Lu-177-DOTATATE (Lutathera) in Therapy of Inoperable Pheochromocytoma/ Paraganglioma

Background:

- Pheochromocytomas/paragangliomas (PHEOs/PGLs) are rare tumors arising from neural crest
tissue that can develop in sympathetic and parasympathetic paraganglia throughout the
body. Those arising in the adrenal gland are called PHEOs while those located
extraadrenally are called PGLs.

- While benign and uni-focal, PHEO/PGL can be effectively treated with surgical resection,
patients with metastatic PHEO/PGL often times have few effective and efficient treatment
options with current treatments aimed more at palliation and symptom control.
Furthermore, some benign head and neck PGLs may be inoperable because of their size and
location.

- Somatostatin receptors (SSTR), especially type 2, have been shown to be over-expressed
in a number of human tumors, including gastroenteropancreatic (GEP), carcinoids,
neuroblastoma, prostate cancer, and PHEO/PGL among many others.

- Ionizing radiation such as the beta particles emitted by Lu-177 cause DNA damage to
target cells through both direct and indirect mechanisms. In addition, ionizing
radiation has also been shown to induce cell death through what is known as the
bystander effect, a phenomenon where cellular signaling from irradiated cells towards
non-irradiated cells induces cellular damage and eventually death in nearby surrounding
cells.

- Lu-177-DOTATATE is a somatostatin analog that predominantly recognizes SSTR2. This
reagent has been used extensively and its well-tolerated safety profile and efficacy has
been shown in a variety of neuroendocrine tumors.

Primary Objective:

To assess the safety and to evaluate the ability of Lu-177-DOTATATE to improve upon
progression-free survival (PFS) at 6 months in patients with inoperable, SSTR positive
PHEO/PGL by comparing PFS of patients treated with Lu-177-DOTATATE to historical controls
from existing literature.

Eligibility:

- Histologically-proven, surgically inoperable, PHEO/PGL patients (both newly diagnosed or
patients with existing diagnoses are eligible)

- Must have presence of SSTR+ disease as documented by positive Ga-68-DOTATATE PET scan

- Positivity of Ga-68-DOTATATE PET scan defined as having at least one lesion that is
greater than or equal to 10 mm in diameter with uptake that is higher than or equal
to liver and is qualitatively higher and distinguishable from background activity.

- Measurable disease

- Age: greater than or equal to 18

- Karnofsky Performance Score greater than or equal to 60 or, ECOG Performance Status of 2
or better

- Able to understand and willing to sign informed consent

Design:

- Open-label, single-arm, single-center, phase 2 study evaluating efficacy and safety of
Lu-177-DOTATATE in the selected patient population divided into two cohorts: 1) SDHx
cohort will include patients with the succinate dehydrogenase mutation, which is the
most common and most aggressive genetic sub-group of patients with PHEO/PGL, and 2)
apparent sporadic cohort which will include patients without a clear genetic mutation

- Simon 2-stage optimal design will be applied to each cohort independently. For each
cohort, if 11/18 patients are progression-free at 6 months, accrual will proceed to the
second stage, where an additional 23 patients will be accrued, for a total of 41
patients per cohort.

- Assuming a loss-to-follow-up rate of 10%, a total of 45 patients will be accrued to each
cohort, with a total accrual ceiling of 90 patients.

- INCLUSION CRITERIA:

1. Surgically inoperable patients with clinical diagnosis of PHEO/PGL who also have
demonstrated disease histologically consistent with pheochromocytoma or
paraganglioma (preferably confirmed by NIH pathology review if initial pathology
was done outside of NIH, but not mandatory)

2. Progressive disease by RECIST with or without symptomswithin the last 12 months
Untreated patients with existing histologic diagnoses are eligible if progression
can be demonstrated.

3. PHEO/PGL that is associated with the SDHx mutations or is not associated with any
known susceptibility genetic mutations for PHEO/PGL (a.k.a. apparent sporadic ),
based on documented genetic testing results obtained prior to study enrollment.
PHEO/PGL that is associated with non-SDHx mutations such as VHL, NF1, and RET
will not be eligible for this study.

4. Patient is or will be enrolled on protocol 00-CH-0093, Diagnosis,
Pathophysiology, and Molecular Biology of Pheochromocytoma and Paraganglioma.

5. Both metastatic and inoperable primary-only patients are eligible

6. Must have presence of SSTR+ disease as documented by positive Ga-68-DOTATATE PET
scan within 26 weeks of anticipated treatment

6.1 Positivity of Ga-68-DOTATATE PET scan defined as having at least one lesion
that is greater than or equal to 10 mm in diameter with uptake that is higher
than or equal to liver and is qualitatively higher and distinguishable from
background activity.

6.2 Measurable disease as defined by RECIST 1.1 OR patients with bone-only
disease (i.e. no RECIST-measurable lesion) will also be eligible as long as the
Ga-68-DOTATATE PET scan is positive

7. Age greater than or equal to 18

8. Karnofsky Performance Score greater than or equal to 60 or ECOG Performance
Status of 2 or better

9. Able to understand and willings to sign informed consent

10. Ability and willingness to obtain all required scans per study schedule.

11. Negative serum pregnancy test for women of child bearing potential or NOTE: A
female is not of childbearing potential if a prior history of hysterectomy with
bilateral oophorectomy or other procedure has render the patient surgically
sterile, or >2 years since last menstruation.

12. Female patients of childbearing potential and male patients who are not
surgically sterile or with female partners of childbearing potential must agree
to use effective, non-hormonal means of contraception (intrauterine contraceptive
device, barrier method of contraception in conjunction with spermicidal gel)
prior to study entry, for the duration of study participation and for 6 months
(10 half-lives of Lu-177) after the last dose of Lu-177- DOTATATE

13. Must have outside endocrinologist/medical oncologist who can follow the patient
after receiving PRRT at the NIH

14. Patients with secreting tumors must be receiving pharmacologic catecholamine
blockade.

EXCLUSION CRITERIA:

1. Either serum creatinine > 1.7 mg/dL, or creatinine clearance <50 mL/min calculated by
the Cockroft Gault method, eventually confirmed by measured creatinine clearance (or
measured glomerular filtration rate (GFR) using plasma clearance methods.

2. Serum albumin less than or equal to 3.0 g/dL unless prothrombin time is within the
normal range.

3. Child s Class C Liver Disease or worse

4. Hb < 8.0 g/dL; WBC < 2.0 x 10^9/L (or Absolute Neutrophil Count < 1000); Platelets <
100 x 10^9/L

5. New York Heart Association (NYHA) classification of grade III or IV

6. Pregnancy or lactation

7. Prior anti-tumoral radionuclide therapy with unsealed sources. Prior therapy with
sealed radioactive sources such as brachytherapy will be allowed.

8. Prior local radiation therapy would be allowed as long as there is at least one
non-irradiated index lesions.

9. Known brain metastases, unless these metastases have been treated and stabilized for
at least 24 weeks, prior to enrollment in the study. Patients with a history of brain
metastases must have a head CT or MRI scan with contrast to document stable disease
for at least 24 weeks prior to enrolment in the study.

10. Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in
situ of the uterine cervix, unless definitively treated and proven no evidence of
recurrence for 5 years.

11. Patients who participated in any therapeutic clinical study with an investigational
agent within the last 30 days.

12. Patients may be on somatostatin analogue therapy (e.g. but not only limited to
sandostatin or lanreotide therapy). However, therapy with somatostatin analogues
should not be initiated or altered within 3 months of study enrolment. Patients on
short term octreotide may have dose held for 24 hours prior to Lu-177-DOTATATE
therapy. Those on long acting octreotide therapy will receive treatment at 1 to 5 days
prior to their next cold octreotide dose, in order to prevent competition for the
receptor.

13. Patient weight > 400 lbs (table limit for PET scanner).

14. Uncontrolled inter-current illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris,
hypertension (>180/110), arrhythmia, or psychiatric illness/social situations that
would limit compliance with study requirements.

15. Inability to tolerate at least one modality of diagnostic anatomic imaging, such as CT
or MRI