Clinical trial NCT01185366
Conditions: Kidney Cancer
Keywords: Advanced non-clear cell renal cell cancer (RCC) Clear-cell renal cell carcinoma Collecting duct carcinoma Translocation carcinoma Chromophobe Everolimus Sunitinib Afinitor RAD001 Sunitinib Malate SUO11248 Sutent ESPN
Sponsor: M.D. Anderson Cancer Center
Start date: 2010-08-01; Completion date: 2019-09-09
Enrollment: 73 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The goal of this clinical research study is to compare the effectiveness of Afinitor (everolimus) and Sutent (sunitinib) for the treatment of advanced renal cell carcinoma (kidney cancer). The safety of each treatment will also be studied.

Detailed description:
The Study Drugs:

Everolimus is designed to stop cells from multiplying. It may also stop the growth of new blood vessels that help tumor growth, which may cause the tumor cells to die.

Sunitinib is designed to block pathways that control important events (such as the growth of blood vessels) that are essential for the growth of cancer.

Study Groups and Study Drug Administration:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the toss of a coin) to 1 of 2 groups.

* If you are assigned to Group 1, you will take 2 everolimus tablets by mouth once every day.
* If you are assigned to Group 2, you will take sunitinib capsules by mouth every day for 4 weeks, followed by 2 weeks off.

If you have any side effects from any of the drugs, tell the study doctor right away. The study doctor may then lower the dose or keep the dose level the same.

Every 6 weeks on this study is called a study "cycle."

If the disease gets worse or you have intolerable side effects while you are on study, you will have the chance to receive the study drug that you did not receive at first. The dosing and follow-up will be the same as for all participants in that group.

Study Visits:

On Day 1 of every cycle:

* You will have a physical exam, including measurement of your vital signs.
* You will be asked about any drugs or treatments you may be receiving.
* Your performance status will be recorded.
* Blood (about 3 teaspoons) and urine will be collected for routine tests and a fasting blood sugar test. Blood or urine will also be used for a pregnancy test for women who are able to have children. If you are in Group 1, you will have an additional 1 teaspoon of blood drawn to test your cholesterol.

On Day 15 and 29 of Cycle 1:

* Your vital signs and weight will be measured.
* Blood (about 2 teaspoons) will be drawn for routine tests. If you are in Group 1, an additional 1 teaspoon of blood will be drawn to measure your cholesterol.

The Day 15 and Day 29 tests may be done at your local doctor's office.

On Day 1 of Cycles 2 and 3, and every other cycle after that (Day 1 of Cycle 5, 7, 9 and so on):

°You will have a CT scan of the chest and a CT scan or MRI of the abdomen to check the status of the disease.

Every 4 cycles (24 weeks):

°If you are in Group 2, you will have an echocardiogram or MUGA scan to check your heart's health.

Length of Study:

You may continue taking the study drugs for as long as you are benefiting. You will be taken off study if the disease gets worse or intolerable side effects occur.

End-of-Treatment Visit:

If you have stopped taking the study drug because of intolerable side effects, the treating physician will make every effort to check the status of the disease before you are taken off of study.

Long-Term Follow-up:

Once you are no longer on this study, the research staff will check up on you about every 6 months. This update will consist of a phone call or a review of your medical and/or other records. You will not have any extra tests, procedures, or study visits. If contacted by phone, the call would only last about 5 minutes.

This is an investigational study. Sunitinib and everolimus are both FDA approved and commercially available for the treatment of advanced kidney cancer.

Up to 108 patients will be enrolled in this multicenter trial. Up to 108 patients will be enrolled at MD Anderson.

Arms: arm 1: Everolimus 10 mg by mouth once a day. arm 2: Sunitinib 50 mg by mouth daily for 4 weeks on / 2 weeks off.
Interventions: intervention 1: Everolimus intervention 2: Sunitinib
Intervention descriptions: intervention 1: 10 mg by mouth once a day. intervention 2: 50 mg by mouth daily for 4 weeks on / 2 weeks off

Protocol documents:
Prot_SAP_000.pdf: 
Protocol 2009-0628
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The University of Texas 
M.D. Anderson Cancer Center 
Division of Cancer Medicine 
Everolimus versus Sunitinib Prospective evaluation in Non-clear cell renal cancer: A randomized 
phase II trial. 
 
Lead Institution: 
The University of Texas M. D. Anderson Cancer Center 
 
 
 
Principal Investigator:   Amado Zurita M.D. 
1155 Pressler Street, Unit 1374 
Houston, TX 77030 
Telephone: (713) 792-2830 
Fax: (713) 745-1625 
E-mail: azurita@mdanderson.org 
 
 
 
Participating Institutions: 
 
Lank Center for Genitourinary Oncology 
Dana-Farber Cancer Institute/Brigham and Women's Hospital 
Harvard Medical School 
Principal Investigator: Toni K. Choueiri, M.D. 
44 Binney Street, Boston, MA 02115 
Phone: (617) 632-5456 
Fax: (617) 632-2165 
E-mail: Toni_Choueiri@dfci.harvard.edu 
 
 
 
Beth Israel Deaconess Medical Center 
Principal Investigator: David McDermott, M.D. 
375 Longwood Ave 
Boston, MA, 02215 
Mailstop: MASCO 428 
Phone: (617)632-9270 
Fax: (617) 632-9260 
E-mail: dmcdermo@bidmc.harvard.edu 
 
 
 
 
 
 
 
 
 
 
 
 
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Huntsman Cancer Institute – University of Utah 
Principal Investigator: Neeraj Agarwal, MD 
2000 Circle of Hope, Ste 2123 
Salt Lake City, Utah 84112 
Phone: (801) 585-0255 
Fax: (801) 585-0124 
E-mail: Neeraj.Agarwal@hci.utah.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.1 
OBJECTIVES 
 
Primary 
 To estimate and compare the progression-free survival (PFS) times of patients with 
advanced non-clear cell renal cell cancer (RCC) treated with everolimus or sunitinib 
as first-line therapy. 
 
Secondary 
 To assess the safety of everolimus and sunitinib in patients with advanced non-clear 
cell RCC. 
 To estimate the overall survival (OS) times of patients with advanced non-clear cell 
RCC treated with everolimus followed by sunitinib, sunitinib followed by everolimus, 
or any single agent as part of this study. 
 To estimate and compare the overall response rate (ORR) associated with each study 
drug given as first-line therapy in patients with advanced non-clear cell RCC. 
 
 
 
2.0 
BACKGROUND AND RATIONALE 
 
Renal cell carcinoma comprises more than 90% of kidney cancer cases and accounts for 
approximately 2-4 % of all adult malignancies.  In 2008, approximately 54,000 people in 
the United States were diagnosed with kidney cancer (renal cell cancer and transitional 
cell carcinoma of the renal pelvis) and approximately 13,000 died secondary to metastatic 
disease. Approximately 25 % of patients with RCC present with metastasis at the time of 
initial diagnosis and up to 20-30 % of patients develop recurrent disease after 
nephrectomy. Surgical removal of the primary tumor is the only effective therapy in the 
non-metastatic setting. No adjuvant therapy has been shown yet to alter the clinical 
course even in patients at high-risk for developing metastatic disease. 
 
 
Metastatic RCC (mRCC) is a heterogeneous disease with variable clinical outcome. Two 
randomized phase III trials have provided support for performing cytoreductive 
nephrectomy in mRCC, although the most optimal timing of this procedure has not been 
determined. Some patients with solitary metastasis, who are candidates for complete 
metastasectomies, can achieve a long-term survival; however, once metastases develop in 
multiple organs, systemic therapies, until recently, have had little effect on the clinical 
course of the majority of patients. In an effort to objectively compare different therapies 
in the same trial, and similar therapies across trials, prognostic models have been 
developed to assign patients to different risk categories, based on pretreatment clinical 
features. Cytokines (interleukin-2, interferon alfa), which were the main therapy for 
mRCC for two decades, have recently been replaced by agents targeting the VEGF or the 
m-TOR pathways. 
 
While conventional-type (clear-cell) RCC constitutes the majority of RCC cases, the rest 
of RCC cases belong to a heterogeneous group comprised of papillary, chromophobe, 
collecting duct carcinoma (CDC), renal medullary carcinoma, or unclassified.6 
 
 
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Sarcomatoid dedifferentiation may be associated with clear-cell RCC, papillary RCC and 
chromophobe RCC, and when present, it confers a worse prognosis. Clear-cell RCC is 
associated with mutation or silencing of the VHL tumor suppressor gene. This leads to 
upregulation of hypoxia-inducible factors (HIF) and to downstream upregulation of 
VEGF, resulting in increased angiogenesis, which is commonly noted in clear-cell RCC.7 
The identification of several key pathways relevant to RCC progression such as the 
VEGF pathway and the mTOR pathway has led to the development of several novel 
agents. The two tyrosine kinase inhibitors (TKIs), sorafenib and sunitinib, and the mTOR 
inhibitor temsirolimus received broad FDA approval for the treatment of advanced renal 
cell carcinoma8, whereas everolimus received FDA approval for RCC patients previously 
treated with TKIs. After it garnered regulatory approval in Europe in combination with 
interferon alfa, bevacizumab is expected to be FDA approved in 2009. 
 
Although the VEGF pathway has not yet been shown to be implicated in the development 
of RCC of non-clear cell histologies, there is evidence that proto-oncogenes involved in 
similar types of pathways do play a role.  For instance, through investigation of a group 
of patients with hereditary papillary type 1 RCC, the c-met oncogene was identified. C- 
Met encodes the receptor for hepatocyte growth factor, part of a cell signaling cascade 
that is important for cell migration and differentiation and has been implicated in the 
development of a variety of cancers 9.  Subsequent studies in sporadic papillary RCC type 
1 have shown that c-met is upregulated in some of these patients as well10.  In 
chromophobe RCC, the BHD and c-kit genes have been implicated in tumorigenesis, 
however the pathways by which these genes work have not yet been clearly elucidated11. 
KIT was also found to be overexpressed in chromophobe as well as sarcomatoid RCC12- 
13. A recent study, based on tissue array conducted in clear cell RCC and papillary RCC, 
suggested that the VEGF pathway may be implicated in papillary RCC14. Jacobsen et al 
demonstrated no difference in VEGF expression as determined by immunohistochemical 
staining among papillary, chromophobe and conventional-type RCC15. 
 
Retrospective reviews indicate that the chromophobe and papillary subtypes have a better 
prognosis relative to other varieties of RCC.  This reflects the fact that these tumors, if 
completely resected, are unlikely to recur.  However, once these tumor types become 
metastatic, these histologies no longer confer benefit with the one exception to this rule 
being chromophobe, which has a more indolent course. In one retrospective study, the 
median overall survival of patients with metastatic papillary RCC and metastatic CDC 
was 5 months and 11 months, respectively. 6   A randomized trial using two interferon 
regimens showed a significantly shorter survival for patients with non-clear cell RCC 
compared to patients with clear-cell RCC.7 
 
Currently, there is no established effective therapy for non-clear cell RCC.  It has been 
difficult to assess the response of these less common RCC subtypes to therapy as most 
trials exclude them, and trials in which they are included do not report results separately 
from those with clear-cell histology.  The available data suggests that these tumors are 
refractory to immunomodulation and cytotoxic therapy, which explains why traditional 
systemic therapy has been ineffective for this patient population. 
 
 
 
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Sunitinib malate, a multi-tyrosine kinase (MTK) inhibitor of VEGFR, PDGFR, FLT-3, 
and KIT, has produced significant tumor shrinkage in renal cell carcinoma. A recent 
retrospective review of patients with advanced papillary or chromophobe renal cell 
carcinoma treated with sunitinib or sorafenib showed a 17% response rate with sunitinib 
with median PFS time of approximately 8 months.  A single-arm phase 2 trial of sunitinib 
in patients with non-clear cell RCC is currently completing accrual at our institution (41 
patients accrued so far). So far, one patient achieved a partial response and several others 
achieved stable disease but the progression-free survival (PFS) was short compared with 
data generated in clear-cell RCC. A subset analysis of patients with non-clear cell RCC 
treated on a phase III trial showed improved survival with the mTOR inhibitor 
temsirolimus compared to IFN 8, lending support to investigate the role of mTOR 
inhibitors in non-clear cell RCC. Because there is no established effective therapy in non- 
clear cell RCC, there is an unmet need to develop therapy for this group of heterogeneous 
tumors. Therefore, it is important to evaluate the role of TKIs such as sunitinib and the 
mTOR inhibitors such as everolimus in a randomized phase II trial, with crossover design 
to allow patients to receive at progression the agent they did not receive upfront. 
 
 
 
3.0 
BACKGROUND DRUG INFORMATION 
 
3.1 
Sunitinib malate 
Sunitinib malate (sunitinib; SU11248; SU011248; Sutent®) is a novel, multi- 
targeted, small molecule inhibitor of the receptor tyrosine kinases (RTKs) 
involved in tumor proliferation and angiogenesis, including vascular endothelial 
growth factor receptor-1 (VEGFR-1), -2, and -3, platelet-derived growth factor 
receptor PDGFRα and β , stem cell factor receptor (KIT), the tyrosine kinase (TK) 
receptor encoded by the ret proto-oncogene (RET; rearranged during 
transfection), and fms-like tyrosine kinase 3 (Flt3) (Investigator’s Brochure 
SU011248, 2005).  Sunitinib selectively and potently inhibits the class III and 
class IV split-domain RTKs (Mendel et al., 2003). 
 
Sunitinib shows significant antitumor and antiangiogenic activity in a number of 
human tumor xenograft and angiogenesis models in mice as well as in phase 1 
and 2 studies in patients with a variety of tumor types (Sakamoto, 2004).  To date, 
over 3500 cancer patients have received sunitinib, including patients with renal 
cell carcinoma (RCC) and those with gastrointestinal stromal tumors (GIST).  In 
phase 2 studies in cytokine-refractory metastatic RCC, sunitinib produced 
objective responses in 40% of patients with a median time to progression (TTP) 
of 8.7 months (Motzer et al., 2006), while data from a phase 3 trial in patients 
with imatinib-resistant GIST indicate that sunitinib is highly superior to placebo 
(p<0.00001) with respect to time-to-progression (TTP) and overall survival (OS) 
(Demetri et al., 2005). 
 
 
 
 
 
 
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Sunitinib was granted approval on January 26, 2006 by Food and Drug 
Administration (FDA) for the treatment of gastrointestinal stromal tumor (GIST) 
after disease progression on or intolerance to imatinib mesylate and advanced 
renal cell carcinoma (RCC).  Approval for advanced renal cell carcinoma is based 
on partial response rates and duration of response. 
 
Mechanism of Action: 
Tumor VEGF expression has been associated clinically with disease prognosis in 
many different types of malignancies.  VEGF expression is increased by diverse 
stimuli including proto-oncogene activation and hypoxia, with the hypoxic state 
frequently arising in solid tumors because of inadequate perfusion.  In addition to 
its angiogenic role, VEGF also profoundly increases the permeability of the 
vasculature thereby potentially contributing to tumor progression.  A leaky tumor 
endothelium enhances nutrient and catabolite exchange and represents less of a 
barrier to tumor cell migration and intravasation during metastasis.  Two high- 
affinity receptors for VEGF with associated TK activity have been identified on 
human vascular endothelium, VEGFR-1/Flt-1 and VEGFR-2/kinase insert domain-
containing receptor (KDR).  Although the relative contributions of KDR and Flt-1 
signaling in mediating tumor progression have not been elucidated, a number of 
studies suggest that KDR performs a predominant role. 
 
In addition to VEGF receptor signaling, increasing evidence implicates PDGFR 
signaling in tumor angiogenesis.  Recent nonclinical evidence suggests that 
inhibition of PDGFR signaling augments the antitumor and antiangiogenic effects 
of VEGFR inhibitors.  In addition, PDGF signaling is implicated in the autocrine 
growth of tumor cells and in the recruitment and regulation of tumor fibroblasts. 
 
Upon chronic oral dosing, sunitinib is expected to inhibit PDGF- and VEGF- 
driven angiogenesis and as a consequence, limit solid tumor growth.  Because 
angiogenesis is necessary for the growth and metastasis of solid tumors, and 
VEGF is believed to have a pivotal role in this process, sunitinib treatment may 
have broad-spectrum clinical utility (Kim et al., 2004; Arora and Scholar, 2005). 
Sunitinib also exerts direct anti-tumor activity on cells that express target RTKs 
associated with tumor cell proliferation, such as KIT, PDGFR and RET.  The 
clinical activity of sunitinib in patients with advanced GIST is an example of this 
anti-tumor effect. 
 
3.1.1 Clinical Studies 
 
Pharmacokinetics 
 
Clinical pharmacology studies of sunitinib demonstrate that Cmax and AUC 
increase in a proportional manner after single doses of 50-350 mg, as well as after 
multiple doses of 25-100 mg (Investigator’s Brochure SU011248, 2005). Cmax 
ranged from 26.0-48.7 ng/mL for the parent compound and from 4.3-8.9 ng/mL 
 
 
 
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for the major metabolite, SU12662. AUC0-24 ranged from 389-819 ng•hour/ml for 
sunitinib and 52-140 ng•hour/mL for SU12662. Peak plasma concentrations of 
the metabolite were much lower than those of sunitinib but declined more slowly. 
The terminal elimination half-lives of sunitinib and SU12662 are approximately 
40 hours and 80 hours, respectively.  After 28 days of dosing, the AUC0-24 for 
sunitinib increased 2.5- to 3.5-fold, while AUC0-24 of SU12662 increased 4- to 12- 
fold compared to day 1.  Plasma concentrations of sunitinib and SU12662 
typically reach steady-state levels after 1 to 2 weeks of dosing.  Concentrations of 
parent drug and metabolite measured through 3 cycles of therapy have shown that 
Cmax, AUC0-24, and trough plasma drug concentrations during cycle 2 or cycle 3 
were not increased above those observed in cycle 1. 
 
The major in vitro studies on metabolism enzymology have been conducted in 
human liver microsomes, human hepatocytes, and expressed human CYP 
enzymes.  Sunitinib is primarily metabolized in human liver microsomes by 
cytochrome P450 (CYP) isoform 3A4 but appears to have minimal potential to 
inhibit CYP3A4-mediated metabolism, and studies in human hepatocytes 
indicated that neither sunitinib nor SU12662 induced CYP3A4. These studies 
suggest that sunitinib and SU12662 are unlikely to have any clinically relevant 
drug-drug interactions with drugs that are substrates for CYP3A4. Concurrent 
administration of sunitinib and ketoconazole, a potent CYP3A4 inhibitor, resulted 
in less than a 2-fold increase in sunitinib exposure (based on Cmax and AUC) and 
a small decrease in SU12662 exposure (Washington et al., 2003).  However, 
concurrent administration of sunitinib and rifampin (a potent CYP3A4 inducer) in 
healthy male Caucasian and Asian volunteers resulted in a 4-fold reduction in 
sunitinib plasma exposure (AUC) and a 2.5-fold reduction in plasma Cmax 
compared with sunitinib alone in both ethnic groups (Bello et al., 2005). 
 
 
 
Scope of Clinical Program 
To date, over 3000 patients with advanced malignancies have been treated with 
Sunitinib malate. 
 
Multiple phase 1, 2 and 3 studies have been conducted or are underway. The 
primary dose limiting toxicity in phase 1 studies was fatigue/asthenia, which 
generally occurred 10 to 15 days after start of daily therapy, and was readily 
reversible upon discontinuation of Sunitinib malate treatment. Overall, the most 
frequent adverse events associated with Sunitinib malate treatment have been 
constitutional symptoms (fatigue/asthenia), gastrointestinal effects (nausea, 
diarrhea, stomatitis, dyspepsia), myelosuppression (eg, neutropenia, 
thrombocytopenia), and dermatologic effects (e.g., dermatitis, skin discoloration, 
hair depigmentation). Clinically significant neutropenia has been observed in 
very few solid tumor patients and febrile neutropenia has rarely been observed in 
this patient population. The degree of adverse event severity has correlated with 
higher drug exposure and/or lower patient performance status for both patients 
treated with previous chemotherapy and chemotherapy-naïve patients. 
 
 
 
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The maximum tolerated dose of Sunitinib malate using the Schedule 4/2 has been 
defined as 50 mg in Phase 1 clinical studies in patients with advanced solid 
tumors. Patients receiving this dose of Sunitinib malate achieved target steady 
state plasma concentrations of Sunitinib malate of greater than 50 ng/mL. 
 
Clinically relevant Sunitinib malate antitumor activity has been demonstrated in 
Phase 1 patients with advanced malignancies, including patients with renal cell 
carcinoma, gastrointestinal stromal tumor, neuroendocrine tumor, sarcoma, 
thyroid cancer, melanoma and non-small cell lung cancer (NSCLC).  In addition, 
a phase 2 study and a Pivotal study of Sunitinib malate in patients with cytokine- 
refractory metastatic renal cell carcinoma demonstrated a response rate of 
approximately 40% with a TTP of greater than 8 months compared to historical 
experience of less than 10% and 3 months respectively. A phase 3 study 
conducted in patients with malignant gastrointestinal stromal tumor (GIST) 
resistant to imatinib mesylate demonstrated a four fold improvement in TTP (1.5 
mo to 6 mo) and a significantly improved OS. Preliminary data from an ongoing 
trial of Sunitinib malate monotherapy in patients previously pre-treated with a 
fluoropyrimidine, oxaliplatin and irinotecan for metastatic colorectal cancer have 
demonstrated a clinical benefit of approximatively 30% (CR+PR+SD for >6 
months). Preliminary data from an ongoing Phase 2 study in patients with 
metastatic breast cancer indicate an approximately 15% ORR in following 
treatment failure with anthracyclines and taxanes. 
 
Safety Profile 
In studies evaluating starting doses that ranged from 75 to 100 mg daily, cardiac 
hypokinesis and clinical signs of congestive heart failure were reported in 4 of 62 
advanced acute myeloid leukemia patients. The relationship to Sunitinib malate 
exposure was confounded by disease morbidities and prior anthracycline 
exposure.  At the 50-mg dose level, asymptomatic decreases in cardiac ejection 
fraction have been observed in <5% of solid tumor patients, either with or without 
a prior history of cardiovascular disease or anthracycline exposure. 
 
 
The most frequent adverse events (AEs) seen following sunitinib treatment are 
constitutional (fatigue/asthenia), gastrointestinal (nausea, vomiting, diarrhea, 
abdominal pain, anorexia, stomatitis, dysgeusia) and hematologic (neutropenia, 
thrombocytopenia) as well as skin discoloration (Investigator’s Brochure 
SU011248, 2005).  Most of the AEs are grade 1 or 2, but at 75 mg daily on an 
early phase 1 trial, grade 3 and 4 fatigue/asthenia were dose-limiting but readily 
reversible on discontinuation of treatment (Rosen et al., 2003). These 
investigators noted that the frequency and severity of AEs appeared to correlate 
with higher drug exposure or with lower performance status of the patients.  In 
another phase 1 study, grade 3 fatigue and hypertension were dose limiting at 59 
mg/m2 and the MTD was defined as 42 mg/m2 daily (Raymond et al., 2003). 
Tumor responses in patients treated at higher doses on this study were often 
associated with reduced intratumoral vascularization and central tumor necrosis 
which led to organ perforation in one patient and fistula in another. These 
 
 
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observations indicate the necessity for careful tumor density monitoring to detect 
early evidence of necrosis. Rapid destruction of bulky solid tumors can occur 
following sunitinib treatment, with pneumothorax, intestinal fistulae, or intestinal 
perforation each occurring at an incidence of less than 1.5% of patients. Across 
all patient populations, fatigue, hematologic AEs, and lipase elevations were the 
most common grade 3 and 4 events. 
 
In addition to the frequent AEs noted above and those which are infrequent but 
severe, the following events have occurred:  grade 2 edema and oral ulceration in 
AML (Fiedler et al., 2005); transient grade 3 and 4 hypertension, asymptomatic 
lipase increases (with or without amylase elevations), skin irritation in imatinib- 
resistant GIST (Desai et al., 2004); and grade 3/4 glossodynia in the NET trial 
(Kulke et al., 2005).  Additional reports from the manufacturer include anemia, 
pyrexia, and dyspnea in AML; and abdominal pain, dyspepsia, skin discoloration, 
headache, constipation, dermatitis, increased lipase, limb pain, and taste 
disturbance in various solid tumor patients (Investigator’s Brochure SU011248, 
2005). Of interest, dyspepsia, dysgeusia, and stomatitis were reported twice as 
often in MRCC as in GIST, although these events occurred in both populations. 
 
Many of the kinase inhibitors including sunitinib, sorafenib, imatinib, and the 
epidermal growth factor receptor (EGFR) inhibitors produce a variety of 
cutaneous side effects that, while not life-threatening, can be very troublesome to 
the patient (Robert et al., 2005). As presented in this review, hair depigmentation, 
splinter subungual hemorrhages, acral erythema, and facial edema (occasional) 
are some of the dermatologic adverse effects seen with sunitinib.  Because the 
severity of certain cutaneous effects appears to correlate with antitumor response 
in the case of the EGFR inhibitors, there is interest in further elucidating the 
mechanisms whereby kinase inhibitors produce these effects and in the potential 
for identification of predictive factors. 
 
3.2 
RAD001 (everolimus) 
Everolimus is a novel oral derivative of rapamycin. 
 
Everolimus has been in clinical development since 1996 as an 
immunosuppressant in solid organ transplantation and has obtained marketing 
authorization (Certican®) for prophylaxis of rejection in renal and cardiac 
transplantation in a number of countries, including the majority of the European 
Union. Everolimus has been in development for patients with various 
malignancies since 2002. 
 
Everolimus is being investigated as an anticancer agent based on its potential to 
act: 
 
 Directly on the tumor cells by inhibiting tumor cell growth and proliferation 
 
 Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via 
potent inhibition of tumor cell HIF-1 activity, VEGF production and VEGF- 
 
 
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induced proliferation of endothelial cells). The role of angiogenesis in the 
maintenance of solid tumor growth is well established, and the mTOR 
pathway has been implicated in the regulation of tumor production of 
proangiogenic factors as well as modulation of VEGFR signaling in 
endothelial cells. 
 
 
At weekly and daily schedules and at various doses explored, everolimus is 
generally well tolerated. The most frequent adverse events (rash, mucositis, 
fatigue and headache) associated with everolimus therapy are manageable. Non- 
infectious pneumonitis has been reported with mTOR inhibitors but is commonly 
low-grade and reversible. 
 
3.2.1 mTOR pathway and mechanism of action 
At cellular and molecular level everolimus acts as a signal transduction inhibitor. 
Everolimus selectively inhibits mTOR (mammalian target of rapamycin), a key 
and a highly conservative serine-threonine kinase, which is present in all cells and 
is a central regulator of protein synthesis and ultimately cell growth, cell 
proliferation, angiogenesis and cell survival. mTOR is the only currently known 
target of everolimus (Reviewed in Boulay and Lane, 2007). 
 
mTOR is downstream of PI3K/AKT pathway, a pathway known to be 
dysregulated in a wide spectrum of human cancers (e.g. through loss/mutation of 
the PTEN negative regulator; through PI3K mutation/amplification; through 
AKT/PKB overexpression/overactivation; through modulation of TSC1/TSC2 
tumor suppressors). In addition, activation of the PI3K/AKT/mTOR pathway is 
frequently a characteristic of worsening prognosis through increased 
aggressiveness, resistance to treatment and progression. 
 
The main known functions of mTOR include the following (Bjornsti and 
Houghton 2004; Boulay and Lane, 2007): 
 
 mTOR functions as a sensor of mitogens, growth factors and energy and 
nutrient levels, facilitating cell-cycle progression from G1 to S phase in 
appropriate growth conditions. 
 The PI3K-mTOR pathway itself is frequently activated in many human 
cancers, and oncogenic transformation may sensitize tumor cells to mTOR 
inhibitors. 
 Through inactivating eukaryotic initiation factor 4E binding proteins (4E- 
BP1) and activating the 40S ribosomal S6 kinases (i.e., p70S6K1), mTOR 
regulates translation of important massages, including those encoding the 
HIF-1 proteins, c-myc, ornithine decarboxylase, and cyclin D1, as well as 
ribosomal proteins themselves. 
 The activation of mTOR pathway leads to the increased production of pro- 
angiogenic factors (i.e., VEGF) in tumors and to tumor, endothelial and 
smooth muscle cell growth and proliferation. 
 
 
 
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 The regulation of mTOR signaling is complex and involves positive 
regulators, such as AKT that phosphorylate and inactivate negative regulators 
such as the Tuberous Sclerosis Complex (TSC1/TSC2). 
 
mTOR is represented by two structurally and functionally distinct multiprotein 
signaling complexes, mTORC1 (mTOR complex 1, rapamycin sensitive) and 
mTORC2 (mTOR complex 2, rapamycin insensitive) (Wullschleger, Loewith and 
Hall 2006). 
 
mTORC1 is mainly activated via the PI3 kinase pathway through AKT (also 
known as PKB, protein kinase B) and the tuberous sclerosis complex 
(TSC1/TSC2) (Bjornsti and Houghton 2004). Activated AKT phosphorylates 
TSC2, which lead to the dissociation of TSC1/TSC2 complex, thus inhibiting the 
ability of TSC2 to act as a GTPase activating protein. This allows Rheb, a small 
G-protein, to remain in a GTP bound state and to activate mTORC1. AKT can 
also activate mTORC1 by PRAS40 phosphorylation, thereby relieving the 
PRAS40-mediated inhibition of mTORC1 (Manning and Cantley 2007; Wang at 
al 2007). 
 
mTORC2 (mTOR complex 2) is activated through a currently unknown 
mechanism, possibly by receptor tyrosine kinase (RTK) signaling (Manning and 
Cantley 2007). It has been suggested that mTORC2 phosphorylates and activates 
a different pool of AKT that is not upstream of mTORC1. PHLPP phospatase 
plays a role of a negative regulator. mTORC2 is rapamycin insensitive and is 
required for the organization of the actin cytoskeleton (Wullschleger, Loewith and 
Hall 2006). 
 
mTORC1-mediated signaling is subject to modulation by the macrocyclic lactone 
rapamycin and its derivatives, such as everolimus. Once these agents bind to the 
12 kDa cytosolic FK506-binding protein immunophilin FKBP12, the resulting 
rapamycin-FKBP12 complexes bind to a specific site near the catalytic domain of 
mTORC1 and inhibit phosphorylation of mTOR substrates. As a consequence, 
downstream signaling events involved in regulation of the G1 to S-phase 
transition are inhibited. This mechanism is thought to be responsible for the 
immunosuppressive effects of rapamycin as well as its putative antineoplastic 
activity (Witzig, et al 2005). As many cancers are characterized by dysregulation 
of G1 transit (for example, overexpression of cyclin or cyclin-dependent kinases), 
inhibition of mTOR becomes an intriguing target for inducing cytostasis (Bjornsti 
and Houghton 2004). 
 
3.2.2 Preclinical studies 
Pre-clinical investigations have demonstrated that everolimus is a potent inhibitor 
of the proliferation of a range of human tumor cell lines in-vitro with IC50s 
ranging from sub/low nM to µM concentrations, concentrations capable of being 
reached in patients at the doses used in clinical trials. 
 
 
 
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Everolimus was shown to have activity in human tumor cell lines originating from 
lung, breast, prostate, colon, kidney, melanoma and glioblastoma. Everolimus was 
also shown to have activity in human pancreatic neuroendocrine cells, where 
induction of apoptosis was reported (Zitzmann, et al 2007), as well as in acute 
myeloid leukemia cells (Zeng, et al 2007), adult T-cell leukemia cells (Ikezoe, et 
al 2007), diffuse large B cell lymphoma cells (DLBCL; Wanner, et al 2006), 
pancreatic tumor cells (Tuncyurek, et al 2007), ovarian cancer cells (Treeck, et al 
2006, Mabuchi, et al 2007) and hepatocellular carcinoma cells (Sieghart, et al 
2007). 
 
As a single agent, everolimus inhibited proliferation in three mantle cell 
lymphoma cell lines (Jeko1, SP49 and NCEB1) approximately 40–65% compared 
to control cells. This was associated with G1 cell-cycle arrest and reduced 
phosphorylation of the mTOR downstream target, 4E-BP1 (Haritunians, et al 
2007). 
 
In a clonogenic assay using cells derived from 81 patient-derived tumor 
xenografts never cultured in vitro (11 human tumor types with 3 to 24 tumors 
each: bladder, colon, gastric, NSCLC [adeno, squamous epithelium and large 
cell], SCLC, breast, ovary, pancreatic, renal, melanoma, and 
pleuramesothelioma), everolimus inhibited colony formation in a concentration- 
dependent manner. In addition, normal hematopoetic stem cells were insensitive 
to everolimus, with an IC50 about 15 fold higher than the tumor lines. 
Everolimus also inhibits the proliferation of human umbilical vein endothelial 
cells (HUVECS), with particular potency against VEGF-induced proliferation. 
The inhibition of endothelial proliferation and antiangiogenic activity of 
everolimus was confirmed in vivo, as everolimus selectively inhibited VEGF- 
dependent angiogenic response. Mice with primary and metastatic tumors treated 
with everolimus showed a significant reduction in blood vessel density when 
compared to controls at well tolerated doses. Additionally, activity in a VEGF- 
impregnated s.c. implant model of angiogenesis and reduced vascularity (vessel 
density) of everolimus-treated tumors (murine melanoma) provided evidence of in 
vivo effects of angiogenesis. 
 
Everolimus also inhibits tumor growth in-vivo in xenografted, syngeneic and 
orthotopic animal models, residing longer in tumor tissue than in plasma and 
demonstrating high tumor penetration in a rat pancreatic tumor model. These 
effects occurred within the dose range of 2.5 to 10 mg/kg p.o. daily. Typically, the 
antitumor activity of everolimus monotherapy was that of reduction of tumor 
growth rates rather than producing regressions or stable disease. 
Everolimus, administred p.o., was a potent inhibitor of tumor growth and well 
tolerated in: 
 
 
 
 
 
 
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 s.c. mouse xenograft model, established from a variety of tumor cell lines of 
diverse histotypes (NSCLC, pancreatic, colon, melanoma, epidermoid), 
including a Pgp170 overexpressing multi-drug resistant tumor line 
 in a series of low-passage tumor xenografts established directly from human 
tumor material, maintained only in vivo and considered highly predictive of 
therapeutic outcome in patients. These included breast (5 lines), colorectal (9 
lines), gastric (3 lines), lung (22 lines including adenocarcinomas, epidermoid 
cell, large cell and small cell histotypes), melanoma (6 lines), ovarian (4 
lines), pancreatic (3 lines) and renal (6 lines) 
 in two syngeneic models (CA20948 rat pancreatic, B16/Bl6 mouse orthotopic 
melanoma) 
 
Taken together, these data indicate the broad antiproliferative potential of 
everolimus. 
 
It is not clear which molecular determinants predict responsiveness of tumor cells 
to everolimus. Molecular analysis has revealed that relative sensitivity to 
everolimus in vitro correlates with the degree of phosphorylation (activation) of 
the AKT/PKB protein kinase and the S6 ribosomal protein. PTEN status alone 
may not be predictive of everolimus relative in vitro sensitivity, however in some 
cases (i.e., GBM) there is also a correlation with PTEN status. 
 
In preclinical models, the administration of everolimus is associated with 
reduction of protein phosphorylation in target proteins downstream of mTOR, 
notably phosphorylated S6 (pS6) and p4E-BP1, and occasionally with an increase 
in phosphorylation AKT (pAKT). 
 
3.2.3 Pre-clinical safety 
In safety pharmacology studies, everolimus was devoid of relevant effects on vital 
functions including the cardiovascular, respiratory and nervous systems. 
Everolimus had no influence on QT interval prolongation. Furthermore, 
everolimus showed no antigenic potential. Although everolimus passes the blood- 
brain barrier, there was no indication of relevant changes in the behavior of 
rodents, even after single oral doses up to 2000mg/kg or after repeated 
administration at up to 40 mg/kg/day. Based on these findings, the potential of 
everolimus to affect vital functions in patients is considered to be low. 
 
Everolimus is considered to have no genotoxicity or carcinogenicity potential. All 
significant adverse events observed in preclinical toxicology studies with 
everolimus in mice, rats, monkeys and minipigs were consistent with its 
anticipated pharmacologic action as an antiproliferative and immunosuppressant 
and at least in part reversible after a 2- or 4-week recovery period with the 
exception of the changes in male reproductive organs, most notably testes. Ocular 
effects (lenticular disorders) observed in rats were not observed in any other 
species and are considered to be a species-specific disorder. 
 
 
 
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More pre-clinical information is provided in the [Investigator’s Brochure]. 
 
3.2.4 Clinical experience 
 
Everolimus Pharmacokinetics 
Everolimus is rapidly absorbed with a median tmax of 1-2 hours. The 
bioavailability of the drug is believed to be 11% or greater. The AUC0-τ is dose- 
proportional over over the dose range between 5 to 70 mg in the weekly regimen 
and 5 and 10 mg in the daily regimen. Cmax is dose-proportional between 5 and 10 
mg for both the weekly and daily regimens. At doses of 20 mg/week and higher, 
the increase in Cmax is less than dose-proportional. The coefficient of variation 
between patients is approximately 50%. 
Trough levels (24 hour post-dose) correlate well with AUC0-τ at steady-state 
during daily administration. 
 
In whole blood, at a daily dose of 10 mg, about 20% of everolimus is confined in 
plasma with 26% being unbound. The remaining 80% is sequestered in blood 
cells. 
 
Everolimus is extensively metabolized in the liver and eliminated in the bile. 
Major metabolites are inactive. Elimination half-life is approximately 30 hours. 
The clearance of everolimus is approximately halved in patients with mild- 
moderate hepatic impairment (Child-Pugh Class A or B), while renal impairment 
has little or no impact on the pharmacokinetics of everolimus. 
 
Age, weight and gender in the adult population do not affect the pharmacokinetics 
of everolimus to a clinically relevant extent. The clearance of everolimus is 
reduced in children. 
 
Pharmacokinetic characteristics are not notably different between Caucasian and 
Japanese subjects, whereas in Black patients population pharmacokinetic studies 
have shown an average 20% higher clearance. 
 
A high-fat meal altered the absorption of everolimus with 1.3 hour delay in tmax, a 
60% reduction in Cmax and a 16% reduction in AUC. 
Everolimus is a substrate of CYP3A4 and a substrate and a moderate inhibitor of 
the multi-drug efflux pump P-glycoprotein (P-gP, MDR1, ABCB1). Hence, its 
metabolism is sensitive to drugs which modify these enzymes (substrates, 
inducers, or inhibitors of these enzymes). Competitive inhibition could occur 
when everolimus is combined with drugs which are also CYP3A4 or P- 
glycoprotein substrates 
 
Appendix D lists examples of clinically relevant CYP3A inhibitors and inducers. 
 
 
 
 
 
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Please refer to Appendix D for more information on the concomitant use of 
CYP3A4 inhibitors/inducers and other medications. 
 
More information on everolimus pharmacokinetics is provided in the 
Investigator’s Brochure. 
 
Everolimus Pharmacodynamic studies 
Pharmacokinetic/pharmacodynamic modeling based on inhibition of the 
biomarker p70S6 kinase 1 [S6K1] in peripheral blood mononuclear cells 
[PBMC]) suggests that 5-10 mg daily should be an adequate dose to produce a 
high-degree of sustained target inhibition ([Study C2101] / [Study 2102], Lane, et 
al 2003). Furthermore, molecular pharmacodynamic (MPD) studies, using 
immunocytochemistry (IHC) in biopsied tumor tissue, assessed the degree of 
inhibition and its duration for pS6, p4E-BP1 and pAKT expression with the daily 
and weekly dosing. There was high inhibition of the downstream markers S6K1 
and 4E-BP1 at 5mg/day, which was complete at 10 mg/day, while preliminary 
results suggest increase in pAKT expression with maximal effect at 10 mg daily 
([Study C2107], Tabernero, et al 2005). 
 
More information is provided in the [Investigator’s Brochure]. 
 
Clinical experience with Everolimus 
Everolimus has been investigated as a component of multi-drug 
immunosuppression in solid organ transplantation since 1996 and was approved 
for the indication of prophylaxis of organ rejection in adult patients receiving an 
allogeneic renal or cardiac transplant on 8 Jul 2003 by the European Union under 
the trade name of Certican®. The most frequent adverse drug reactions in this 
context are highly specific to the transplant context. However, certain events are 
generalizable, most notably myelosuppression, skin disorders and increases in 
blood lipid levels. 
 
Everolimus has been in development for patients with cancer since 2002. 
Approximately 4000 patients with various malignancies have been treated in 
either Novartis sponsored or non-Novartis sponsored, and 3 healthy volunteer 
clinical studies as of 31 Aug 2008. Overall, Novartis sponsored a total of 28 
studies of everolimus administered either as single-agent (n=13), or in 
combination with other anti-tumor agents (n=15). Ongoing or completed 
Investigator sponsored studies also enrolled over 1000 patients globally. 
 
Eight single-agent Novartis sponsored trials have or are being conducted in 
various advanced malignancies. Five Phase I studies evaluated several escalating 
doses with either weekly or daily administration (Studies C2101/02, C2106, 
C2107, C1101) of everolimus with the objective to identify an optimal regimen 
and dosage, based on safety, pharmacokinetics and knowledge of the drug’s 
molecular effects on various tumors. The 10 mg/day and 50-70 mg/week dosages 
 
 
 
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were proposed for further studies, when using everolimus as a single agent, and as 
a target maximum dose in combination studies. In addition the Phase I studies, 
conducted in prostate cancer (Study C2106) and in Japanese patients with 
advanced cancers (Study C1101), evaluated the safety and the molecular changes 
in tumor, associated with the administration of everolimus. 
 
Two Phase II monotherapy studies were designed to evaluate the safety and 
efficacy of a single dose of 10 mg administered daily including Study C2235 in 
advanced NSCLC (n=81) and Study C2239 in advanced pancreatic neuroendrine 
tumors (n=160). 
 
A Phase III, randomized, double blind, placebo controlled study in patients with 
mRCC who progressed on a VEGFr TKI demonstrated that everolimus, 
administered daily at an oral dose of 10 mg, was superior to placebo for the 
primary endpoint of progression free survival. Median PFS was prolonged from 
1.9 months for patients receiving placebo to 4.9 months for everolimus-treated 
patients, assessed by central independent review blinded to clinical data (hazard 
ratio 0.33, 95% CI 0.25-0.43, p<0.001) (Kay et al, 2009). 
 
On 30 March 2009 everolimus was approved for use in the United States for the 
treatment of patients with advanced renal cell carcinoma after failure of treatment 
with sunitinib or sorafenib. 
Overall, the most frequent adverse effects suspected to be related to everolimus 
have been stomatitis, rash, anemia, fatigue, asthenia, diarrhea, anorexia, nausea, 
hypercholesterolemia, mucosal inflammation, vomiting, hypertriglyceridemia, 
cough, peripheral edema, dry skin, epistaxis, pruritus and dyspnea. The most 
common Grade 3 or 4 adverse reactions suspected to be related to treatment were 
anemia, infections, hyperglycemia, stomatitis, fatigue, lymphopenia, 
hypercholesterolemia, pneumonitis, and elevated gammaglutamyltransferase 
concentrations. 
 
Non-infectious low-Grade (Grade 1/2) pneumonitis has led to development of 
treatment guidelines for the disorder (Table 3-2). The primary DLT has been 
severe (Grade 3) stomatitis, and occasionally fatigue, hyperglycemia, and 
neutropenia. 
 
Further detailed information regarding everolimus clinical development, safety 
and efficacy is provided in the [Investigator’s Brochure]. 
 
 
3.2.5 Everolimus Safety Profile 
 
Adverse events most frequently observed with everolimus are rash, stomatitis/oral 
mucositis, fatigue, headache, anorexia, nausea, vomiting, and diarrhea. Infections 
have not been notably frequent or severe. Non-infectious pneumonitis has also 
been observed. The majority of these AEs have been of mild to moderate severity 
(CTC grade 1-2). Overall, the most frequently observed laboratory abnormalities 
 
 
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include reduced blood counts, hyperlipidemia mostly reported as 
hypercholesterolemia and/or hypertriglyceridemia. 
 
The principal DLT in Phase 1 trials has been Grade 3 stomatitis. For guidance on 
management of stomatitis refer to Section 9.4.1. 
 
Hyperlipidemia was reported as a serious adverse reaction. It is a recognized side- 
effect of rapamycins. Use of lipid-lowering drugs should be associated with 
dietary recommendations. Monitoring of blood lipid levels requires patients to be 
fasting so that this aspect must be verified when interpreting results. For guidance 
on management of hyperlipidemia refer to Section 9.4.2. 
 
Hyperglycemia was reported as a serious adverse reaction. Similarly, the fasting 
state of patients should be verified when interpreting results. For guidance on 
management of hyperglycemia refer to Section 9.4.2. 
 
Pneumonitis is a recognized adverse effect of rapamycins (sirolimus, 
temsirolimus, and everolimus). Numerous case reports in the literature suggest 
that rapamycin-associated pneumonitis is relatively unaggressive, limited in 
extent, and reversible upon drug discontinuation.  The term ‘pneumonitis’ is used 
here to describe non-infectious/non-malignant infiltration in the lungs which is 
evident radiologically. More precise diagnosis should follow histocytological 
examination following lung biopsy, generally during bronchoscopy which may or 
may not be symptomatic. Advice on the management of pneumonitis has been 
provided in Table 4. 
 
In oncology studies with everolimus, severe pneumonitis suspected as drug- 
related has been reported as a serious adverse event on 13 occasions and 
additionally in the following associated preferred terms including acute 
respiratory distress syndrome (n=2), alveolitis (n=1) and allergic alveolitis (n=1), 
interstitial lung disease (n=10), lung infiltration (n=23), cryptogenic organizing 
pneumonia, lung consolidation, pulmonary alvealoar haemorrhage, pulmonary 
toxicity and pulmonary fibrosis (n=1, each). One fatal case of drug-related 
pneumonitis was reported for a patient with metastatic infiltrating ductal 
carcinoma of the breast treated with 10 mg/day, which developed approximately 
two months after starting everolimus. Cytology for both the pleural and 
pericardial fluids were positive for malignancy.  The death was considered 
possibly related to the underlying late stage tumor and study drug. Additionally, 
one patient treated with 10 mg/day died due to severe acute respiratory distress 
syndrome and septic shock. Thoracic CT scan demonstrated condensation in the 
majority of the left lower lobe and frosted glass appearance in the left upper lobe, 
lingula, and right lung. 
 
Along with the cases of non-infectious pneumonitis, serious opportunistic 
infections have also been reported in cancer patients treated with everolimus: 
mycobactrium, aspergillus, and fatal candidal sepsis, and fatal pneumocystis 
carnii in particular. Because everolimus, as other rapamycins, inhibits 
proliferation of activated lymphocytes and reduces neutrophil counts, treatment 
 
 
 
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with everolimus must be considered as predisposing patients to the risk of 
infection. This risk will be higher in patients severely immunocompromised 
because of their underlying disease and/or co-medications. Outcome may be fatal 
in case of serious infections. 
 
A reduction in blood cell counts is frequent when everolimus therapy is initiated. 
Without clinical significance and infrequently, anemia and thrombocytopenia 
have been reported. In heavily pretreated patients with aggressive lymphoma, the 
incidence of grade 3 anemia, neutropenia, and thrombocytopenia was reported to 
be 11%, 16%, and 30%, respectively. Serious, suspected drug-related 
hemorrhages have been exceptional. Nevertheless, everolimus should be 
considered as predisposing patients to hemorrhage, potentially fatal, should they 
develop severe drug-related thrombocytopenia. 
 
Discrete, reversible changes in liver enzymes have been found to occur in 
numerous patients during treatment with everolimus in oncology clinical studies, 
and in a study in rheumatoid arthritis. In oncology studies, these changes may be 
evident only in patients without severe underlying morbidity. The increase in 
transaminase’s (AST and ALT) generally appears after 4 weeks of treatment. In 
all but a few cases it does not exceed Grade 1 (≤ 2.5 x ULN). Similarly, mild 
increases in alkaline phosphatases can coexist. Spontaneous corrections or 
intermittent correction with continued treatment can occur. Serum bilirubin is not 
increased.  In studies of patients with advanced cancers, clinically relevant 
changes in liver enzymes have been invariably associated with the presence of 
liver metastases and/or progression of the underlying cancer. 
 
Renal failure has been reported in five suspected cases to date. One patient with 
no alternative explanation made a complete recovery following study drug 
adjustment and no treatment/therapy for the event. The rest or the patients had 
concurrent morbidities, which might have contributed to the reported events. 
 
Hypophosphatemia, hypomagnesemia, hyponatremia and hypocalcemia have 
been reported as serious adverse reactions. Electrolytes should be monitored in 
patients treated with everolimus. 
 
Table 4 provides general recommendations for the management of patients, with 
suspected drug toxicities while on treatment with everolimus as single-agent 
therapy. 
 
More detailed information regarding everolimus reported suspected toxicities and 
individual cases is provided in the Investigator’s Brochure. 
 
 
 
 
 
 
 
 
 
 
 
 
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4.0 
ELIGIBILITY CRITERIA 
 
4.1 
Inclusion: 
 
1. Patients must have advanced non-clear cell RCC, which may include but is 
not limited to the following subtypes: papillary I or II, chromophobe, 
collecting duct carcinoma (CDC), translocation or unclassified.  Patients with 
conventional-type renal cell carcinoma who have ≥ 20% sarcomatoid 
component in their primary tumor are eligible.  Patients who have sarcomatoid 
features in FNA or core biopsy of any metastatic site are eligible, if they have 
an underlying renal cell carcinoma primary tumor. 
 
 
2. Patients must have at least one measurable site of disease that has not been 
previously irradiated. If the patient has had previous radiation to the marker 
lesion(s), there must be evidence of progression since the radiation 
 
3. ECOG performance status 0-1 
 
 
4. Age ≥ 18 years 
 
5. Patients must have adequate organ and marrow function within 14 days prior 
to study entry as defined below: 
 Hemoglobin 
9 g/dl (tx allowed) 
 absolute neutrophil count 
1,500/L 
 platelets 
100,000/L 
 total bilirubin 
1.5 mg/dl 
 AST(SGOT) or ALT (SGPT) 
2.5 X institutional uln, 
except in known hepatic 
metastasis, wherein may 
be < 5 x ULN 
 Serum Creatinine 
< 1.5 x ULN (as long as 
patient does not require 
dialysis) 
 
6. INR and PTT ≤ 1.5 x ULN within 14 days prior to study entry. Therapeutic 
anticoagulation with warfarin is allowed if target INR ≤ 3 on a stable dose of 
warfarin or on a stable dose of LMW heparin for > 2 weeks (14 days) at time 
of randomization. 
 
7. Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting 
triglycerides ≤ 2.5 x ULN within 14 days prior to study entry. 
 
 
 
8. Female patients of childbearing potential (not postmenopausal for at least 12 
months and not surgically sterile) must have a negative serum or urine 
 
 
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pregnancy test within 14 days before study entry.  Pregnancy test must be 
repeated if performed > 14 days before starting study drug. 
 
 
 
9. Patients must give written informed consent prior to study entry, in keeping 
with the policies of each institution. 
 
10. Patients with a history of major psychiatric illness must be judged (by the 
treating physician) able to fully understand the investigational nature of the 
study and the risks associated with the therapy. 
 
11. Patients with controlled brain metastases are allowed on protocol if they had 
solitary brain metastases that was surgically resected or treated with 
radiosurgery or Gamma knife, without recurrence or edema for 3 months 
(90days). 
 
 
 
4.2 
Exclusion: 
 
 
1. No other malignancies within the past 2 years except for adequately treated 
carcinoma of the cervix or basal (without recurrence post-surgery or post- 
radiotherapy) or squamous cell carcinomas of the skin. 
 
 
2. No prior systemic therapy for RCC including prior adjuvant therapy, or 
investigational drug is allowed. 
 
 
3. Patients currently receiving anticancer therapies or who have received 
anticancer therapies within 4 weeks (28 days) from enrollment into this study 
(including chemotherapy and targeted therapy) are excluded. However, 
patients are permitted to receive bisphosphonates.  Also, patients who 
completed palliative radiation therapy prior to enrollment in this trial are 
eligible. 
 
 
4. Patients, who have had a major surgery or significant traumatic injury (injury 
requiring > 4 weeks (28 days) to heal) within 4 weeks (28 days) of start of 
study drug, patients who have not recovered from the side effects of any major 
surgery (defined as requiring general anesthesia) or patients that may require 
major surgery during the course of the study. 
 
 
5. Concomitant treatment with rifampin, St. John’s wort, or the cytochrome p450 
enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine or 
Phenobarbital) or CYP3A4 inhibitors is not recommended on this study. 
 
 
 
 
 
 
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6. Patients who have any severe and/or uncontrolled medical conditions or other 
conditions that could affect their participation in the study such as: 
 Symptomatic congestive heart failure of New York heart Association 
Class III or IV 
 unstable angina pectoris, symptomatic congestive heart failure, myocardial 
infarction within 6 months of start of study drug, serious uncontrolled 
cardiac arrhythmia or any other clinically significant cardiac disease 
 severely impaired lung function as defined as 02 saturation that is 88% or 
less at rest on room air 
 uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN 
 active (acute or chronic) or uncontrolled severe infections requiring 
antibiotic intervention 
 liver disease such as cirrhosis, chronic active hepatitis or chronic 
persistent hepatitis 
 
7. Patients must not have history of other diseases, metabolic dysfunction, 
physical examination finding, or clinical laboratory finding giving reasonable 
suspicion of a disease or condition that contraindicates the use of sunitinib or 
everolimus or that might affect the interpretation of the results of the study or 
render the subject at high risk from treatment complications. 
 
8. Concomitant treatment with drugs with dysrhythmic potential (terfenadine, 
quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, 
haloperidol, risperidone, and indapamide) is not recommended. 
 
 
9. Patients receiving chronic, systemic treatment with corticosteroids or another 
immunosuppressive agent. Topical or inhaled corticosteroids are allowed. 
 
 
10. Patients should not receive immunization with attenuated live vaccines within 
one week (7 days) of study entry or during study period. 
 
 
11. Uncontrolled brain or leptomeningeal metastases, including patients who 
continue to require glucocorticoids for brain or leptomeningeal metastases. 
 
 
12. A known history of HIV sero-positivity. 
 
 
13. Impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of everolimus and/or sunitinib (e.g., 
ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption 
syndrome or small bowel resection). 
 
 
14. Patients with an active, bleeding diathesis. 
 
 
 
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15. Female patients who are pregnant or breast feeding, or adults of reproductive 
potential who are not using effective birth control methods. If barrier 
contraceptives are being used, these must be continued throughout the trial by 
both sexes. Hormonal contraceptives are not acceptable as a sole method of 
contraception.  (Women of childbearing potential must have a negative urine 
or serum pregnancy test within 7 days prior to study entry.  Pregnancy test 
must be repeated if performed  > 7 days before administration of everolimus 
and sunitinib) 
 
4.3 
Inclusion of Women and Minorities 
 
This trial is open to women and men and members of all races and ethnic groups. 
 
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Registration 
This is a randomized phase II trial of sunitinib vs. everolimus in advanced non- 
clear cell renal cell carcinoma. 
 
All patients will be registered in the approved Office of Research Administration 
(ORA) database at MD Anderson.  For registration procedures for this protocol, 
please refer to Section 15.2 of the protocol and the Data Quality Management Plan 
(Appendix F). 
 
5.2 
Randomization and crossover design 
Patients will be stratified by MSKCC risk grouping (Motzer et al, 2002) and 
histological RCC subtype (papillary vs. other non-clear cell subtypes), then they 
will be randomized (1:1) to receive everolimus or sunitinib. At disease 
progression, patients will be allowed to receive the agent that they did not receive 
upfront, i.e., patients who received sunitinib and had progressive disease will be 
treated with everolimus and vice versa. In most cases, treatment with the second 
agent will be initiated within 4 weeks (28 days) of completing the last dose of the 
first agent. In the case of patients receiving sunitinib after everolimus, patients 
have to wait 2 weeks (14 days) from the last dose of everolimus before they start 
treatment with sunitinib. 
 
Note: Patients who develop progressive disease while receiving the 1st-line agent 
may receive radiation therapy or undergo surgery if indicated and continue to 
receive treatment on protocol, as long as the 2nd-line agent is commenced within 
8 weeks from discontinuation of the 1st-line agent. Patients who develop toxicity 
necessitating discontinuation of the 1st agent may continue treatment on protocol 
but will cross over to receive the 2nd agent after recovery from the toxicity of the 
1st agent. 
 
 
 
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We will use the Pocock-Simon minimization algorithm to ensure balancing with 
respect to treatment assignment over the stratification factors.  We will balance 
treatment assignment with respect to the following stratification factors:  Risk 
category (favorable intermediate poor); and histology (papillary versus other). 
 
5.3 
Data Collection 
Data will be entered in the MD Anderson Genitourinary (GU) departmental oracle 
system. Registration data entry and randomization will occur prior to initiation of 
therapy. 
 
5.4 
Administration of Study Agent 
The study drugs everolimus and sunitinib will be self-administered by the 
patients. The investigator will instruct the patient to take the study drugs exactly 
as specified in the protocol. Treatment must begin within fourteen days of 
randomization. 
 
Everolimus will be administered orally as once daily dose of 10 mg. Patients will 
be instructed to take everolimus in the morning, at the same time each day. 
 
Sunitinib will be taken orally as a once daily dose of 50mg on a 4-week (28 days) 
on, 2-week (14 days) off schedule. 
 
5.4.1 Formulation and Packaging 
Sunitinib will be obtained commercially as hard gelatin oral capsules containing 
12.5mg, 25mg and 50mg equivalents of sunitinib. Please refer to the package 
insert for formulation and handling information. 
 
Everolimus is formulated as tablets for oral administration of 10 mg and 5mg 
strength. Tablets are provided in blister-packs. Please refer to the package insert 
for formulation and handling information. Everolimus will be provided free of 
charge by Novartis. 
 
Patients will continue taking everolimus or sunitinib until they have progressive 
disease or develop toxicity, then they will have the option of crossover to receive 
the agent they did not receive in the first-line setting. 
 
5.5 
Compliance 
Patients will be required to return all empty bottles and blister packs of study 
medication at the beginning of every other cycle, for destruction.  Patients will 
keep a drug diary to document administration compliance (Appendix H). The 
completed diaries will be brought to clinic for review. 
 
5.6 
Drug Storage and Drug Accountability (Everolimus only) 
The investigator, or an approved representative, e.g. pharmacist, will ensure that 
all study medications are stored in a secured area, under recommended storage 
conditions and in accordance with applicable regulatory requirements.  All study 
 
 
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drug supplies must be kept in a locked limited access room. The study drug must 
not be used outside the context of this protocol. Everolimus will be stored at 15- 
30°C. 
 
The investigator must maintain adequate records documenting the receipt, use, 
loss, or other deposition of the investigational product. The records must identify 
the investigational product, including batch or code numbers, and account for its 
disposition on patient-by-patient basis, including specific dates and quantities. 
 
Unless otherwise instructed by Novartis in writing, our institutions will destroy 
any unused supplies of everolimus that expire during the term of this agreement, 
as well as all supplies that remain unused at the termination of this agreement. 
Institutions will destroy these materials in accordance with all applicable 
regulations, governmental guidelines, and institutional policies. 
 
5.7 
Concomitant Medications 
 
Sutent 
Caution is recommended when administering sunitinib with CYP3A4 inhibitors 
(e.g. ketoconazole, itraconazole, erythromycin, clarithromycin) see examples in 
Appendix D, since these inhibitors may decrease sunitinib malate metabolism and 
increase sunitinib plasma concentrations.  There is a mean 1.8-fold increase in 
exposure to sunitinib when sunitinib malate is co-administered with ketoconazole. 
 
Substances that induce CYP3A4 activity may increase sunitinib metabolism and 
decrease sunitinib plasma concentrations.  Co-administration of sunitinib and 
CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, Phenobarbital, St. 
John’s wort) may significantly reduce exposure to sunitinib. Co-administration of 
sunitinib and rifampin decreased mean sunitinib 4-fold. 
 
In addition, concomitant treatment with drugs with dysrhythmic potential 
(terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, 
haloperidol, risperidone, and indapamide) is not recommended. 
 
Other concomitant therapies considered necessary for the patient’s well being 
may be prescribed at the investigator’s discretion as described below. Every 
medication including herbal supplements (e.g. St. John’s wort) or treatment taken 
by the patient during the trial and the reason for its administration must be 
recorded in source documents and entered into the data collection system. 
 
Everolimus 
Patients will be instructed not to take any additional medications (including over- 
the-counter products) during the course of the study without prior consultation 
with the investigator. At each visit, the investigator will ask the patient about any 
new medications he/she is or has taken after the start of the study drug. 
 
 
 
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All Concomitant medications/Significant non-drug therapies taken ≤ 30 days prior 
to start and after start of study drug, including physical therapy and blood 
transfusions, should be recorded. 
 
 
 
The following restrictions apply during the entire duration of the study: 
 No other investigational therapy should be given to patients. 
 No anticancer agents other than the study medication should be given to 
patients. If such agents are required for a patient then the patient must first be 
withdrawn from the study. Surgery or radiation therapy for treatment of 
progressive disease is allowed (see Note in Section 5.2). 
 Growth factors (e.g.G-CSF, GM-CSF, erythropoietin, platelets growth factors 
etc.) are not to be administered prophylactically but may be prescribed by the 
investigator for rescue from severe hematologic events, if this is thought to be 
appropriate. 
 Concurrent administration of everolimus and strong CYP3A4 inhibitors (such 
as ketoconazole, itraconazole, ritonavir) and inducers (such as rifampin, 
rifabutin) should be avoided. Provided there is no alternative treatment 
available, patients should be closely monitored for potential toxicities. 
 Concurrent administration of everolimus and moderate CYP3A4 inhibitors 
(such as erythromycin, fluconazole, calcium channel blockers, 
benzodiazepines) and moderate CYP3A4 inducers (e.g. carbamazepine, 
phenobarbital, phenytoin) should also be avoided if possible, or used subject 
to caution (e.g. increased frequency of safety monitoring, temporary 
interruption of everolimus). 
 Competitive inhibition could occur when everolimus is combined with drugs 
which are also CYP3A4 substrates. Therefore caution should be exercised in 
such cases. 
 Co-administration with substrates, inducers, or inhibitors of P-glycoprotein 
should be avoided, if possible, or used subject to caution (e.g. increased 
frequency of safety monitoring, temporary interruption of everolimus). 
 Grapefruit and grapefruit juice affect cytochrome P450 and P-glycoprotein 
activity and should therefore be avoided. 
 In addition, patients should avoid Seville oranges and star fruit, as well as the 
juice of these fruits, which are potent CYP3A4-inhibitors. 
 No chronic treatment with systemic steroids or another immunosuppressive 
agents. Topical or inhaled corticosteroids are allowed. 
 Everolimus may affect the response to vaccinations making the response to 
the vaccination less effective. Live vaccines should be avoided while a patient 
is treated with everolimus. 
Oral anticoagulants such as warfarin are CYP2C9 substrates and, as such, no 
interaction with everolimus is expected. However, drug-drug interaction 
studies between macrolide antibiotics and warfarin have produced mixed 
 
 
 
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outcomes and the disparity in these findings has led to the conclusion that 
multiple factors may alter the clearance of warfarin. The coadministration of 
everolimus and oral anticoagulants is possible but should be subject to 
verification of coagulation (INR) once steady state is reached (after one 
week’s treatment). 
 
5.7.1 Other Anticancer or Experimental Therapy 
No other approved or investigational anticancer treatment will be permitted 
during the study period, including chemotherapy, biologic agents, hormone 
therapy or immunotherapy except for bisphosphonates. No other investigational 
drug may be used during treatment on this protocol, and concurrent participation 
in another clinical trial is not allowed. 
 
 
 
6.0 
CORRELATIVE STUDIES (Optional procedures) MD Anderson Only 
 
When feasible, pre-treatment tissue samples leftover from routine diagnostic procedures 
will be collected for the proposed correlative studies.  In addition, residual pathological 
material may be collected for patients who undergo procedures while on therapy. 
 
Specific biological markers will be assayed, focusing on factors associated with 
angiogenic signaling, and the activity and viability of specific cell types within the tumor, 
including the MAP kinase pathway, and the PI3K pathway with a focus on signaling 
molecules downstream of mTOR. 
 
6.1 
Epigenetic Analysis 
Digital Restriction Enzyme Analysis of Methylation (DREAM) will be performed 
to obtain an overview of the aberrant methylated genes in patients with primary 
sensitivity and resistance to everolimus and sunitinib. DREAM data of healthy 
individuals is available. DREAM is a digital restriction enzyme analysis of 
methylation for quantitative mapping of DNA methylation with high resolution on 
the genome-wide scale. To perform the analysis, genomic DNA is sequentially 
digested with a pair of enzymes recognizing the same restriction site (CCCGGG) 
containing a CpG dinucleotide. The first enzyme, SmaI, cuts only at unmethylated 
CpG and leaves blunt ends. The second enzyme, XmaI, is not blocked by 
methylation and leaves a short 5’ overhang. The enzymes thus create methylation- 
specific signatures at ends of digested DNA fragments. These are deciphered by 
next generation sequencing. Methylation levels for each sequenced restriction site 
are calculated based on the numbers of DNA molecules with the methylated or 
unmethylated signatures. The M. D. Anderson Epigenetics Center operates a 
Solexa core with the Illumina GA II machine that will be available for these 
studies. Genes of interest in this whole genome screen will be validated using 
DNA methylation analysis by bisulfite pyrosequencing. The expression of the 
pyrosequenced genes will be measured with quantitative RT-PCR using 
 
 
 
 
 
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LightCycler technology. The obtained results will be correlated with the response 
to treatment. 
 
Particular emphasis will be put on PTEN and RASSF1. To reassess their 
expression in RCC samples, quantitative RT-PCR and immunohistochemical 
studies of these genes will be performed and will be correlated with the 
methylation status obtained by pyrosequencing. As the DREAM methods need to 
be applied in frozen tissues, we aim to identify potential predictive markers of 
response and resistance in the available frozen specimens, A validation of the 
potential predictive markers of sensitivity and resistance will be achieved by 
pyrosequencing of the paraffin-embedded specimens when available. 
 
6.2 
Gene expression analysis 
We aim also to evaluate the potential effect of everolimus and sunitinib on the 
expression of TGF-, which has been suggested to be a prognostic factor in RCC 
patients, and may increase RCC growth via an autocrine loop17. Oligonucleotide 
array analysis will also be performed to detect global patterns in pre-treatment 
tumor samples. 
 
6.3 
Immunohistochemical and immunofluorescence studies 
A tissue microarray will be generated from nephrectomy or metastasectomy 
blocks from patients enrolled on the trial. For patients where blocks are not 
available selected staining may be performed on biopsy material where indicated. 
Specifically, to evaluate the MAP kinase and PI3K pathways, ERK, phospho 
ERK, p38, phospho p38, Akt phospho Akt, S6 kinase, phospho S6 kinase S6, 
phospho S6 and EIF4E and VEGF isoforms will be assayed using 
immunohistochemical techniques.  In addition, p27 levels and its subcellular 
localization, Ki67 levels, and the TUNEL assay will be performed to evaluate the 
effect of everolimus and sunitinib on cell cycle, proliferation and apoptosis in 
endothelial, stromal and tumor cells. In addition, c-kit over-expression by 
immunohistochemistry will be assessed in patients with chromophobe RCC. 
Other biomarkers will be added as appropriate to contextualize the information 
gathered from the DREAM and the pyrosequencing analysis. 
 
Moreover, we will assess the effect of everolimus and sunitinib on angiogenesis, 
endothelial FGFR, VEGFR2, Tie-2 and PDGFR levels and phosphorylation states 
will be assayed using coimmunofluorescence techniques. 
 
Since chromosome copy number alterations have been shown to be associated 
with outcomes of clear-cell RCC, we will determine whether chromosomal 
imbalances identified with SNP arrays could be used as predictors of response to 
these agents. We will obtain archival FFPE tumor samples and extract DNA from 
the FFPE tissue sections for analysis with Affymetrix 250K Nsp SNP microarrays 
to identify genomic imbalances and loss of heterozygosity (LOH). SNP analysis 
will be performed at MDACC Sequencing and Microarray Facility (SMF). 
 
 
 
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6.4 
Circulating endothelial cells 
Venous blood (26ml) will be collected from patients to see if these tissue types 
can be used as surrogates for tumor tissue.  Cellular biomarkers including 
circulating endothelial cells, circulating progenitor cells and molecular-target- 
expressing monocytic populations will be assessed by flow cytometry. A panel of 
vascular and inflammation-related cytokines including VEGF, FGF-2, sVEGFR- 
2, PDGF, and HGF among others will be assessed in plasma by the multiplex 
beads technology and/or ELISA. These circulating biomarker studies will be 
conducted by Dr. Shixia Huang, director of the Antibody-based 
Proteomics Core at Baylor College of Medicine. 
 
Blood will be collected on day 1 of cycle 1, day 1 of all subsequent cycles, and at 
the end of treatment.  Blood and tissue will be stored in the GU Biorepository. 
 
6.5 
Immunological Studies 
Immunological studies will be conducted to define changes in effector and 
regulatory T cell populations and/or function and changes in cytokine profiles that 
occur after patients have started treatment. Laboratory techniques will follow 
previously published methods (Sharma et al., Cancer Immunity 2003; Sharma et 
al., J. Immunotherapy 2008; Gnjatic et al., Clinical Cancer Research 2009; Liakou 
et al., PNAS 2008; Tibes et al., Mol Cancer Ther 2006; Chen et al., PNAS, 2009) 
and will include flow cytometry, ELISA assays, ELISPOT assays, Affymatrix 
analyses, microRNA analyses, Western blot and reverse-phase protein array 
analyses. 90 cc of blood will be collected pre-therapy and at the time of 
administration of each dose of study drug. Blood will be processed by standard 
ficoll methods and immunological studies will be conducted on obtained PBMCs 
and plasma. 
 
7.0 
PRE-TREATMENT EVALUATION 
 
7.1 
Within 6 months (180 days) of study entry 
 Doppler echocardiogram or MUGA scan for patients randomized to sunitinib 
 
7.2 
Within 28 days of study entry 
 Signed and dated informed consent 
 Physical Exam and updated medical history 
 Updated evaluation of concurrent non-malignant diseases and recent medical 
therapy (within the thirty days prior to the evaluation). 
 Imaging: CT scan of chest and abdomen (MRI of abdomen may be 
substituted).  CT scan or MRI of the brain. 
 CT scan of pelvis, plain films of bones/skeletal survey and bone scan will not 
be ordered routinely on all patients but only if clinically indicated 
 12-lead ECG 
 
 
 
 
 
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7.3 
Within 14 days (+/- 3 days) of study entry 
 Interim history 
 Assessment of ECOG performance status, weight, temperature, blood 
pressure, heart rate, respiratory rate 
 Physical Examination 
 Laboratory testing: CBC with differential & platelets, chemistry panel 
including electrolytes (Na, K, Cl, CO2), albumin, alkaline phosphatase, ALT, 
AST, calcium, LDH, total bilirubin, BUN, creatinine, phosphorus, INR/PTT, 
fasting lipid profile, fasting blood sugar, serum amylase and lipase, serum free 
T4 and TSH. For fasting blood sugar, patients should have nothing to eat or 
drink, except for water, for 8 hours leading up to the tests. 
 Urinalysis 
 
Serum or urine pregnancy test for females of childbearing potential 
 
7.4 
Risk Grouping (MSKCC Prognostic Factors - see Appendix E) to be assessed 
within 14 days prior to randomization. 
 
Risk Group: Good, Intermediate, or Poor 
 
7.5 
Treatment can not start until at least 1 week after any minor surgical procedure, 
excluding placement of a vascular access device and core biopsies. 
 
 
 
8.0 
EVALUATION DURING TREATMENT 
 
8.1 
A course of treatment is defined as 6 weeks (42 days +/- 4 days). The following 
must be performed on Day 1 of each course. All testing must occur within 3 days 
prior to dosing on all courses. If assessment and tests were completed within 7 
days of Course 1 Day 1, procedures will not be repeated. Patients are required to 
come to the registering institution at the beginning of every course. 
 
 Interim history 
 Assessment of ECOG performance status, weight, temperature, blood 
pressure, heart rate. 
 Physical examination 
 Assessment of all concomitant medications and treatments taken since the last 
assessment. 
 Assessment of adverse events and tumor-related signs and symptoms 
 Assessment of treatment related toxicities 
 Laboratory testing: CBC with differential & platelets, chemistry panel 
including electrolytes (Na, K, Cl, CO2), albumin, alkaline phosphatase, ALT, 
AST, calcium, LDH, total bilirubin, BUN, creatinine, phosphorus, fasting 
blood sugar 
 Urinalysis. 
 
 
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 Fasting lipid profile for patients randomized to receive everolimus (nothing to 
eat or drink, except water, for 8 hours) 
 
(Patients who have demonstrated stability on treatment can return to 
MDACC every 12 weeks for the above mentioned assessments and tests, at 
the discretion of the PI.) 
 
 Doppler echocardiogram or MUGA scan every 24 wks (180 days) for patients 
randomized to receive sunitinib. 
 
Patients receiving sunitinib will have serum free T4 and TSH testing every 
other cycle (about every 12 weeks) 
 
8.2 
On days 15 and 29 (+/- 4 days) of course 1, all patients will be followed with vital 
signs (blood pressure and pulse only), CBC with differential & platelets, platelet 
count, electrolytes, BUN, creatinine, AST, ALT and total bilirubin. For patients 
randomized to receive everolimus, a fasting lipid profile should also be added. 
Day 15 and day 29 testing may be done locally. 
 
8.3 
Imaging scans (CT of chest and CT scan or MRI of abdomen) will be performed 
to determine disease response every 6 weeks (42 days)(+/- 4 days) for the first 
two cycles, then every other cycle [about every 12 weeks (84 days)], for as long 
as patients are receiving therapy on protocol.  A follow-up CT scan of the pelvis 
will only be ordered if clinically indicated.  A follow-up CT or MRI of the brain 
will only be ordered if clinically indicated. 
 
8.4 
On day 1 (+/-4 days) of each course, and at the end of treatment, blood will be 
collected for correlative studies (MD Anderson only) Patients who have 
demonstrated stability on treatment can return to MDACC every 12 weeks and 
have this sample collected, at the discretion of the PI. 
 
8.5 
Serum or urine pregnancy test will be repeated every 6 weeks (42 days +/- 4 days) 
while on-study for women of childbearing potential.  Patients who have 
demonstrated stability on treatment can return to MDACC every 12 weeks and 
have this test completed, at the discretion of the PI. 
 
8.6 
End of Treatment Evaluation:  Adverse events and tumor-related signs and 
symptoms will be assessed.  For patients who develop toxicity related to study 
drug necessitating discontinuation of protocol therapy before restaging to assess 
tumor response, physicians treating these patients will make every effort to repeat 
the appropriate imaging studies if feasible and indicated to assess tumor response 
at the time the patients are taken off protocol treatment. 
 
8.7 
Long-term Follow-Up 
Patients will be followed for survival every 6 months (180 days ± 1 month or 31 
days) by record review or telephone correspondence. 
 
 
 
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STUDY CALENDAR 
 
 
Pre-Study 
Course 1 
(D15, D29) 
(+/- 4 days) 
Day 1 of 
subsequent 
courses 
(+/- 4 days) 
Every 12 
weeks 
(84 days 
+/- 4 days) 
 
 
End of 
treatment 
 
Medical History 
Xo 
Physical Examination 
Xp 
X 
Imaging 
Xb,o 
Xb 
Xb 
Xl 
Weight, temperature, 
blood pressure, heart rate 
and respiratory rate 
Xp 
Xj 
X 
CBC with differential & 
 c,p 
c 
c 
platelets 
X 
X 
X 
Chemistry Panel                        Xd,p                          Xi                              Xd 
Serum Free T4 + TSH                Xp                                                               Xe                            Xe 
Urinalysis                                   Xp                                                                X 
Pregnancy Test                         Xh,p                                            X h 
Fasting Lipid Profile                  Xp                  Xf                   Xf 
Amylase and Lipase                   Xp 
Echocardiogram/MUGA           Xa,n                                           Xa 12-
Lead ECG                             Xo 
ECOG Performance 
p 
Status 
X 
X 
Concomitant Medications 
X 
Adverse Events 
X 
X 
Long Term Follow Up 
Xm 
Optional Procedures 
Blood 
Xg 
Xg 
Tissue Sample 
Xk 
 
 
 
 
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a. For patients randomized to sunitinib every 24 weeks (180 days). During Pre-Study, must 
be within six months of study entry. 
b. CT scan of chest, CT scan or MRI of abdomen [every 6 weeks (42 days)(+/- 4 days)] for 
the first two cycles, then every 12 weeks (84 days)(+/- 4 days), and CT scan or MRI of 
the brain.  CT scan of pelvis, plain films of bones/skeletal survey and bone scan will not 
be ordered routinely on all patients but only if clinically indicated; any follow-up CT scan 
or MRI will be ordered if clinically indicated. 
c. Differentials include neutrophils, lymphocytes, monocytes, eosinophils and basophils 
d. Includes electrolytes (Na, K, Cl, Co2), albumin, alkaline phosphatase, ALT, AST, 
calcium, LDH, total bilirubin, BUN, creatinine, phosphorus, glucose, INR/PTT (pre- 
study only) 
e. Patients receiving sunitinib will have serum free T4 and TSH every 12 weeks (84 days) 
(+/- 4 days) 
f. For patients randomized to everolimus 
g. (+/- 4 days), and at the end of treatment 
h. Only for women of childbearing potential, repeated every 6 weeks (42 days) while on 
study.   May be serum or urine. 
i. Only includes electrolytes, ALT, AST, total bilirubin, BUN, and creatinine 
j. Only blood pressure and heart rate 
k. Pre-treatment tissue sample leftover from routine diagnostic procedure. 
l. For patients who develop toxicity related to study drug necessitating discontinuation of 
protocol therapy before restaging to assess tumor response, physicians treating these 
patients will make every effort to repeat the appropriate imaging studies if feasible and 
indicated to assess tumor response at the time the patients are taken off protocol 
treatment. 
m. Patients will be followed for survival every 6 months (180 days ± 1 month or 31 days) by 
record review or telephone correspondence. 
n. Within 6 months (180 days) of study entry 
o. Within 28 days of study entry 
p. Within 14 days (+/- 3 days) of study entry 
 
 
 
9.1 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 
 
9.1 
Sunitinib Dose Modifications 
Individual dose reductions will be permitted once a patient has experienced 
unexpected toxicity provided the criteria for patient withdrawal from study 
treatment have not been met.  All individual dose reductions are relative to the 
lowest dose of the current cycle.  Dose modifications may involve sunitinib in 
single decrements of 12.5 mg to a minimum dose of 25 mg. Dose modifications 
may involve everolimus in a single decrement of 5mg to a dose of 5 mg daily 
(dose level -1) or 5 mg every other day (dose level -2). 
 
Table 1 describes the recommended dose modifications for sunitinib related 
toxicities: 
 
 
 
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Table 1 - Dose modifications for sunitinib malate associated Toxicity 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Non- 
hematologic 
Continue at the 
same dose level 
Continue at the 
same dose level 
Withhold dose 
until toxicity is 
grade ≤ 1 or has 
returned to 
baseline, then 
resume 
treatment at the 
same dose 
level, or reduce 
the dose by 1 
level at the 
discretion of 
the 
investigator* 
Withhold dose 
until toxicity is 
grade ≤ 1 or has 
returned to 
baseline, then 
resume 
treatment at the 
same dose 
level, or reduce 
the dose by 1 
level at the 
discretion of 
the 
investigator* 
Hematologic 
Continue at the 
same dose level 
Continue at the 
same dose level 
Withhold dose 
until toxicity is 
grade ≤ 2 or has 
returned to 
baseline, then 
resume 
treatment at the 
same dose level 
** 
Withhold dose 
until toxicity is 
grade ≤ 2 or has 
returned to 
baseline, then 
resume 
treatment at the 
same dose level 
** 
* Patients who develop grade 3 or 4 lipase or amylase without clinical or other evidence 
of pancreatitis, or grade 4 hyperuricemia or grade 3 hypophosphatemia without clinical 
symptoms may continue study treatment without interruption at the discretion of the 
investigator.  Nausea, vomiting and diarrhea must persist at grade 3 or 4, despite 
maximal medical therapy, to reduce the dose. 
 
** Patients with recurrent grade 3 neutropenia or thrombocytopenia for > 7 days will 
dose reduce in the next cycle. Patients who develop grade 3 or grade 4 lymphopenia 
may continue study treatment without interruption. 
 
Table 2 describes the recommended dose modifications for sunitinib related toxicities. 
 
 
 
 
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Table 2 - Sunitinib dose level modification guidelines 
Dose level 
Dose and schedule 
0 (starting dose) 
50 mg daily, 4 wks (28 days) on / 2 wks 
(14 days) off 
-1 
37.5 mg daily, 4 wks (28 days) on / 2wks 
(14 days) off 
-2 
25 mg, 4 wks (28 days) on / 2wks (14 
days) off 
 
 
9.1.2 Dose Re-Escalation 
Doses reduced for drug related toxicity should generally not be re-escalated. 
However, individual re-escalation back to the previous dose level may be 
permitted provided the toxicity responsible for dose reduction has not recurred at 
a grade 2 for at least 4 weeks and with the agreement of the principal investigator 
of the study. 
 
9.1.3 Overdose Instructions 
In the event of an overdose, the PI and the manufacturers should be contacted to 
discuss the details of the overdose and formulate a clinical management plan. 
However, this contact will not delay patient care under any circumstance. 
 
 
 
9.2 
Everolimus Dose Modifications 
Individual dose reductions will be permitted once a patient has experienced 
unexpected toxicity provided the criteria for patient withdrawal from study 
treatment have not been met.  All individual dose reductions are relative to the 
lowest dose of the current cycle. 
 
Table 3 describes the recommended dose modifications for everolimus related 
toxicities. 
 
Table 3 - Everolimus dose level modification guidelines 
Dose level 
Dose and schedule 
0 (starting dose) 
10 mg daily 
-1 
5 mg daily 
-2 
5 mg every other day 
 
 
 
 
 
 
 
 
 
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Table 4 - Criteria for dose-modification in case of suspected toxicity and re-initiation of 
everolimus treatment 
 
Toxicity 
Actions 
Non-hematological toxicity 
Grade 2 
(except pneumonitis – refer to Table 5. 
If the toxicity is tolerable to the patient, 
maintain the same dose. If the toxicity is 
intolerable to patient, interrupt 
everolimus until recovery to grade <1. 
Then reintroduce everolimus at same 
dose. 
If event returns to grade 2, then interrupt 
everolimus until recovery to grade 1 or 
baseline, then resume treatment at the 
same dose level, or reduce the dose by 1 
dose level at the discretion of the treating 
physician. 
Grade 3 
(except hyperlipidemia*) 
(except pneumonitis – refer to Table 5 
Interrupt study drug until recovery to 
grade <2 then resume treatment at the 
same dose level, or reduce the dose by 1 
dose level at the discretion of the treating 
physician.  For pneumonitis consider the 
use of a short course of corticosteroids. 
Grade 4 
Discontinue everolimus. 
Hematological toxicity 
Grade 2 Thrombocytopenia (platelets <75, ≥ 
50x109/L) 
Interrupt study drug until recovery to 
grade 1 (>75 x109/L). Then reintroduce 
study drug at initial dose. 
If thrombocytopenia again returns to 
grade 2, interrupt study drug until 
recovery to grade 1 or baseline then 
resume treatment at the same dose level, 
or reduce the dose by 1 dose level at the 
discretion of the investigator. 
Grade 3 Thrombocytopenia (platelets <50, ≥ 25 x109/L) 
Interrupt study drug until recovery to 
grade 2 (platelets ≥ 75 x109/L), then 
resume treatment at the same dose level, 
or reduce the dose by 1 dose level at the 
discretion of the treating physician.  If 
grade 3 thrombocytopenia recurs, 
discontinue study drug at the discretion 
of the treating physician. 
 
 
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Grade 4 Thrombocytopenia (platelets < 25 
x109/L) 
Discontinue study drug. 
Grade 3 Neutropenia (neutrophils <1, ≥0.5 
x109/L) 
Interrupt study drug until recovery to 
grade 2 (neutrophils ≥ 1.5 x 109/L). 
Then resume treatment at the same dose 
level, or reduce the dose by 1 dose level 
at the discretion of the investigator.  If 
ANC again returns to Grade 3, hold 
study drug until the ANC ≥ 1.5 x 109/L. 
Then resume study drug dosing at the 
lower dose level at the discretion of the 
treating physician.  Discontinue patient 
from study therapy for a third episode of 
grade 3 neutropenia. 
Grade 4 Neutropenia (neutrophils < 0.5 x109/L) 
Interrupt study drug until recovery of ≥ 
neutrophils ≥ 1.0 x 109/L. Then resume 
study drug at the lower dose level at the 
discretion of the treating physician. If 
grade 3 or grade 4 neutropenia occurs 
despite this dose reduction, discontinue 
study drug. 
Grade 3 febrile neutropenia (not life-threatening) 
Interrupt study drug until resolution of 
fever and neutrophils ≥ 1.0 x 109/L. Then 
resume treatment at lower dose level at 
the discretion of the investigator.  If 
febrile neutropenia recurs, discontinue 
study drug. 
Grade 4 febrile neutropenia (life-threatening) 
Discontinue study drug. 
Any hematological or non-hematological 
toxicity requiring interruption for > 4 weeks 
Discontinue study drug. 
*Grade 3 hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) should be managed 
using medical therapies (see Sec. 3.2.5.2). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.3 
Monitoring of everolimus and sunitinib suspected toxicities 
 
For patients who are unable to tolerate the protocol-specified dosing schedule, 
dose adjustments are permitted in order to keep the patient on study drug. If 
administration of everolimus and/or sunitinib must be interrupted because of 
unacceptable toxicity, drug dosing will be interrupted or modified according to 
rules described below. Toxicity will be assessed using the NIH-NCI Common 
Terminology Criteria for Adverse Events, version 3.0 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3 
.pdf). 
 
 
 
9.3.1 Management of abnormal laboratory values 
Patients whose treatment is interrupted or permanently discontinued due to an 
adverse event or abnormal laboratory value suspected to be related to study drug 
must be followed at least weekly until the adverse event or abnormal laboratory 
resolves or returns to grade 1. This may be done by telephone correspondence. If 
a patient requires a dose delay of > 21 days from the intended day of the next 
scheduled dose, then the patient must be discontinued from the study. 
 
9.3.2 Management of stomatitis/oral mucositis/mouth ulcers 
Stomatitis/oral mucositis/mouth ulcers due to study drug should be treated using 
local supportive care. Please note that investigators in earlier trials have described 
the oral toxicities associated with study drug 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: 
 
 
1. For mild toxicity (Grade 1), use conservative measures such as non-alcoholic 
mouth wash or salt water (0.9%) mouth wash several times a day until 
resolution. 
 
 
2. 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®). 
 
 
3. Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend 
to worsen mouth ulcers. It is preferable to avoid these agents. 
 
 
 
 
 
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4. 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 metabolism of study drug, thereby leading to higher drug level 
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. 
 
Note:  Stomatitis/oral mucositis should be appropriately graded using the 
functional grading given on the NCI-CTC for adverse events, version 3.0. 
 
9.3.3 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 hypercholesterolemia (> 300 mg/dL or 7.75 mmol/L) or Grade 2 
hypertriglyceridemia (>2.5 x ULN) should be treated with a 3-hydroxy-3-methyl- 
glutaryl (HMG)-CoA reductase inhibitor (e.g., atorvastatin, pravastatin) 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. 
 
Note: 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 everolimus 
therapy. In many cases in study everolimus, the affected patients had an abnormal 
fasting glucose at baseline. Based on this finding, it is suggested that optimal 
glucose control should be achieved before starting a patient on everolimus and 
should be monitored during everolimus therapy. 
 
9.3.4 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 everolimus therapy. Non-infectious pneumonitis has been 
associated with everolimus and other mTOR inhibitors (Atkins 2004). In order to 
monitor for asymptomatic (grade 1) pulmonary infiltrates, a chest X-ray is required 
if a CT scan of chest is not used for bi-monthly disease evaluations. Additional 
chest CT scans may be performed, when clinically necessary. If non-infectious 
pneumonitis develops, a consultation with a pulmonologist should be considered. 
 
 
 
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Protocol 2009-0628
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If the patient develops grade 3 pneumonitis, treatment with everolimus 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 
everolimus and dose modifications instructions are provided. 
 
 
 
 
Table 5 - Management of non-infectious pneumonitis 
 
 
 
Worst 
Grade 
Pneumo 
nitis 
Required Investigations 
Management of 
Pneumonitis 
Everolimus Dose Adjustment 
Grade 1 
CT scans with lung windows 
and pulmonary function testing 
including: spirometry, DLCO, 
and room air O2 saturation at 
rest. Repeat chest x-ray/CT 
scan every 2 Cycles until 
return to baseline. 
No specific 
therapy is 
required 
Administer 100% of everolimus 
dose. 
Grade 2 
CT scan with lung windows 
and pulmonary function testing 
including: spirometry, DLCO, 
and room air O2 saturation at 
rest. Repeat each subsequent 
Cycle until return to baseline. 
Consider bronchoscopy * 
Symptomatic 
only. Prescribe 
corticosteroids if 
cough is 
troublesome. 
Reduce everolimus dose until 
recovery to ≤ Grade 1. 
Everolimus 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 
including: 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. 
39 
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Protocol 2009-0628
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*A bronchoscopy with biopsy and/or bronchoalveolar lavage is recommended. 


Protocol 2009-0628 
September 15, 2015 
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All interruptions or changes to study drug administration must be recorded. 
 
 
9.3.5 Management of pulmonary embolism 
Pulmonary embolisms confirmed by CT scan that are uncomplicated where 
medical intervention (anticoagulants) is indicated may be treated and stay on 
protocol at the discretion of the investigator. 
 
 
 
10.1 CRITERIA FOR RESPONSE OR PROGRESSION 
 
Evaluation of response will follow the Response Evaluation Criteria in Solid Tumors18. 
All tumor measurements must be recorded in centimeters. 
 
 Target Lesions: 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in 
total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis of 
their size (those with the longest diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically).  A sum of the longest 
diameter for all target lesions will be calculated and reported as the baseline sum 
longest diameter.  The baseline sum of longest diameters will be used as the reference 
by which the objective tumor response is characterized. 
 
 Non-target Lesions: 
All other lesions (or sites of disease) up to five lesions per site and ten lesions in total 
should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence or absence of each 
should be noted throughout follow-up. 
 
Evaluation of Target Lesions: 
 
 Complete Response: 
The disappearance of all target lesions. 
 
 Partial Response: 
At least a 30% decrease in the sum of the longest diameter of target lesions, taking as 
reference the baseline sum longest diameter. 
 
 Progressive Disease: 
At least a 20% increase in the sum of the longest diameter of target lesions, taking as 
reference the smallest sum longest diameter recorded since the treatment started or 
the appearance of one or more new lesions. 
 
 
 
 
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 Stable Disease: 
Insufficient shrinkage to qualify for partial response, or insufficient increase to 
qualify for progressive disease, taking as reference the smallest sum longest diameter 
since the treatment started. 
 
Evaluation of Non-target Lesions: 
 
 Complete Response: 
The disappearance of all non-target lesions. 
 
 Incomplete Response/Stable Disease: 
The persistence of one or more non-target lesion(s) 
 
 Progressive Disease: 
The appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions. 
 
 Evaluation of Best Overall Response: (see table below ) 
 
The best overall response is the best response recorded from the start of treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
 
  
Evaluation of Best Overall Response (RECIST)  
 
 
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 
CR= complete response; PR= partial response; SD= stable disease; and PD= progressive 
disease 
 
 
 
 
 
 
 
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11.1 CRITERIA FOR REMOVAL FROM PROTOCOL TREATMENT 
 
 Progressive disease:  Patients, who develop rapidly progressive disease (clinically or 
by RECIST) before the scheduled evaluation every 6 weeks, may be taken off 
protocol treatment at the discretion of the investigator. Patients can continue to 
receive their assigned targeted agent, even if they develop progressive disease 
radiographically, as long as in the judgment of the treating physician, they are 
benefitting from their targeted agent. 
 Intercurrent illness that prevents continuation of treatment. 
 Unacceptable adverse event(s), or delay of treatment for > 4 weeks due to treatment- 
related toxicity. Note: Patients who require emergency surgery (e.g. for 
appendectomy or because of trauma complications) or who require a procedure (e.g. 
Kyphoplasty/vertebroplasty) may remain on trial, even if administration of the 
targeted agent is interrupted, as long as the targeted agent is resumed within 4 weeks 
from date of interruption. 
 Patient non-compliance with therapy. 
 Decision of the patient to withdraw from the study 
 
11.1 
Withdrawal from Study 
 
A patient may be withdrawn from the study for any of the following reasons: 
 adverse event(s) 
 disease progression 
 subject withdrew consent 
 lost to follow-up 
 death 
 
The consequence of study withdrawal is that no new information will be collected 
from the withdrawn patient and added to the existing data or any database. 
 
 
 
12.1 SAFETY ASSESSMENTS AND REPORTING REQUIREMENTS 
 
12.1 
All patients will be evaluated for safety. The safety parameters include all 
laboratory tests and hematological abnormalities, physical examination findings, 
and spontaneous reports of adverse events reported to the investigator by patients. 
An adverse event is any untoward or unfavorable medical occurrence in a human 
subject, including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with the subject’s 
participation in the research, whether or not considered related to the subject’s 
participation in the research.  All adverse events encountered after the patient has 
provided informed consent and until 4 weeks after the patient has stopped 
treatment will be evaluated according to the NCI Common Toxicity Criteria 
(CTCAE) version 3.0.  Prior treatment associated toxicities present at the time of 
 
 
 
 
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Protocol 2009-0628 
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informed consent but before study treatment initiation, will be recorded as 
baseline abnormalities and graded according to CTCAE version 3.0 criteria. 
 
Information about all adverse events, whether volunteered by the subject, 
discovered by investigator questioning, or detected through physical examination, 
laboratory test or other means, will be collected and reported  as described in the 
data submission schedule 
 
A serious adverse event (SAE) is any adverse experience that results in any of 
the following outcomes: Death, a life-threatening adverse surgical experience, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant disability/incapacity, or a congenital anomaly/birth defect.  Important 
medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
Events not considered to be serious adverse events are hospitalizations for the 
purposes of this protocol and include: 
 
 
 Routine treatment or monitoring of the studied indication not associated with 
any deterioration in condition. 
 Treatment, which was elective or pre-planned, for a pre-existing condition that 
did not worsen 
 Treatment on an emergency, outpatient basis for an event not fulfilling any of 
the definitions of serious given above and not resulting in hospital admission. 
 Symptoms related to progressive disease such as bone pain will not be 
reported as toxicity or serious adverse events 
 
Serious Adverse Events will be reported immediately to the MD Anderson 
Principal Investigator who will notify MD Anderson IRB per the IRB policy for 
reporting adverse events. 
 
12.2 
Reporting to Novartis (Everolimus only) 
To ensure patient safety, every SAE, regardless of suspected causality, 
occurring 
 
 after the patient has provided informed consent and until 4 weeks after the 
patient has stopped study treatment/participation 
 after the patient is randomized and until 4 weeks after the patient has stopped 
study treatment 
 after the patient begins taking study drug and until 4 weeks after the patient 
has stopped study treatment 
 
 
 
 
 
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 after protocol-specified procedures begin (e.g., placebo run-in, washout 
period, double-blind treatment, etc.) and until 4 weeks after the patient has 
stopped study treatment 
 after the start of any period in which the study protocol interferes with the 
standard medical treatment given to a patient (e.g., treatment withdrawal 
during washout period, change in treatment to a fixed dose of concomitant 
medication) and until 4 weeks after the patient has stopped study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 4-week period should only be reported to 
Novartis if the investigator suspects a causal relationship to the study drug. 
Recurrent episodes, complications, or progression of the initial SAE must be 
reported as follow-up to the original episode within 24 hours of the 
investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
 
The investigator must assess and record the relationship of each SAE to each 
specific study drug (if there is more than one study drug), complete the SAE 
Report in English, and send the completed, signed form by fax (888-299-4565) 
within 24 hours to the Novartis Clinical Safety and Epidemiology Department. 
 
The original copy of the SAE Report and the fax confirmation sheet must be kept 
within the Trial Master File at the study site. 
 
Follow-up information is sent to the same person to whom the original SAE 
Report Form was sent, using a new SAE Report Form stating that this is a follow- 
up to the previously reported SAE and giving the date of the original report. Each 
re-occurrence, complication, or progression of the original event should be 
reported as a follow-up to that event regardless of when it occurs. The follow-up 
information should describe whether the event has resolved or continues, if and 
how it was treated, whether the blind was broken or not (if applicable), and 
whether the patient continued or withdrew from study participation. 
 
If the SAE is not previously documented in the [Investigator’s Brochure] or 
Package Insert (new occurrence) and is thought to be related to the Novartis study 
drug, a Clinical Safety and Epidemiology Department associate may urgently 
require further information from the investigator for Health Authority reporting. 
Novartis may need to issue an Investigator Notification (IN), to inform all 
investigators involved in any study with the same drug that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees 
in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries. 
 
 
 
 
 
 
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Novartis instructions for rapid notification of serious adverse events 
The MD Anderson principal investigator has the obligation to report all serious 
adverse events to the FDA, IRB, and Novartis Pharmaceuticals Clinical Safety 
and Epidemiology Department (CS&E). 
 
All events reported to the FDA by the investigator are to be filed utilizing the 
Form FDA 3500A (MedWatch Form). 
 
All events must be reported, by FAX (888-299-4565), to Novartis 
Pharmaceuticals CS&E Department within 24 hours of learning of it’s 
occurrence. This includes serious, related, labeled (expected) and serious, related, 
unlabeled (unexpected) adverse experiences. All deaths during treatment or within 
30 days following completion of active protocol therapy must be reported within 
5 working days. 
 
Any serious adverse event occurring after the patient has provided informed 
consent and until 4 weeks after the patient has stopped study participation must be 
reported. This includes the period in which the study protocol interferes with the 
standard medical treatment given to a patient (e.g. treatment withdrawal during 
washout period, change in treatment to a fixed dose of concomitant medication). 
 
Serious adverse events occurring more than 4 weeks after study discontinuation 
need only be reported if a relationship to the Novartis study drug (or therapy) is 
suspected. 
 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all 
serious adverse experiences will be forwarded to the product manufacturer by the 
investigator. 
 
Pregnancies 
Any pregnancy that occurs during study participation should be reported. To 
ensure patient safety each pregnancy must also be reported to Novartis within 24 
hours of learning of its occurrence. The pregnancy should be followed up to 
determine outcome, including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. 
 
 
 
13.0 
STATISTICAL CONSIDERATIONS / DATA ANALYSIS 
This is a randomized, two-arm, parallel group, phase II trial for patients with advanced 
non-clear cell RCC.  Patients will be randomized in a 1:1 scheme to receive either 
sunitinib (control arm) or everolimus (experimental arm). Patients must have advanced 
non-clear cell RCC, which may include, but is not limited to the following subtypes: 
papillary I or II, chromophobe, collecting duct carcinoma (CDC), translocation, or 
unclassified. Patients with conventional-type renal cell carcinoma who have ≥ 20% 
 
 
 
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Protocol 2009-0628 
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sarcomatoid component in their primary tumor are eligible. Patients who have 
sarcomatoid features in FNA or core biopsy of any metastatic site are eligible, if they 
have an underlying renal cell carcinoma primary tumor. 
 
Patients will be stratified as discussed above in section 5.2. Also, as discussed in section 
5.2, at the time of disease progression or toxicity, patients will have the option to 
crossover to receive the agent they did not receive upfront. 
 
For this randomized phase II study, we use a method advocated by Rubenstein et al for 
randomized phase II screening designs. In these screening designs, one conducts a direct, 
but non-definitive, “screening” comparison of the “experimental versus control 
treatments”. Within this framework, we set the one-sided type I error rate to 0.05 and the 
power to 0.80. 
 
The maximum sample size to be accrued is 108 patients. We estimate that 4 patients will 
be accrued per month. A total of 54 patients will be randomized to the sunitinib arm and 
54 patients will be randomized to the everolimus arm.  The primary measure of efficacy 
is PFS. Note: patients who develop toxicity related to study drug necessitating 
discontinuation of protocol therapy before restaging to assess tumor response will 
not be included in the primary endpoint analysis of progression-free survival but 
will be included in the secondary endpoint analysis of time to failure. Differences in 
PFS will be monitored at 3 time points and will take place as follows: 1) after 33 events 
(to monitor futility), 2) after 65 events, and 3) after at least 97 events occur.  The test 
statistic used will be based on the log-rank test. An early stopping rule for futility will 
serve as guidance for early termination of patient accrual. The interim stopping rule 
consists of a group sequential test based on a Gamma family Type I error spending 
function.  Results from the interim analysis will be reported to an independent Data 
Monitoring Committee (DMC) convened at MD Anderson Cancer Center. The DMC will 
assess the results along with supportive data including other efficacy outcomes, and 
safety data.  It will use this data to possibly recommend early stopping or other study 
modifications. 
 
 
Descriptive and inferential statistics will be used to summarize the treatment effects. The 
mean, standard deviation, median, 25% percentile, 75% percentile, minimum, and 
maximum will be reported for continuous variables by treatment group. For discrete 
(qualitative) outcomes, descriptive analyses will be based on the distribution of these 
discrete outcomes and will be reported as percentages and patient counts by treatment. 
Time to event endpoints will be descriptively summarized by Kaplan-Meier curves. 
Point and interval estimates of treatment effects will be based on maximum likelihood 
methods. For binomially distributed variables, we will report proportions, their 95% 
confidence intervals, differences in proportions and 95% confidence intervals for the 
difference in proportions. Confidence intervals will be constructed using two-sided 95% 
and will be based on the normal approximation.  Although multiple secondary endpoints 
will be evaluated we will make no adjustment for multiplicities associated with these 
multiple tests. 
 
 
 
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13.1 
Power, Sample Size and DMC Considerations 
The statistical hypothesis is stated as: 
 
H0: 
= 1 
Versus 
HA: 
<1 
 
where is the hazard rate for PFS (experimental versus control).  Under the 
alternative hypothesis, the median PFS is 12 weeks for the control arm (sunitinib) 
and 20 weeks for the experimental arm (everolimus). We will use a GF group 
sequential test of futility (GF parameter equal to –3) calculated using EAST 5.0. 
Based on these assumptions, a 1:1 randomization between everolimus and 
sunitinib,  and 2 interim futility looks when 33 and 65 events have occurred, one- 
sided =0.05 and power=80%, the group sequential sample size requirement is 
108 total patients. 
 
The DMC will review the progress, efficacy, and safety profile of this study while 
it is ongoing. The committee will convene at the beginning of the study and at 2 
interim time points (after 33 and 65 events have been observed). The test statistic 
used will be based on the stratified log-rank statistic.  Stopping rules for futility 
will serve as guidelines for early termination of patient accrual. The interim 
stopping rule will consist of a group sequential test based on Gamma Family (GF) 
error spending functions with parameter value set to –3, (Hwang, Shih, and De 
Cani, 1990). We will stop for futility at the interim looks if the p-value is > 0.742 
or > 0.3125 at the first and second interim looks, respectively. 
 
13.2 
Secondary Objectives 
 
(1) Overall survival: Overall survival is calculated from the date of start of 
therapy to the date of death. Patients who are lost to follow-up will be censored at 
date of last contact. 
 
We will use the Kaplan-Meier estimator to estimate the OS for each group of 
patients (control, experimental), and the log-rank statistic will be used to test for 
treatment differences. We will also use the Cox proportional hazards regression 
model to estimate the hazard ratio (experimental, control) for OS with 95% 
confidence intervals. 
 
We will also assess the response rate and report 95% confidence intervals. 
 
 
 
 
 
 
 
 
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13.3 
Additional analyses 
 
Demographics: 
For  each  treatment  group  (control,  experimental),  summary 
statistics will be provided for age, baseline disease status and prior treatments. 
 
Toxicity: Adverse effects that will be evaluated include, but are not limited to 
infections, renal toxicity, hepatic toxicity, and pulmonary toxicity. Methods of 
assessment will include monitoring blood counts, and performing laboratory tests 
as indicated by clinical signs and symptoms. Evidence of toxicity or adverse 
events will be recorded at all clinic visits. All observed adverse effects will be 
graded for all patients and the degree of association of each with therapy assessed. 
The incidence and severity of adverse events will be compared between the two 
treatment arms with Fisher’s exact test. 
 
13.4 
Analysis of Circulating Endothelial Cells 
 
These samples will be analyzed to complete the angiogenic profile of advanced 
renal cell carcinoma, in addition to the soluble protein (biomarker) evaluation. 
 
Analysis of circulating endothelial cells will be reported by data tabulations, 
descriptive statistics, and graphical presentations and as appropriate in relation to 
clinical response and pharmacokinetic endpoints. 
 
 
 
14.0 
DATA AND PROTOCOL MANAGEMENT 
 
Protocol Compliance: All required interim and pretreatment data should be available, and 
the physician must assess tumor response and must provide a detailed description of 
toxicity, when appropriate.  If dose modifications or treatment interruptions are 
necessary, the details must be carefully documented.  Performance status must be 
documented at each toxicity assessment. 
 
 
Data Capture: Data will be entered in the MD Anderson GU departmental oracle system. 
Registration data entry and randomization will occur prior to initiation of therapy.  All 
eligibility criteria must be satisfied. 
 
Accuracy of Data Collection: The MD Anderson Principal Investigator will be the final 
arbiter of response and toxicity, should a difference of opinion exist. 
 
14.1 
Schedule of Data Submission 
 
MD Anderson protocol specific Case Report Forms and/or electronic Case Report 
Forms will be used for collection of all study data. The schedule for submission of 
case report forms and pertinent source documents to MD Anderson is as follows: 
 
 
 
 
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Protocol 2009-0628 
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Case Report Forms/Source Documents 
Schedule for Submission 
Informed Consent/Patient 
Authorization for the Release of 
Personal Health Information 
Prior to study registration 
Eligibility Checklist 
Prior to study registration 
On-Study Form 
Supporting Source Documents (e.g. 
Pathology reports, Medical 
Administration Records, 
Radiology/Laboratory Reports, History 
and Physical, Progress Notes) 
14 days after treatment initiation 
Chemotherapy/Treatment by Cycle 
Form (Chemotherapy, Laboratory 
Results, Concomitant Medications) 
Supporting Source Documents 
14 days after cycle completion 
Adverse Event Form 
Supporting Source Documents 
14 days after cycle completion 
Response Assessment Forms (Disease 
Measurements) 
Supporting Source Documents 
14 days after protocol defined 
imaging assessment 
Off Treatment 
Supporting Source Documents 
14 days after last treatment date 
Survival Update Form 
Supporting Source Documents 
14 days after protocol defined 
survival review 
Off Study Form 
Supporting Source Documents 
14 days after patient removed from 
study 
 
 
 
 
 
 
 
 
 
 
 
 
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15.0 
MULTICENTER PROCEDURES 
 
Participating multicenter institutions will follow the guidelines as addressed below, in the 
MD Anderson Multicenter Management Plan (Appendix F), and throughout this protocol. 
 
15.1 
Principal Investigators 
 
The principal investigator(s) will be responsible for the conduct of the study and 
monitoring its progress.  The responsibility for all reports and data required by 
MD Anderson will be that of the principal investigator(s). 
 
15.2 
Centralized Patient Registration and Randomization 
 
Patients who are candidates for the study will first be evaluated for eligibility by 
the local investigator. All patients will be registered by designated research staff 
in the GU department. 
 
All multicenter patients must be registered both locally and centrally with MD 
Anderson. 
 
At the time of registration, participating institutions will be required to submit a 
completed and signed eligibility checklist and informed consent document. No 
additional source documentation will be required for patient registration. 
 
15.2.1  Eligibility Exceptions 
 
All exceptions to eligibility must first be approved by the Protocol Chair with 
appropriate rationale following MD Anderson guidelines. If eligibility 
clarifications are required from participating institutions, all eligibility questions 
should be routed to the MD Anderson GU Department in order to document the 
question and Protocol Chair response. 
 
15.3 
Guidelines for Reporting Participating Site Serious Adverse Events to MD 
Anderson: 
 
Any Serious Adverse Event (SAE) will be reported to the MD Anderson GU 
Department within 24 hours of knowledge of the event.   The participating 
institution will submit the SAE to its own IRB according to institutional policy 
and must forward a copy of the report to MD Anderson within 5 calendar days. 
The MD Anderson GU department will submit participating site SAE reports to 
the MDACC IRB and Novartis. 
 
 
 
 
 
 
 
 
 
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Protocol 2009-0628 
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SAE notifications and reports will be submitted to: 
 
Fax or email a completed SAE Form to: 
 
MD Anderson GU Department (notifications and reports) 
Attn: 2009-0628 
Fax: 713-563-0857 
Email: GU2009-0628@mdanderson.org 
 
 
 
MD Anderson will maintain documentation of all Serious Adverse Events from 
each institution. MD Anderson will notify all investigators of any serious and 
unexpected adverse experiences that are possibly related to the study therapy. 
The investigators are to file a copy in the protocol file and send a copy to their 
IRB according to their local IRB’s policies and procedures. 
 
15.4 
Guidelines & Procedures for reporting Violations, Deviations and Unanticipated 
Problems. 
 
The Protocol Chair: is responsible for ensuring that clear documentation is 
available in the medical record to describe all protocol deviations, violations, and 
unanticipated problems. The Protocol Chair will also be responsible for ensuring 
that all protocol deviations, violations, and unanticipated problems are reported to 
the MD Anderson IRB per MD Anderson institutional guidelines. 
Participating Institutions: Protocol deviations, violations, and unanticipated 
problems occurring at a participating institution will be submitted to that 
institution’s own IRB. A copy of the participating institution’s IRB deviations, 
violations, and unanticipated problems report will be forwarded to MD Anderson 
by facsimile or via email within 7 calendar days after the original submission. 
 
 
 
15.4.1  Definitions 
 
The definitions for protocol violation and deviation as described by the MD 
Anderson IRB will be applied for reporting purposes for all institutions 
participating in the trial. 
 
Protocol Deviation: Noncompliance with the protocol that does not have a 
significant effect on the subject’s rights, safety, welfare, and/or the integrity of the 
data. Deviations may be caused by the action of the subject, the investigator, the 
research staff, or natural events. 
 
Protocol Violation: Changes to protocol procedures without prior approval of the 
IRB/Sponsor. Violations may significantly alter the clinical effectiveness of the 
treatment or the evaluation of its toxicity and adversely affect patient's safety and 
rights. 
 
 
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Unanticipated Problems: An incident, experience or outcome, that is 
unexpected, related or possibly related to participation in the research and 
suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) that was previously 
known or recognized. These incidents do not meet the definition of an adverse 
event. Unanticipated problems are not limited to study participants, and may also 
include others such as family members and research staff. 
 
MD Anderson GU Department: Upon receipt of the 
violation/deviation/unanticipated problem report from the participating institution, 
the Protocol Chair will review and submit the report to the MD Anderson IRB for 
review. 
 
15.5 
Research Team Teleconferences 
 
The  MD  Anderson  and  participating  institution’s  PIs  and  study  teams  will 
participate in teleconferences as needed to discuss the following information: 
 
 Status of patients enrolled at sites including 
o Eligibility for trial 
o Status of treatment 
o Adverse Events 
o Response evaluation 
o Any questions or concerns 
 
 
 
16.1 
REFERENCES 
 
1. Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 55:10- 
30, 2005 
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