perversion 
E 
vomiting (5-6%); mild to moderate 
I 
hepatic 
hepatic necrosis and hepatic encephalopathy (rare) 
D 
infection 
febrile neutropenia (12%) 
I 
neurology 
ataxia (<1%) 
E 
encephalopathy (rare) 
E 
ethanol intoxication 
I 
seizures (rare) 
E 
myopathy (25-50%) 
E 
peripheral neuropathy (64%, severe 4%) 
E 
metabolic/laboratory 
mild increase in liver enzymes (18%) 
I 
ocular/visual 
optic nerve and/or visual disturbances (rare) 
E 
pain 
arthralgia/myalgia (54%, severe 12%) 
I 
E 
pulmonary 
interstitial pneumonia, lung fibrosis (rare) 
D 
vascular 
pulmonary embolism (rare) 
I 
phlebitis (2%) 
I 
Table 4 
 
Hypersensitivity reactions (HSR) are common with paclitaxel and appear to be due to a 
nonimmunologically-mediated release of histamine and other vasoactive substances. The exact 
cause is not known but may result from either the Cremophor EL in the paclitaxel injection or 
from the paclitaxel itself. HSR most often occur in the first hour of an infusion (75% occur within 
the first 10 minutes). The frequency and severity of these reactions are not affected by the dose 
or schedule of paclitaxel administration. Delayed onset of urticarial rash, 7-10 days following 
completion of a course of treatment, has been seen in some Kaposi’s sarcoma patients. 

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Stop infusion and do not restart. 
Give diphenhydramine 50 mg IV push and/or hydrocortisone sodium succinate 100 
mg IV push per physician orders. 
Oxygen if needed for dyspnea (see SCDRUGRX). 
Normal saline if needed for hypotension (see SCDRUGRX). 
Epinephrine or bronchodilators if indicated (see SCDRUGRX). 
Either permanently discontinue the drug or attempt to retreat on another occasion 
after premedication (see SCDRUGRX) and using slower infusion rate. 
Initiate Emergency Response System appropriate for facility if patient condition 
warrant. 
Table 5 
Severe 
(potentially 
life 
threatening) 
i.e., to be used if reaction 
escalates (e.g., one or more 
of 
respiratory 
distress 
requiring 
treatment, 
angioedema, 
hypotension 
requiring therapy) 
Stop infusion. 
Give diphenhydramine 25-50 mg IV and/or hydrocortisone sodium succinate 100 
mg per physician orders. 
After recovery of symptoms, resume infusion at a rate per protocol. If no direction in 
protocol consider resuming at 25% of previous rate for at least 5 minutes, 50% for 
at least 5 minutes, 75% for at least 5 minutes and then full rate if no reaction. 
Depending on severity of reaction, may increase to full rate at physician’s 
discretion. 
Premedication for all future cycles (see Prophylaxis section in SCDRUGRX). 
Initiate infusion at slower rate (consider 50% of full rate) per physician orders. 
Moderate 
e.g., moderate rash, flushing, 
pruritus, mild dyspnea, chest 
discomfort, 
abdominal 
discomfort, lower back pain, 
mild hypotension 
Incidence of HSR are significantly reduced by premedication. Corticosteroids (e.g., 
dexamethasone), histamine H1-antagonists (e.g., diphenhydramine) and H2-antagonists (e.g., 
ranitidine) should be administered prior to paclitaxel administration to minimize the potential for 
anaphylaxis. The following is one suggested regimen for adults: 
 45 minutes before paclitaxel, dexamethasone 20 mg IV
 30 minutes before paclitaxel, diphenhydramine 50 mg IV and ranitidine 50 mg IV.
A more protracted premedication scheme, which may be more effective, particularly where a 
patient has exhibited HSR would be: 12 hours and 6 hours before paclitaxel, dexamethasone 20 
mg po and then following the above premedication regime. In the event of a treatment delay 
(e.g., admixture is unavailable), additional doses are required. In premedicated patients, 
symptoms of HSR are reported in as many as 41%, although severe HSR occur in less than 2% 
of patients. 
The occurrence of HSR does not preclude rechallenge with paclitaxel. If there is a 
hypersensitivity reaction, the patient may be rechallenged after further premedication and with 
close monitoring. Prolonging the infusion to > 6 hours may decrease the incidence of 
hypersensitivity reactions; 24, 96 and 120 hour infusions have been studied and show 
decreased HSR with increased infusion times. 
Treatment for hypersensitivity reactions, including general management, and management of 
hypotension, dyspnea and bronchospasm can be found in the BC Cancer Agency Protocol 
Summary of Hypersensitivity Reactions to Chemotherapeutic Agents (SCDRUGRX). See below 
for general management. 
General Management: It is recommended that patients are assessed by a physician if having a 
reaction requiring the administration of medications or as patient condition warrants. 48 
 
IF there is a true anaphylactic reaction with paclitaxel despite premedication and a slow initial 
infusion rate the patient should not have a further rechallenge. 
Very rarely, fatal reactions have occurred in patients despite pre-treatment. Docetaxel has been 
successfully substituted in some patients who experienced severe HSR with paclitaxel; 
however, cross-sensitivity has also been reported. 
Arthralgia/myalgia is dose and schedule dependent; worse with higher doses and shorter 
infusions. The symptoms are usually transient, occur within two or three days after paclitaxel 

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administration, and resolve after a few days. If arthralgia/myalgia from paclitaxel is grade 2 
(moderate) or higher and is not relieved by adequate doses of NSAIDS or acetaminophen with 
codeine a suggested symptomatic treatment includes: 
 gabapentin 300 mg po on day prior to paclitaxel, 300 mg po bid on treatment day and 
then 300 mg po tid x 7-10 days
 prednisone 10 mg po bid x 5 days starting 24 hours post-paclitaxel
Peripheral neuropathy is usually sensory in nature. Paclitaxel-induced neurotoxicity often 
appears as mild paresthesia characterized by numbness and tingling in a stocking-and-glove 
distribution. Perioral numbness may also occur, and many patients experience burning pain 
particularly in the feet. Onset may be rapid, occurring within a few days of an infusion. 
Frequency and severity are related to cumulative doses; toxicity may be dose-limiting. Sensory 
manifestations usually improve or resolve several months after discontinuing paclitaxel. Pre- 
existing neuropathies resulting from prior therapies are not a contraindication for treatment with 
paclitaxel; however, the incidence of paclitaxel-related neuropathy appears to be increased in 
this population of patients. 
Bradycardia and hypotension during paclitaxel administration is usually asymptomatic and 
generally does not require treatment. In some cases, paclitaxel administration may have to be 
interrupted or discontinued. Based on nursing experience with paclitaxel administration, and 
consultation with medical oncology and pharmacy, the BC Cancer Agency has found that 
clinical observation of patients by nurses for early signs of a reaction is more valuable than 
taking vital signs every15 minutes. Severe cardiac conduction abnormalities have rarely 
occurred during paclitaxel therapy. If patients develop significant conduction abnormalities 
during administration, appropriate treatment should be administered and continuous 
electrocardiographic monitoring should be performed during subsequent infusions. 
Ethanol is contained in the paclitaxel formulation at a concentration of 396 mg/mL. 
Consideration should be given to possible CNS effects including impaired ability to drive and 
operate machinery. 
INTERACTIONS: 
AGENT 
EFFECT 
MECHANISM 
MANAGEMENT 
doxorubicin 
increased 
doxorubicin 
efficacy and toxicity 
decreased clearance of 
doxorubicin 
monitor 
for 
increased 
cardiotoxicity 
(e.g., 
congestive heart failure) or 
consider using docetaxel 
instead 
of 
paclitaxel 
(docetaxel 
does 
not 
appear to share this same 
interaction potential) 
epirubicin 
toxicity of both agents may 
be increased when given 
concurrently, regardless of 
which drug is given first; 
lower 
neutrophil 
and 
platelet nadirs, and slower 
neutrophil recovery, have 
been observed 
increased 
levels 
of 
epirubicin 
metabolites, 
decreased 
paclitaxel 
clearance 
separate administration by 
24 hours if possible 
gemcitabine 
delayed, 
moderate, 
possible; 
increased 
gemcitabine efficacy and 
toxicity 
unknown 
monitor for gemcitabine 
toxicity 
during 
coadministration 
platinum derivatives 
(e.g., carboplatin, cisplatin) 
increased 
paclitaxel 
toxicity; 
paradoxical 
decreased platelet toxicity 
from carboplatin 
decreased clearance of 
paclitaxel 
paclitaxel should be given 
first when administering as 
sequential infusions with 
either of these drugs 

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AGENT 
EFFECT 
MECHANISM 
MANAGEMENT 
trastuzumab53 
may increase efficacy of 
paclitaxel 
unknown 
preferred method is to give 
trastuzumab 
first 
when 
administering 
as 
sequential infusions 
warfarin52 
delayed, 
moderate 
suspected; 
the 
anticoagulant 
effect 
of 
warfarin may be increased 
decreased 
warfarin 
metabolism 
monitor 
coagulation 
parameters 
 
during 
coadministration 
 
or 
consider use of LMWH 
during course of 
chemotherapy 
Table 6 
Paclitaxel is a major CYP2C8/9 substrate; therefore drugs that are CYP2C8/9 inducers (e.g., 
carbamazepine, phenobarbital, phenytoin, rifampin and secobarbital) may decrease the 
levels/effects of paclitaxel. Likewise, drugs that are CYP2C8/9 inhibitors (e.g., fluconazole, 
gemfibrozil, ketoconazole, NSAIDS and sulfonamides) may increase the levels/effects of 
paclitaxel. 
Paclitaxel is a major CYP3A4 substrate, therefore drugs that are CYP3A4 inducers (e.g., 
aminoglutethimide, carbamazepine, nafcillin, phenobarbital and phenytoin) may decrease the 
levels/effects of paclitaxel. Herbs that are CYP3A4 inducers (e.g., St John’s Wort) may also 
decrease the levels/effects of paclitaxel. Likewise, drugs that are CYP3A4 inhibitors (e.g., azole 
antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, 
isoniazid, propofol, protease inhibitors, quinidine and verapamil) may increase the levels/effects 
of paclitaxel. Paclitaxel is also a weak CYP3A4 inducer. 
DOSAGE GUIDELINES: 
If myelosuppression modify dosage as follows: 
PLATELET COUNT 
(x 109/L) 
ABSOLUTE NEUTROPHIL (ANC)* 
(x 109/L) 
Table 7 
> 1.8 
1.5-1.8 
1.0-1.5 
<1.0 
> 100 
100% 
75% 
50% 
0% 
70-100 
75% 
75% 
50% 
0% 
50-70 
50% 
50% 
50% 
0% 
<50 
0% 
0% 
0% 
0% 
* ANC = WBC x (% polys + % stabs) 
** 0% Indicates treatment should be postponed a week until the counts return to a level at which drugs may be given. 
 
Concurrent radiation: 
Generally not administered concurrently due to additive toxicity. 
Dosage in hepatic failure: 
 
 
 
 
 
 
 
 
 
 
 
Dosage in dialysis: 
No significant removal by hemodialysis. 48 
Suggested guidelines for first course; subsequent courses should be 
based on individual tolerance 
paclitaxel 24 h infusion: 
ALT 
bilirubin 
dose 
<2 X ULN 
and 
<26 µmol/L 
135 mg/m2 
2 to <10 X ULN 
and 
<26 µmol/L 
100 mg/m2 
<10 x ULN 
and 
27-128 µmol/L 
50 mg/m2 
>10 x ULN 
or 
>128 µmol/L 
not recommended 
paclitaxel 3 h infusion: 
ALT 
bilirubin 
dose 
<10 X ULN 
and 
<1.25 x ULN 
175 mg/m2 
<10 X ULN 
and 
1.26-2.0 x ULN 
135 mg/m2 
<10 X ULN 
and 
2.01-5.0 x ULN 
90 mg/m2 
>10 x ULN 
or 
>5.0 x ULN 
not recommended 
Table 8 

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9.1.3 Docetaxel 
DRUG NAME: Docetaxel 
SYNONYM(S): RP56976 
COMMON TRADE NAME(S): TAXOTERE® 
CLASSIFICATION: Mitotic inhibitor, cytotoxic 
Special pediatric considerations are noted when applicable, otherwise adult provisions apply. 
MECHANISM OF ACTION: 
Docetaxel is a semi-synthetic drug derived from precursor extracted from the needles of the 
European yew tree, Taxus baccata. It acts by disrupting the microtubular network that is 
essential for mitotic and interphase cellular functions. It promotes the assembly of tubulin into 
stable microtubules and inhibits their disassembly, causing inhibition of cell division and 
eventual cell death. Both docetaxel and paclitaxel bind to the same microtubule site, although 
the affinity of docetaxel is 1.9-fold higher. Cross-resistance between docetaxel and paclitaxel 
does not occur consistently. Docetaxel is a radiation-sensitizing agent. It is cell cycle phase- 
specific (G2/M phase). 49 
 
SPECIAL PRECAUTIONS: 
Contraindicated in patients with a history of hypersensitivity reaction to docetaxel or to drugs 
formulated with polysorbate 80. Patients with prior severe hypersensitivity reactions should 
generally not be rechallenged with docetaxel. However, in patients with objective tumor 
responses and without other options to docetaxel therapy, re-treatment may be attempted with 
extreme caution and aggressive premedication by experienced practitioners. Contraindicated in 
patients with severe liver impairment. Patients hypersensitive to paclitaxel may also react to 
docetaxel. 
Preexisting effusions: Patients with preexisting effusion should be closely monitored from the 
first dose for the possible exacerbation of the effusions. 
Table 9 
no clinically significant difference 
Elderly 
no clinically significant difference 
Gender 
21 L/h/m2 
clearance 
11.1 h 
terminal half life 
75% recovered in feces over 7 days, 80% of 
which was excreted during the first 2 days; < 
8% was unchanged docetaxel. 
feces 
6% recovered in urine over 7 days 
urine 
primarily biliary/fecal elimination 
Excretion 
one major and 3 minor 
inactive metabolite(s) 
none 
active metabolite(s) 
CYP3A involved in docetaxel metabolism 
in vitro 
Metabolism 
> 95% 
plasma protein binding 
113 L 
volume of distribution 
Very low levels were found in the brain in 
animal studies. In a single patient with 
leptomeningeal carcinomatosis, docetaxel was 
detected in CSF 2 hours after cessation of 
docetaxel infusion. 
Cross blood brain barrier? 
distributed to all tissues and organs except 
the brain in animal studies 
Distribution 
wide interpatient variability, probably due 
to interpatient differences in cytochrome 
P450 3A4 (CYP3A4) activity. 
PHARMACOKINETICS: 
Interpatient variability 

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Liver impairment: Patients treated with docetaxel 100 mg/m2 are at a higher risk of developing 
severe adverse reactions if they have elevated transaminase (ALT and/or AST greater than 1.5 
times the upper limit of normal [ULN]) and alkaline phosphatase (greater than 2.5 times ULN). 
Liver impairment reduces clearance and increases systemic exposure to docetaxel. Adverse 
reactions include life-threatening sepsis and gastrointestinal hemorrhage, febrile neutropenia, 
infections, thrombocytopenia, stomatitis and asthenia. 
Alcohol abuse: When docetaxel is used in patients who abuse alcohol, or have abused 
alcohol, the risk of severe neurotoxic reactions may be increased. 
Carcinogenicity: No information found. 
Mutagenicity: Not mutagenic in Ames test or mammalian in vitro mutation test. Clastogenic in 
mammalian in vitro and in vivo chromosome tests. 
Pregnancy: FDA Pregnancy Category D. There is positive evidence of human fetal risk, but the 
benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is 
needed in a life-threatening situation or for a serious disease for which safer drugs cannot be 
used or are ineffective). 
Breastfeeding is not recommended due to the potential secretion into breast milk. 49 
SIDE EFFECTS: ORGAN SITE 
SIDE EFFECT 
allergy/immunology 
hypersensitivity reaction 
(21%, severe 4%); 
see paragraph following 
Side Effects table 
moderate immunosuppression 
blood/bone marrow febrile neutropenia 
anemia (90%, severe 9%) 
death, septic (1.7%) 
death, nonseptic (0.3%) 
febrile neutropenia (11%) 
infection with neutropenia (severe 6%) 
leukocytopenia (96%, severe 75%) 
neutropenia (96%, severe 32%) 
nadir 8 days, duration of severe neutropenia 7 days 
thrombocytopenia (8%) 
cardiovascular (arrhythmia) 
dysrhythmia (2%, severe 0.4%) 
tachycardia (1%) 
cardiovascular (general) 
fluid retention, with premedication (52%, severe 6%); see paragraph 
following Side Effects table 
fluid retention, without premedication (82%, severe 22%); see 
paragraph following Side Effects table 
heart failure (0.3%) 
hypertension (2%) 
hypotension (3%, severe 0.5%) 
constitutional symptoms 
fatigue, 3-weekly schedule (62%, severe 13%) 
fatigue, weekly schedule (72%, severe 14%)26 
fever (32%, severe 2%) 
dermatology/skin 
extravasation hazard: irritant27 
alopecia (56-85%, severe 0.5%)28,29; see paragraph following Side 
Effects table 
injection site reactions (6%); see paragraph following Side Effects 
table 
nail changes (19-51%, severe 2-22%)2,30-32; see paragraph following 
Side Effects table 
hand-foot skin reaction (rare)1; see paragraph following Side Effects 

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table 
radiation recall reaction33,34 
rash/pruritus (48%, severe 5%); see paragraph following Side Effects 
table 
gastrointestinal 
emetogenic potential: low moderate9 
diarrhea (39%, severe <5%) 
nausea (39%, severe <5%) 
perforation (rare) 
stomatitis (42%, severe 6%) 
vomiting (22%, severe <5%) 
hemorrhage 
bleeding episode (1%) 
bleeding episode with thrombocytopenia (0.1%) 
infection 
infection, including sepsis and pneumonia (22%) 
metabolic/laboratory 
elevated AST, ALT, bilirubin, and alkaline phosphatase (<2%) 
neurology 
neuropathy, motor (14%%, severe 4%); see paragraph following Side 
Effects table 
neuropathy, sensory (49%, severe 4%); see paragraph following Side 
Effects table 
ocular/visual 
tearing/watery eyes, weekly schedule (52%)13; see paragraph following 
Side Effects table 
pain 
arthralgia (9%, severe 0.6%) 
Table 10 
myalgia (19%, severe 2%) 
 
Pretreatment administration of dexamethasone is recommended to decrease the frequency 
and severity, and to delay the onset of docetaxel-induced fluid retention. Dexamethasone also 
reduces the severity of docetaxel-induced hypersensitivity reactions and cutaneous toxicity. 
3-weekly regimen: A commonly used regimen consists of dexamethasone 8 mg PO twice a day 
for 3 consecutive days starting one day prior to each docetaxel infusion. This regimen has also 
been shown to decrease the occurrence of severe stomatitis and infection.2 Patients must 
receive a minimum of 3 doses of dexamethasone prior to docetaxel treatment. If 
dexamethasone has not been taken prior to treatment, it should be started and the docetaxel 
infusion delayed until the following day. If treatment delay is not possible, diphenhydramine 50 
mg IV and dexamethasone 10 mg IV may be given 30 minutes before starting docetaxel.35 
Note that this premedication regimen has not been shown to reduce the incidence and severity 
of fluid retention, but is only an attempt to ameliorate hypersensitivity reactions. The patient 
should then be instructed to take dexamethasone 8 mg PO twice a day for two days. 
Weekly regimen: An abbreviated course of dexamethasone may be used for the “weekly” 
schedule (i.e., 8-week cycle). This regimen consists of dexamethasone 8 mg PO for 3 doses 
starting the night before, morning of and evening after treatment (total dose, 24 mg/week). 
Alternatively, a single 8 mg dexamethasone dose 1 hour prior to docetaxel administration may 
be used. 
Dexamethasone dose for children: Dexamethasone in a dose of 3 mg/m² PO or IV for two doses 
12 hours and 6 hours prior to the dose of docetaxel may be used for children. 
Hypersensitivity reactions are most likely to occur during the first two cycles of docetaxel 
treatment, generally within the first few minutes after the infusion is started. Signs and 
symptoms usually abate within 15 minutes after the infusion is stopped.3 The most frequent 
minor manifestations were flushing, rash with or without pruritus, chest tightness, back pain, 
dyspnea, drug fever or chills. If minor reactions occur, therapy with docetaxel does not have to 
be discontinued. For severe reactions such as hypotension requiring treatment, bronchospasm, 
and generalized rash/erythema; stop the docetaxel, and have a physician assess the patient 
and order appropriate treatment. 49 

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Rechallenge after severe hypersensitivity reaction: Patients who have developed severe 
hypersensitivity reactions should generally not be rechallenged with docetaxel. However, in 
patients with objective tumor responses and without other options to docetaxel therapy, re- 
treatment may be attempted with extreme caution and aggressive premedication by 
experienced practitioners. It is recommended that a slower rate of infusion be used. One patient 
experienced major hypersensitivity symptoms during the first two cycles of docetaxel therapy 
despite prophylaxis with a corticosteroid and a histamine H1 blocking antagonist. Treatment  
was continued without further difficulty after sodium cromoglycate (400 mg PO four times a day, 
starting immediately after the second cycle) was added to the prophylactic regimen. 
Fluid retention includes edema, and less frequently, pleural effusion, ascites, pericardial 
effusion and weight gain. Fluid retention occurs in 52% of patients receiving dexamethasone 
premedication, and in 82% of patients without premedication. It usually begins at the lower 
extremities and may become generalized with a weight gain of 3 kg or more. Fluid retention is 
not accompanied by acute episodes of dehydration, oliguria or hypotension. Fluid accumulation 
is due to increased capillary permeability rather than hypoalbuminemia or cardiac, hepatic or 
renal damage. It is slowly reversible after treatment is discontinued (median 29 [range, 0 to > 
42] weeks). However, early, aggressive diuretic treatment may occasionally be required. 
Antihistamines have not been shown to be useful in controlling fluid retention. 
Neuropathy: Rarely, neurologic effects result in moderate to severe neuropathy, leading to 
decreased dexterity and/or disturbances in gait, usually after cumulative doses of 600 mg/m2. 
Alopecia: Loss of hair, including on the head, eyebrows, eyelashes, pubic area, and underarm, 
occurs in most patients. Alopecia has a sudden onset, and occurs 14-21 days after treatment 
has begun. Hair should grow back once treatment has been completed; however cases of poor 
hair regrowth and/or persistent hair loss have been reported. Reports suggest some patients 
may experience prolonged hair loss lasting beyond 24 months, and possibly irreversibly. 
Rash/pruritus: Cutaneous reactions are characterized by a rash, including localized eruptions 
mainly on feet and hands, but also on arms, face or thorax. These reactions are observed in 
48% of patients. They are occasionally associated with pruritus. Eruptions generally occur within 
one week following the docetaxel infusion, resolve before the next infusion, and are not 
disabling. 
Injection site reactions include skin sensitivities such as hyperpigmentation, inflammation, 
local erythema, dryness of the skin, or swelling of the vein. Injection site reactions occur in 6% 
of patient and are generally mild. Phlebitis or extravasations are observed less frequently. 
Leakage into surrounding tissue during intravenous administration (i.e., extravasation) may 
cause irritation, local tissue necrosis and/or thrombophlebitis. 
Nail changes are characterized by hyperpigmentation, splinter hemorrhage, subungual 
hematoma and hyperkeratosis, orange discoloration, Beau-Reil lines (which indicate the 
cessation of nail growth), and acute paronychia. Some changes are cosmetic and 
asymptomatic, whereas others can be accompanied by discomfort or pain. Changes are usually 
transient and disappear with treatment withdrawal, although there are reports of persistent 
changes. Loosening or loss of nails (onycholysis) occurs in 2-22%. Nail bed infections may be a 
complication and the application of topical antibiotics or antifungals may be necessary. Applying 
the principle of cold-induced vasoconstriction by wearing frozen gloves on the hands during 
treatment may reduce the incidence of nail and skin toxicity. In one study, overall incidence of 
nail toxicity was reduced with frozen glove treatment from 51% to 11%, and the incidence of 
grade 2 toxicity (onycholysis) was reduced from 22% to 0%. Additionally, median time of 
occurrence of nail toxicity was delayed to 106 days with frozen glove treatment as opposed to 
58 days without. 
Hand-foot skin reaction that occurs despite dexamethasone prophylaxis may respond to 
administration of pyridoxine 50 mg orally three times a day. 

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Weekly schedule toxicity profile: The toxicity profile of docetaxel is markedly altered when the 
drug is administered on a weekly schedule. Myelosuppression, a severe and dose-limiting 
toxicity of the 3 weekly schedule, is not usually a clinically important problem when docetaxel is 
administered weekly. At the maximum tolerated dose of 43 mg/m²/week (equivalent in dose 
intensity to 129 mg/m² every 3 weeks), grade 3 leukopenia occurs in 14% of courses, with no 
grade 4 leukopenia. With this dosing schedule, fatigue and asthenia are the dose-limiting 
toxicities. 
Tearing/watery eyes: An unexpected toxicity with the weekly schedule is excessive tearing, 
which was reported by half of the patients in a phase II study in women with metastatic breast 
cancer. Patients reported increased tearing and, in some cases, mild conjunctivitis or eye 
irritation. Formal ophthalmologic examination of several patients revealed no abnormalities. As 
with fluid retention, the onset of tearing seems to be related to cumulative dose and occurs after 
a median of 400 mg/m² (range, 120-960 mg/m²). Ten of 15 patients with tearing also developed 
some degree of fluid retention. Treatment with artificial tears or other ocular moisturizers 
ameliorated symptoms in some patients. Eye irritation led to a dose reduction in one patient. 
 
INTERACTIONS: 
AGENT 
EFFECT 
MECHANISM 
MANAGEMENT 
dexamethasone 
does not affect protein 
binding of docetaxel 
doxorubicin 
AUC of docetaxel 
increased, one hour interval 
between drugs does not 
change the results 
doxorubicin may interfere 
at hepatic microsomal 
enzyme level 
avoid concurrent therapy outside 
of clinical trial 
epirubicin 
increased exposure to 
active metabolite of 
epirubicin 
altered metabolism of 
epirubicin 
avoid concurrent therapy outside 
of clinical trial 
etoposide 
clearance of docetaxel 
decreased 
avoid concurrent therapy outside 
of clinical trial 
ifosfamide 
when docetaxel given first it 
is associated with increased 
ifosfamide plasma 
clearance and decreased 
AUC 
may be due to increased 
ifosfamide metabolism 
caused by corticosteroid 
premedication for 
docetaxel 
avoid concurrent therapy outside 
of clinical trial 
Table 11 
 
There have been no formal clinical studies to evaluate the drug interactions of docetaxel with 
other medications. In vitro studies have shown that the metabolism of docetaxel may be 
modified by the concomitant administration of compounds which induce, inhibit or are 
metabolized by (and thus may inhibit the enzyme competitively) cytochrome P450-3A such as 
cyclosporine, ketoconazole and erythromycin. 
 
DOSAGE GUIDELINES: 
PLATELET COUNT 
(x 109/L) 
ABSOLUTE NEUTROPHIL (ANC)* 
Table 12 
(x 109/L) 
> 1.8 
1.5-1.8 
1.0-1.5 
<1.0 
> 100 
100% 
75% 
50% 
0% 
70-100 
75% 
75% 
50% 
0% 
50-70 
50% 
50% 
50% 
0% 
<50 
0% 
0% 
0% 
0% 
* ANC = WBC x (% polys + % stabs) 
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Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage 
may be reduced, delayed or discontinued in patients with bone marrow depression due to 
cytotoxic/radiation therapy or with other toxicities. 49 
 
Dosage in hepatic failure*: 
 
Cycle length 
Alkaline 
Phosphatase 
AST +/or ALT 
Dose 
3 weeks: 
< 2.5 x ULN 
and 
<1.5 x ULN 
100% 
2.5 – 5 x 
ULN 
and 
1.6 – 5 x ULN 
75% 
> 5 x ULN 
or 
> 5 ULN 
discuss with 
contact physician 
 
 
 
Cycle length 
AST 
Dose 
8 weeks: 
< 1.5 x ULN 
100% 
> 1.5 x ULN 
delay until levels have subsided, then 
restart at a 75% dose 
Table 13 
*Liver enzymes are recommended before cycle 1 and then prior to each treatment if clinically indicated (e.g., if liver enzymes are elevated, liver 
metastases are present or there is severe toxicity such as neutropenia). If liver enzymes are normal and there is no evidence of liver metastases or 
severe toxicity, check liver enzymes after 3 cycles (ie, at cycle 4). 
 
Dosage in severe peripheral 
neuropathy: 
Cycle length 3 weeks: 
reduce by 25% to 75 mg/m2; further reduce by 
25% to 55 mg/m2 if reactions continue; 
discontinue if patient experiences ≥ grade 3 
peripheral neuropathy3 
Dosage in severe or cumulative 
cutaneous reactions: 
Cycle length 3 weeks: 
reduce by 25% to 75 mg/m2; further reduce by 
25% to 55 mg/m2 if reactions continue 
Table 14 
Dosage in dialysis: 
Hemodialysis: no significant removal; no dose adjustment required, may 
be administered before or after hemodialysis. 
 
9.1.4 Abraxane 
DRUG NAME: Paclitaxel, nanoparticle, albumin-bound (nab) 
SYNONYM(S): protein-bound paclitaxel 
COMMON TRADE NAME(S): ABRAXANE® 
CLASSIFICATION: antimicrotubule agent 
Special pediatric considerations are noted when applicable, otherwise adult provisions apply. 
MECHANISM OF ACTION: 
Paclitaxel, the active ingredient of nanoparticle, albumin-bound (nab) paclitaxel, is an 
antimicrotubule agent that promotes the assembly and stabilization of microtubules, thus 
inhibiting normal dynamic reorganization of the microtubule network. Paclitaxel induces 
abnormal bundles of microtubules throughout the cell cycle and multiple asters of microtubules 
during mitosis. It is thought that albumin-bound paclitaxel (nab-paclitaxel) facilitates the 
transport of paclitaxel across the endothelial cell via an albumin-receptor mediated pathway. 
Nab-paclitaxel is cell cycle phase-nonspecific. 50 
 
PHARMACOKINETICS: 
Distribution 
extensive extravascular distribution and tissue binding 

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USES: Primary uses: * Breast cancer 
SPECIAL PRECAUTIONS: 
Caution: nab-paclitaxel is NOT interchangeable with other paclitaxel formulations and should 
not be substituted. nab-paclitaxel has not been studied in patients previously exhibiting 
hypersensitivity to paclitaxel or human albumin, routine premedication to prevent 
hypersensitivity reactions is not required before administration. nab-paclitaxel contains albumin 
which, although no cases have been identified, carries a remote risk for transmission of viral 
diseases. 
Mutagenicity: not mutagenic in Ames test and mammalian in vitro mutation test. Paclitaxel is 
clastogenic in mammalian in vitro and in vivo chromosome tests. 
Fertility: In animal studies with paclitaxel, testicular atrophy/degeneration in males, as well as 
significantly reduced fertility, decreased pregnancy rates and increased loss of embryos in 
untreated female mates have been observed. Skeletal and soft tissue fetal anomalies were also 
observed. Men are advised not to father a child while receiving treatment with nab-paclitaxel. 
Pregnancy: FDA Pregnancy Category D. In animal studies, paclitaxel has demonstrated 
embryo- and fetotoxicity, including fetal anomalies and intrauterine mortality. No studies have 
been conducted in women. There is positive evidence of human fetal risk, but the benefits from 
use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life- 
threatening situation or for a serious disease for which safer drugs cannot be used or are 
ineffective). 
Breastfeeding is not recommended due to the potential secretion into breast milk. 
Concentrations in milk were detectable in animal studies. 
SIDE EFFECTS: 
The table includes adverse events that presented during drug treatment but may not necessarily 
have a causal relationship with the drug. Because clinical trials are conducted under very 
specific conditions, the adverse event rates observed may not reflect the rates observed in 
clinical practice. Adverse events are generally included if they were reported in more than 1% of 
patients in the product monograph or pivotal trials, and/or determined to be clinically important. 
 
ORGAN SITE 
SIDE EFFECT 
blood 
and 
lymphatic system/ 
febrile neutropenia 
anemia (20-33%, severe 1%); sometimes requiring blood transfusion 
bleeding (2%) 
febrile neutropenia (2%) 
leucopenia (72%) 
neutropenia (80%, severe 9%); dose-limiting; see paragraph following Side Effects table 
thrombocytopenia (2%, severe <1%); may require dose reduction 
cardiac 
bradycardia (<1%); usually asymptomatic, intervention not required 
Table 15 
15 L/h/m2 
clearance 
27 h 
terminal half life 
20% 
feces 
3’-p- 
and 
hydroxypaclitaxel 
hydroxypaclitaxel) 
4% (unchanged drug); <1% (6α- 
urine 
extensive non-renal clearance 
Excretion 
no information found 
inactive metabolite(s) 
6α-hydroxypaclitaxel (major), 3’-p- 
hydroxypaclitaxel 
(minor), 
and 
6α,3’-p-dihydroxypaclitaxel (minor) 
active metabolite(s) 
extensive; primarily via CYP 2C8, minor metabolites via CYP 3A4 
Metabolism 
89-98% 
plasma protein binding 
632 L/m2 
volume of distribution 
no information found 
cross blood brain barrier? 

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cardiovascular events (3%), including cardiac arrest, chest pain, edema, hypertension, pulmonary 
emboli, supraventricular tachycardia, and thrombosis 
hypotension (5%); usually asymptomatic, intervention not required 
eye 
(see 
paragraph 
following  
Side 
Effects table) 
blurred vision (1%) 
keratitis (1%)3 
gastrointestinal 
emetogenic potential: low 
anorexia (>10%) 
constipation (>10%) 
diarrhea (27%, severe <1%) 
mucositis (7%, severe <1%); occurs a few days post treatment, usually decreases or disappears within 1 
week 
nausea (30%, severe 3%) 
vomiting (18%, severe 4%) 
general 
disorders 
and administration 
site conditions 
extravasation hazard: irritant. 
immune system 
fever (14%) 
fluid retention/edema (10%) 
injection site reactions (1%); usually mild; rarely has included phlebitis, cellulitis, induration, exfoliation, 
necrosis, and fibrosis 
hypersensitivity reactions (4%); see paragraph following Side Effects table 
infections 
and 
infestations 
infections (24%, severe 3%); oral candidiasis, pneumonia, and respiratory tract infections most frequently 
reported 
investigations 
alkaline phosphatase increase (36%) 
metabolism 
and 
nutrition 
AST increase (39%) 
bilirubin increase (7%) 
ECG abnormalities (60%, 35% in patients with normal baseline); usually asymptomatic; not dose-limiting, 
intervention not required 
gamma-glutamyltransferase increase (50%, severe 3-14%) 
serum creatinine increase (11%, severe <1%); dose reductions or delays not required 
dehydration (1-10%) 
musculoskeletal 
and 
connective 
tissue 
arthralgia/myalgia (44%, severe 8%); occurs two to three days post treatment, usually transient 
nervous system 
asthenia (47%, severe 8%), including fatigue, weakness, lethargy, and malaise; may affect ability to drive 
and operate machines 
sensory neuropathy (71%, severe 10%); may require dose reduction; see paragraph following Side 
Effects table 
respiratory, thoracic 
and mediastinal 
cough (6-7%)6 
skin 
and 
subcutaneous 
tissue 
dyspnea (12%) 
pneumothorax6 (<1%) 
pulmonary embolism 
alopecia (90%) 
vascular 
nail changes (1%); includes changes in pigmentation or discoloration of nail bed 
pruritus (6%) 
rash (9%) 
Table 16 
flushing (2%) 
 
Bone marrow suppression, primarily neutropenia, is a dose-dependent and dose-limiting 
toxicity. Neutropenia is usually rapidly reversible. Frequent blood count monitoring is 
recommended, and treatment should not be initiated if baseline neutrophil counts are less than 
1.5 x 109/L. Dose reduction is recommended for severe neutropenia lasting one week or longer 
and further reduction is recommended for recurrence of the same. 
Hypersensitivity reactions are reported in 4%, with none reported as severe. On the day of 
dosing, grades 1 and 2 dyspnea are reported in 1%, and flushing, hypotension, chest pain, and 
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each. Nab-paclitaxel has not been studied in patients previously exhibiting hypersensitivity to 
paclitaxel or human albumin. 
Neurologic toxicity is dose-dependent and is influenced by prior and/or concomitant therapy 
with neurotoxic agents. In clinical trials, the frequency of sensory neuropathy increased with 
cumulative dose, and sometimes required discontinuation of treatment. It is suggested that 
grade 3 sensory neuropathy requires treatment interruption until resolution, followed by dose 
reduction for subsequent courses. Severe sensory symptoms typically improved a median of 22 
days after treatment interruption. Cases of autonomic neuropathy resulting in paralytic ileus 
have 
been 
reported. 
Ischemic 
stroke, 
metabolic 
encephalopathy, 
confusion, 
dizziness/lightheadedness, and mood alteration/depression are neurologic events reported in 
less than 1%. 
Ocular/visual disturbances have been reported in 13%, with 1% of cases reported as severe. 
The severe cases (keratitis and blurred vision) were reported in patients receiving doses higher 
than recommended, and were usually reversible. Rarely, persistent optic nerve damage has 
been reported. 50 
INTERACTIONS: 
Drug interaction studies have not been conducted. However, nab-paclitaxel is a substrate of 
CYP 2C8 and 3A4 and caution should be exercised during concurrent therapy with known 
inhibitors or inducers of these enzymes. The clinical significance of these interactions is 
unknown. 
 
DOSAGE GUIDELINES: 
PLATELET COUNT 
(x 109/L) 
ABSOLUTE NEUTROPHIL (ANC)* 
(x 109/L) 
Table 17 
> 1.8 
1.5-1.8 
1.0-1.5 
<1.0 
> 100 
100% 
75% 
50% 
0% 
70-100 
75% 
75% 
50% 
0% 
50-70 
50% 
50% 
50% 
0% 
<50 
0% 
0% 
0% 
0% 
* ANC = WBC x (% polys + % stabs) 
** 0% Indicates treatment should be postponed a week until the counts return to a level at which drugs may be given. 
 
Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage 
may be reduced, delayed or discontinued in patients with bone marrow depression due to 
cytotoxic/radiation therapy or with other toxicities. 50 
 
mild 
AST 
< 10xULN 
Serum bilirubin 
≤ 1.25xULN 
Dose 
260 mg/m2 (100%) 
moderate 
< 10xULN 
1.26-2xULN 
reduce to 200 mg/m2 * 
severe 
< 10xULN 
> 10xULN 
2.01-5xULN 
> 5xULN 
reduce to 130 mg/m2 ** 
not recommended 
Table 17a 
* For subsequent cycles: dosing based on patient tolerability. 
** For subsequent cycles: may consider dose escalation to 200 mg/m2 based on patient tolerability. 
 
 
9.1.5 Ixabepilone 
DRUG NAME: Ixabepilone 
SYNONYM(S): 
COMMON TRADE NAME(S): IXEMPRA® 
CLASSIFICATION: miscellaneous, antineoplastic 

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Special pediatric considerations are noted when applicable, otherwise adult provisions apply. 
MECHANISM OF ACTION: 
Ixabepilone is a semi-synthetic analog of epothilone B that binds to beta-tubulin subunits on 
microtubules, leading to suppression of microtubule dynamics; specifically, the dynamic 
instability of alpha-beta-II and alpha-beta-III microtubules, which leads to apoptosis. Ixabepilone 
is cell cycle phase-specific. 51 
USES: Primary uses: Breast cancer 
SPECIAL PRECAUTIONS: 
Caution: premedication with H1 and H2 antagonists is recommended dosage adjustment may 
be necessary for hepatic dysfunction and for concomitant use with strong CYP 3A4 inhibitors 
Fertility: impaired fertility in animal studies 
Pregnancy: FDA Pregnancy Category D. There is positive evidence of human fetal risk, but the 
benefits from use in pregnant women may be acceptable despite the risk(e.g., if the drug is 
needed in a life-threatening situation or for a serious disease for which safer drugs cannot be 
used or are ineffective). 
Breastfeeding is not recommended due to potential secretion into breast milk. 
SIDE EFFECTS: 
The table includes adverse events that presented during drug treatment but may not necessarily 
have a causal relationship with the drug. Because clinical trials are conducted under very 
specific conditions, the adverse event rates observed may not reflect the rates observed in 
clinical practice. Adverse events are generally included if they were reported in more than 1% of 
patients in the product monograph or pivotal trials, and/or determined to be clinically important. 
 
ORGAN SITE 
SIDE EFFECT 
allergy/immunology 
hypersensitivity reactions (5%) 
auditory/hearing 
vertigo (4%) 
blood/bone marrow/ febrile 
neutropenia 
anemia (6%) 
leukopenia (36%) 
neutropenia (23%) 
thrombocytopenia (2%) 
cardiovascular (general) 
myocardial ischemia (2%) 
constitutional symptoms 
fatigue (56%) 
hot flush (6%) 
dermatology/skin 
extravasation hazard: none 
alopecia (48%) 
nail disorder (9%) 
palmar-plantar erythrodysesthesia (8%) 
pruritis (6%) 
skin rash (9%) 
gastrointestinal 
emetogenic potential: low 
abdominal pain (13%) 
anorexia (19%) 
diarrhea (22%) 
nausea (42%) 
stomatitis/mucositis (29%) 
hepatobiliary/pancreas 
acute hepatic failure, jaundice 
infection 
upper respiratory tract infection (6%) 
musculoskeletal 
myalgia/arthralgia (49%) 
neurology 
headaches (11%) 
peripheral neuropathy (62%) 
ocular/visual 
lacrimation increased (4%) 
pain 
musculoskeletal pain (20%) 
pain (8%) 

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DOSAGE GUIDELINES: 
PLATELET COUNT 
(x 109/L) 
ABSOLUTE NEUTROPHIL (ANC)* 
(x 109/L) 
Table 19 
> 1.8 
1.5-1.8 
1.0-1.5 
<1.0 
> 100 
100% 
75% 
50% 
0% 
70-100 
75% 
75% 
50% 
0% 
50-70 
50% 
50% 
50% 
0% 
<50 
0% 
0% 
0% 
0% 
* ANC = WBC x (% polys + % stabs) 
** 0% Indicates treatment should be postponed a week until the counts return to a level at which drugs may be given. 
Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage 
may be reduced, delayed or discontinued in patients with bone marrow depression due to 
cytotoxic/radiation therapy or with other toxicities. 51 
9.2 Discontinuation of Subjects from Treatment: 
Subjects MUST discontinue study treatment (investigational or non-investigational treatment) for 
any of the following reasons: 
• Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
• Any clinical adverse event (AE), laboratory abnormality, or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the subject. 
• Pregnancy. 
• Termination of the study by the sponsor, by the local IRB or by the supporting/funding 
organization (The Methodist Hospital Cancer Center) 
• Loss of ability to freely provide consent through imprisonment or involuntary incarceration for 
treatment of either a psychiatric or physical (e.g., infectious disease) illness. 
All subjects who discontinue study treatment should comply with protocol-specified follow-up 
procedures. The only exception to this requirement is when a subject withdraws consent for all 
study procedures or loses the ability to consent freely (i.e., is imprisoned or involuntarily 
incarcerated for the treatment of either a psychiatric or physical illness). If a subject was 
withdrawn before completing the study, the reason for withdrawal must be entered on the 
appropriate case report form (CRF) page. 
 
10.0 CRITERIA FOR RESPONSE 
Tumor Assessment by RECIST 1.1 
Tumor assessments will be made by the investigator according to RECIST 1.1. 
10.1. Definition of Target and Non-target Lesions According to RECIST 1.1 
Numbers will be assigned to the lesions chosen as target and non-target. These assigned 
numbers must remain the same throughout the study. Lesion numbers should be recorded in 
the radiology report and transcribed to the CRF. To assess objective response or future 
progression, it is necessary to estimate the overall tumor burden at baseline and use this as a 
comparator for subsequent measurements. 
Measurable disease is defined by the presence of at least one measurable lesion. 
At baseline, tumor lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of 10mm by CT 
scan. At baseline, lesions will be categorized as follows: 
10.1.1. Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
dyspnea (9%) 
Table 18 
cough (2%) 
pulmonary 

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measured at baseline. Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion that can be measured reproducibly should be selected. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. Target lesion criteria are listed for CR, PR, stable 
disease (SD), and PD in Table 20. 
10.1.2. Non-target lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at 
baseline. Measurements of these lesions are not required, but the presence, absence, or in rare 
cases unequivocal progression of each should be noted throughout follow-up. 
Non-target lesion criteria are listed for CR, Non-CR/Non-PD, and PD in Table 21. 
 
Target Lesion Response Criteria 
Non-target Lesion Response Criteria 
 
 
11 Study Materials: 
Table 21 
Table 20 

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11.1 Chloroquine 
DOSAGE AND ADMINISTRATION 
The dosage of chloroquine phosphate is often expressed in terms of equivalent chloroquine 
base. Each 500 mg tablet of ARALEN contains the equivalent of 300 mg chloroquine base. 
HOW SUPPLIED 
Tablets containing 500 mg chloroquine phosphate USP, equivalent to 300 mg of chloroquine 
base, bottles of 25 (NDC 0024-0084-01). 
White, film-coated convex, discoid tablet, 1/2 inch in diameter with an uncoated core, printed in 
black ink with a stylized "W" on one side and an "A77" on the other side. 
Dispense in tight, light-resistant container as defined in the USP/NF. 47 
Store at 25° C (77° F); excursions permitted to 15° – 30° C (59° – 86° F) [see USP Controlled 
Room Temperature] 
 
11.2. Paclitaxel 
SUPPLY AND STORAGE: 
Injection: Biolyse Pharma supplies paclitaxel as a 6 mg/mL preservative-free solution in single- 
dose vials of 5 mL, 16.7 mL and 50 mL. Non-medicinal ingredients: dehydrated ethanol 49.7% 
and Cremophor EL (polyethoxyethylated castor oil). Refrigeration is recommended for long term 
storage. The potency of paclitaxel is not affected when transported or stored for up to two 
months at room temperature. Protect vials from light (keep intact vials in their container until 
use). Discard unused portion within 8 hours after puncture. Bristol-Myers Squibb supplies 
paclitaxel as a 6 mg/mL preservative-free solution in multidose vials of 5 mL, 16.7 mL and 50 
mL. Non-medicinal ingredients: dehydrated ethanol 49.7% and Cremophor EL (polyethoxylated 
castor oil) 527 mg. Store vials at room temperature and protect from light (keep intact vials in 
their container until use). Both the 5 mL vial and the 16.7 mL vial are stable for 48 hours at room 
temperature after puncture. The 50 mL vial is stable for 24 hours at room temperature after 
puncture. 48 
SOLUTION PREPARATION AND COMPATIBILITY: 
Additional information: Non-polyvinyl (non-PVC) equipment (e.g., polyethylene) is used to 
minimize leaching. The surfactant, Cremophor EL (polyoxyethylated castor oil), leaches the 
plasticizer, diethylhexyl phthalate (DEHP), from polyvinyl chloride (PVC) bags and 
administration sets. Actual hazardous exposure levels to DEHP are not known; however, it is 
hepatotoxic and exposure should be minimized. Use of a plastic syringe to measure a dose is 
acceptable but drug-syringe contact time should be minimized. 
Bacterial challenge: Paclitaxel (Bristol) 0.7 mg/mL diluted in NS did not exhibit an antimicrobial 
effect on the growth of three of four organisms inoculated into the solution. Microbiological 
growth should be considered when assigning expiration periods. 
Compatibility: The following are compatible with paclitaxel via Y-site injection: acyclovir, 
amikacina, aminophylline, ampicillin, bleomycin, butorphanol, calcium, carboplatin, cefepime, 
cefotetan, ceftazidime, ceftriaxone, cimetidine, cisplatin, cladribinea, cyclophosphamide, 
cytarabinea, 
dacarbazine, 
dexamethasone, 
diphenhydramine, 
doxorubicin, 
droperidol, 
etoposide, etoposide phosphate, famotidine, floxuridine, fluconazole, fluorouracil, furosemide, 
ganciclovir, 
gatifloxacina, 
gemcitabine, 
gentamicin, 
granisetron, 
haloperidol, 
heparin, 
hydrocortisone, hydromorphone, ifosfamide, linezolid, lorazepam, magnesium, mannitol, 
meperidine, mesna, methotrexate, metoclopramide, morphine, nalbuphine, ondansetron, 
pentostatin, potassium, prochlorperazine, propofol, ranitidine, sodium bicarbonate, thiotepa, 
topotecan, certain TPN formulations, vancomycin, vinblastine, vincristine, zidovudine. The 
following are compatible with paclitaxel in the same infusion solution at certain concentrations 
and diluents: carboplatin, cisplatin, doxorubicin. Incompatibility: The following are  
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sulphate complex, chlorpromazine, doxorubicin liposomal, hydroxyzine, methylprednisolone, 
mitoxantrone. 48 
 
PARENTERAL ADMINISTRATION: 
Intermittent infusion 
in appropriate volume of NS or D5W over 1-3 h (range 1-24 h) 
dilute in non-PVC bags 
Table 22 
dilute to final concentration of 0.3-1.2 mg/mL 
premedication required to prevent hypersensitivity reactions 
administer through non-PVC tubing and a 0.22 micron (non-PVC) in-line filter equipment 
Continuous infusion 
as for intermittent infusion except given over 24 h 
 
11.3. TAXOTERE 
SUPPLY AND STORAGE: 
Injection: sanofi-aventis supplies concentrated drug solution in 20 mg/0.5 mL and 80 mg/2 mL 
vials and diluent in 1.5 mL and 6 mL vials. Concentrated drug solution vials contain polysorbate 
80; diluent vials contain ethanol 95%. Refrigerate. Protect from bright light. 
SOLUTION PREPARATION AND COMPATIBILITY: 
Additional information: Both docetaxel and diluent vials contain overfill to ensure that the 
extractable volume of premixed docetaxel solution corresponds to the labeled amount. The 
combined solution of concentrate and supplied diluent should be clear; however, there may be 
some foam on top of the solution due to the polysorbate 80. Allow the combined solution to 
stand for 5 minutes to allow foam to dissipate. It is not required that all foam dissipate prior to 
continuing the preparation process. 
Contact of the concentrate with plasticized polyvinyl chloride (PVC) equipment or devices used 
to prepare solution for infusion is not recommended. To minimize patient exposure to the 
plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or 
sets, docetaxel infusion solution should be stored in bottles (e.g., glass, polypropylene) or non- 
PVC plastic bags (e.g., polypropylene, polyolefin), and administered through non-PVC or 
polyethylene-lined administration sets. 49 
 
PARENTERAL ADMINISTRATION: 
Direct intravenous 
not recommended, due to need to initiate injection slowly to reduce the risk of allergic 
reactions 
Intermittent 
infusion 
in 250 mL NS over 1 h (use non-PVC equipment) 
Patient must have received a minimum of 3 doses of dexamethasone before each 
treatment. slow initiation of infusion is not routinely needed to reduce the risk of allergic 
reactions if slow initiation of infusion is needed, start infusion at 30 mL/h x 5 min, then 60 
mL/h x 5 min, then 120 mL/h x 5 min, then complete infusion at 250 mL/h (for 500 mL bag, 
continue 250 mL/h for 5 min and then complete infusion at 500 mL/h) 
Observe patient constantly for signs of hypersensitivity during the first 10-15 min of the 
infusion. A volumetric cassette infusion pump may be used to ensure that the docetaxel is 
infused at a consistent and accurate rate. A pump is not mandatory, but is suggested if the 
IV cannot be monitored closely so that it is on time. 
Table 23 
 
11.4. ABRAXANE 
SUPPLY AND STORAGE: 
Injection: Abraxis BioScience Canada, Inc. supplies nanoparticle, albumin-bound (nab) 
paclitaxel in single use vials of sterile lyophilized powder containing 100 mg of paclitaxel and 
900 mg of human albumin. Store at room temperature. Protect from light. 
SOLUTION PREPARATION AND COMPATIBILITY: 
Additional information: Gently swirl or slowly invert vial after reconstitution to avoid foaming. If 
foaming or clumping occurs, stand solution for a minimum 15 minutes until foaming subsides. 

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Reconstituted product should be milky and homogeneous without visible particulates. Some 
settling may occur upon standing and vial should be gently inverted to ensure complete 
resuspension prior to use. Product must be discarded if precipitates are observed. Neither 
freezing nor refrigeration adversely affects stability of the product. 50 
PARENTERAL ADMINISTRATION: 
Intermittent infusion 
Over 30 minutes*, do NOT filter; Non-PVC bags and tubing are NOT required. 
* Limiting infusion time to 30 minutes reduces the likelihood of infusion-related reactions. 
 
11.5. IXABEPILONE 
SUPPLY AND STORAGE: 
Injection: Bristol-Myers Squibb supplies ixabepilone as a kit containing a 15 mg or 45 mg vial of 
ixabepilone for injection together with an 8 mL or 23.5 mL vial of supplied diluent which both 
provide ixabepilone 2 mg/mL solution after reconstitution. Refrigerate. Retain in original 
package until time of use. 
Additional information: Administer using an in-line filter with a microporous membrane of 0.2 
to 1.2 microns. Non-PVC (i.e., DEHP-free) infusion containers and administration sets must be 
used. 51 
PARENTERAL ADMINISTRATION: Intermittent infusion over 3 hours. 
12. Investigational Product Records at Investigational Site(s) 
The study drug will be kept in the investigational pharmacy at the sponsor site The Methodist 
Hospital Cancer Center (TMHCC). It is the responsibility of the Investigator to ensure that a 
current record of investigational product disposition is maintained at each study site where 
investigational product is inventoried and disposed. Records or logs must comply with 
applicable regulations and guidelines, and should include: 
 Amount received and placed in storage area. 
 Amount currently in storage area. 
 Label ID number or batch number. 
 Dates and initials of person responsible for each investigational product inventory 
entry/movement. 
 Amount dispensed to and returned by each subject, including unique subject identifiers. 
 Amount transferred to another area for dispensing or storage. 
 Non-study disposition (e.g., lost, wasted, broken). 
 Amount destroyed at study site. 
 
13. Destruction of Investigational Product 
N/A 
Drug Ordering and Accountability 
The Methodist Hospital Cancer Center (TMHCC) will assume all the cost related with the 
Chloroquine tablets during the length of the study. 
Initial Orders 
Following submission and approval of the required regulatory documents, the TMHCC will 
supply the participating patient (s) with an initial dose of Chloroquine. 
Re-supply 
Re-supply of chloroquine will be provided accordingly with the number of patients enrolled in the 
trial. The research coordinator will ensure that enough study drug is kept in the investigational 
pharmacy at all times. 
 
14. Study Discontinuation 

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Participants developing toxicities of any grade will be permitted to take a drug holiday of up to 
five (5) days. After the drug holiday, if the adverse event has resolved to the satisfaction of the 
investigator, the study medication may be resumed. If the adverse event recurs, the participant 
may be taken off study at the discretion of their physician. NOTE: Patients who develop any of 
the following adverse events must be permanently discontinued from study: 
A patient will be considered to have withdrawn from investigational treatment if the principle 
reason for ending treatment falls into 1 of the following categories: 
 Unacceptable toxicity, as defined by the study protocol and/or at the discretion of the 
principle investigator. 
 Insufficient therapeutic effect (lack of efficacy/progressive disease), at any timepoint 
throughout the study. 
 Non-compliance with protocol, as defined by a pill count of less than 75% on more than one 
occasion. 
 Lost to follow-up. 
 Pregnancy. 
 Withdrawal of consent. 
 
 
 
14.1 Withdrawal Procedures 
Treatment with investigational drugs must be stopped at the time of investigational treatment 
discontinuation. The patient will be asked to return to the clinic with all unused study drug and to 
see their study doctor if they are discontinued from the study. If the subject agrees, an exit 
biopsy will be performed at this time. The study doctor will examine the subject and the subject 
will be discontinued from the trial. The reason for discontinuation will be clearly documented in 
the subject’s medical records and recorded on the CRF. Subjects will be followed for safety as 
described in section 15.1.3. 
All data up to the time of withdrawal/discontinuation will be included in the analyses. 
 
14.2 Lack of Efficacy 
The investigational therapeutic regimen will be discontinued immediately if at any timepoint the 
patient shows signs of disease progression. Patients who are discontinued prematurely due to 
disease progression will be switched to standard of care therapy chosen by the treating 
physician. 
 
15. Adverse Events 
15.1 Definition of an Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation patient, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated 
with the use of a medicinal product. For marketed medicinal products, this also includes failure 
to produce expected benefits (i.e. lack of efficacy), abuse or misuse. Anticipated day-to-day 
fluctuations of the disease under study that do not represent a clinically significant exacerbation 
or worsening need not be considered an adverse event. All adverse events occurring from the 
first dose of investigational product until thirty days after the last dose must be reported 
regardless of whether or not they are considered drug related. In addition, any SAEs which 
occur as a result of protocol specific diagnostic procedures or interventions must also be 
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It is the responsibility of the IND holder to comply with IND safety reporting as set forth in the 
Code of Federal Regulations, Section 312.32. 
A serious AE is any untoward medical occurrence that at any dose: 
 results in death 
 is life-threatening (defined as an event in which the patient was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe) 
 requires inpatient hospitalization or causes prolongation of existing hospitalization, 
NOTE: In general, hospitalization signifies that the patient has been detained (usually 
involving at least an overnight stay) at the hospital or emergency room for observation 
and/or treatment that would have not been appropriate in the physician’s office or outpatient 
setting. Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is NOT considered an AE. 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
 results in the development of drug dependency or drug abuse 
 is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the patient or may require intervention (e.g., medical, 
surgical) to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.) Also is considered the occurrences of pregnancy or 
overdose (regardless of adverse outcome), and cancer as events which must be reported 
as important medical events. 
 
15.1.1 Reporting of SAEs 
Following the subject’s written consent to participate in the study, all SAEs should be collected 
and reported, including those thought to be associated with clinical trial procedures. All serious 
adverse events must be reported to the FDA, the coordinating center, and The Methodist 
Hospital Research Institute by the investigator. 
SAE terminology and severity grading will be based on (CTCAEv4). 
The following categories and definitions of causal relationship to study drug should be 
considered for use for this clinical study. 
 Certain: There is a known causal relationship between the study drug and the SAE. The 
event responds to withdrawal of study drug (dechallenge), and recurs with rechallenge 
when clinically feasible. (>95% certainty) 
 
Probable: There is reasonable causal relationship between the study drug and the SAE. 
The event responds to dechallenge. Rechallenge is not required. (65%-95% probability) 
 
Possible: There is reasonable causal relationship between the study drug and the SAE. 
Dechallenge information is lacking or unclear. (35%-65% probability of relatedness) 
 
Not likely: There is temporal relationship to study drug administration, but there is not a 
reasonable causal relationship between the study drug and the SAE. (5-35% probability of 
relatedness) 
 
Not related: There is not a temporal relationship to study drug administration (too early, or 
late, or study drug not taken), or there is known causal relationship between the SAE and 
another drug, concurrent disease, or other circumstance. (<5% chance of relatedness) 
 
Adverse events classified as “serious” require expeditious handling and reporting to the 
sponsor The Methodist Hospital Cancer Center (TMHCC) and local IRB to comply with 
regulatory requirements. 

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 
All serious AEs whether related or unrelated to chloroquine must be immediately reported 
to the coordinating site (TMHCC) by the investigator or designee within 24 hours of 
becoming aware of the event. If only limited information is initially available, follow-up 
reports are required. The original SAE form must be kept on file at the study site. 
All SAEs should be faxed or emailed to 
The Methodist Hospital Cancer Center at: 
Afroehlich@tmhs.org 
Fax Number: 713-793-1642 
 
For studies conducted under an Investigator IND, any event that is both serious and 
unexpected must be reported to the FDA as soon as possible and, in no event, later than 7 
days (death or life-threatening event) or 15 days (all other SAEs) after the investigator’s or 
institution’s initial receipt of the information. 
 
 
The Methodist Hospital Cancer Center will be provided with a simultaneous copy via 
facsimile of all adverse events filed with the FDA. SAEs should be reported on the 
MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/MedWatch/ 
MedWatch forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
 
 
Collection of complete information concerning SAEs is extremely important. Full 
descriptions of each event will be followed by the sponsor. Thus, follow-up information 
which becomes available as the SAE evolves, as well as supporting documentation 
(e.g., hospital discharge summaries and autopsy reports), should be collected 
subsequently, if not available at the time of the initial report, and immediately sent using 
the same procedure as the initial SAE report. 
 
An overdose is defined as the accidental or intentional ingestion of any dose of a 
product that is considered both excessive and medically important. For reporting 
purposes, the sponsor considers an overdose, regardless of adverse outcome, as an 
important medical event. 
 
AEs should be followed to resolution or stabilization, and reported as SAEs if they 
become serious. This also applies to subjects experiencing AEs that cause interruption 
or discontinuation of chloroquine or those experiencing AEs that are present at the end 
of their participation in the study; such subjects should receive post-treatment follow-up 
as appropriate. 
 
15.1.2 Reporting SAEs “Pregnancy” 
A subject who has a positive serum β-HCG pregnancy test result at any time after the first dose 
of investigational therapy will be immediately withdrawn from participation in the study. All study 
conclusion/withdrawal assessments will be collected at the time of discontinuation as described 
in section 14.1 
The investigator will collect pregnancy information on any female patient who becomes 
pregnant during study participation. The investigator will record pregnancy information on the 
appropriate form and submit it to TMHRI within 2 weeks of learning of a patient’s pregnancy. 
Information on the status of the mother and child will be forwarded to TMHRI. Generally, follow- 
up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature 
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is identical to the time period for collecting AEs. Pregnancy information is collected from the first 
dose of investigational product to 30 days after the last dose. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
A spontaneous abortion is always considered to be an SAE and will be reported as such. 
Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered 
reasonably related to the investigational product(s) by the investigator, will be reported to 
TMHRI. 
 
15.1.3 Follow-up Adverse Events 
Investigators should follow-up subjects with adverse events until the event has subsided 
(disappeared) or until the condition has stabilized. Subjects will be followed for adverse events 
and serious adverse events for 30-days from the last dose of study drug. During the 30-day 
follow-up period, new onset adverse events should only be recorded if, in the opinion of the 
investigator, there is a possibility the event is attributable to the investigational  product.  
Adverse events that are clearly related to the next phase of the patient’s treatment (e.g. 
alopecia in a patient receiving chemotherapy) should NOT be recorded. 
 
15.2 Reporting of Results to Subjects and their Physicians 
The results of the immunohistochemical staining are purely investigational and thus will not be 
reported back to the patient or their physician. As the biomarker analyses will be done in 
batches, the results may not be available for many months after the tissue sampling is done. 
 
16. Data Management 
TMHRI utilizes Velos eResearch, a web-based Clinical Trial Management System. Reusable 
system components allow patient information to be tracked and managed on an organization, 
disease and department specific basis. Researchers use Velos eResearch Patient Profiling to 
screen patients, track clinical outcomes, and introduce routine clinical data capture, 
management and research practices in their organizations. Velos eResearch provides full 
Electronic Data Capture (EDC) compliant with HIPAA and 21 CFR Part 11 regulations. Custom- 
built case report forms allow data capture over the web from any study site. A robust data query 
engine enables granular data and study queries across multiple forms, patients, and studies. 
eResearch was originally designed for use at Cancer Centers, and incorporates standard NCI 
reports in the application. Velos eResearch is powered by an Oracle database engine. The 
configuration at TMHRI will be adequate to handle the data generated from these projects. All 
patients who received any amount of study drug will be included in the safety analysis. Subjects 
will be monitored at each clinic visit and at any contact with the subject throughout the study for 
the occurrence of AEs and SAEs. The investigator or site staff will inquire about the occurrence 
of AEs/SAEs at every clinic visit or contact during the study. Adverse events will be graded 
according to the NCI Common Terminology Criteria v. 4.0. All AEs that occur during active 
treatment will be recorded in subject source documents and on CRFs, regardless of grade or 
relationship to investigational treatment. Non-serious adverse events that occur within the 30 
day follow-up period will only be recorded on the CRFs if the investigator believes there to be a 
possible relationship to study medication. Serious adverse events should be recorded, 
regardless of relationship to drug. 
Safety analyses will include summaries of adverse event rates (both frequency and incidence 
tables), baseline laboratory parameters and changes from baseline, frequency of CTC toxicity 
grades for both laboratory and non-laboratory data. 
During the clinical trial, clinical data on all participants enrolled on the study will be reviewed in 
our Data and Safety Monitoring Committee meeting and monthly in Cancer Center Clinical 
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17. Statistical Design and Analyses 
A sample size of 47 patients achieves 80% power to detect the difference between the null 
median overall response rate (ORR) of 30% and the alternative hypothesis median ORR 50% at 
a 0.05 significance level (alpha) using a two-sided binomial test. 
 
18. RESPONSIBI L I T I ES 
18.1. Investigator Responsibilities 
18.1.1. Good Clinical Practice 
The investigator will ensure that this study is conducted in full compliance with the principles of 
the Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South 
Africa), ICH guidelines, or with the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the study subjects. The investigator will 
ensure that the basic principles of Good Clinical Practice, as outlined in 21 CFR 312, subpart D, 
Responsibilities of Sponsor and Investigators, 21 CFR, part 50, 1998, and 21 CFR, part 56, 
1998, are adhered to. Since this is a covered clinical trial, the investigator will ensure that 21 
CFR, part 54, 1998, is adhered to; a covered clinical trial is any study of a drug or device in 
humans submitted in a marketing application or reclassification petition subject to this part that 
the applicant or FDA relies on to establish that the product is effective (including studies that 
show equivalence to an effective product) or that make a significant contribution to the 
demonstration of safety. This requires that investigators and all sub-investigators must provide 
documentation of their financial interest or arrangements with the Sponsor or proprietary 
interests in the drug being studied. This documentation must be provided prior to the 
participation of the investigator and any sub-investigator. The investigator and sub investigator 
agree to notify the Sponsor of any change in reportable interests during the study and for one 
year following completion of the study. Study completion is defined as the date that the last 
subject has completed the protocol-defined activities. 
 
18.1.2. Institutional Review Board or Independent Ethics. 
Committee Prior to initiation of the study, the study protocol will be submitted with its associated 
documents (e.g., Schedule of Assessments, Subject Information and Consent Forms, 
Investigator’s brochure) to the relevant Institutional Review Board (IRB) or independent Ethics 
Committee (IEC) for approval. The approval of the relevant IRB/IEC will be filed in the 
Investigator Site File and a copy will be kept in the Study Master Files. The study will only 
commence following a written approval. Documentation of the date of the IRB/IEC meeting, 
constitution of the committee and voting members present at the meeting, and a statement 
confirming that the IRB/IECs operate in accord with GCP will be requested by the Sponsor. The 
Sponsor also requires written evidence that clearly identifies the study number, clinical study 
protocol version, informed consent documents, and Investigator’s Brochure Version reviewed. 
Any amendments to the protocol will be submitted to the relevant IRB/IEC for approval and the 
IRB/IEC will be informed about SAEs in accordance with local and national requirements. 
Amendments may only be implemented after approval by the IRB/IEC and submission to the 
appropriate regulatory authority unless required to eliminate an immediate safety risk to the 
subject. Regulatory Authority approvals/authorizations/notifications, where required must be in 
place and fully documented prior to trial start. 
 
18.1.3. Subject Information and Informed Consent 
Written informed consent must be obtained from the subject prior to study participation. The 
informed consent document must be signed and dated by the subject and properly witnessed 
before initiation of any study procedures including any change in medication or initiation of study 
drug dosing. Subjects must be consented in accordance with all local regulatory and legal 

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requirements. This process must include a verbal explanation of the nature, scope, and possible 
consequences of the study provided in plain language. The information should be presented by 
the investigator unless a designee is permitted by local regulations. The potential study subject 
should be encouraged to ask questions about the study. The informed consent document must 
be prepared in accordance with GCP guidelines and with local regulatory and legal 
requirements. A copy of the signed consent form will be given to the subject and the original 
document must be safely archived by the investigator so that the forms can be retrieved at any 
time for monitoring, auditing, and inspection purposes. The site will retain the original 
signed/dated consent form and any associated HIPAA authorization, if applicable for all 
consented subject candidates. If applicable, the document will also be provided in a certified 
translation of the local language. The informed consent will be updated as appropriate (e.g.,  
due to protocol amendment or if significant new safety information that may be relevant to 
consent of the subjects becomes available). If the informed consent ids revised, it is investigator 
responsibility to ensure that an amended consent form is reviewed and signed by all subjects 
subsequently entered into the study and those currently in the study. 
 
18.1.4. Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and regulations, will not be made publicly available. Subject names will not be 
supplied to the sponsor. Only the subject number and subject identifier will be recorded in the 
case report form, and if the subject name appears on any other document (e.g., pathologist 
report), it must be de-identified before a copy of the document is supplied to the sponsor. The 
investigator must assure that subject’s anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials and an identification code 
(i.e., not names) should be recorded on any form submitted to the sponsor and IRB. The 
investigator must keep a screening log showing codes, names, and addresses for all subjects 
screened and for all subjects enrolled in the trial. The subjects will be informed in writing that 
representatives of the sponsor, IRB/IEC, or Regulatory Authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in the strictest confidence and in accordance with local data 
protection laws. 
 
18.1.5. Study Files and Retention of Records. 
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These documents 
should be classified into 2 separate categories (although not limited to) the 
Following: (1) investigator’s study file, and (2) subject clinical source documents. It is the 
responsibility of the investigator to ensure that the study center file is maintained in accord with 
Section 8 of the ICH GCP Guidelines. The investigator’s study file will contain the 
protocol/amendments, CRF and query forms, IRB/IEC and governmental approval with 
correspondence, informed consent, drug records, staff curriculum vitae and authorization forms, 
and other appropriate documents and correspondence. Subject clinical source documents 
(usually defined by the project in advance to record key efficacy/safety parameters independent 
of the CRFs) would include (although not limited to) the following: subject hospital/clinic records, 
physician‘s and nurse’s notes, appointment book, original laboratory reports, CT MRI scan, X- 
ray, pathology and special assessment reports, consultant letters, screening and enrollment log, 
etc. 
All clinical study documents must be retained by the investigator until at least two years after the 
last approval of a marketing application in an International Conference on Harmonization (ICH) 
region (i.e., United States, Europe, or Japan) and until there are no pending or contemplated 
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approved for such indication, until two years after the investigation is discontinued and 
regulatory authorities have been notified. Investigators may be required to retain documents 
longer if required by applicable regulatory requirements or an agreement with Abbott. The 
investigator must notify Abbott prior to destroying any clinical study records. Should the 
investigator wish to assign the study records to another party or move them to another location, 
Abbott must be notified in advance. If the investigator cannot guarantee this archiving 
requirement at the study site for any or all of the documents, special arrangements must be 
made between the investigator and Abbott to store these in sealed containers outside of the site 
so that they can be returned sealed to the investigator in case of a regulatory audit. Where 
source documents are required for the continued care of the Subject, appropriate copies should 
be made for storage outside of the site. 
 
 
19. CONSENT PROCEDURES 
Written informed consent will be obtained from all participants by the investigators or their 
designee. The investigator or his/her designee will introduce the study, assist in obtaining the 
signed informed consent, and provide the participant with a copy of the signed consent form. A 
signed, written informed consent must be obtained prior to performing any study specific 
procedures or assessments. 
 
19.1 CONFIDENTIALITY PROCEDURES 
Copies of the signed informed consents will be kept in a secure location. Participating sites will 
be expected to secure their patient private health information in a similar manner, in accordance 
with HIPAA guidelines. Each additional site must allow the coordinating center to perform on- 
site inspections of study data. 
 
19.2 SUBJECT COSTS 
There will be no additional costs to the patients. Any costs resulting from evaluating abnormal 
histology results will be considered standard medical practice for assessment of a suspicious 
breast biopsy result. As this is considered standard medical practice, the participant or their 
health care provider will be expected to pay these costs. It is also important to point out that 
costs of studies to investigate or treat any abnormalities found on physical exam or through the 
blood tests are not covered by the study. 
 
19.3 PAYMENTS TO SUBJECTS 
Participants will not be paid for participation in this study. 

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31. Kallen, M.E., et al., Occasional Staining for p63 in Malignant Vascular Tumors: A 
Potential Diagnostic Pitfall. Pathol Oncol Res. 
 
32. Du, Z., et al., Overexpression of DeltaNp63alpha induces a stem cell phenotype in 
MCF7 breast carcinoma cell line through the Notch pathway. Cancer Sci. 101(11): p. 
2417-24. 
 
33. Lin, Y.L., et al., p63 and p73 transcriptionally regulate genes involved in DNA repair. 
PLoS Genet, 2009. 5(10): p. e1000680. 
 
34. Foschini, M.P., et al., E-cadherin loss and Delta Np73L expression in oral squamous cell 
carcinomas showing aggressive behavior. Head Neck, 2008. 30(11): p. 1475-82. 
 
35. Cho, M.S., I.L. Chan, and E.R. Flores, DeltaNp63 transcriptionally regulates brachyury, a 
gene with diverse roles in limb development, tumorigenesis and metastasis. Cell Cycle. 
9(12): p. 2434-41. 
 
36. Boldrup, L., et al., DeltaNp63 isoforms regulate CD44 and keratins 4, 6, 14 and 19 in 
squamous cell carcinoma of head and neck. J Pathol, 2007. 213(4): p. 384-91. 
 
37. Mohamed F. Elshal, Ph.D. and J. Philip McCoy Jr., PhD Multiplex Bead Array Assays: 
Performance Evaluation and Comparison of Sensitivity to ELISA Methods. 2006 April ; 
38(4): 317–323. 
 
38. Michael F. Marmor, MD, et al. Revised Recommendations on Screening for Chloroquine 
and Hydroxychloroquine Retinopathy Ophthalmology 2011; 118:415–422 © 2011 by the 
American Academy of Ophthalmology. 

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39. Horan PK, Wheeless LL. Quantitative Single Cell Analysis and Sorting. Science 
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40. Copeland S, Siddiqui J, Remick D. Direct Comparison of Traditional ELISAs and 
Membrane Protein Arrays for Dtection and Quantification of Human Cytokines. J 
Immunol Meth 2004;284:99–106. 
 
41. Edward Morgan,a Rudi Varro,b Homero Sepulveda,a Julia A. Ember,a John Apgar,a 
Jerry Wilson,a Larry Lowe,b Roy Chen,b Lalita Shivraj,a Anissa Agadir,a Roberto 
Campos,a David Ernst,a and Amitabh Gaura,* Cytometric bead array: a multiplexed 
assay platform with applications in various areas of biology Clinical Immunology 110 
(2004) 252– 266 
 
42. J. Frengen, R. Schmid, B. Kierulf, K. Nustad, E. Paus, A. Berge, T. Lindmo, 
Homogeneous immunofluorometric assays of alpha-fetoprotein with macroporous, 
monosized particles and flow cytometry, Clin. Chem. 39 (1993) 2174– 2181. 
 
43. J.E. Bishop, K.A. Davis, A flow cytometric immunoassay for beta2- microglobulin in 
whole blood, J. Immunol. Methods 210 (1997) 79–87. 
 
44. T.M. McHugh, Flow microsphere immunoassay for the quantitative and simultaneous 
detection of multiple soluble analytes, Methods Cell. Biol. 42 (Pt. B) (1994) 575– 595. 
 
45. M. Fulwyler, T. McHugh, R. Schwadron, J. Scillian, D. Lau, M.P. Busch, S. Roy, G. 
Vyas, Immunoreactive bead (IRB) assay for the quantitative and simultaneous flow 
cytometric detection of multiple soluble analytes, Cytometry (Suppl. 2) (1988) 19. 
 
46. D.P. Collins, B.J. Luebering, D.M. Shaut, T-lymphocyte functionality assessed by 
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47. Chloroquine package insert. 
 
48. Paclitaxel package insert. 
 
49. Docetaxel package insert. 
 
50. Abraxane package insert. 
 
51. Ixabepilone package insert. 

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21. APPENDICES 
 
Appendix A: ECOG Performance Status Criteria 

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Appendix B: New York Heart Association (NYHA) Classifications 

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This table is an excerpt from the Oxford Textbook of Medicine, 2nd ed. Oxford; New York: Oxford University Press, 1987, p. 2228. 

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Appendix C: Version 4.0 (dated June-14-2010) 
 
 
 
CTCAE Files 
NCI Common Terminology Criteria for Adverse Events (CTCAE) v.4 data files and related documents are 
published here. The most current release files appear in this directory: 
 
Files: Booklet 
Content 
CTCAE_4.03_2010-06- 
14_QuickReference_5x7.pdf 
Most recent release of core terminology: PDF 
document, traditional small booklet format. 
 
 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 

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Appendix D: WOCBP & Determination of Menopausal Status 
 
 
WOCBP 
Women of childbearing potential and men must agree to use adequate contraception (one of the 
following listed below) prior to study entry, for the duration of study participation and up to 90 
days following completion of therapy. Additionally, male subjects (including those who are 
vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms 
for the duration of the study and for 90 days following completion of therapy. 
● Total abstinence from sexual intercourse (minimum one complete menstrual cycle). 
● Vasectomized male subjects or vasectomized partner of female subjects. 
● Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months prior to study 
drug administration. 
● Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with 
spermicidal jellies or cream). 
● Intrauterine device (IUD). 
 
 
 
 
 
 
The following criteria will be used in the CAT trial to define postmenopausal: 
 
Age 56 or older with no spontaneous menses for at least 12 months prior to study entry; Or 
 
Age 55 or younger with no spontaneous menses for at least 12 months prior to study entry (e.g., 
spontaneous or secondary to hysterectomy) and with a documented estradiol level in the 
postmenopausal range according to local institutional/laboratory standard; 
Or 
 
Documented bilateral oophorectomy. 
 
Women failing to meet one of these criteria will be classified as pre-menopausal. 
 
 
 
 
 
 
 
 
Appendix E: Chloroquine Drug Interactions 

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Appendix F: List of Abbreviations 

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AE 
adverse event 
ALT (SGPT) 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST (SGOT) 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
CI 
confidence interval 
CMF 
cyclophosphamide, methotrexate, and fluorouracil 
CMP 
comprehensive metabolic profile 
CR 
complete response 
CRF 
Case Report Form 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Center for Therapy Evaluation Programs 
CYP450 
cytochrome P450 
DFS 
disease-free survival 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
ER 
estrogen receptor 
FDA 
Food and Drug Administration 
FEC 
fluorouracil, epirubicin, and cyclophosphamide 
FISH 
fluorescence in situ hybridization 
FSH 
follicle-stimulating hormone 
G-CSF 
granulocyte colony-stimulating factor 
GCP 
Good Clinical Practice 
HCl 
hydrochloride 
HER2 
human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 

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HRT 
hormone replacement therapy 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous 
LD 
longest diameter 
LVEF 
left ventricular ejection fraction 
MI 
myocardial infarction 
MRI 
magnetic resonance imaging 
MUGA 
multigated (radionuclide) angiogram 
N/A 
not applicable 
NCI 
National Cancer Institute 
N/D 
not done 
NYHA 
New York Heart Association 
ORR 
overall response rate 
pCR 
pathologic complete response 
PD 
progressive disease 
PET 
positron emission tomography 
PHI 
protected health information 
PR 
partial response 
Pr 
progesterone receptor 
PVC 
polyvinyl chloride 
QA 
quality assurance 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SD 
stable disease 
TTP 
time to tumor progression 
ULN 
upper limit of normal 
WOCBP 
woman of childbearing potential