A 3-Arm Randomized Phase II Trial Evaluating Single Agent and Combined Efficacy of Pasireotide and Everolimus in Adult Patients With Radioiodine-Refractory Differentiated and Medullary Thyroid Cancer

Inclusion Criteria:

1. Histologic or cytologic confirmation of thyroid cancer (papillary, follicular,
medullary); histologic variants such as Hurthle and tall cell variants are allowed.

2. Biochemical or radiologic documentation of disease progression within the last 12
months prior to enrollment.

3. Presence of at least one site of measurable disease according to RECIST criteria
version 1.1

4. Patient must have radioiodine refractory disease as defined by one or more of the
following conditions:

- All cases of medullary thyroid carcinoma

- No iodine-uptake on a post- radioactive iodine treatment scan (in presence of
low iodine diet and thyroid stimulating hormone (TSH) suppression) in an
anatomically defined lesion that qualifies as target lesion by RECIST criteria
OR

- If there is demonstrable iodine-uptake: the last radioiodine therapy of (≥ 100
mCi) was given within the last 16 months OR if given more than 16 months before
enrollment, there is evidence of disease progression after each of the last two
radioiodine treatment performed within 16 months of each other (each dose should
be ≥ 100mCi) OR

- If the patient has received the maximum cumulative life time dose of radioactive
iodine treatments of at least 600 mCi

5. Age ≥ 18 years.

6. Minimum of four weeks since any major surgery or since completion of radiation
(patients should have adequately recovered from the acute toxicities of any prior
therapy).

7. ECOG performance status less than or equal to 2.

8. Life expectancy of at least 6 months.

9. Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x
109/L, Hgb > 9 g/dL.

10. Adequate liver function as shown by: serum bilirubin ≤ 1.5 x upper limit of normal
(ULN), and serum transaminases activity ≤ 2.5 x ULN, with the exception of serum
transaminases (< 5 x ULN) if the patient has liver metastases.

11. Adequate renal function as shown by serum creatinine ≤ 1.5 x ULN or GFR of 60cc/ml
using the formula of Cockroft and Gault.

12. Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5
x 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.

13. Women of childbearing potential must have a negative serum pregnancy test within 14
days of the administration of the first study treatment. Women must not be
lactating. Both men and women of childbearing potential must be advised of the
importance of using effective birth control measures during the course of the study.

14. Signed informed consent to participate in the study must be obtained from patients
after they have been fully informed of the nature and potential risks by the
investigator (or his/her designee) with the aid of written information.

15. INR and PTT ≤1.5 x ULN. (Anticoagulation is allowed if target INR ≤ 1.5 on a stable
dose of warfarin or on a stable dose of LMW heparin for >2 weeks at time of
randomization.)

Exclusion Criteria:

1. More than one prior treatment with a cytotoxic chemotherapy, biologic agent or an
investigational drug

2. Patients who have undergone major surgery within 4 weeks prior to study enrollment

3. Chronic treatment with systemic steroids or another immunosuppressive agent.

4. Patients should not receive immunization with attenuated live vaccines during study
period or within 1 week of study entry.

5. Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases.

6. Patients with prior or concurrent malignancy except for the following: adequately
treated basal cell or squamous cell skin cancer, or other adequately treated in situ
cancer, or any other cancer from which the patient has been disease free for five
years.

7. Patients with uncontrolled diabetes mellitus or a fasting plasma glucose > 1.5 ULN.
Note: At the principle investigator's discretion, non-eligible patients can be
re-screened after adequate medical therapy has been instituted.

8. Patients with symptomatic cholelithiasis (asymptomatic gall stone discovered on
screening US should be reviewed by the PI but will not lead to automatic exclusion)

9. Patients who have congestive heart failure (NYHA Class III or IV), unstable angina,
sustained ventricular tachycardia, ventricular fibrillation, clinically significant
bradycardia, advanced heart block or a history of acute myocardial infarction within
the six months preceding enrollment

10. Patients with established QT-prolongation (i.e. baseline QT > 450-480 ms), or at risk
for torsades de pointes (uncorrected hypokalemia or hypomagnesemia; family history of
long QT syndrome, or on concomitant medications known to prolong the QT interval)

11. Patients with the presence of active or suspected acute or chronic uncontrolled
infection or with a history of immunocompromise, including a positive HIV test
result (ELISA and Western blot).

12. Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as:

- Severely impaired lung function (as defined as spirometry and DLCO that is 50%
of the normal predicted value and/or 02 saturation that is 88% or less at rest
on room air)

- Any active (acute or chronic) or uncontrolled infection/ disorders.

- Nonmalignant medical illnesses that are uncontrolled or whose control may be
jeopardized by the treatment with the study therapy

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of RAD001

- Patients who have a history of alcohol or drug abuse in the 6 month period prior
to receiving treatment with pasireotide or RAD001

13. Women who are pregnant or breast feeding, or women/men able to conceive and unwilling
to practice an effective method of birth control. (Women of childbearing potential
must have a negative serum pregnancy test within 14 days prior to administration of
pasireotide and RAD001). Oral, implantable, or injectable contraceptives may be
affected by cytochrome P450 interactions, and are therefore not considered effective
for this study.

14. Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins
(sirolimus, temsirolimus) or to its excipients

15. Known hypersensitivity to somatostatin analogues or any component of the pasireotide
or octreotide LAR formulations

16. History of noncompliance to medical regimens

17. Patients unwilling to or unable to comply with the protocol

18. Patients taking medications known to be strong CYP3A inhibitors (Table 6-5).