Study to Evaluate the Safety of Combining Two Radionuclide Therapies to Treat Mid-gut Neuroendocrine Tumors

[131]Iodine-MIBG and [90]Yttrium-DOTATOC are radioactive drugs designed to treat specific
tumor cells. These drugs are a combination of the radiation (131-Iodine, 90-Yttrium) and a
protein that targets the tumor cell (MIBG or DOTATOC). Because these proteins are attracted
to, and stick to, the tumor, the radiation is centered in the tumors. This kills more tumor
cells and minimizes radiation-damage to healthy tissues, like the heart and lungs.

Two organs still absorb some of the radiation, though: bone marrow and the kidney. These
organs limit how much radiation can be given to tumors, but we don't know how much radiation
is too much. Too much radiation to bone marrow can result in anemia. Too much radiation to
the kidneys can result in kidney failure. From prior radiation therapies, we have a general
idea of how much radiation we can give safely.

131I-MIBG and 90Y-DOTATOC have never been given together. We want to give them together
because many times, tumors are actually groups of different types of cells. This means, not
all the cells respond to therapy the same way. If some tumor cells survive therapy, the tumor
will continue to grow and eventually come back. We know some mid-gut neuroendocrine tumors
(NETs) have targets for DOTATOC and some other mid-gut NETs have targets for MIBG. We also
have now identified that some people with mid-gut NETs have different tumors: some with
targets for MIBG and some with targets for DOTATOC. For these people, this means treating
only with 131I-MIBG or 90Y-DOTATOC will not be enough to treat their cancer. They need both
radioactive drugs.

Because we are combining these radioactive drugs, this study is known as a first-in-man
study. We are also using a special imaging to help us estimate the radiation dose to the bone
marrow and to the kidneys. This is what decides the final dose of 131I-MIBG and 90Y-DOTATOC.

Before receiving therapy, participants will be asked to undergo imaging to verify they have
both MIBG and DOTATOC tumor types:

- participants are given very small doses of radioactive drugs

- a special camera (SPECT/CT) collects images (scans)

- imaging (scans) are done over 3 calendar days

- blood samples are taken at that time, too, to measure the circulating amount of tracer
doses

If the scans show a participant has both MIBG and DOTATOC tumors, therapy is given:

- a customized dose of 90Y-DOTATOC is given on day 1 of a treatment cycle. This is given
outpatient.

- a customized dose of 131I-MIBG is given on day 2 of a treatment cycle. This is given
inpatient (admitted to the hospital).

- participants are monitored through blood tests to identify the side effects of therapy.

Each participant can have up to 2 cycles of therapy. The cycles are 12 weeks apart.

The doses for 90Y-DOTATOC and 131I-MIBG are decided based on radiation to the bone marrow and
radiation to the kidney. Doses are decided by how well other participants have done on this
study.

Participants have life long follow-up for this study. This is very important, because a study
like this has not been done.

A 2-step eligibility is utilized for this study.

STEP 1:

Inclusion Criteria:

- Ability to understand and the willingness to provide informed consent.

- A pathologically confirmed (histology or cytology) malignant neoplasm that is
determined to be well-differentiated neuroendocrine tumor (i.e. grade 1 or grade 2).
The primary tumor location should be known or believed to be midgut, or
pheochromocytoma, or paraganglioma.

- Disease not amenable to curative intent treatment (primarily surgery) and in addition
has shown either clinical or radiographic progression on all available
(non-radionuclidic) therapies known to confer clinical benefit.

- SSTR positive sites as demonstrated by either SSTR2 positivity (2+ or 3+ intensity and
greater than 10% tumor cell occupying the receptors) or a nuclear medicine scan
utilizing 111In-DTPA-Phe3-Octreotide (Octreoscan™) or 68Ga-DOTA-tyr3-Octreotide within
12 months prior to anticipated C1D1 demonstrating SSTR positive tumor sites

- ≥1 tumor site must have demonstrated uptake equal to or greater than normal liver as
documented by nuclear scan imaging

- ≥1 evaluable site of disease measuring ≥ 1.5 cm in diameter on CT or MRI as measured
per RECIST

- ≥ 18 to 70 years at the time of study drug administration.

- Karnofsky Performance Status at least 70%

- Agrees to contraception.

Exclusion criteria:

- Patients who are considered a fall risk.

- Women who are pregnant or breast feeding.

- Surgery, radiation or chemotherapy within 4 weeks of proposed step 1 start date.

- Prior peptide-receptor radiotherapy (PRRT).

- Investigational drug within 4 weeks of proposed step 1 start date.

- More than one concurrent, malignant disease.

- History of congestive heart failure and cardiac ejection fraction ≤ 40%.

- Patients for whom, in the opinion of their physician, a 24-hour discontinuation of
somatostatin analogue therapy represents a health risk.

- Patients who are unable to discontinue medications known to affect MIBG uptake

- Proteinuria, grade 2 (i.e., ≥ 2+proteinuria).

- Long-acting somatostatin analogue treatment within 14 days of proposed step 1 start
date.

- Prior external beam radiation involving kidneys (scatter doses of < 500 cGy to a
single kidney or radiation to < 50% of a single kidney is acceptable).

- Prior external beam radiation (including brachytherapy) involving 25% of bone marrow
(excluding scatter doses of ≤ 5 Gy).

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to 90Y-DOTA-tyr3-Octreotide, Octreoscan®, 68Ga-Octreotide, or 131I-MIBG.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

If a subject meets STEP 1 criteria, a serial SPECT scan is performed for dosimetry. Step 2
criteria must be met and verified prior to therapy initiation.

STEP 2:

Inclusion Criteria:

- Subjects must demonstrate at least one of the following:

- One or more MIBG+ and DOTATOC- tumors in addition to one or more DOTATOC+ tumors,
and/or,

- One or more tumor sites where the calculated "safe" radiation tumor dose is
higher by at least 25% with a combination of 131I-MIBG and 90Y-DOTATOC than it is
with 90Y DOTATOC alone, or,

- Within 2 weeks of study drug administration for therapeutic intent, patients must have
normal organ and marrow function as defined below:

- absolute neutrophil count ≥ 2000 cells/mm3

- platelets ≥100,000 cells/mm3

- total bilirubin <1.5 x institutional ULN for age and weight

- AST(SGOT) ≤ 2.5 x institutional ULN

- ALT (SGPT) ≤ 2.5 x institutional ULN

- eGFR ≥ 50 mL/min/1.73 m2 (Cockroft Gault formula)