Conditions: Breast Cancer
Keywords: stage IIIA breast cancer stage IIIB breast cancer stage IIIC breast cancer stage IV breast cancer HER2-negative breast cancer recurrent breast cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 27
Healthy volunteers: no

Brief summary:
RATIONALE: Drugs used in chemotherapy, such as paclitaxel albumin-stabilized nanoparticle formulation, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving paclitaxel albumin-stabilized nanoparticle formulation together with everolimus may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of everolimus when given together with paclitaxel albumin-stabilized nanoparticle formulation and to see how well it works in treating women with locally advanced or metastatic breast cancer.

Detailed description:
OBJECTIVES:

Primary

* To determine the maximum tolerated dose and recommended phase II dose of everolimus when administered in combination with paclitaxel albumin-stabilized nanoparticle formulation in women with locally advanced or metastatic breast cancer. (Phase I)
* To determine the antitumor activity of this regimen, as measured by clinical tumor response according to RECIST criteria, in these patients. (Phase II)

Secondary

* To determine the safety and tolerability of everolimus when administered at the recommended phase II dose in combination with paclitaxel albumin-stabilized nanoparticle formulation in these patients.

OUTLINE: This is a multicenter, phase I dose-escalation study of everolimus followed by a phase II study.

Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Patients also receive oral everolimus once daily or once every other day on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Arms:
arm 1: Phase I:

* Abraxane will be given by IV for 30 minutes on the first day of the first three weeks of each 28 day cycle.
* RAD001 will be given by tablet. The first group of patients will receive RAD001 once daily depending on side effects seen drug could be increased later to twice a day for a 28 day cycle.

Once a safe and effective drug range is established, the study moves into Phase II.

Phase II:

The maximum tolerated dose (established in Phase I) will be given as scheduled below and we will measure the effectiveness of the study drug combination.

* Abraxane will be given by IV (intravenous infusion) for 30 minutes on the first day of the first three weeks of each 28 day cycle (Day 1, Day 8, and Day 15 of each cycle).
* RAD001 will be given by tablet based on the dose established in the Phase I part of the study.

Interventions: intervention 1: everolimus intervention 2: abraxane
Intervention descriptions: intervention 1: Orally administered RAD001 will be initiated at 5 mg daily. Each cohort Phase I: administration will proceed based on escalation criteria. RAD001 will be given initially once every day. Doses will be adjusted per the dosing regimen for each cohort throughout the Phase I portion of the study intervention 2: Doses of Abraxane will be calculated on Day 1 of each cycle using the patient's actual weight in the determination of body surface area. A variance of 5% of the calculated total dose will be allowed.

Protocol document:
Prot_SAP_000.pdf: 
 
 
Official Title: 
Phase I/II Study of Weekly Abraxane and RAD001 in 
Women with Locally Advanced or Metastatic Breast 
Cancer. A Study of the Cancer Institute of New Jersey 
Oncology Group 
NCT number: 
00934895 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
7/14/2014 
 
 


 
 
Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or 
Metastatic Breast Cancer 
 
Principal Investigator:  
Deborah L. Toppmeyer, M.D. 
Rutgers Cancer Institute of New Jersey 
195 Little Albany Street 
New Brunswick, NJ 08903 
Telephone: (732) 235-6789 
FAX: (732) 235-4321 
Email: toppmede@cinj.rutgers.edu 
Sub-investigators:  
Kim Marie Hirshfield, M.D., Ph.D. 
Nicola Barnard, M.D. 
Serena Wong, M.D. 
Thomas J. Kearney, M.D. 
Shridar Ganesan, M.D., Ph.D 
David A. August, M.D. 
Cancer Institute of New Jersey Oncology Group (CINJOG) 
 
Rutgers Cancer Institute of New Jersey 
 
Rutgers Cancer Institute of New Jersey  
Operations Center 
 
 
 
 
Biostatistical Center 
Office of Human Research Services 
 
 
Biometrics Department 
Rutgers Cancer Institute of New Jersey  
 
Rutgers  Cancer Institute of New Jersey 
195 Little Albany Street 
 
 
 
120 Albany Street, 5th Floor 
New Brunswick, NJ 08903 
 
 
 
New Brunswick, NJ 08903 
Telephone: (732) 235-8675 
 
 
             Telephone: (732) 235-6791 
FAX: (732) 235-7690  
 
 
 
FAX: (732) 235-7350 
 
Supported by: Novartis Pharmaceuticals will be providing support and RAD001.  This is a 
Cancer Institute of New Jersey Oncology Group (CINJOG) investigator-initiated study.   
 
Drug(s) Under Investigation:   
Company 
 
IND #  
Drug Supply  
RAD001 (Everolimus) 
Novartis Pharmaceuticals 
105009  
Yes 
Abraxane (nab paclitaxel) 
Abraxis Oncology 
NA 
 
No 
 
 
CONFIDENTIAL 
This document is the property of the Rutgers Cancer Institute of New Jersey.  No part of it may be transmitted, reproduced, published, 
or used without prior written authorization from the study sponsor. 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
 
TABLE OF CONTENTS   
1. 
PURPOSE/SPECIFIC OBJECTIVES ............................................................................................................. 5 
1.1 PRIMARY ENDPOINT............................................................................................................................................. 5 
1.2 SECONDARY ENDPOINT(S) ................................................................................................................................... 5 
2. 
BACKGROUND AND SIGNIFICANCE ......................................................................................................... 5 
2.1 SUPPORTING DATA AND RATIONALE .................................................................................................................... 6 
3. 
PARTICIPATING INSTITUTIONS .............................................................................................................. 14 
4. 
EXPERIMENTAL DESIGN AND METHODS ............................................................................................ 14 
5. 
PATIENT SELECTION CRITERIA ............................................................................................................. 14 
5.1 INCLUSION CRITERIA ......................................................................................................................................... 14 
5.2 EXCLUSION CRITERIA ........................................................................................................................................ 15 
5.3 INCLUSION OF WOMEN AND MINORITIES ........................................................................................................... 16 
5.4 PARTICIPATION OF CHILDREN ............................................................................................................................ 16 
5.5 SOURCES OR METHODS OF RECRUITMENT ......................................................................................................... 17 
5.6 STUDY ENROLLMENT PROCEDURES ................................................................................................................... 17 
6. 
STUDY PARAMETERS ................................................................................................................................. 18 
7. 
TREATMENT PLAN ...................................................................................................................................... 19 
7.1 GENERAL CONSIDERATIONS ............................................................................................................................... 19 
7.2 DOSE CALCULATION .......................................................................................................................................... 19 
7.3 TREATMENT ADMINISTRATION .......................................................................................................................... 19 
7.4 DOSE MODIFICATIONS OR ESCALATIONS............................................................................................................ 22 
7.5 CONCOMITANT MEDICATIONS............................................................................................................................ 31 
7.6 SUPPORTIVE CARE GUIDELINES ......................................................................................................................... 32 
7.7 ADHERENCE/COMPLIANCE................................................................................................................................. 33 
8. 
TOXICITY MONITORING AND ADVERSE EVENT REPORTING ...................................................... 33 
8.1 ADVERSE EVENT REPORTING REQUIREMENTS ................................................................................................... 33 
8.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAES) ........................................................................................... 35 
8.3 DEFINITION OF RELATED .................................................................................................................................... 36 
8.4 DEFINITION OF UNEXPECTED ............................................................................................................................. 36 
8.5 DEATH ............................................................................................................................................................... 36 
9. 
TREATMENT EVALUATION/CRITERIA FOR RESPONSE .................................................................. 36 
10. 
REMOVAL OF PATIENTS FROM STUDY/OFF STUDY CRITERIA ............................................... 41 
11. 
LABORATORY EVALUATIONS AND PROCEDURES/CORRELATIVE AND 
PHARMACOKINETIC STUDIES .......................................................................................................................... 42 
11.1 IMMUNOHISTOCHEMISTRY ANALYSIS ............................................................................................................... 42 
11.2 SHIPPING INSTRUCTIONS FOR ARCHIVAL TUMOR TISSUE ................................................................................. 42 
12. 
PHARMACEUTICAL INFORMATION ................................................................................................. 42 
12.1 ABRAXANE ...................................................................................................................................................... 42 
12.2 RAD001 .......................................................................................................................................................... 45 
13. 
DATA COLLECTION AND RECORDS TO BE KEPT ......................................................................... 45 
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Deborah L. Toppmeyer, M.D. 
 
13.1 CASE REPORT FORMS ...................................................................................................................................... 45 
13.2 RESEARCH CHARTS.......................................................................................................................................... 46 
13.3 REPORTS .......................................................................................................................................................... 46 
14. 
DATA AND SAFETY MONITORING ..................................................................................................... 46 
15. 
MULTI-INSTITUTIONAL GUIDELINES .............................................................................................. 46 
15.1 IRB APPROVALS .............................................................................................................................................. 46 
15.2 OTHER PRE-STUDY DOCUMENTS ..................................................................................................................... 47 
15.3 INITIATION SITE VISITS .................................................................................................................................... 47 
15.4 IRB CONTINUING APPROVALS ......................................................................................................................... 47 
15.5 AMENDMENTS AND CONSENTS ........................................................................................................................ 47 
15.6 PATIENT REGISTRATION ................................................................................................................................... 47 
15.7 DATA COLLECTION AND TOXICITY REPORTING................................................................................................ 47 
15.8 DATA MONITORING AND SOURCE DOCUMENT VERIFICATION ......................................................................... 47 
15.9 DATA AND CENTER AUDITS ............................................................................................................................. 48 
16. 
STATISTICAL CONSIDERATIONS ....................................................................................................... 48 
16.1 TRIAL DESIGN .................................................................................................................................................. 48 
16.2 SAMPLE SIZE JUSTIFICATION ............................................................................................................................ 48 
16.3 STUDY DURATION ............................................................................................................................................ 48 
16.4 DATA ANALYSIS .............................................................................................................................................. 48 
17. 
HUMAN SUBJECTS .................................................................................................................................. 49 
17.1 PATIENT POPULATION ...................................................................................................................................... 49 
17.2 POTENTIAL RISKS ............................................................................................................................................. 49 
17.3 CONSENT PROCEDURES ................................................................................................................................... 49 
17.4 POTENTIAL BENEFITS ....................................................................................................................................... 50 
17.5 RISK-BENEFIT RATIO ....................................................................................................................................... 50 
17.6 GENDER AND MINORITIES ................................................................................................................................ 50 
18. 
ECONOMIC/FINANCIAL CONSIDERATIONS ................................................................................... 50 
19. 
PUBLICATION OF RESEARCH FINDINGS ......................................................................................... 51 
REFERENCES .......................................................................................................................................................... 52 
APPENDIX A - PERFORMANCE STATUS CRITERIA ..................................................................................... 56 
APPENDIX B - EXAMPLES OF DRUGS OR SUBSTANCES KNOWN TO BE INHIBITORS OR 
INDUCERS OF THE ISOENZYME CYP3A ......................................................................................................... 57 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
LIST OF ABBREVIATIONS  
AE 
Adverse Event 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CINJOG 
Cancer Institute of New Jersey Oncology Group 
CT 
Computer tomography 
CR 
Complete response 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
dl 
Deciliter 
DSMP 
Data Safety Monitoring Plan 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
G-CSF 
Granulocyte Colony Stimulating Factor 
HHS 
Department of Health and Human Services 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenously 
kg 
Kilograms 
L 
Liter 
mg 
Milligram 
mL 
Milliliters 
mmol 
Millimolar 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
OHRS 
Office of Human Research Services 
OHRP 
Office of Human Research Protection 
PBMC 
Peripheral blood mononuclear cells 
PD 
Progressive disease 
PHI 
Protected health information 
PI 
Principal Investigator 
PR 
Partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RWJUH 
Robert Wood Johnson University Hospital 
SAE 
Serious adverse event 
SD 
Stable disease 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
ULN 
Upper limit of normal 
USP 
United States Pharmacopeia 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
 
1. Purpose/Specific Objectives 
 
1.1 Primary Endpoint  
Phase I: 
• To determine the MTD of RAD001 in combination of weekly Abraxane and 
determine the Phase II dose of RAD001. 
 
Phase II: 
• To determine the anti-tumor activity, as measured by clinical tumor response 
according to RECIST criteria, of the combination of RAD001 and Abraxane at the 
Phase II dose in patients with advanced breast cancer. 
 
1.2 Secondary Endpoint(s)  
• To determine the safety and tolerability of weekly RAD001 administered at the 
Phase II determined dose in combination with Abraxane at 150 mg/m2 weekly for 
3 of 4 weeks on a 28-day cycle. 
 
2. Background and Significance 
Approximately 215,000 new cases of breast cancer were diagnosed in the United States in 
2005 and ~43,000 died from this disease.  Single agent or combination chemotherapy 
produces response rates of 40-70% in the treatment of advanced breast cancer.  Although 
numerous regimens are effective in palliating symptoms and inducing tumor regression, the 
complete response rate is less than 20%.  Moreover, the median duration of response is nine 
months with a median survival of 12-24 months.  Thus, most responses are of limited 
duration and nearly all patients with stage IV disease eventually die of disease progression.  
Similarly, the prognosis for inflammatory or locally advanced breast cancer is dismal, with 
fewer than 25% of diagnosed patients alive at five years (1).  Therefore, the treatment of 
patients with metastatic and locally advanced breast cancer warrants investigation of novel 
therapeutic strategies including more rationale design and sequencing of combination 
chemotherapy regimens. 
 
The choice of cancer chemotherapy is usually empirical, based more on the histological 
appearance of the tumor than on an understanding of the molecular determinants of drug 
sensitivity.  This may account for the suboptimal response rates in many treated patients.  
Recently, important gene products have been discovered that affect the action of cancer 
chemotherapeutic agents.  These drug-resistance genes appear to be selected for the survival 
advantage they impart to tumors.  We now appreciate that activation of several oncogenes 
and loss of tumor suppresser gene products increase cellular viability and lead to resistance to 
radiation and chemotherapy (2). Recently, new molecularly-targeted, non-cytotoxic therapies 
have emerged as an option for treatment of a select set of malignancies, whereby inhibition of 
a pathologically-significant molecular target is thought to be responsible for disease 
regression.  Given the comparatively non-toxic characteristics of these molecularly-targeted 
pharmacotherapeutic agents, a logical next step in the search for more effective 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
chemotherapeutic regimens is their combination with standard cytotoxics. Additionally, the 
use of molecularly targeted therapies in combination with cytotoxic agents may maximize the 
antitumorigenic properties of the latter. 
 
Genes in the PI3K/AKT pathway are key to the regulation of cell growth, cell viability, cell 
motility, and resistance to chemotherapeutic and hormonal agents. Deregulation of these 
genes is found in many tumor types, including breast cancer in which pathway activation is 
felt to be an early event in carcinogenesis. The serine-threonine kinase Akt plays a vital role 
in stimulation of cell growth, cell proliferation, and tumor transformation. It acts as a signal 
transducer for growth factor-controlled processes. Transformation, e.g. such as that 
associated with amplification of Her2/neu, occurs due to activation of the PI3-K/Akt pathway 
(1, 2). Tumor cells also have altered metabolism with a shift to glycolysis. Akt, a direct 
regulator of glucose metabolism and protein translation, produces its effects on nutrient 
transport and protein production through its action on the downstream mediator: mammalian 
target of resistance (mTOR). In turn, there is potential positive feedback from 
phosphorylation of Akt by mTOR (Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. 
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005, 
307: 1098-101). Previous work shows correlation between activated Akt and mTOR levels. 
Preclinical studies on cells with chemotherapy-, trastuzumab-, tamoxifen-, and radiation-
resistant phenotypes secondary to up-regulation of Akt indicate that Akt-pathway inhibitors 
and mTOR inhibitors can modify this resistance (3-5). In vitro resistance to paclitaxel can 
occur through up-regulation of Akt and mTOR activityVanderWeele et al. (6) have shown 
that this resistance that can be abrogated by concomitant use of paclitaxel and an mTOR 
inhibitor. Elevated phosphorylation of Akt and mTOR are highly associated with invasive 
breast tumors. Phosphorylated mTOR is found in 25-45% of breast cancers at moderate to 
high levels, consistent with studies on breast cancer cell lines, while activated mTOR is 
nearly undetectable in normal primary mammary epithelial cell lines. 38-80% of invasive 
breast tumors demonstrate moderate to high levels of phosphorylated Akt (8,9). Akt-1 levels 
are enriched in Stage III/IV invasive breast cancers with 80% demonstrating protein 
overexpression (1,7). Paclitaxel is a standard cytotoxic agent used in stage IV disease. 
Inhibition of mTOR activity may represent a target for increasing sensitivity of advanced 
breast cancers to paclitaxel. We, therefore, propose to study the combination of the mTOR 
inhibitor RAD001 with Abraxane in women with advanced breast cancer. We anticipate that 
RAD001 will enhance the effect of Abraxane by targeting the PI3K/Akt/mTOR pathway. 
 
2.1 Supporting Data and Rationale 
2.1.1 
RAD001 (everolimus) 
RAD001 (everolimus) has been in clinical development since 1996 for patients undergoing 
solid organ transplantation. The drug has been approved in several countries, including the 
majority of European Union states, as prophylaxis to prevent rejection in patients following 
renal and cardiac transplantation in combination with cyclosporin A and glucocorticosteroids. 
Its first commercialization (as Certican) dates from March 2004 in Germany. 
 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
The following is a brief summary of the main characteristics of RAD001. More complete 
information can be obtained from the Investigators’ Brochure (10). 
2.1.1.1 
Pharmacology of RAD001 
RAD001 (INN: everolimus) is a novel macrolide derivative or rapamycin formulated for oral 
administration, which is being developed as an antiproliferative drug with applications as an 
immunosuppressant and anticancer agent. 
 
At the cellular or molecular level, RAD001 has the same mechanism of action as an 
immunosuppressant or as an anti-tumor agent. It acts by selectively inhibiting mTOR 
(mammalian target of rapamycin), an intracellular protein kinase implicated in the control of 
cellular proliferation of activated T-lymphocytes or neoplastic cells. TOR is a ubiquitous 
protein kinase implicated in cell cycle control and specifically in the progression of cells from 
the G1 to S phase. TOR is considered to be a downstream component of the PI3/Akt 
pathway, its own primary downstream substrates being the eIF-4E-binding protein (4E-BP1) 
and p70 S6 kinase 1 (S6K1) which both play a role in the translational regulation of mRNAs 
encoding proteins involved in G1-phase progression. In this context, there is an increasing 
body of evidence suggesting that AKT regulates mTOR activity (11, 12, 13), and that the 
activation status of the PI3K/AKT pathway may be indicative of responsiveness to 
rapamycins such as RAD001. 
 
RAD001 acts on interleukin and growth-factor-dependent proliferation of cells through high 
affinity for an intracellular receptor protein, the immunophilin FKBP-12. The resulting 
FKBP-12/RAD001 complex then binds with mTOR to inhibit downstream signaling events. 
In vitro studies have shown that RAD001 can inhibit the proliferation of numerous cell lines 
originating from solid tumors, including lung cancer, with the most sensitive cell lines having 
IC50's at the sub nanomolar/low nanomolar level. All of the four investigated lung cancer cell 
lines were sensitive to RAD001 with A549 human lung carcinoma being the most sensitive 
cell line overall (IC50 ~2nM). On the other hand, rapamycin has shown to be a potent 
inhibitor of proliferation of NSCLC and SCLC cell lines in vitro (IC50 range 2-40 nM) with 
sensitivity linked to higher levels of phosphorylated AKT and PTEN status (14, 15). In 
addition, rapamycin inhibited growth and metastatic progression in 3 different NSCLC 
animal models (16). 
 
Experiments in vitro with human umbilical endothelial cells (HUVECs) and in animal 
models of angiogenesis suggest an additional antiangiogenic effect of RAD001, presumably 
through mTOR inhibition in proliferating endothelial cells. 
 
In vivo studies in rodent models have shown orally-administered RAD001 to be a potent 
inhibitor of tumor growth at well-tolerated doses. This included several different mouse 
models, including lung xenograft models (NCI-H596, NCI-H520 and A549), and was 
associated with no animal deaths or significant body weight loss. Moreover, persistent tumor 
regressions (41%) were seen in A549 tumors [Investigators’ Brochure-Section 4.1.2.6]. In 
general, RAD001 was better tolerated in mouse xenograft models than standard cytotoxic 
agents (i.e. doxorubicin and 5-fluorouracil), while possessing similar antitumor activity. In 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
combination experiments in vitro with conventional cytotoxic agents, RAD001 potentiate the 
induction of A549 lung carcinoma cell death at sub-optimal gemcitabine concentrations with 
little effect of drug schedule on the antiproliferative effect. In vivo experiments involved 
combination of RAD001 with suboptimal doses of paclitaxel, cisplatinum, gemcitabine and 
doxorubicin using NCI-H596 lung xenograft model, showing weak increased antitumor 
effect. In addition, a mouse model bearing a ras codon 12 mutation, ras mutations being 
frequent in adenocarcinoma with BAC features (17, 18, 19, 20) bears a striking resemblance 
to adenocarcinoma with BAC features and has been shown in extensive studies to manifest p-
AKT and p-S6R expression in the progression of lesions to adenocarcinoma. The tumors 
formed in these mice are sensitive to mTOR inhibition both in terms of numbers and tumor 
volume (J.Kurie personal communication). 
 
Molecular Determinants of Sensitivity to RAD001 
The molecular determinants predicting responsiveness of tumor cells to RAD001 are only 
now becoming evident. The mTOR pathway is downstream of the PI3K/AKT/TSC pathway, 
a signalling module known to be heavily deregulated in many human cancers (21, 11). In this 
context, there is an increasing body of evidence suggesting that AKT regulates mTOR 
activity (11, 12), and that the activation status of the PI3K/AKT pathway may be indicative of 
responsiveness to rapamycins such as RAD001. Specifically, loss of PTEN or 
constitutive/hyper-activation of AKT has been suggested to sensitize tumors to the effects of 
inhibition of mTOR (12, 13, 22). Indeed, RAD001 preferentially inhibits the proliferation of 
tumor cells displaying high AKT activity [Investigators’ Brochure-Section 4.1.2] and totally 
reverses AKT-driven prostate intraepithelial neoplasia in a mouse transgenic model (13). 
Moreover, a correlation between increased RAD001 sensitivity and high levels of S6 
ribosomal protein phosphorylation has also been observed in vitro. 
 
Preclinical studies also demonstrated that inhibition of p70S6kinase 1 (S6K1) activity and 
4E-BP1 phosphorylation, downstream effectors of the mTOR pathway, are markers of drug 
activity. In terms of the S6K1, in vitro, short-term exposure to RAD001 led to S6K1 
inactivation for as long as 120 hours. In vivo, in a syngeneic rat pancreatic tumor model, a 
single dose of RAD001 led to S6K1 inhibition for up to 72 hours in tumors and skin and for 
up to seven days in peripheral blood mononuclear cells (PBMCs). Dramatically, inhibition of 
PBMC-derived S6K1 for ≥7 days correlated with the antitumor activity of weekly 
administration schedules. Moreover, in tumor, this inhibition of S6K1 correlated with a 
dramatic dephosphorylation of the ribosomal protein S6 (23). Hence, analysis of molecular 
determinants predicting predisposition for response (such as these and perhaps others yet to 
be identified) may aid patient selection in oncology. 
 
2.1.1.2 
Clinical Background Information 
In oncology, clinical experience with RAD001 is based on ongoing Phase 1 studies of single-
agent RAD001 and Phase 1b studies of RAD001 in combination with systemic anticancer 
agents (imatinib, paclitaxel, gemcitabine and letrozole). Clinical experience in non-oncology 
indications comes from single-dose studies in healthy volunteers, studies in solid organ 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
transplant patients, where RAD001 is co-administered with other immunosuppressive drugs, 
and a study in patients with severe rheumatoid arthritis. 
 
2.1.1.3 
Clinical Pharmacology of RAD001 
RAD001 is administered orally, its bioavailability being estimated at approximately 11%. 
Absorption is intestinal and is delayed moderately by food (60% reduction in Cmax and 16% 
reduction in AUC when drug administration follows a fat-rich meal). The AUC is 
consistently dose-linear with moderate inter-patient variability (CV approx 50%). The Cmax is 
dose-linear until 20mg, increasing in a non-linear manner thereafter. The terminal half-life is 
30-35 hours. 
 
The main elimination route for RAD001 is by hepatic metabolism, mainly hydroxylation. The 
parent compound is the major component in the blood. Metabolism to rapamycin is of minor 
importance. The main metabolites are not bioactive. Excretion is through the bile and the 
intestinal tract (>80%). 
 
RAD001 is a substrate of the CYP3A4 isoenzyme and P-gp and its metabolism is sensitive to 
3A4 inhibitors/inducers. In combination with micro-emulsion cyclosporin A (Neoral®), a 
3A4 and P-gp inhibitor, the bioavailability of RAD001 is significantly increased: for AUC by 
a mean of 168% (range: 46-365%); for Cmax by 82% (range: 25-158%). RAD001 itself does 
not appear to have an enzyme-inducing/inhibiting effect at the levels achieved in solid organ 
transplantation and current oncology studies. 
 
Mild to moderate hepatic impairment will increase exposure to RAD001. Caucasians and 
Japanese patients appear to be similar as regards clearance, while clearance in blacks is 
approximately 20% higher. 
 
Renal function has only marginal influence on the clearance of RAD001 so that no dosage 
adjustment is necessary in patients with renal failure. 
 
2.1.1.4 
Clinical Studies in Oncology 
Since 2002, RAD001 has been used in Phase 1 in cancer patients both as monotherapy and in 
combination with a number of other anticancer agents (10). Phase 1 clinical studies of 
RAD001 as a single agent are ongoing and explore two regimens: weekly dosing (range 5-
70 mg) and daily dosing (5-10 mg). Preliminary data are available for 84 patients, 74 
advanced cancer patients, and 10 patients with newly-diagnosed prostate carcinoma. At the 
weekly schedule, dose-limiting toxicity (DLT) in the first four weeks of treatment has been 
observed at 50mg (1/12) and 70 mg (3/14). At the daily dosage, DLT has been observed at 
10 mg only (1/12). DLT was principally Grade 3 stomatitis, but also Grade 3 fatigue and 
neutropenia. 
 
Apparent adverse drug reactions (ADR) include mild-moderate rash (approx. 40%), 
stomatitis/mucositis and fatigue (30% each), headache (20%), nausea, vomiting, diarrhea 
(10% each). 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
 
Reduced blood cell counts at the initiation of treatment are frequent but remain mostly within 
normal range or limited to Grade 1 although a Grade 3 neutropenia was dose-limiting in one 
patient (as was a Grade 3 thrombocytopenia in a patient receiving RAD001 with letrozole 
where a pharmacodynamic interaction is unlikely). This suggests that some patients may be 
particularly sensitive to the myelosuppressive effect of RAD001 making it necessary to 
monitor carefully blood cell counts at initiation of treatment. 
 
Hyperlipidemia has been reported as ADR in 10% of patients although review of the 
laboratory values suggests that as many as a quarter of patients develop Grade 1-2 
hyperlipidemia on treatment, mostly hypercholesterolemia. 
 
Infectious episodes have not been more frequent than might have been expected. Herpes 
infections (zoster, labialis), observed in 5 patients on the monotherapy were not severe. 
 
Pharmacokinetic-pharmacodynamic modeling based on inhibition of a peripheral molecular 
marker (S6 kinase 1 activity in peripheral blood mononuclear cells) suggests that 5-10 mg 
daily should be an adequate dose to produce a high degree of sustained target inhibition. 
Pharmacodynamic studies are underway to investigate this by investigating changes in the 
molecular pathology of biopsied tumor by immunohistochemistry in treated patients. 
Preliminary indications from these studies are that treatment with RAD001 at 5 and 10mg 
daily is associated with dephosphorylation of protein effectors known to be immediately 
downstream of mTOR. This inhibition is quasi-total in patients as regards S6 and partial as 
regards 4EBP1, a picture similar to that observed preclinically in in vivo models in which 
RAD001 demonstrated clear anti-tumor activity.  
 
Four Phase 1B oncology studies are ongoing to investigate the feasibility of combining 
RAD001 with imatinib (Glivec®/Gleevec), gemcitabine, paclitaxel or letrozole in patients 
with various types of cancer (10). 
 
2.1.1.5 
RAD001 Safety 
The most frequent adverse drug reactions in the context of renal and cardiac transplantation 
are highly specific to the transplant context. However, certain events are generalizable, most 
notably myelosuppression, skin disorders and increases in blood lipid levels. 
 
Phase 1 studies with RAD001 alone, as both weekly regimen (up to 70 mg/week) and daily 
regimen (10 mg/day) have explored the drug’s activity in 147 patients with advanced cancers 
[RAD001C Investigators’ brochure, Section 5].  Pre- and on-treatment molecular 
pharmacodynamic studies on the tumor of patients, by immunohistochemistry assay, have 
shown target inhibition at both daily dosage (5-10mg) and weekly dosage (50-70mg) with 
satisfactory tolerability in most patients. The 10mg/d dosage is proposed for further studies in 
similar patient populations. The most frequent adverse effects have been rash, stomatitis, 
fatigue and, to a lesser extent, gastrointestinal disorders (nausea, anorexia, diarrhea, 
vomiting) and headache. The adverse events are mild-moderate (CTC Grade 1-2) in majority 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
of patients. Severe (Grade 3), suspected drug-related, dose-limiting events occurred in 19% 
of patients, these being mainly stomatitis, and occasionally severe fatigue, hyperglycemia and 
neutropenia. Reduced blood counts, hyperlipidemia (mainly hypercholesterolemia) and 
hyperglycemia are relatively frequent laboratory findings. Infections have not been notably 
frequent or severe. Preliminary indications of anti-tumor activity are encouraging. 
 
2.1.2 
Abraxane (nab paclitaxel) (paclitaxel protein-bound particles for injectable 
suspension) (albumin-bound) Abraxane is a novel biologically interactive albumin-bound 
paclitaxel combining a protein with a chemotherapeutic agent in the particle form. This 
composition provides a novel approach of increasing intra-tumoral concentration of the drug 
by a receptor-mediated transport process allowing transcytosis across the endothelial cell 
wall, thereby breaching the blood/tumor interface. This albumin-specific receptor mediated 
process involves the binding of a specific receptor (gp60) on the endothelial cell wall, 
resulting in activation of a protein caveolin-1, which initiates an opening in the endothelial 
wall with formation of a little caves or caveolae, with transport of the albumin-bound 
chemotherapeutic complex via these caveolae to the underlying tumor interstitium (24). A 
protein specifically secreted by the tumor (SPARC) binds and entraps the albumin, allowing 
release of the hydrophobic drug to the tumor cell membrane (24). Abraxane is the first 
biologically interactive nanoparticle leveraging this gp-60/caveolin-1/caveolae/SPARC 
pathway to increase intra-tumoral concentration of the drug and reducing toxic drug in 
normal tissue. 
 
Preclinical Studies with Abraxane  
Preclinical studies comparing Abraxane to Taxol demonstrated lower toxicities, with a MTD 
approximately 50% higher for Abraxane compared to Taxol.  At equal doses there was less 
myelosuppression and improved efficacy in a xenograft tumor model of human mammary 
adenocarcinoma.  At equitoxic doses of paclitaxel, Abraxane was found to be markedly more 
efficacious than Taxol (25).   
 
Clinical Studies with Abraxane 
Every 3 Weeks Schedule 
In a Phase I study, the maximum tolerated dose (MTD) of Abraxane was determined to be 
300 mg/m2 by 30 minute infusion every 3 weeks, without premedication or G-CSF support 
(26). No severe hypersensitivity reactions occurred with Abraxane despite the absence of 
premedication.  Dose-limiting toxicities included sensory neuropathy, stomatitis, and 
superficial keratopathy, which occurred at a dose of 375 mg/m2. Two multicenter Phase II 
studies have evaluated 2 dose levels of Abraxane (300 mg/m2, n=63, and 175 mg/m2, n=43) 
in patients with metastatic breast cancer (26,27). The overall response rates in these 2 Phase 
II trials were 40% (95% CI 25-54%) for the 175 mg/m2 dose, and 48% (95% CI 35-60%) for 
the 300 mg/m2 dose.  Of 39 patients receiving 300 mg/m2 as first-line therapy for metastatic 
breast cancer, 64% (95% CI 49-79%) responded.  This was contrasted with a 45% response 
rate in similar patients at the lower dose level. Grade 4 neutropenia was noted in 24% of 
patients at the higher dose level, occurred primarily during the first cycle and resolved 
rapidly.   
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
A Phase III trial in patients with metastatic breast cancer compared Abraxane 260 mg/m2 to 
Taxol 175 mg/m2 given every 3 weeks (28).  Significantly higher efficacy for Abraxane vs 
Taxol was demonstrated as measured by overall response rates (33% vs 19%, p<0.001) and 
time to tumor progression (5.8 vs 4.2 months, p=0.006). The Overall Response Rate (ORR) 
was superior for all patients, patients who received Abraxane as first-line therapy, patients 
who received Abraxane as second- or greater-line therapy, patients with prior anthracycline 
exposure, elderly patients, and patients with poor prognostic factors, including visceral tumor 
involvement. The overall median survival was 65.0 weeks for the Abraxane group and 55.7 
weeks for the Taxol group (p = 0.374). In second line or greater patients, median survival in 
the Abraxane group was significantly improved (56.4 weeks vs 46.7 weeks, p=0.024; HR = 
0.73). Despite the 49% higher dose of paclitaxel administered to patients in the Abraxane 
group compared to the Taxol group, the incidence of treatment-related Grade 4 neutropenia 
was significantly less (9% vs 22%; p = <0.001). The Abraxane group also had a higher mean 
neutrophil nadir (1.67 vs 1.31 x 109/L;  p = 0.046) suggesting that Cremophor may have 
contributed to this toxicity. Grade 3 sensory neuropathy occurred in 10% of Abraxane treated 
patients compared with 2% of those treated with Taxol. Of the patients who developed 
Grade 3 sensory neuropathy while on Abraxane, 58% had documented rapid improvement in 
symptoms after a median of 22 days and 42% of patients were able to resume treatment at a 
reduced dose. Only 3% of patients that received Abraxane discontinued treatment due to 
peripheral neuropathy. 
 
Weekly for 3 Weeks, Every 4 Weeks Schedule 
A Phase I study of Abraxane administered weekly for 3 weeks followed by a 1 week rest in 
patients with advanced solid tumors has recently been completed (29).  The MTDs for 
heavily and lightly pre-treated patients were 100 and 150 mg/m2 respectively.  Dose limiting 
toxicities included Grade 4 neutropenia and Grade 3 sensory neuropathy.  Premedication was 
not required, and unexpected, non-taxane associated toxicities were not observed.  In a Phase 
II trial in heavily pretreated patients with taxane-refractory metastatic breast cancer, objective 
antitumor responses occurred in 15% of women treated with Abraxane 100 mg/m2 on this 
schedule (30).  Abraxane weekly regimen was well tolerated. 91% of patients were treated at 
the full dose of 100 mg/m2 of Abraxane without dose reductions. Based on the activity and 
low toxicity documented with the Abraxane 100 mg/m2 weekly regimen, this study was 
expanded to evaluate the efficacy and safety/tolerability of a higher dose of Abraxane 125 
mg/m2 weekly regimen in 75 additional patients. Results of this dose-finding study confirm 
the dose of Abraxane 100 mg/m2 as the appropriate dose for further study in this patient 
population (31).  A phase II study examined the efficacy of Abraxane 125 mg/m2 in women 
with previously untreated metastatic breast cancer or locally advanced disease (32). Twenty-
seven patients received 285 cycles of therapy. Grade 3 neutropenia occurred in 7.4% of the 
patients treated. No grade 4 non-hematologic toxicities occurred, thus confirming the safety 
of this dose for first-line therapy.  
 
2.1.3 
Rationale for Combination of Abraxane and RAD001 
As a key role in the PI3-K/AKT pathway, the serine-threonine kinase Akt plays a vital role in 
stimulation of cell growth, cell proliferation, and tumor transformation. Transformation, e.g. 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
such as that associated with amplification of Her2/neu, occurs due to activation of the PI3-
K/Akt pathway (1, 2). Tumor cells also have altered metabolism with a shift to glycolysis. 
Akt, a direct regulator of glucose metabolism, produces its effects on nutrient transport 
through its action on the downstream mediator: mammalian target of rapamycin (mTOR). 
Preclinical studies on cells with chemotherapy-, trastuzumab-, tamoxifen-, and radiation-
resistant phenotypes secondary to up-regulation of Akt indicate that Akt-pathway inhibitors 
and mTOR inhibitors can modify this resistance (3-5). In vitro resistance to paclitaxel can 
occur through up-regulation of Akt and mTOR activity. VanderWeele et al. (6) have shown 
that this resistance that can be abrogated by concomitant use of paclitaxel and an mTOR 
inhibitor. Because increased Akt-1 activity is found in approximately 38% of all breast 
cancers but 80% of Stage III/IV (1,7), inhibition of mTOR activity may represent a target for 
increasing sensitivity of advanced breast cancers to paclitaxel. An additional mechanism of 
drug resistance pertinent to the PI3-K/AKT pathways has been studied by Drs. Arnold Levine 
and Shengkan Jin. Autophagy is a novel tumor suppression mechanism whereby damaged 
organelles are eliminated or entire cells undergo self-digestion. Inhibition of mTOR results in 
autophagy in MCF-7 breast cancer cell lines (33). Beclin 1 is a gene product that functions in 
and is essential to the process of autophagy. Mono-allelic deletion of beclin-1 in human 
breast tumors and other tumors has been demonstrated and in mouse models, is associated 
with reduction of autophagy levels. As autophagy is negatively regulated by mTOR, Jin 
postulates that the use of mTOR inhibitors will reactivate autophagy in beclin-deficient 
tumors. RAD001 (INN: everolimus), an orally active derivative of rapamycin, can be 
considered a signal transduction modifier. After forming a complex with FKBP-12, this 
complex subsequently interacts with the mTOR protein kinase. We, therefore, propose to 
study the combination of RAD001 with Abraxane in women with advanced breast cancer. 
We anticipate that RAD001 will enhance the effect of Abraxane by targeting the 
PI3K/Akt/mTOR pathway. Importantly, working in collaboration with the laboratories of 
Drs. Levine and Jin, we propose to measure potential molecular predictors of response, 
including AKT over-expression and Beclin 1 gene expression in the primary breast tumor. 
This will also be correlated with germline determination of gene haplotype in both Akt and 
beclin 1. 
 
There is increasing evidence that the effectiveness of small molecular protein-inhibitors can 
be highly dependent on intratumoral molecular characteristics. Therefore, there is the 
possibility that only a subpopulation might benefit from the addition of RAD001 to 
Abraxane. Consequently, this study places particular emphasis on the assessment of the 
molecular characterization of the tumor to allow correlative analyses (see Section 11 for 
details). 
 
Rationale for starting doses: 
Based on non-overlapping non-hematological toxicities, it is expected that when 
administered together, both drugs will be able to be given safely at full single-agent doses.  
However, as described in Section 7.4, a reduction in doses of both drugs will be implemented 
if more than 1 of the first 6 patients experiences a Grade 3 non-hematological toxicity (with 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
the exception of increased transaminases, or nausea in the absence of aggressive anti-
emetics), or Grade 4 neutropenia with fever.   
 
3. Participating Institutions  
The Rutgers Cancer Institute of New Jersey, Robert Wood Johnson University Hospital and 
the Cancer Institute of New Jersey Oncology Group (CINJOG) affiliate hospitals.   
 
4. Experimental Design and Methods  
This is an open label Phase I/II study of RAD001 in combination with Abraxane.  Initially, 
six patients will be accrued and evaluated for toxicity at Cancer Institute of New Jersey. PK 
data will be collected. It is not anticipated that RAD001 will modify the DLT of Abraxane.  If 
the toxicity data suggests increased toxicity (any related ≥ Grade 3 non-hematologic toxicity), 
a dose de-escalation schema will be implemented (See Sections 7.3 and 7.4) and toxicity data 
reassessed.  After a Phase II dose is established, 39 to 72 total patients will be accrued to 
assess for response. 
 
This study will require approximately 15 to 24 months to complete accrual of 39 to 72 total 
patients onto this study. 
 
5. Patient Selection Criteria 
 
5.1 Inclusion Criteria 
A patient is eligible for enrollment if all of the following inclusion criteria are met. 
5.1.1 Adult women (≥ 18 years of age) with metastatic or locally recurrent breast 
cancer, not amenable to treatment by surgery or radiotherapy 
5.1.2 Histological confirmation of breast cancer that is Her2/neu negative 
5.1.3 Patients may not have received prior chemotherapy for metastatic breast cancer.  
Prior adjuvant chemotherapy is allowed. 
5.1.4 Patients may have received prior systemic endocrine treatment for advanced 
breast cancer (i.e. metastatic or locally recurrent breast cancer, not amenable to 
treatment by surgery or radiotherapy). 
5.1.5 Patients must have at least one measurable lesion.  Measurable disease 
documented and defined as by RECIST criteria (see Section 9). Baseline 
measurements must be obtained within 4 weeks prior to enrollment. 
• As the only exception regarding the requirement for at least one 
measurable lesion, patients with bone metastases as the sole site of disease can 
be included, provided they have at least 2 lytic bone lesions, detected by either 
X-Ray, CT scan or MRI. 
5.1.6 Prior radiation therapy allowed to < 25% of the bone marrow and patients must 
have recovered from the toxic effects of the treatment prior to study enrollment 
(except for alopecia). Prior radiotherapy must be completed 30 days before study 
entry. Lesions that have been radiated in the advanced setting cannot be included 
as sites of measurable disease unless clear tumor progression has been 
documented in these lesions since the end of radiation therapy. 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
5.1.7 Patients must have an ECOG performance status ≤ 2 (Appendix A). 
5.1.8 Patients on antiangiogenic agents are not excluded from this study. 
5.1.9 Patients must have normal organ and marrow function as defined below: 
• ANC ≥ 1.5 x 109 cells/L, 
• Platelets ≥ 100 x 109 cells/L,  
• Hb >9 g/dL, 
• Serum Bilirubin ≤ 1.5 x ULN,  
• Absence of ascites and encephalopathy due to liver disease,  
• INR < 1.5 x ULN,  
• ALT and AST, ≤ 2.5x ULN ( ≤ 5x ULN in patients with liver metastases). 
• Serum Creatinine ≤ 1.5 mg/dL  
• Fasting serum cholesterol ≤ 300 mg/dl or 7.75 mmol/L and fasting 
triglycerides ≤ 2.5 x ULN  
• 
In case one or both of these thresholds are exceeded, the patient 
can only be included after initiation of statin therapy. 
5.1.10 Estimated life expectancy of at least 3 months. 
5.1.11 Give written informed consent. 
 
5.2 Exclusion Criteria 
A patient will not be eligible for this study if any of the following exclusion criteria are 
met. 
5.2.1 Grade ≥ 2 neuropathy. 
5.2.2 Prior chemotherapy for advanced breast cancer. 
5.2.3 Patients with only non-measurable lesions other than bone metastasis (e.g. pleural 
effusion, ascites etc.) 
5.2.4 Impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). 
5.2.5 Patients with an active, bleeding diathesis or on oral anti-vitamin K medication 
(except low dose coumadin). 
5.2.6 CNS metastases (except patients with stable CNS metastases are allowed on this 
study), bilateral diffuse lymphangitis carcinomatosa of the lung (>50% of lung 
involvement), evidence of metastases estimated as more than a third of the liver as 
defined by sonogram and/or CT scan. 
5.2.7 Patients in whom localized radiotherapy (for analgesic purposes) is considered an 
actual requirement (inclusion should be delayed until radiation therapy has been 
completed and the patient’s condition stabilized). 
5.2.8 Patients with a known history of HIV seropositivity. 
5.2.9 History of other malignancies with exception of: 
• in-situ carcinoma of the cervix or non-melanomatous skin cancer which 
have received curative therapy 
• cancer treated ≥5 years previously and considered as cured. 
5.2.10 Known hypersensitivity to everolimus or sirolimus (rapamycin), to Abraxane or 
lactose (contained in formulations of RAD001) 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
5.2.11 Patients with a history of noncompliance to medical regimens. 
5.2.12 Patients who received any other investigational drugs within the preceding 30 
days. 
5.2.13 Patients being treated with drugs recognized as being strong inhibitors or inducers 
of the isoenzyme CYP3A (Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, 
Itroconazole, Voriconazole, Ritinavir, Telithromycin) within the last 5 days from 
randomization (please also refer to Section 7.5 for prohibited concomitant 
medications). 
5.2.14 Women who are pregnant or breast feeding, or women able to conceive and 
unwilling to practice an effective method of birth control. (Women of 
childbearing potential must have a negative urine or serum pregnancy test within 7 
days prior to administration of RAD001 and Abraxane). Oral, implantable, or 
injectable contraceptives may be affected by cytochrome P450 interactions, and 
are therefore not considered effective for this study. 
5.2.15 Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), megestrol acetate and selective estrogen-receptor modulators (e.g. 
raloxifene) are prohibited. 
5.2.16 Require chronic treatment with systemic steroids or another immunosuppressive 
agent. 
5.2.17 Patients should not receive immunization with attenuated live vaccines within one 
week of study entry or during study period. 
5.2.18 Patients who have any severe and/or uncontrolled medical conditions or other 
conditions that could affect their participation in the study such as: 
• unstable angina pectoris, symptomatic congestive heart failure, myocardial 
infarction ≤ 6 months prior to first study treatment, serious uncontrolled 
cardiac arrhythmia 
• severely impaired lung function 
• any active (acute or chronic) or uncontrolled infection/ disorders 
• nonmalignant medical illnesses that are uncontrolled or whose control may 
be jeopardized by the treatment with the study therapy 
• liver disease such as cirrhosis, chronic active hepatitis or chronic persistent 
hepatitis 
 
5.3 Inclusion of Women and Minorities 
Women from all racial/ethnic groups are eligible for this study if they meet the eligibility 
criteria.  Males will not be eligible for this study.  Breast cancer in men is rare and the 
efficacy of chemotherapy combinations in males is limited.    
 
5.4 Participation of Children 
Patients under the age of 18 will be excluded from study participation. 
 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
5.5 Sources or Methods of Recruitment 
Referrals from within the Cancer Institute of New Jersey and from community oncologists 
will be encouraged.  Patients will also be recruited through participating CINJOG affiliate 
hospitals. 
 
5.6 Study Enrollment Procedures  
A copy of the institution’s IRB-approved informed consent document and written 
justification for any changes made to the informed consent for this protocol must be on file at 
the Cancer Institute of New Jersey’s Office of Human Research Services (OHRS) before any 
participating institution may enter patients.  The participating institution’s consent form must 
be reviewed and approved by the OHRS Regulatory Affairs Manager and all documents must 
be received (i.e., IRB approved documentation, IRB approved consent form, See Section 15.2 
for a complete list of regulatory items). 
 
To register eligible patients on this study, each site will contact the Cancer Institute of New 
Jersey’s OHRS Registration Desk (732) 235-7251 and fax (732) 235-6404 the signed and 
dated eligibility checklist, the signed consent form, a copy of the pathology report and 
additional source documents if requested by OHRS. Once the OHRS Registration Desk 
verifies eligibility, a treatment assignment and unique patient study number will be issued.  
This is the point that the patient is considered on study.  Patients must not start protocol 
treatment prior to registration.  
 
If a patient does not receive any protocol therapy, baseline data will be collected and 
submitted on the pre-study and follow-up electronic case report forms (eCRF). The reason for 
not starting protocol therapy will be documented in the “follow-up eCRF”.  Case report form 
completion instructions and training will be provided to each participating institution prior to 
study activation at the participating institution. 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
 
6. Study Parameters  
The tests and evaluations will be performed according to the schedule below.  Baseline (i.e. pre-
study) evaluations must be performed ≤ 4 weeks (+/- 3 days) of enrollment, unless otherwise 
indicated below.   
 
Evaluations 
Pre-study 
Prior to 
each 
cycle 
Every 
2 
Cycles 
After 
Cycle 
1 
Off 
study 
within 4 
weeks of 
enrollment 
within 2 
weeks of 
enrollment 
Initial history and physical 
 
x 
 
 
 
 
Interim history and physical 
 
 
x 
 
 
x 
Weight and height 
x(a) 
 
x 
 
 
x 
ECOG Performance Status 
x 
 
x 
 
 
x 
Toxicity assessment 
 
 
x 
 
 
x 
CBC with differential 
  
x 
x(g) 
 
 
x 
Prothrombin time (INR) 
x 
 
 
 
 
 
Serum electrolytes(b)(h) 
 
x 
x 
 
 
x 
Fasting lipid profile(h) 
x 
 
 
x 
 
 
Hepatic panel(c) (h) 
 
x 
x 
 
 
x 
Pregnancy test(h) 
 
x(f) 
 
 
 
 
ECG 
x 
 
 
 
 
 
Radiographic assessments(d) 
x 
 
 
x 
 
x 
Compliance assessment 
 
 
x 
 
 
x 
Archived tumor tissue 
   x(e) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(a) Height to be measured only at baseline. 
(b) Serum electrolytes include:  sodium, potassium, chloride, bicarbonate, phosphorus, fasting 
glucose, BUN and creatinine.  
(c) Hepatic panel includes: ALT/SGPT, AST/SGOT, alkaline phosphatase, and total bilirubin. 
(d) Radiographic assessments will be selected by the attending physician as clinically 
indicated and in accordance with the criteria for tumor measurement assessments.  
Confirmatory scans should be obtained ≤ 4 weeks following initial documentation of 
response.  Response will be evaluated every 2 cycles 
(e) Obtain archived tumor tissue (from time of original diagnosis) for immunohistochemical 
analysis; can be obtained at anytime after enrollment.   
(f) Women of childbearing potential must have a negative pregnancy test within 7 days prior to 
treatment. 
(g) CBC will be checked prior to each weekly treatment. 
 (h) Within 7 days. 
 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
7. Treatment Plan 
7.1 General Considerations 
A cycle is defined as an interval of 28 days (delays due to holidays, weekends and bad 
weather will be permitted and will not be counted as a protocol violation). No investigational 
or commercial agents or therapies other than those described below may be administered with 
the intent to treat the patient’s malignancy.  Patients will receive treatment until disease 
progression, unacceptable toxicity or withdrawal of consent.  Patients may discontinue 
therapy at any time for any reason. 
 
7.2 Dose Calculation 
Doses of Abraxane will be calculated on Day 1 of each cycle using the patient’s actual weight 
in the determination of body surface area. A variance of 5% of the calculated total dose will 
be allowed. 
 
BSA (m2) = 
3131
)
(
)
(
lbs
xweight
in
height
      or         
3600
)
(
)
(
kg
xweight
cm
height
 
 
7.3 Treatment Administration 
 
7.3.1 Phase I  
Abraxane will be initially administered at 80 mg/m2 without premedication as a 30 minute 
intravenous infusion weekly for the first 3 of the 4 weeks of a 28 day cycle (Day 1, Day 8, 
and Day 15 of each cycle).  
 
Orally administered RAD001 will be initiated at 5 mg daily. Each cohort administration will 
proceed based on escalation criteria. RAD001 will be given initially once every day. Doses 
will be adjusted per the dosing regimen (Section 7.3.1.1) for each cohort throughout the 
Phase I portion of the study.  RAD001 may be taken with or without food. Patients will be 
advised to take their tablets at the same time of the day and at the same time in relation to 
meals.  Tablets must be swallowed whole with a glass of water.  
 
Abraxane Premedication 
Patients do not require premedication prior to Abraxane administration, as hypersensitivity 
reactions are not expected.  However, during post market surveillance, rare occurrences of 
severe hypersensitivity reactions have been reported. 
 
Patients who experience a severe hypersensitivity reaction to Abraxane should not be 
rechallenged with the drug. 
 
In the rare event of a severe hypersensitivity reaction, discontinue Abraxane. 
 
 
 
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Deborah L. Toppmeyer, M.D. 
 
7.3.1.1 Dosing Regimen 
 
 
Dose Level 
 
Abraxane (mg/m2) 
 
RAD001 (mg) 
-2 
60 
5 every other day 
-1 
60   
5 daily 
0 
80 
5 daily  
1 
100 
5 daily  
2 
125 
5 daily 
3 
125 
10 daily 
 
For the Phase I portion of the study, patients will be enrolled according to the following 
with the first 3 patients starting at Dose Level 0. 
 
Dose Level 0: 
• If 0 patients treated at Level 0 are observed with dose limiting toxicity (DLT) 
during Cycle 1, then the dose will be escalated to the next dose level.   
• If 1 of 3 patients experience DLT in Cycle 1, then 3 more patients will be treated 
at this dose level for a total of 6 patients. 
• If 1 of these 6 patients experiences DLT in Cycle 1, the dose will be escalated.  
• If 2 or more patients at this dose level experience DLT in Cycle 1, then we will 
have exceeded the maximum tolerated dose (MTD) and will de-escalate to Level -
1 and enroll as outlined in the table.  
 
Dose Level 1: 
• If 0 patients experience DLT in Cycle 1, the dose will be escalated to the next 
dose level.  
• If 1 of 3 patients experience DLT in Cycle 1, then 3 more patients will be treated 
at this dose level for a total of 6 patients. 
• If 1 of these 6 patients experiences DLT in Cycle 1, the dose will be escalated.  
• If 2 or more patients experience DLT in Cycle 1, we will have exceeded the MTD 
and Level 0 will be the recommended dose.  
 
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Deborah L. Toppmeyer, M.D. 
 
 
Dose Level 2: 
• If 0 patients experience DLT in Cycle 1, the dose will be escalated to the next 
dose level.  
• If 1 of 3 patients experience DLT in Cycle 1, then 3 more patients will be treated 
at this dose level for a total of 6 patients. 
• If 1 of these 6 patients experiences DLT in Cycle 1, the dose will be escalated.  
• If 2 or more patients experience DLT in Cycle 1, we will have exceeded the MTD 
and Level 1 will be the recommended dose.  
 
Dose Level 3: 
• If 0 patients experience DLT in Cycle 1, then this will be the recommended dose.  
• If 1 of 3 patients experience DLT in Cycle 1, then 3 more patients will be treated 
at this dose level for a total of 6 patients. 
• If 1 of these 6 patients experiences DLT in Cycle 1, this will be our recommended 
dose.  
• If 2 or more patients experience DLT in Cycle 1, we will have exceeded the MTD 
and Level 2 will be the recommended dose.  
 
DLT will be evaluated in the first cycle of therapy and defined as:  Any ≥Grade 3 non-
hematologic toxicity (except alopecia, nausea, emesis that resolves to ≤ Grade 1 with 
symptomatic treatment) or ≥ Grade 4 hematologic toxicity that is definitely, probably or 
possibly related to study drug.  All adverse events are considered related to study drug 
unless proven to be unlikely or definitely unrelated to study drug. 
 
7.3.2 Phase II Treatment Administration 
The Phase II treatment schedule will continue following the same 28 day cycle schedule as 
Phase I.  
 
Abraxane will be administered without premedication as a 30 minute intravenous infusion 
weekly for the first 3 of the 4 weeks of a 28 day cycle (Day 1, Day 8, and Day 15 of each 
cycle).  The dose of Abraxane to be used in the Phase II portion of the trial will be based 
upon the MTD established in the Phase I portion of this trial. 
 
RAD001 will be administered on the schedule and at the maximum tolerated dose as 
determined by the Phase I results.  RAD001 may be taken with or without food. Patients will 
be advised to take their tablets at the same time of the day and at the same time in relation to 
meals.  Tablets must be swallowed whole with a glass of water 
 
ADDENDUM TO DEFINE PHASE II DOSE:  Two of 6 participants enrolled to this study 
experienced dose-limiting toxicities at dose level 2; therefore, as specified in section 7.3.1.1 
above, the Phase II portion of this study will be initiated and patients enrolled to the Phase II 
portion will receive Abraxane 100 mg/m2 in combination with RAD001, 5 mg daily. 
 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
7.4 Dose Modifications or Escalations 
To address the safety concerns of these drugs being given in combination, a toxicity analysis 
will be performed after all of the first 6 patients complete the first cycle of therapy.  In the 
event that more than one patient experiences a ≥ Grade 3 non-hematologic toxicity (with the 
exception of alopecia, nausea or vomiting in the absence of aggressive anti-emetics), they 
will cease to receive further study drug. The subsequent dose cohort enrolled will be at a 
reduced intermediate dose.    
 
Chemotherapy dose adjustments are to be made according to the system showing the greatest 
degree of toxicity.  Toxicities/adverse events will be graded using the NCI Common 
Terminology Criteria for Adverse Events (CTCAE), Version 3. 
 
• All dose reductions will be permanent. 
• No more than 2 dose reductions are allowed. Patients requiring >2 dose 
reductions will be removed from the study. 
• If the starting dose is reduced to Dose Level –1 no further dose reductions will be 
made below Dose Level −2. 
• Unless specified in the following sections, adverse events that do not resolve to 
< Grade 1 within 4 weeks of maximum toxicity grade will require discontinuation 
of further treatment. 
• Starting dose (Dose Level 0) will be determined by the Phase I part of this study.  
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
 
Phase II - Modifications 
 
 
Dose Level 
 
Abraxane (mg/m2) 
 
RAD001 (mg) 
-2 
60   
5 daily 
-1 
80 
5 daily  
0 
100 
5 daily  
 
• All dose reductions will be permanent. 
• No more than 2 dose reductions are allowed. Patients requiring >2 dose 
reductions will be removed from the study. 
• Unless specified in the following sections, adverse events that do not resolve to 
< Grade 1 within 4 weeks of maximum toxicity grade will require discontinuation 
of further treatment. 
 
7.4.1 Hematologic Toxicity - Abraxane 
Abraxane dosing should not be administered at the start of each cycle until the absolute 
neutrophil count returns to ≥ 1.5 x 109 cells/L and the platelet count returns to >100 x 109 
cells/L.  For each subsequent dose of Abraxane within a cycle (Days 8 and 15), patients 
must have an ANC ≥ 1.0 x 109 cells/L and platelets > 75 x 109 cells/L.  If the ANC and 
platelets are not adequate for treatment on Day 8 and/or 15, the dose is to be omitted and 
the total cycle length remains 28 days.  A guideline for implementing dose reductions and 
growth factor treatment for hematologic toxicity is presented in Table 7.4.1.1. 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
 
7.4.1.1 Dose Reductions for Abraxane and Use of Growth Factors for Hematologic Toxicity 
Adverse Event 
Occurrence 
Action to be Taken 
ANC < 0.5 x 109 cells/L (nadir count) 
with neutropenic fever > 38°C 
OR 
Delay of next cycle due to persistent 
neutropenia (ANC < 1.5 x 109 cells/L) 
OR 
For patients on weekly treatment 
whose next treatment within the cycle 
(Day 8 or Day 15) is omitted due to 
persistent neutropenia (ANC < 1 x 109 
cells/L). 
OR 
Neutropenia < 0.5 x 109 cells/L for > 1 
week 
Any Occurrence 
At the first occurrence of a hematological 
toxicity (as outlined in the Adverse Event 
column), the same dose is maintained and G-
CSF is given as outlined in 7.4.1.2.  In the event 
that a hematological toxicity re-occurs in the 
face of G-CSF, dose reduction of Abraxane to 
the next lower level will be required for 
subsequent cycles once ANC is ≥ 1.5 x 109 
cells/L  (see Section 7.4).  
 
If G-CSF is given concurrently with weekly 
Abraxane, administration may begin the day 
after Abraxane is given and should stop at least 
48 hours prior to when Abraxane is given the 
following week.   
Thrombocytopenia Grade 3 or Grade 
4* 
1st Occurrence 
Dose reduction to next lower level 
Recurrence 
Dose reduction to next lower level 
*Refer to NCI CTCAE Version 3 for definition of Grade 3 and Grade 4 events. 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
 
7.4.1.2 G-CSF Administration 
For weekly study drug administration (Days 1, 8, 15) administer G-CSF 5 mcg/kg/day 
(rounded to the nearest vial size per Investigator/Institution’s standard of care) 24 hours 
after chemotherapy and hold 48 hours prior to the next dose s.c. on Days 2-5, 9-12, and 
16-19. 
 
For patients who are receiving RAD001 on a dose level lower than 5 mg daily, for 
example, every other day, the treating physician in consultation with the principal 
investigator may opt to omit G-CSF from the  regimen. 
 
7.4.2 Non-Hematologic Toxicity - Abraxane 
7.4.2.1 Hepatotoxicity 
Abraxane should not be administered at the beginning of a cycle if hepatic function 
parameters are out of the range that was established for entry into the study. 
 
Study drug should only be administered if hepatic function is within the parameters 
established in the eligibility criteria.  Hepatic toxicity from taxanes may occur but it is 
uncommon.  Therefore, hepatic dysfunction that occurs while the patient is on study 
should prompt an evaluation to determine the cause, including the possibility of 
progressive metastatic disease and hepatotoxicity from concurrent medications. 
 
7.4.2.2 Sensory Neuropathy 
Abraxane should be withheld in patients who experience ≥ Grade 2 sensory neuropathy.  
Treatment may be resumed at the next lower dose level in subsequent cycles after the 
sensory neuropathy improves to ≤ Grade 1. The time to resolution to Grade ≤ 1 should be 
the adverse event duration used for adverse event reporting.  In those patients who 
experience Grade 4 sensory neuropathy, study drug should be withheld, and treatment 
resumed at a reduced dose in subsequent cycles after the sensory neuropathy improves to 
≤ Grade 1.  Patients in whom neuropathy does not resolve to ≤ Grade 1 in 4 weeks should 
be removed from further treatment. 
 
7.4.2.3 Hypersensitivity Reactions 
Hypersensitivity reactions may occur with either study drug. In the event of Grade 1 or 
Grade 2 hypersensitivity reactions, temporary discontinuation of the study drug may be 
required.  In the event of any Grade 1 or 2 hypersensitivity reaction which does not abate 
with supportive measures or any ≥ Grade 3 hypersensitivity reactions, immediately 
discontinue the administration of study drug.   Patients who develop severe 
hypersensitivity reactions to Abraxane should not be re-challenged.  
 
 
 
 
 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
7.4.2.4 Other Toxicities 
If toxicities are ≤ Grade 2, manage symptomatically if possible, and retreat without dose 
reduction.  If toxicities are ≥ Grade 3, except for anemia, treatment should be withheld 
until resolution to ≤ Grade 1 or baseline if baseline was greater than Grade 1, then 
reinstituted, if medically appropriate, at the next lower dose level (see Table 7.4.1.1 
above). 
 
7.4.3 RAD001 Toxicity 
 
Table 7.4.3 – Criteria for Dose-Modification in Case of Suspected RAD001 Toxicity and 
Re-Initiation of RAD001 Treatment 
Toxicity 
Actions 
Non-hematological toxicity 
 
Grade 2 (except pneumonitis, refer to section 
7.4.3.5) 
If the toxicity is tolerable to the patient, 
maintain the same dose. If the toxicity is 
intolerable to patient, interrupt RAD001 until 
recovery to Grade ≤ 1. Then reintroduce 
RAD001 at same dose. 
If event returns to Grade 2, interrupt RAD001 
until recovery to Grade ≤ 1. Then reintroduce 
RAD001 at the lower dose level. 
Grade 3 
(except hyperlipidemia) 
Interrupt RAD001 until recovery to Grade ≤1. 
Then reintroduce RAD001 at the lower dose 
level. For pneumonitis consider the use of a 
short course of corticosteroids. 
Grade 3 hyperlipidemia (hypercholesterolemia 
and/or hypertriglyceridemia) 
Should be managed using standard medical 
therapies. 
Grade 4 
Discontinue RAD001. 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
 
Hematological toxicity 
 
Grade 2 Thrombocytopenia (platelets < 75, 
≥ 50x109/L)  
Interrupt RAD001 until recovery to Grade ≤ 1 
(>75 x109 cells/L). Then reintroduce RAD001 at 
initial dose. 
If thrombocytopenia again returns to Grade 2, 
interrupt RAD001 until recovery to Grade ≤ 1. 
Then reintroduce RAD001 at the lower dose 
level.  
Grade 3 Thrombocytopenia (platelets < 50, ≥ 25 x109/L)  
Interrupt RAD001 until recovery to Grade ≤ 1 
(platelets ≥ 75 x109 cells/L). Then resume 
RAD001 at one dose level lower. If Grade 3 
thrombocytopenia recurs, discontinue RAD001. 
Grade 4 Thrombocytopenia (platelets < 25 
x109/L) 
Discontinue RAD001. 
Grade 3 Neutropenia (neutrophils (<1, ≥0.5 
x109/L) 
Interrupt RAD001 until recovery to Grade ≤1 
(neutrophils ≥ 1.5 x 109 cells/L). Then resume 
RAD001 at the initial dose. If ANC again returns 
to Grade 3, hold RAD001 until the ANC ≥ 1.5 x 
109/L.  Then resume RAD001 dosing at the lower 
dose level.  Discontinue patient from study 
therapy for a third episode of Grade 3 
neutropenia. 
Grade 4 Neutropenia (neutrophils (< 0.5 x109/L) 
Interrupt RAD001 until recovery to Grade ≤ 1 
(neutrophils ≥ 1.5 x 109 cells/L). Then resume 
RAD001 at the lower dose level. If Grade 3 or 
Grade 4 neutropenia occurs despite this dose 
reduction, discontinue RAD001. 
Grade 3 febrile neutropenia (not life-threatening) 
Interrupt RAD001 until resolution of fever and 
neutropenia to Grade ≤ 1. Hold further RAD001 
until the ANC ≥ 1.5 x 109 cells/L and fever has 
resolved. Then resume RAD001 at the lower 
dose level. If febrile neutropenia recurs, 
discontinue RAD001. 
 
Grade 4 febrile neutropenia (life-threatening) 
Discontinue RAD001. 
Any hematological or non-hematological toxicity 
requiring interruption for ≥ 4 weeks 
Discontinue RAD001 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
 
7.4.3.1 Known Undesirable Side Effects of RAD001 
Adverse events most frequently observed with RAD001 are rash, stomatitis/oral 
mucositis, fatigue, headache, anorexia, nausea, vomiting, diarrhea, ocular toxicity and 
infections. Non-infectious pneumonitis has also been observed. Overall, the most 
frequently observed laboratory abnormalities include neutropenia, thrombocytopenia, 
hypercholesterolemia, and/or hypertriglyceridemia. The majority of these AEs have been 
of mild to moderate severity (Grade 1-2). 
 
7.4.3.2 Monitoring of RAD001 Suspected Toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse 
event or abnormal laboratory value suspected to be related to RAD001 must be followed 
at least weekly until the adverse event or abnormal laboratory resolves or returns to 
Grade 1. If a patient requires a dose delay > 28 days from the intended day of the next 
scheduled dose, then the patient must be discontinued from the study. 
 
7.4.3.3 Management of Stomatitis/Oral Mucositis/Mouth Ulcers 
Stomatitis/oral mucositis/mouth ulcers due to RAD001 should be treated using local 
supportive care. Please note that investigators in earlier trials have described the oral 
toxicities associated with RAD001 as mouth ulcers, rather than mucositis or stomatitis. If 
your examination reveals mouth ulcers rather than a more general inflammation of the 
mouth, please classify the adverse event as such. Please follow the paradigm below for 
treatment of stomatitis/oral mucositis/mouth ulcers: 
 
• For mild toxicity (Grade 1), use conservative measures such as non-alcoholic 
mouth wash or salt water (0.9%) mouthwash several times a day until resolution. 
• For more severe toxicity (Grade 2 in which case patients have pain but are able to 
maintain adequate oral alimentation, or Grade 3 in which case patients cannot 
maintain adequate oral alimentation), the suggested treatments are topical 
analgesic mouth treatments (i.e., local anesthetics such as, benzocaine, butyl 
aminobenzoate, tetracaine hydrochloride, menthol, or phenol) with or without 
topical corticosteroids, such as triamcinolone oral paste 0.1% (Kenalog in 
Orabase®). 
• Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers. It is preferable to avoid these agents. 
• Antifungal agents must be avoided unless a fungal infection is diagnosed. In 
particular, systemic imidazole antifungal agents (ketoconazole, fluconazole, 
itraconazole, etc.) should be avoided in all patients due to their strong inhibition 
of RAD001 metabolism, therefore leading to higher RAD001 exposures. 
Therefore, topical antifungal agents are preferred if an infection is diagnosed. 
Similarly, antiviral agents such as acyclovir should be avoided unless a viral 
infection is diagnosed. 
 
 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
7.4.3.4 Management of Hyperlipidemia and Hyperglycemia 
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary 
habits. Blood tests to monitor hyperlipidemia must be taken in the fasting state. Grade 2 
or higher hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) or Grade 2 or higher 
hypertriglyceridemia (>2.5 x upper normal limit) should be treated with a statin or 
appropriate lipid-lowering medication, in addition to diet. Patients should be monitored 
clinically and through serum biochemistry for the development of rhabdomyolysis and 
other adverse events as required in the product label/data sheets for HMG-CoA reductase 
inhibitors. 
 
Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated 
with an increased risk of a rare but serious skeletal muscle toxicity manifested by 
rhabdomyolysis, markedly elevated creatine kinase (CPK) levels and myoglobinuria, 
acute renal failure and sometimes death. The risk versus benefit of using this therapy 
should be determined for individual patients based on their risk of cardiovascular 
complications of hyperlipidemia. 
 
Grade 3 hyperglycemia has been observed in patients receiving RAD001 therapy. In 
many cases the affected patients had an abnormal fasting glucose at baseline. Based on 
this finding, it is recommended that optimal glucose control is achieved before starting a 
patient on RAD001. Study patients should have their glucose levels monitored during 
RAD001 therapy. 
 
7.4.3.5 Management of Non-infectious Pneumonitis 
Both asymptomatic radiological changes (Grade 1) and symptomatic non-infectious 
pneumonitis (Grade 2 = not interfering with activities of daily living or Grade 3 = 
interfering with activities of daily living and oxygen indicated) have been noted in 
patients receiving RAD001 therapy. Non-infectious pneumonitis has been associated with 
RAD001 and other mTOR inhibitors [34]. In order to monitor for asymptomatic 
(Grade 1) non-infectious pneumonitis, a chest X-ray or CT scan is required in addition to 
the by-monthly CT or MRI tumor examinations. Additional chest X-rays or CT scans 
may be performed, when clinically necessary. If non-infectious pneumonitis develops, a 
consultation with a pulmonologist should be considered. If the patient develops Grade 3 
pneumonitis, treatment with RAD001 should be interrupted and the patient should be 
treated as medically indicated (short course corticosteroids, oxygen, etc). Management of 
non-infectious pneumonitis suspected to be associated with RAD001 and dose 
modifications instructions are provided in Tables 7.4.3 and 7.4.3.5 
 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
 
Table 7.4.3.5 Management of Non-infectious Pneumonitis 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of 
Pneumonitis  
RAD001 Dose Adjustment 
Grade 1 
CT scans with lung windows 
and required pulmonary 
function testing includes: 
spirometry, DLCO, and 
room air O2 saturation at 
rest. Repeat a chest x-ray/CT 
scan every 2 Cycles until 
return to baseline. 
No specific 
therapy is 
required 
Administer 100% of RAD001 
dose. 
Grade 2 
CT scan with lung windows 
and pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 
saturation at rest. Repeat 
each subsequent Cycle until 
return to baseline. Consider 
a bronchoscopy  
Symptomatic 
only. Prescribe 
corticosteroids 
if cough is 
troublesome. 
Reduce RAD001 dose until 
recovery to ≤Grade 1. RAD001 
may also be interrupted if 
symptoms are troublesome. 
Patients will be withdrawn from 
the study if they fail to recover to 
≤ Grade 1 within 3 weeks. 
Grade 3 
CT scan with lung windows 
and pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 
saturation at rest. Repeat 
each subsequent Cycle until 
return to baseline. 
Bronchoscopy is 
recommended. 
Prescribe 
corticosteroids 
if infective 
origin is ruled 
out. Taper as 
medically 
indicated. 
Hold treatment until recovery to 
≤ Grade 1. May restart protocol 
treatment within 3 weeks at a 
reduced dose (by one level) if 
evidence of clinical benefit. 
Patients will be withdrawn from 
the study if they fail to recover to 
≤ Grade 1 within 3 weeks. 
Grade 4 
CT scan with lung windows 
and required pulmonary 
function testing includes: 
spirometry, DLCO, and 
room air O2 saturation at 
rest. Repeat each subsequent 
Cycle until return to 
baseline. Bronchoscopy is 
recommended. 
Prescribe 
corticosteroids 
if infective 
origin is ruled 
out. Taper as 
medically 
indicated. 
Discontinue treatment. 
 
All interruptions or changes to study drug administration must be recorded. 
 
 
 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
It will be documented whether or not each patient completed the clinical study. If for any patient 
either study treatment or observations were discontinued the reason will be recorded. Reasons 
that a patient may discontinue participation in a clinical study are considered to constitute one of 
the following: 
1. adverse event(s) 
2. abnormal laboratory value(s) 
3. abnormal test procedure result(s) 
4. disease progression 
5. protocol violation 
6. subject withdrew consent 
7. lost to follow-up 
8. administrative problems 
9. death 
 
7.5 Concomitant Medications 
Patients must be instructed not to take any additional medications (including over-the-counter 
products) during the study without prior consultation with the investigator. All medications taken 
within 30 days of screening should be recorded. If concomitant therapy must be added or 
changed, the reason and name of the drug/therapy should be recorded. 
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
patient are allowed, including drugs given prophylactically (e.g. antiemetics +/- steroids), with 
the following exceptions: 
• no other investigational therapy should be given to patients 
• no chronic treatment with systemic steroids or another immunosuppressive agent 
• no anticancer agents other than the study medications administered as part of this study 
protocol should be given to patients. If such agents are required for a patient then the 
patient must first be withdrawn from the study. 
• No live vaccines should be administered to patient due to immunosuppressant potential of 
RAD001. 
• Concurrent treatment with bisphosphonates is allowed.  All concomitant treatments, 
including blood and blood products, must be reported on the case report form. 
• For patients with radiographic evidence of bone destruction, intravenous pamidronate 90 
mg delivered over 2 hours or zoledronic acid 4 mg over 15 minutes every 3 to 4 weeks is 
recommended according to the ASCO guidelines on the use of bisphosphonates in 
women with breast cancer (35). 
• leukocyte growth factors (e.g. G-CSF and GM-CSF) are not to be administered 
prophylactically but may be prescribed by the investigator for severe neutropenia if this is 
thought to be appropriate.  
• drugs or substances known to be inhibitors or inducers of the isoenzyme CYP3A should 
be avoided in association with RAD001 as these can alter metabolism. Strong inhibitors 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
or inducers of the isoenzyme CYP3A should not be administered as systemic therapy (see 
Appendix B). 
• Lipid-lowering drugs may be given in case of hyperlipidemia, a known side-effect of 
RAD001. Treatment should be for ≥ Grade 1 hypercholesterolemia with or without 
hypertriglyceridemia in addition to, and ideally after failure of, dietary advice to patients. 
HMG-CoA reductase inhibitors (e.g. atorvastatin, pravastatin, fluvastatin) are the 
preferred therapy. Patients should be monitored clinically and through serum 
biochemistry for the development of rhabdomyolysis and other adverse events. 
• Prolonged systemic corticosteroid treatment, except for topical applications (e.g. rash), 
inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-
articular) should not be given. A short duration (< 2 weeks) of systemic corticosteroids is 
allowed (e.g. chronic obstructive pulmonary disease). 
The investigator should instruct the patient to notify the study staff about any new medications 
he/she takes after the start of the study drug. All medications (other than study drug/s) and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient starts treatment with study drug/s must be recorded.  
 
7.6 Supportive Care Guidelines 
Supportive care, including but not limited to anti-emetic medications, may be administered at 
the discretion of the Investigator.  Erythropoietin may be administered at the discretion of the 
Investigator, consistent with Institutional guidelines. G-CSF should be administered 
according to the guidelines in this protocol. 
 
Symptomatic anemia should be treated with appropriate red blood cell support and 
transfusion is recommended if the hemoglobin falls below 8 g/dl.  Alternately recombinant 
erythropoietin may be used if desired by the patient’s physician. 
 
Thrombocytopenia should be treated conservatively.  In the absence of bleeding or a planned 
invasive procedure, platelet transfusions should only be given for a platelet count below 10 x 
109 cells/L.  If invasive procedures are planned or the patient develops bleeding, platelet 
transfusions should be administered in accordance with the Institution’s standard of practice, 
usually maintaining a platelet count greater than 50 x 109 cells/L. 
 
Nutritional assessment and psychological support: Refractory neoplasms are commonly 
complicated by malnutrition.  Patients with weight loss or evidence of wasting syndrome 
should have a nutritional consult.  Patients who are having emotional difficulties dealing with 
their treatment, and disease, or those patient’s who request assistance, will be referred to a 
Social Worker for evaluation and support. 
 
 
 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
7.7 Adherence/Compliance 
Patient compliance in daily self-administration of the oral tablets will be assessed at each 
clinic visit.  They will be given a medication diary and instructed to fill out how many tablets 
were taken each day and the time of day the drug was taken.  At the end of each cycle of 
treatment, the actual amount of unused drug will be compared to the anticipated amount of 
unused drug and the patient’s medication diary. 
 
8. Toxicity Monitoring and Adverse Event Reporting 
All patients who receive one dose of protocol therapy will be evaluable for assessment of 
toxicity.  Prior to each cycle the treating physician or their designee will fully assess the 
patient’s condition with respect to possible treatment related toxicities.  All adverse events, 
whether observed by the physician or reported by the patient, occurring during the active 
portion of therapy, or up to 30 days after the last dose of treatment will be graded by a 
numerical score according to the NCI’s Common Terminology Criteria for Adverse Events 
(CTCAE), Version 3.0 (http://ctep.cancer.gov/reporting/ctc.html) and recorded in the 
patient’s medical record. Toxicities (including laboratory abnormalities) will be reported as 
outlined in the data capture plan.  
 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
will be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
The Investigator will follow all patients who experienced an adverse event until there is a 
return to the patient’s baseline condition or until a clinically satisfactory resolution is 
achieved. 
 
8.1 Adverse Event Reporting Requirements  
An adverse experience is defined as any unintended or abnormal clinical observation that is 
not of benefit to the patient.  Either the condition was not present prior to exposure to the 
study therapy, or it has worsened in intensity or frequency following exposure to the study 
therapy.   
 
All “unexpected” (see Section 8.4) and/or “serious” (See Section 8.2) adverse events 
occurring during the active portion of therapy, or up to 30 days after the last dose of 
treatment, will be reported to the OHRS at (732) 235-7577. Events will be promptly reported, 
in writing, to the local IRB in accordance with IRB policy.  If a death occurs the IRB will be 
notified within 24-hours of initial receipt of information.  All other SAEs must be reported to 
the IRB within three to ten days of initial receipt of information. Written follow-up reports 
are required when additional information is needed to fully characterize the event. Copies of 
each report sent to the IRB will be kept in the study regulatory file. 
 
In addition to reporting to the local IRB, the Novartis Clinical Safety and Epidemiology 
Department must also be notified.   
 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
CINJOG affiliates will report all SAEs to the OHRS who will be responsible for forwarding 
SAE reports to the IRB, FDA and Novartis Pharmaceuticals.  
 
Reporting SAEs using commercially available drugs: 
In addition, any unexpected (not listed in the package insert) serious adverse events that are 
associated (definitely, probably or possibly related) with the use of Abraxane, must be 
reported to the FDA within 7 working days using a FDA Form MedWatch 3500 form 
http://www.fda.gov/medwatch/safety/3500.pdf (fax # 1-800-FDA-0178).  CINJOG affiliates 
will report all unexpected, related SAEs to the OHRS who will be responsible for submitting 
the MedWatch forms to the FDA. 
 
Expedited reporting requirement for adverse events experienced by patients with commercial 
agents only 
Attribution 
Grade 4 
Grade 5a 
 
Protocol Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated or 
Unlikely 
 
 
 
 
See footnote (b) for 
special 
requirements. 
 
Possible, 
Probable, 
Definite 
 
REPORT 
 
 
REPORT 
 
FDA MedWatch form 3500:  Indicates that an expedited report is to be submitted to the FDA 
within 7 working days 
a:  This includes all deaths within 30 days of the last dose of treatment with a commercial 
agent(s), regardless of attribution.  Any death that occurs more than 30 days after the last dose of 
treatment with a commercial agent(s) and is attributed (possibly, probably, definitely) to the 
agent(s) and is not due to cancer recurrence must be reported according to the instructions above. 
b Protocol-specific expedited reporting requirements: All SAEs must be reported to Novartis 
as outlined below. 
 
All CINJOG affiliates continue to report all SAEs to the OHRS.  
 
Reporting SAEs to Novartis: 
Each serious adverse event (but not pregnancies) must be reported by the Investigator to 
Novartis within 24 hours of learning of its occurrence, even if it is not felt to be treatment-
related. Follow-up information about a previously reported serious adverse event must also 
be reported to Novartis within 24 hours of receiving it. If the serious adverse event has not 
been previously documented (new occurrence) and it is thought to be related to study drug (or 
therapy), the Medical Safety Expert of the Clinical Safety & Epidemiology (CS&E) 
Department may contact the Investigator to obtain further information. If warranted, an 
Investigator alert may be issued, to inform all Investigators involved in any study with the 
same drug (or therapy) that this serious adverse event has been reported. 
The Investigator must complete the FDA MedWatch 3500a form and Novartis SAE 
coversheet, assess the relationship to study treatment and send the initial completed 
MedWatch form and Novartis SAE coversheet by fax to: 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
 
• 1.888.299.4565 within 24 hours to the local Novartis Clinical Safety & Epidemiology 
(CS&E) Department.   
 
The Investigator must then ensure that the form and coversheet are accurately and fully 
completed with follow-up information and fax those to Novartis CS&E Department within 2 
to 3 calendar days for deaths or life-threatening events and 5 calendar days for other serious 
adverse events. The original and the duplicate copies of the FDA MedWatch form and 
Novartis SAE coversheet must be kept with the case report forms at the study site. 
 
Novartis CS&E department a must be copied on any study related safety information sent to 
the IRB.   
 
Pregnancy, although not itself a serious adverse event, should also be reported on a serious 
adverse event form or pregnancy form and be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any 
birth defects or congenital abnormalities. 
 
Follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, and whether the patient continued or discontinued study participation. The 
MedWatch form and Novartis SAE coversheet must be retained. Pregnancy follow-up should 
describe the outcome of the pregnancy, including any voluntary or spontaneous termination, 
details of the birth, and the presence or absence of any congenital abnormalities or birth 
defects. 
 
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be approved by Novartis and the IRB of each participating institution 
before implementation.  A copy of the written approval of the IRB must be sent to Novartis.  
These requirements for approval should in no way prevent any immediate action from being 
taken by the Investigator in the interests of preserving the safety of all patients included in the 
trial.  If an immediate change to the protocol is felt to be necessary by the Investigator and is 
implemented for safety reasons, Novartis must be notified and the IRB at the center must be 
informed immediately. 
 
8.2 Definition of Serious Adverse Events (SAEs) 
A serious adverse event (experience) is one occurring at any dose level that results in any of 
the following outcomes:   
 Death 
 Life-threatening- immediate risk of death from the reaction. 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant disability/incapacity. 
 Results in a congenital anomaly/birth defect. 
 Requires intervention to prevent one of the outcomes listed in this definition. 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
 
The definition of serious adverse event (experience) also includes important medical events.  
Medical and scientific judgment will be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in the definition above.  
These events will usually be considered serious.  Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization. 
 
8.3 Definition of Related 
There is a reasonable possibility that the drug caused the adverse experience.  That is, the 
event is judged by the investigator to be possibly, probably or definitely related to the 
treatment.   
 
8.4 Definition of Unexpected 
Any adverse drug experience and/or specificity, that is not included in the current 
investigator’s brochure and/or package insert. 
 
8.5 Death 
Any death while a patient is receiving treatment on this study or up to 30 days after the last 
protocol treatment, or any death which occurs more than 30 days after protocol treatment has 
ended, but which is felt to be treatment related must be reported within 24 hours (i.e., one 
working day from the date of discovery) to the OHRS. 
 
9. Treatment Evaluation/Criteria for Response 
For the purposes of this study, patients should be reevaluated for response following every 
second cycle of therapy. In addition to baseline scan(s), confirmatory scans should also be 
obtained not less than 4 weeks following initial documentation of objective response. To be 
assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response are 
first met.  In the case of SD, follow-up measurements must have met the SD criteria at least 
once after study entry at a minimum interval, not less than 6 weeks. 
 
The main goal of confirmation of objective response is to avoid overestimating responses.  
In cases where confirmation of response is not feasible, it should be made clear when 
reporting the outcome that the response(s) is/are not confirmed. 
 
Response and progression will be evaluated in this study using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (36).  
Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are 
used in the RECIST criteria. Note:  Lesions are either measurable or non-measurable using 
the criteria provided below. The term “evaluable” in reference to measurability will not be 
used because it does not provide additional meaning or accuracy. 
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Deborah L. Toppmeyer, M.D. 
 
 
9.1 Measurable Disease  
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm with conventional techniques (CT, 
MRI, x-ray) or as >10 mm with spiral CT scan.  All tumor measurements must be recorded 
in millimeters (or decimal fractions of centimeters). 
 
9.2 Non-Measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm 
with conventional techniques or <10 mm using spiral CT scan), are considered non-
measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not 
followed by CT or MRI), and cystic lesions are all non-measurable. 
 
9.3 Target Lesions 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs, will be identified as target lesions and recorded and 
measured at baseline.  Target lesions will be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically).  A sum of the longest diameter (LD) for all target lesions 
will be calculated and reported as the baseline sum LD.  The baseline sum LD will be used 
as reference by which to characterize the objective tumor response.  There may be occasions 
when progressive disease is suspected but cannot be fully characterized. In these cases, the 
treating physician may decide to continue treatment for one or two cycles before 
reassessment, if he/she feels it is in the patients’ best interest and the patient agrees to 
continue treatment. 
 
9.4 Non-Target Lesions 
All other lesions (or sites of disease) will be identified as non-target lesions and will be 
recorded at baseline.  Non-target lesions include measurable lesions that exceed the 
maximum numbers per organ or total of all involved organs as well as non-measurable 
lesions.  Measurements of these lesions are not required, but the presence or absence of each 
will be noted throughout follow-up.  
9.5 Guidelines for Evaluation of Measurable Disease 
All measurements will be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations will be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique will be used whenever possible to 
characterize each identified and reported lesion at baseline and during follow-up. Imaging-
based evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the antitumor effect of a treatment. 
 
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Deborah L. Toppmeyer, M.D. 
 
9.5.1 Clinical lesions- Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion.  
 
9.5.2 Chest x-ray- Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
9.5.3 Conventional CT and MRI- These techniques will be performed with cuts of 10 
mm or less in slice thickness contiguously.  Spiral CT will be performed using a 5 mm 
contiguous reconstruction algorithm.  This applies to tumors of the chest, abdomen, and 
pelvis.   
 
9.5.4 Ultrasound (US)- Because one of the endpoints of the study is objective response 
evaluation, US will not be used to measure tumor lesions.  US might be used, at the 
discretion of the investigator, to confirm the complete disappearance of superficial lesions 
assessed by clinical examination. 
 
9.5.6 Tumor markers- Tumor markers alone will not be used to assess response.  If 
markers are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response.   
 
9.5.7 Cytology, histology- These techniques may be used to differentiate between partial 
responses (PR) and complete responses (CR) if necessary and determined by the 
investigator. Cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or stable disease 
(an effusion may be a side effect of the treatment) and progressive disease. 
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Deborah L. Toppmeyer, M.D. 
 
 
9.6 Response Criteria 
 
 
   9.6.1 Evaluation of Target Lesions 
Complete Response (CR): 
Disappearance of all target lesions 
Partial Response (PR): 
At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions, taking as reference the 
baseline sum LD. 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD 
recorded since the treatment started or the appearance of 
one or more new lesions. 
Stable Disease (SD):  
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference 
the smallest sum LD since the treatment started. 
 
 
   9.6.2 Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and 
*normalization of tumor marker level. 
Incomplete Response/ 
Stable Disease (SD):  
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
Although a clear progression of “non-target” lesions only is exceptional, in such 
circumstances the opinion of the investigator will prevail. 
*Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
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Deborah L. Toppmeyer, M.D. 
 
 
 
   9.6.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
 
Target Lesions 
 
Non-Target Lesions 
 
New Lesions 
 
Overall Response 
 
CR 
 
CR 
 
No 
 
CR 
 
CR 
 
Incomplete 
response/SD 
 
No 
 
PR 
 
PR 
 
Non-PD 
 
No 
 
PR 
 
SD 
 
Non-PD 
 
No 
 
SD 
 
PD 
 
Any 
 
Yes or No 
 
PD 
 
Any 
 
PD 
 
Yes or No 
 
PD 
 
Any 
 
Any 
 
Yes 
 
PD 
 
Notes: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration.”  Every effort will be made to 
document the objective progression. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of complete response depends on this determination. The 
residual lesion will be investigated (fine needle aspirate/biopsy if possible) before 
confirming the complete response status. 
 
9.7 Confirmatory Measurement/Duration of Response 
 
9.7.1 Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that will be performed no less than 4 weeks after the 
criteria for response are first met.  In the case of SD, follow-up measurements must 
have met the SD criteria at least once after study entry at a minimum interval of not 
less than 6 weeks. 
 
9.7.2 
Duration of Overall Response 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
The duration of overall response is measured from the time measurement criteria are 
met for CR or PR (whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
9.7.3 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the 
treatment started.  
 
9.8 Reporting of Results 
All patients initially considered evaluable will be assessed for response to treatment, even 
if there are major protocol treatment deviations or if they are ineligible.  Each patient will 
be assigned one of the following categories: 1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 8) unknown (not assessable, 
insufficient data). 
 
All of the patients who met the eligibility criteria and are evaluable, will be included in 
the main analysis of responses.  Patients in response categories 4-8 will be considered as 
failing to respond to treatment (disease progression).  Thus, an incorrect treatment 
schedule or drug administration will not result in exclusion from the analysis of a 
response.  All conclusions will be based on all eligible patients. 
 
10. Removal of Patients from Study/Off Study Criteria 
In the absence of treatment delays due to adverse events, treatment may continue until one of 
the following criteria applies: 
a) Disease progression/relapse during active treatment, 
b) Intercurrent illness that prevents further administration of treatment, 
c) Unacceptable adverse event(s).   
d) In the event of any drug-related life-threatening toxicity or laboratory abnormality the 
patient will be withdrawn from further treatment, 
e) Patient decides to withdraw from the study, 
f) 
Noncompliance with treatment plan, 
g) General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator, or 
h) Protocol violation - any patient found to have entered this study in violation of the 
protocol might be discontinued from the study at the discretion of the Principal 
Investigator. 
i) 
In the event of any drug-related life-threatening toxicity or laboratory abnormality the 
patient will be withdrawn from further treatment.  When a patient is taken off study, this 
information should be communicated to the OHRS.   
 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
11. Laboratory Evaluations and Procedures/Correlative and Pharmacokinetic Studies 
11.1 Immunohistochemistry analysis 
Our Tissue Analytical Service will perform immunohistochemical staining on formalin-fixed 
and paraffin-embedded tissues. If substantial normal tissue is felt to be present within the 
biopsied tissue and quantification is attempted, a board-certified pathologist, Dr. Nicola 
Barnard or qualified designee, will assist in identifying malignant and non-malignant tissue.   
 
11.2 Shipping Instructions for Archival Tumor Tissue 
All samples are to be identified with the patient’s assigned registration number and shipped 
with reference to Breast study CINJ # 040803.  Slides and Tissue blocks are to be sent by 
overnight express to the Cancer Institute of New Jersey Tissue Analytical Service (TAS). 
 
Paraffin Blocks 
Please wrap paraffin blocks in bubble wrap or some material that will cushion them. During 
spring and summer months, paraffin blocks must be shipped with a cooler pack inside the 
shipping container or the wax will melt and the specimen will be compromised. 
 
Glass Slides 
Glass slides must be mailed/shipped in appropriate protective slide containers. These can be 
made of cardboard (flat slide holder) or plastic (slide box or slide shipper).  
 
Documentation 
Please have the name, address and the appropriate laboratory or office phone number of the 
institution that the patient specimens were shipped from.  For any questions relating to 
shipment of samples please call (732) 235-8065. 
 
Cancer Institute of New Jersey mailing address:  
Rutgers Cancer Institute of New Jersey 
Attention: Dr. Deborah L. Toppmeyer c/o Julie Friedman RM 2034 
Protocol: Breast Study CINJ# 040803 
195 Little Albany Street 
New Brunswick, N.J. 08903 
 
12. Pharmaceutical Information 
 
12.1 Abraxane 
Source: Abraxane is commercially available by the pharmaceutical company, Abraxis 
Oncology. 
 
How Supplied: Abraxane is available, in single-use vials.  Each single-use 50 mL vial will 
contain paclitaxel (100 mg) and approximately 900 mg human albumin (HA) as a stabilizer. 
Each vial will be labeled according to country-specific regulatory requirements for labeling of 
investigational products.  
 
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Phase I/II Study of Weekly Abraxane and RAD001 in Women with Locally Advanced or Metastatic Breast Cancer 
Deborah L. Toppmeyer, M.D. 
 
Storage and Stability:  Unreconstituted Abraxane should be stored at controlled room 
temperature (20° to 25°C or 68° to 77°F) in its carton.  Reconstituted Abraxane should be 
used immediately.  If not used immediately, the vial of reconstituted ABRAXANE must be 
placed in its carton and be placed in a refrigerator at 2° to 8°C (36° to 46°F) for a maximum 
of 8 hours.  Both forms should be stored in an area free of environmental extremes and must 
be accessible only to study personnel. 
Study Medication Administration 
 
NOTE: It is not a requirement to use filter needles in the preparation of, or in-line 
filters during the administration of Abraxane. In any event, filters of pore-size less than 
15 micrometers must not be used. 
 
Abraxane will be reconstituted by appropriate study personnel and administered to the 
patient in the study site.  The investigator will calculate the body surface area (BSA) of the 
patient in order to determine the total amount of Abraxane to be administered. 
 
Reconstitution and use of Abraxane: 
1. Calculate the patient’s body surface area at the beginning of the study. A variance of 5% 
of the calculated dose will be allowed. 
2. Calculate the total dose (in mg) to be administered by:  
 
Total Dose (mg) = BSA x (study dose mg/m2) 
3. Calculate the total number of vials required by: 
 
Total Number of Vials = Total Dose (mg) 
                             
100 (mg/vial) 
Round up the number of vials to be reconstituted to the next higher whole number when a 
fractional number of vials is obtained by the above formula (eg, if the total number of 
vials = 4.05 or 4.5, then 5 vials would be reconstituted).  
4. Using sterile technique, prepare the vials for reconstitution. 
5. Swab the rubber stoppers with alcohol. 
6. Reconstitute each Abraxane vial by injecting 20 mL of 0.9% Sodium Chloride Injection, 
USP or equivalent into each vial over a period of not less than 1 minute.  
• Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum 
of 1 minute, using the sterile syringe directing the solution flow onto the inside wall 
of the vial. 
• DO NOT INJECT the 0.9% Sodium Chloride Injection, USP solution directly onto 
the lyophilized cake as this will result in foaming. 
• Once the injection is complete, allow the vial to sit for a minimum of 5 (five) 
minutes to ensure proper wetting of the lyophilized cake/powder.   
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Deborah L. Toppmeyer, M.D. 
 
• Gently swirl and/or invert the vial slowly for at least 2 minutes until complete 
dissolution of any cake/powder occurs.  Rapid agitation or shaking will result in 
foaming. 
• If foaming or clumping occurs, stand solution for at least 15 minutes until foam 
subsides. 
• Each ml of reconstituted product will contain 5 mg of paclitaxel. 
7. Calculate the exact total dosing volume of 5 mg/ml suspension required for the patient: 
Dosing volume (ml) = Total dose (mg) / 5 (mg/ml) 
8. The reconstituted sample should be milky and homogeneous without visible particulates.  
If unsuspended powder is visible, the vial should be gently inverted again to ensure 
complete resuspension, prior to use. 
9. Once the exact volume of reconstituted Abraxane has been withdrawn from the vials, 
discard any excess solution left over in accordance with standard operating procedures. 
10. Further dilution is not necessary. Abraxane suspension will be drawn into a syringe and 
placed on a syringe pump for administration.   
11. Administer the calculated dosing volume of reconstituted Abraxane suspension by IV 
infusion over 30 minutes.  The use of in-line filters is not necessary.  If used, in-line 
filters with pore sizes of < 15µ should not be used. 
12. Use within 8 hours of reconstitution.  If not used immediately, store reconstituted 
Abraxane in a refrigerator for no longer than 8 hours. 
 
Toxicities 
Most Frequent: Alopecia, Anemia, Arthralgia, Cough, Diarrhea, Dysgeusia, Dyspnea, 
Edema, General Weakness, Infection, Myalgia, Nausea, Neutropenic Disorder, Optic 
Neuropathy, Oral Candidiasis, Pneumonia, Stomatitis, Upper Respiratory Infection, Vomiting 
 
Less Frequent: Bradycardia, Cardiac Arrest, Chest Pain, Hemorrhage, Hypersensitivity Drug 
Reactions, Hypertension, Hypotension, Injection Site Sequelae, Nail Disorders, Neuropathy, 
Neutropenia from Cancer Chemotherapy, Paroxysmal Supraventricular Tachycardia, 
Pulmonary Thromboembolism, Thrombocytopenic Disorder, Thrombotic Disorder, Visual 
Changes 
 
Rare: Cerebrovascular Accident, Interstitial Pneumonitis, Pneumothorax, Pulmonary 
Fibrosis, Transient Cerebral Ischemia 
 
Drug interactions: Based on two pharmacokinetic drug interaction studies (warfarin, 
cimetidine), review of data from large Phase III trials, and the in vitro results on cytochrome 
P450 enzymes, the potential of Abraxane to interact with other drugs is low.  No dose 
adjustments are recommended nor required for patients with renal or liver impairment. 
 
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12.2 RAD001 
Source: RAD001 will be supplied to patients by Novartis.   
 
How supplied: Formulated as tables for oral administration of 5 mg and 10 mg strength, 
blister-packed under aluminum foil in units of 10 tablets. Blister packs should be opened only 
at the time of administration as drug is both hygroscopic and light-sensitive. 
 
Storage and stability: The commercial product bears an expiration date.  Store below 30oC 
an in the original blister packs.  Shelf-life will be described on the investigational medication 
label. 
 
Route of administration: Oral. RAD001 may be taken with or without food. Patients will be 
advised to take their tablets at the same time of the day and at the same time in relation to 
meals. Tablets must be swallowed whole with a glass of water. 
 
Toxicities 
Most frequent:  fatigue, mouth sores, nausea, vomiting, headache, rash and diarrhea. 
 
Less 
Frequent: 
hypercholesterolemia 
(increased 
cholesterol 
blood 
levels), 
hypertriglyceridemia (increased triglyceride blood level), increased liver function blood 
levels, neutropenia and thrombocytopenia. 
 
Rare:  hemorrhagic gastritis and epistaxis.  Lenticular alteration ocular disorders have been 
observed in rats in preclinical toxiclogy studies and have not been reported in human 
subjects.  However, patients treated with RAD001 who complain of a sudden reduction in 
visual acuity should have an ophthalmic exam to rule out lenticular alteration.  
 
The Investigator Drug Brochure for RAD001 should be referenced for any additional information 
regarding RAD001. 
 
13. Data Collection and Records to be Kept  
 
 
13.1 Case Report Forms 
The Principal Investigator (PI) at each institution will be responsible for assuring that all 
data specified in the study-specific data capture plan is collected and entered onto the 
electronic case report forms (eCRFs).  In accordance with FDA instructions any abnormal 
test results including laboratory tests, radiologic examinations, and findings on physical 
examinations will be collected, graded and causality assigned and resolution reported. 
 
Data submission guidelines are in concordance with those expected by the National 
Cancer Institute, i.e.: Baseline data is to be entered onto eCRFs within 2 weeks of 
initiation of treatment.  Subsequent eCRFs are to be completed within 2 weeks of the date 
in which the previous cycle was completed.  All e-CRFs will be submitted to the OHRS 
at the Cancer Institute of New Jersey via its secure web-based data management system.  
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The e-CRFs are found in the study specific calendar that has been created in the data 
management system.  The system will prompt the user to the forms that are required 
based upon the patient’s enrollment and treatment dates. 
 
Periodically, monitoring and /or auditing visits will be conducted by staff from the Cancer 
Institute of New Jersey monitoring/auditing staff for the purpose of verifying data entered 
onto eCRFs with source documentation. The participating institution will provide access 
to his/her original records to permit verification data entry.  
 
13.2 Research Charts 
A research chart (i.e., shadow chart) is maintained at OHRS for each patient enrolled.  
Completed paper CRFs and copies of the most significant study source documents will be 
maintained in the research chart.  Examples of source document copies that will be 
maintained in the research chart include: signed informed consent form, documents that 
verify eligibility and treatment and documents that verify Grade 3-4 adverse events and 
response. This information will be updated on a prospective basis and will be confidentially 
maintained at the OHRS.  It is recommended that CINJOG centers maintain research charts 
as indicated above. 
 
13.3 Reports 
Publications and annual reports for submission to the IRB will be written by the Cancer 
Institute of New Jersey PI using the data captured on the CRFs. Study progress reports will be 
provided to CINJOG participants for submission to local IRBs. 
 
14. Data and Safety Monitoring 
Monitoring of this study will occur in accordance with the Cancer Institute of New Jersey’s 
NCI approved Data and Safety Monitoring Plan (DSMP).  An “initiation audit” will be 
conducted at the Cancer Institute of New Jersey in accordance with the DSMP following 
enrollment of the first two (2) or three (3) patients.  Subsequent audits will occur on an 
annual basis prior to annual IRB continuing review, if the findings from the initiation audit 
were satisfactory.  More frequent audits of patient data and study conduct will occur if 
necessary.  All CINJOG centers will be monitored at least quarterly and audited annually.  
Prior audit findings and/or situations that may arise during the course of the study will 
determine the need for more frequent auditing.  All audit findings will be reported to Cancer 
Institute of New Jersey’s Human Research Oversight Committee and the PI.  
 
15. Multi-Institutional Guidelines  
 
15.1 IRB Approvals   
As the Coordinating Center for a trial, it is the Cancer Institute of New Jerse’s responsibility 
to ensure that no patients are entered on the trial at a participating institution without full IRB 
approval.   Thus, OHRS will approve the addition of each participating institution to the 
study. A copy of the IRB approval document from each participating institution will be 
obtained prior to activation of the study at the participating institution.  
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15.2 Other Pre-Study Documents 
Each participating center is required to have the following documents on file at the Cancer 
Institute of New Jersey OHRS: 
• Curricula Vitae of all physician Investigators 
• Signed FDA form 1572 of all physician Investigators 
• Medical license from each Investigator 
 
15.3 Initiation Site Visits 
Initiation site visits will be conducted at each participating CINJOG institution prior to 
enrollment of patients from the institution.  OHRS staff will conduct the initiation visit in 
close proximity to IRB approval of the study at the participating center. 
 
15.4 IRB Continuing Approvals 
The CINJOG investigators must provide, through the OHRS, a copy of the institution’s 
approved continuing review.  Registration will be halted at any participating institution in 
which a current continuing approval is not on file at the Cancer Institute of New Jersey.   
 
15.5 Amendments and Consents 
The OHRS will maintain a copy of all amendments, consent forms and approvals from each 
participating institution. Consent forms will be reviewed and approved by OHRS to ensure 
consistency with the Rutgers Biomedical Health Sciences Institutional Review Board 
approved consent form.  Should changes to the protocol become necessary, protocol 
amendments will be submitted in writing to the Cancer Institute of New Jersey PI and local 
IRB for approval prior to implementation; unless the patient’s best interest is endangered.  In 
that case, notification to PI and local IRB will be made as soon as possible.  
 
15.6 Patient Registration 
All patients from participating institutions must register patients with the OHRS central 
registration desk, as described in Section 5.6 of this protocol.  
 
15.7 Data Collection and Toxicity Reporting 
The PI at each institution will be responsible for assuring that all the required data is 
collected and entered onto the CRFs accurately and completed CRFs submitted at the time 
points specified in Section 13.2 and the study data collection plan.  
 
15.8 Data Monitoring and Source Document Verification 
Each site participating in the accrual of patients to this protocol will be audited for protocol 
and regulatory compliance, data verification and source documentation. 
 
The Cancer Institute of New Jersey staff will conduct monitoring visits to participating 
institutions of CINJOG no less frequently than every 3 months.  The monitoring visits will 
focus on verifying CRF data with source documents.  Adherence to the protocol(s), including 
the prompt reporting of serious adverse events, will be assessed.  Findings of all monitoring 
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Deborah L. Toppmeyer, M.D. 
 
visits are recorded in a CINJOG Monitors Report, which is sent to the Cancer Institute of 
New Jersey PI and the CINJOG PI.  All CINJOG Monitor’s Reports are reviewed at regular 
meetings of the Human Research Oversight Committee. 
 
15.9 Data and Center Audits 
Cancer Institute of New Jersey staff will conduct annual audits to each participating center in 
accordance with OHRS Standard Operating Procedures (SOPs).  The audit guidelines are in 
accordance with the Cancer Institute of New Jersey Data and Safety Monitoring Plan. 
  
16. Statistical Considerations 
 
16.1 Trial Design  
This is a one-arm Phase I/II trial combining Abraxane and RAD001 in the treatment of 
women who have receive no prior chemotherapy regimens for the treatment of locally 
advanced or metastatic breast cancer.  The primary end point for efficacy is response as 
defined by the Response Evaluation Criteria in Solid Tumor (RECIST).  Data with regard to 
secondary endpoints (see Section 1.2) will be descriptive and considered exploratory and 
hypothesis generating. 
 
16.2 Sample Size Justification  
The combination treatment will be considered effective if the response probability is 40% or 
higher.  We will thus test the null hypothesis p0 ≤ .40 against the alternative hypothesis p > 
.40.  We also require that the power of the test be at least 80% if the true response probability 
of the combination treatment is p ≥ .55.  For α = .05, Simon’s two-stage Phase II design (with 
admissible solution) will be used to monitor the study as follows:  The study will first accrue 
39 patients in the first stage.  If there are 17 or fewer responses among these 39 patients, the 
study will be terminated and the combination therapy will be rejected.  Otherwise, the study 
will continue until another 33 patients are accrued (i.e. for a total of 72 patients).  If stage two 
is conducted, the null hypothesis will be accepted if 35 or fewer responses are observed in the 
two stages combined. Otherwise, the null will be rejected. Therefore, the proposed sample 
size is a minimum of 39 patients and a maximum of 72 patients.   
 
16.3 Study Duration 
This study will require approximately 15 to 24 months to complete accrual of 39 to 72 total 
patients onto this trial.  It is estimated that three to six patients per month may be accrued 
onto this trial between the Cancer Institute of New Jersey and its partners and affiliate 
institutions (i.e., CINJOG). 
 
16.4 Data Analysis 
The time to progression will be summarized using the standard Kaplan-Meier method.  The 
frequency of serious adverse events as outlined in Section 6 will be described by summary 
statistics.  Biological end points obtained from biopsy specimens are likely to be assessed 
semi-quantitatively, and compared using nonparametric methods to determine correlations 
with tumor response and disease progression. 
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17. Human Subjects 
 
17.1 Patient Population  
Women with locally advanced or metastatic breast cancer who have received no prior 
chemotherapy regimens for metastatic disease may participate in this trial if they meet the 
eligibility criteria.  The inclusion and exclusion criteria detailed in this protocol are designed 
to exclude patients solely for medical reasons.  Study participants will be patients who are 
receiving care for their disease at the Cancer Institute of New Jersey or at CINJOG affiliated 
medical oncology practices and community hospitals.  The Principal Investigator and Cancer 
Institute of New Jersey research personnel will closely monitor the status of the study (and 
individual patient data) at all centers.  Males will not be eligible for this study.  Breast cancer 
in men is rare and the efficacy of Abraxane in males is limited.    
 
17.2 Potential Risks 
All care will be taken to minimize side effects, but they can be unpredictable in nature and 
severity.  Reported side effects of Abraxane and RAD001 are presented Section 12. 
 
This study may involve risks to patients that are currently unforeseeable.  Patients enrolled in 
this trial will receive their treatment in an outpatient setting.  In addition, monthly blood work 
will be taken to monitor side effects. Evaluations at each cycle to monitor the treatment of 
patients will be performed and recorded in the patient chart.  For patients at the Cancer 
Institute of New Jersey or at the affiliated sites who do not customarily receive their care at the 
affiliated institution, a local oncologist should be identified to monitor for complications and 
to improve long term care.  Although no compensation is available, any injury will be 
evaluated and treated in keeping with the benefits or care to which patients are entitled under 
applicable regulations. 
 
17.3 Consent Procedures  
Informed consent must be obtained prior to commencing any research procedures.  The PI 
shall seek such consent only under such circumstances that provide the prospective patient 
opportunity to consider whether or not to participate and that minimizes the possibility of 
coercion or undue influence.  The information given to the patient, or the representative, shall 
be in a language understandable to the subject or representative.  The informed consent 
document may not include any exculpatory language through which the subject or 
representative is made to waive any of the patient’s legal rights or releases, or appears to 
release the investigator, the sponsor or the institution from liability for negligence. 
 
The investigational nature and objectives of this trial, the procedures and treatments involved 
and their attendant risks, discomforts, and potential benefits will be carefully explained to the 
patient.  This process will include a general description of the disease process, as well as a 
description of the patient’s expected clinical course.  Alternative therapies will be fully 
described, and outlined in the consent document.  The patient will be asked to read the 
consent at his/her convenience and will be encouraged to ask questions.  Enrollment on this 
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Deborah L. Toppmeyer, M.D. 
 
study will only occur if the patient meets all eligibility criteria, is judged by the Principal 
Investigator or participating investigator to potentially benefit from the therapy, is able and 
willing to provide full consent, and has signed the consent document.  Moreover, any 
experimental invasive procedure will require a separate consent form (standard procedure 
consent form). 
 
17.4 Potential Benefits 
It is likely that a significant proportion of patients who participate in this clinical trial will 
receive direct clinical benefit because they will be receiving a drug that is commonly used for 
their disease.  This benefit may be reduction in the size of their tumor, stability in the size of 
their tumor, and/or improvement in symptoms related to their disease. 
 
17.5 Risk-Benefit Ratio 
The potential benefit that may result from this study balances the potential risks to the 
patients.  There is extensive data to support the efficacy of Abraxane in patients with 
metastatic breast cancer. However, it is not clear whether the combination of Abraxane and 
RAD001 are superior to Abraxane alone, however the mechanism of RAD001 provides 
substantial rationale to suggest that the combination will be more effective than Abraxane 
alone. This protocol may or may not be helpful to a specific patient, but the results may help 
the investigators learn about the administration and effectiveness of Abraxane and RAD001 
in breast cancer and may aid in the treatment of other patients.  This research treatment is not 
curative, but may offer temporary control of the disease.  Benefit cannot be promised nor can 
the chance of benefit be accurately predicted. 
 
17.6 Gender and Minorities  
The National Institute of Health and NCI have stressed the importance of gender and 
minority inclusion in clinical services and research.  Female patients accounted for 58% of 
cancer patients seen within The Cancer Institute of New Jersey’s clinical programs within the 
last year.  African-Americans comprised 7%, Hispanics 8%, and Asians 3% of female 
patients, respectively.  For all patients entering clinical trials, the percentages were 52% 
women, 6% African-American, 5% Hispanic, and 3% Asian. 
 
No person shall on the grounds of race, color or national origin, be excluded from 
participation in, be denied the benefits of, enrollment in this study.  There is a restriction 
regarding the sex of the patient (see Section 5.3).  Minorities are prevalent in the New 
Brunswick area. 
 
18. Economic/Financial Considerations 
Patients and/or their insurance carriers will be expected to pay for costs related to monitoring 
and follow-up.  Patients will be expected to pay for any costs not paid by their insurance 
carrier.  The cost of correlative studies will not be billed to the patient or insurer.  The study 
drug, RAD001, will be provided for free and will not be charged to the patient or their 
insurance carrier.  The study drug, Abraxane, is commercially available and will be charged 
to the patient or their insure carrier. 
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Deborah L. Toppmeyer, M.D. 
 
 
19. Publication of Research Findings 
The policies and procedures of The Rutgers University legal department (see: Investigator’s 
Handbook) will govern publication of the trial.  It is expected that the results of this trial will 
be submitted for publication in a timely manner following the conclusion.  The Cancer Institute 
of New Jersey PI, and all co-authors prior to submission or use, must review any abstract or 
manuscript.  
 
Any formal presentation or publication of data from this trial may be published after review 
and comment by Novartis and prior to any outside submission.  Novartis must receive copies 
of any intended communication in advance of publication (at least fifteen working days for 
presentational materials and abstracts and thirty working days for manuscripts).   These 
requirements acknowledge Novartis’ responsibility to provide peer input regarding the 
scientific content and conclusions of such publications or presentations.  Principal 
Investigation/Institution shall have the final authority to determine the scope and content of its 
publications, provided such authority shall be exercised with reasonable regard for the 
interests of Novartis and, in accord with the trial contract and shall not permit disclosure of 
Novartis confidential or proprietary information. 
 
 
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Deborah L. Toppmeyer, M.D. 
 
38. Scripture CD, Saprreboom A, Figg WD Oncology The Lancet 2005; 6: 780-789), whereas 
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40. Ibrahim NK, Desai N, Legha S, Soon-Shiong P, Theriault RL, Rivera E, Esmaeli B, Ring 
SE, Bedikian A, Hortobagyi GN, and Ellerhorst JA Phase I pharmacokinetic study of 
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Appendix A 
 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
 
 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  Restricted 
in physically strenuous activity, but 
ambulatory and able to carry out work 
of a light or sedentary nature (e.g., 
light housework, office work). 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
 
 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but unable 
to carry out any work activities.  Up 
and about more than 50% of waking 
hours. 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
 
 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
 
 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
 
 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 
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Appendix B 
Based on: Ingelman-Sundberg M, Human drug metabolising cytochrome P450 enzymes: properties an 
polymorphisms, 
Naunyn 
Schmiedebergs 
Arch 
Pharmacol. 
2004 
Jan;369(1):89-104. 
 
and 
[http://www.medicine.iupui.edu/flockhart/clinlist.htm as of July 13, 2006] 
Examples of Drugs or substances known to be inhibitors or inducers of the isoenzyme CYP3A 
Inducers  note: strong inhibitor implies that it can cause ≥5-fold increase in AUC or ≥80% decrease in clearance of sensitive CYP 
substrates 
Carbamazepine  
Dexamethasone 
Ethosuximide 
Glucocorticoids 
Griseofulvin 
Nafcillin 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenylbutazone 
Phenytoin 
Primidone 
Progesterone 
Rifabutin 
Rifampicin 
Rofecoxib 
St John’s wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
Inhibitors  note: moderate inhibitor implies that it can cause 2 to 5-fold increase in AUC values or 50-80% decrease  
in clearance  of sensitive CYP substrates. 
Amiodarone 
Anastrozole 
Aprenavir 
Azithromycin 
Bromocriptine 
Cannabinoids 
Cimetidine 
Cisapride 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delavirdine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazem 
Dirithromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
lndinavir 
lsoniazid, ltraconazole 
Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole 
Nefazodone 
Nelfinavir 
Nevirapine 
Norfloxacin 
Norfluoxetine 
Omeprazole 
Oxiconazole 
Paroxetine 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir 
Saquinavir 
Sertindole 
Sertraline 
Telithromycin 
Troglitazone 
Troleandomycin 
Valproic acid 
Verapamil 
Zafirlukast 
Zileuton 
 
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