Study of Mutation-Targeted Therapy With Sunitinib or Everolimus in People With Advanced Low- or Intermediate-Grade Neuroendocrine Tumors of the Gastrointestinal Tract and Pancreas With or Without Cytoreductive Surgery

Background:

- Neuroendocrine tumors (NETs) of the gastrointestinal tract and pancreas are a rare and
heterogeneous group of neoplasms with unique tumor biology, natural history, and
clinical management issues.

- Most NETs are sporadic, but they can be part of familial cancer syndromes such as
multiple endocrine neoplasia type 1 (MEN1), neurofibromatosis type 1 (NF1) or Von
Hippel-Lindau (VHL) syndrome.

- Well-differentiated, low or intermediate grade NETs have a heterogeneous natural
history.

- Surgery is the only curative treatment option in patients with localized early stage
NETs.

- The optimal management strategy for patients with advanced NETs is unknown.

- The majority of NETs have somatic mutations in MEN1 and CDKN1B, and genes involved in
the PI3K/AKT/mTOR signaling pathway, and/or overexpression of growth factors and their
receptors such as VEGF, VEGFR, PDGF, and PDGFR that can be targeted for therapy.

- Survival in patients with NETs and somatic mutations is better than patients with wild
type NETs.

- Sunitinib (multi-tyrosine kinase inhibitor) and everolimus (mTOR signaling pathway
inhibitor) are currently approved for the treatment of progressive, unresectable,
locally advanced or metastatic pancreatic NETs.

- However, mutation targeted therapy with sunitinib or everolimus has not been studied in
this patient population.

- The present proposal aims to determine if mutation targeting therapy for patients with
advanced low- or intermediate grade NETs is more effective than historically expected
results.

Objectives:

-To determine the progression-free survival in patients with NETs of the gastrointestinal
tract and pancreas treated with sunitinib or everolimus based on tumor genotyping.

Eligibility:

-Patients with:

- progressive, histologically or cytologically diagnosed low or intermediate grade locally
advanced or metastatic NETs.

- Age greater than or equal to 18 years

Design:

- Phase II open labeled clinical trial.

- Tumor biopsy for tumor genotyping will be performed if the patient does not have
archival tissue available and does not have MEN1, VHL or NF1.

- Patients with somatic or germline mutations in MEN1/PDGFR/KIT/FMS-like tyrosine kinase-3
will be treated with sunitinib. (Arm 1)

- Patients with somatic/germline mutations in NF1/PTEN/PI3K/AKT/mTOR/VHL will be treated
with everolimus. (Arm 2)

- Patients with wildtype tumor will be treated with sunitinib. (Arm 1)

- Patients who have disease-progression on either sunitinib or everolimus will cross-over
to the other drug.

- Treatment will continue until disease progression, unacceptable toxicity, or consent
withdrawal.

- Up to 120 patients will be accrued to the study. It is anticipated that 20-30 patients
per year may enroll into this trial; thus accrual may be completed in 4-5 years.

-INCLUSION CRITERIA:

1. Progressive, histologically or cytologically diagnosed low or intermediate grade,
neuroendocrine tumors confirmed by the Laboratory of Pathology, NCI. Disease
progression is defined according to RECIST criteria for progression of disease or any
new lesions seen on 68-Gallium DOTATATE within the 18 months prior to enrolment.

2. Age greater than or equal 18 years, because the incidence and prevalence of metastatic
pancreatic and gastrointestinal neuroendocrine tumors in the pediatric patient
population is exceedingly rare (children are excluded from this study, but will be
eligible for future pediatric trials).

3. Patients must have measurable disease according to RECIST criteria on anatomic imaging
studies (CT scan or MRI).

4. Willingness to undergo tumor biopsy if the patient does not have a known familial
cancer syndrome (MEN1, VHL and NF1). Archival tissue available.

5. ECOG performance status <2.

6. Patients must have normal organ and bone marrow function as defined below:

- hemoglobin greater than or equal 9 g/dL *

- leukocytes greater than or equal 3,000/mcL *

- absolute neutrophil count greater than or equal 1,500/mcL *

- platelets greater than or equal institutional lower limit of normal

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) less than or equal 2.5 times institutional upper limit of
normal

(less than or equal 5 times ULN in patients with liver metastases)

- creatinine within normal institutional limits

OR

- creatinine clearance greater than or equal 60 mL/min/1.73 m(2) for patients with
creatinine levels above institutional normal.

- INR less than or equal 2;

- If a patient s bone marrow function falls below the indicated values and it
is not thought to be related to prior treatments a hematology consult will
be ordered. If Hematology deems the patients safe to proceed with treatment
they will be allowed to enroll on study. In such cases, the patient s
absolute neutrophil count must be greater than 1,000/mcl, hemoglobin must be
greater than 7.5 g/dL and the platelet count must be > 75,000 mcL. Each
patient will also be seen by a medical oncologist at follow-up visits if
possible.

7. Fasting serum cholesterol less than or equal 300 mg/dL OR less than or equal 7.75
mmol/L AND fasting triglycerides less than or equal 2.5x ULN. NOTE: In case one or
both of these thresholds are exceeded, the patient can only be included after
initiation of appropriate lipid lowering medication;

8. Women of childbearing potential (WOCBP)or partners of WOCBP participating in this
study must agree to use highly effective contraception while on treatment and for at
least 8 weeks after end of treatment, because the effects of sunitinib and everolimus
on the developing human fetus are unknown. Should a woman become pregnant or suspect
she is pregnant while she or her partner is participating in this study, she should
inform her treating physician immediately.

Highly effective contraception methods include combination of:

1. Any two of the following:

- Use of oral, injected or implanted hormonal methods of contraception or;

- Placement of an intrauterine device (IUD) or intrauterine system (IUS);

- Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal
suppository;

2. Total abstinence or;

3. Male/female sterilization.

Women are considered post-menopausal and not of child-bearing potential if they have
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior
to enrollment. In the case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment is she considered
not of child-bearing potential.

9. Must have fully recovered from toxicities of any prior treatment with cytotoxic drugs,
radiotherapy, surgery, or other anti-cancer modalities (returned to baseline status as
noted before most recent treatment or less than or equal grade 1).

10. Ability of subject to understand and the willingness to sign a written informed
consent document.

EXCLUSION CRITERIA:

- Uncontrolled hypertension (>150/100 mmHg).

- Prior external beam radiation therapy to the target lesion(s) within 1 months prior to
enrollment

- Prior systemic chemotherapy or therapy with one of the investigational agents within 1
month prior to enrollment.

- Patients who had therapy with one of the investigational agents more than 1 month
prior to enrollment in whom tumor genotyping show assignment to the same
investigational agent.

- Patients who are receiving any other investigational agents.

- Patients with known brain metastases will be excluded from this clinical trial because
of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to sunitinib or everolimus.

- Patients who have any severe and/or uncontrolled medical conditions such as:

1. unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction less than or equal 6 months prior to start of everolimus, serious
uncontrolled cardiac arrhythmia, or any other clinically significant cardiac
disease

2. symptomatic congestive heart failure of New York heart Association Class III or
IV

3. active (acute or chronic) or uncontrolled severe infection, liver disease such as
cirrhosis, decompensated liver disease

4. known severely impaired lung function

5. QTc interval > 450 msec for males or > 470 msec for females

6. active, bleeding diathesis;

7. psychiatric illness/social situations that would preclude informed consent, limit
compliance with study requirements

- Pregnant or nursing patients will be excluded from the study, because the effects of
sunitinib and everolimus on the developing human fetus are unknown. Because there is
an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with sunitinib or everolimus, breastfeeding should be
discontinued if the mother is treated with sunitinib or everolimus.

- Current treatment with therapeutic doses of Coumadin-derivative anticoagulants (low
dose Coumadin up to 2 mg PO daily for deep vein thrombosis prophylaxis is allowed).

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with study agents.

- Lack of physical integrity of the upper gastrointestinal tract or malabsorption
syndrome, or the inability to take oral medication

- Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy.
Patients with a known history or diagnosis of diabetes mellitus who are on therapy and
have had good blood sugar control may be included,even if the HbA1c is > 8% because

this value can take up to 3-4 months to normalize

- Patients who have received live attenuated vaccines within 1 week of start of
everolimus and during the study. Patient should also avoid close contact with others
who have received live attenuated vaccines. Examples of live attenuated vaccines
include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever,
varicella and TY21a typhoid vaccines

- Patients who are on chronic treatment with corticosteroids or other immunosuppressive
agents (topical or inhaled corticosteroids are allowed)

- Patients with a history of non-compliance to medical regimens or who are considered
potentially unreliable or will not be able to complete the entire study

- Patients who are taking medications that are strong inhibitors of CYP3A4 or PgP and
need to remain on these medications. For a current table of Substrates, Inhibitors and
Inducers please access the following
website:http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResourc
es/DrugInteractionsLabeling/ucm093664.htm

- Patients who have a history of another primary malignancyfrom which the patient has
been disease free for < 3 years at the time of enrolment, with the exceptions of: a
patient with a familial cancer syndrome-associated NETs including MEN1, VHL, NF-1, and
TS;