Fosbretabulin With Everolimus in Neuroendocrine Tumors With Progression

A variety of treatment options are available for NETs with carcinoid syndrome including
surgical and medical therapies. Most subjects require somatostatin analogs to control the
symptoms of carcinoid syndrome. Subjects who no longer respond to somatostatin and other
liver-directed therapies, who experience progression of disease and increasing symptoms have
limited options, including participation in a clinical trial. Recently everolimus and
sunitinib have been approved for the treatment of subjects with progressive locally advanced
or metastatic neuroendocrine tumors. Based on the preclinical data in models of NETs and the
clinical activity seen in NETS and other tumor types that have existing tumor vascculature,
this study will examine the effectiveness of fosbretabulin given in combination with
everolimus in subjects with GI-NETs and PNETs.The vasoconstrictive effect of fosbretabulin is
potent, though short-lived (4-8 hours), with no cumulative adverse effect. Everolimus
inhibits angiogenesis, slows tumor growth and has a prolonged half-life (30 hours). Combining
these two agents with distinctly different mechanisms of action may improve tumor control
without additional toxicities, and has the potential of reducing drug resistance.

Inclusion Criteria:

- Patients must have histologically confirmed neuroendocrine tumor (grades 1-3) that is
metastatic or unresectable, and for which standard curative or palliative measures do
not exist or are no longer effective.

- Prior treatment with fosbretabulin is allowed, if not given in combination with
everolimus.

- Prior treatment with everolimus is allowed, if the patient was able to tolerate 10 mg
daily everolimus with acceptable side effects, and if everolimus was not given in
combination with fosbretabulin. A 1 week washout period will be required if patient
was previously on everolimus.

- Age ≥18 years.

- ECOG performance status ≤2.

- Life expectancy greater than 6 months.

- Progressive disease based on radiological imaging within 12 months. RECIST 1.1 would
be used to assess measurable disease burden.

- Patients must have normal organ and marrow function as defined below:

- absolute neutrophil count ≥1,000/mcL

- platelets ≥75,000/mcL

- total bilirubin ≤2.5 × institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

- creatinine within normal institutional limits OR

- creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above
institutional normal

- Women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation. 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.

- Men treated or enrolled on this protocol must also agree to use adequate contraception
prior to the study, for the duration of study participation, and 4 months after
completion of fosbretabulin and everolimus administration.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Patients who have had prior everolimus but were not able to tolerate a 10 mg daily
dose.

- Prior chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or
mitomycin C) prior to entering the study or those who have not recovered from adverse
events due to agents administered more than 4 weeks earlier.

- Child Pugh Class B or greater hepatic dysfunction.

- Patients who are receiving any other investigational agents.

- Patients with known brain metastases because of their poor prognosis and likelihood to
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 fosbretabulin

- Uncontrolled hypertension (HTN); sustained blood pressure (BP) greater than 150/100
mmHg

- Must not have had any unstable angina or myocardial infarction within 4 months prior
to enrollment to treatment, NYHA Class III or IV heart failure, uncontrolled angina,
history of severe coronary artery disease, severe uncontrolled ventricular
arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia
or Grade 3 conduction system abnormalities unless subject has a pacemaker.

- Must not have any evidence of other clinically active cancer and have no history of
prior malignancy within the past 3 years with the exception of: a) adequately treated
basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in
situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less and with
stable prostatespecific antigen levels; or d) cancer considered cured by surgical
resection or unlikely to impact survival for the duration of the study, such as
localized transitional cell carcinoma of the bladder or benign tumors of the adrenal
glands or pancreas.

- Patients receiving any medications or substances that are strong inhibitors or
inducers of CYP3A4 are ineligible. Because the lists of these agents are constantly
changing, it is important to regularly consult a frequently-updated list such as
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as
the Physicians' Desk Reference may also provide this information. As part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or herbal
product.

- Pregnant women are excluded from this study because everolimus and fosbretabulin have
the potential for teratogenic or abortifacient effects. Because there is an unknown
but potential risk for adverse events to nursing infants secondary to treatment of the
mother with these agents, breastfeeding should be discontinued if the mother is
treated with everolimus and fosbretabulin.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with everolimus and fosbretabulin. In
addition, these patients are at increased risk of lethal infections when treated with
marrowsuppressive therapy. Appropriate studies will be initiated for patients
receiving combination antiretroviral therapy when indicated.

- History of prior cerebrovascular event, (including transient ischemic attack) within 6
months of start of screening.

- Current thrombotic or hemorrhagic disorder/event or history of prior event within 6
months of start of Screening

- Corrected QT interval ([QTc] Fridericia) > 480 ms

- Significant vascular disease or recent peripheral arterial thrombosis