QUILT-3.006 for Recurrent Medullary Thyroid Cancer

BACKGROUND:

- CEA is overexpressed in multiple malignancies, including medullary thyroid cancer where
CEA is universally expressed on tumor cells.

- There is no standard treatment for patients with asymptomatic or minimally symptomatic,
metastatic medullary thyroid cancer. The only effective FDA-approved therapy
(vandetanib) comes with significant toxicity, so it is not used until patients have
symptomatic or rapidly progressing disease.

- Preclinical studies have shown that GI-6207 can induce a strong immune response to CEA
as well as therapeutic anti-tumor responses.

- A previous Phase I GI-6207 study has demonstrated safety and enhanced immune response in
some patients.

- Preliminary data suggests that tumor growth rates can be calculated in medullary thyroid
cancer patients within 3 months

- Retrospective data from prostate cancer studies suggest that vaccines can alter tumor
growth rates within 3-4 months

OBJECTIVES:

Primary:

-To determine the effect of GI-6207 on calcitonin growth rate kinetics after 6 months of
therapy in patients with medullary thyroid cancer

ELIGIBILITY:

- Patients will have evidence of metastatic medullary thyroid cancer including disease
that is evaluable on bone or CT scan.

- Patients with minimal or no disease related-symptoms (minimal symptoms will include
those that do not affect activities of daily living or pain that does not require
regularly schedule narcotics.)

- ECOG 0-1

- No previous chemotherapy

- No previous vandetanib

- Should have no autoimmune diseases; no evidence of being immunocompromised; no serious
inter-current medical illness; no cardiac disease; no prior splenectomy. (History of
previous thyroid autoimmune disease will be allowed as these patients will have had
total thyroidectomy.)

- No brain metastasis, history of seizures, encephalitis, or multiple sclerosis

- No pericardial-based masses greater than 1 cm or thoracic lesions larger than 2 cm

Design:

- Randomized, phase 2 study to determine the effect of GI-6207 on calcitonin growth rate
after 6 months of GI-6207

- Patients will be randomized to either initial GI-6207 therapy or 6 months of
surveillance followed by GI-6207 therapy.

- GI-6207 will be administered subcutaneously at 4 sites at dose of 10 yeast units per
site, biweekly for 7 visits (day 1, 15, 29, 43, 57, 71, 85), then monthly up to 1 year
of treatment. (For patients randomized to surveillance and then GI-6207, they will get a
full year of GI-6207 after a 6 month surveillance period.)

- Once patients have completed one year of therapy with GI-6207, patients without
radiographic progression will have the option to receive vaccine every 3 months for an
additional 12 months. Patients who remain on vaccine will continue to be scanned every 3
months.

- Immune monitoring via apheresis will be done prior to enrollment and at 6 months for all
appropriate and consenting patients. Patients who are evaluable for immunologic response
by the ELISPOT Assay (HLA 02, 03 and 24) will have apheresis at start of GI-6207 therapy
and then every 3 months while on GI-6207 treatment when feasible.

- INCLUSION CRITERIA:

Participants must meet the following criteria for participation:

- Diagnosis: Patients must have histologically confirmed medullary thyroid cancer by the
Laboratory of Pathology or a pathology report and history consistent with medullary
thyroid cancer. It is not uncommon for a secondary, minor pathologic focus of another
form of thyroid cancer to be coincidentally found in 15-20% of patients with medullary
thyroid cancer. In such cases, eligibility is based on the discretion of the
investigator.

- Patients must have evidence of metastatic medullary thyroid cancer including disease
that is evaluable on bone, CT scan or MRI. (Patients who are surgical candidates and
potentially rendered disease free with surgical resection are not eligible.)

- Patients must have elevated calcitonin levels, greater than 8 pg/mL in females and 16
pg/mL in males

- Patients with minimal or no disease related-symptoms (Minimal symptoms will include
those that do not affect activities of daily living or pain that does not require
regularly scheduled narcotics.)

- No brain metastasis, history of seizures, encephalitis, or multiple sclerosis.

- Age greater than or equal to 18 years

- ECOG performance status of 0-1 at study entry (Karnofsky greater than or equal to 70)

- No systemic steroid use within 2 weeks prior to initiation of experimental therapy.
Limited doses of systemic steroids to prevent IV contrast, allergic reaction or
anaphylaxis (in patients who have known contrast allergies) are allowed.

- Hematological eligibility parameters

- Granulocyte count greater than or equal to 1,500/mm^3

- Platelet count greater than or equal to 100,000/mm^3

- Hemoglobin greater than or equal to 9 g/dL

- Biochemical eligibility parameters (within 16 days of starting therapy)

- Baseline renal function:

--- Serum creatinine less than or equal to 1.5 x upper limit of normal OR
creatinine clearance on a 24-h urine collection of greater than or equal to 60
mL/min.

- Hepatic function:

- Bilirubin less than or equal to 1.5 mg/dl, in patients with Gilbert's
syndrome, a total bilirubin less than or equal to 3.0 mg/dL

- AST and ALT< 2.5 times upper limit of normal

- No other active malignancies within the past 3 years (with the exception of
nonmelanoma skin cancers, prostate cancer patients with stable biochemical
recurrence/not on systemic therapy or carcinoma in situ of the bladder).

- Willing to travel to the NIH for follow-up visits

- Able to understand and sign informed consent.

- Must agree to use effective birth control (such as a condom) or abstinence during and
for a period of 6 months after the last vaccination therapy.

EXCLUSION CRITERIA:

Patients with any of the following will not be eligible for participation in this study:

- Patients should have no evidence of immune dysfunction as listed below.

- 1 Human immunodeficiency virus (HIV) positivity due to the potential for
decreased immune response to the vaccine.

- Active autoimmune diseases requiring treatment or a recent history of autoimmune
disease requiring therapy, including, but not limited to, inflammatory bowel
disease, Crohn's disease, ulcerative colitis, or active diverticulitis. This
requirement is due to the potential risks of exacerbating autoimmunity. However,
patients with vitiligo may be enrolled. (Patients with history of autoimmune
thyroid conditions will be allowed as these patients will be on replacement
medications.)

- Concurrent use of systemic steroids, except for physiologic doses of systemic
steroid replacement or local (topical, nasal, eye drops or inhaled) steroid use.
Limited doses of systemic steroids (e.g., in patients with exacerbations of
reactive airway disease or to prevent IV contrast allergic reaction or
anaphylaxis in patients who have known contrast allergies) are allowed.

- Pregnant or breast-feeding women, due to the unknown effects of GI-6207 on the fetus
or infant.

- Serious inter-current medical illness which would interfere with the ability of the
patient to carry out the treatment program.

- Untreated brain metastases (or local treatment of brain metastases within the last 6
months) due to the poor prognosis of these patients and difficulty ascertaining the
cause of neurologic toxicities.

- Patients with pericardial masses >1 cm or thoracic lesions larger than 2 cm will be
excluded.

- Concurrent chemotherapy.

- Chronic hepatitis infection, including B and C, because potential immune impairment
caused by these disorders may diminish the effectiveness of this immunologic therapy.

- Participation in another interventional clinical trial at the time of enrollment.

- Any significant disease that, in the opinion of the investigator, may impair the
patient's tolerance of study treatment.

- Significant dementia, altered mental status, or any psychiatric condition that would
prohibit the understanding or rendering of informed consent.

- Patients with second malignancy within 3 years of enrollment; patients treated
surgically with a curative intent, such as non-melanoma skin cancers, localized kidney
cancer or carcinoma in situ of the bladder, are not excluded. Patients with MEN2 and a
history of pheochromocytoma will also not be excluded. In addition patients with
prostate cancer who do not require systemic therapy will not be excluded. (A
secondary, minor pathologic focus of another form of thyroid cancer may be
coincidentally found in 15-20% of patients with medullary thyroid cancer. In such
cases, eligibility is based on the discretion of the investigator.