A Phase II Trial of the DNA Methyl Transferase Inhibitor, Guadecitabine (SGI-110), in Children and Adults With Wild Type GIST,Pheochromocytoma and Paraganglioma Associated With Succinate Dehydrogenase Deficiency and HLRCC-associated Kidney Cancer

Background

- Loss of activity of the Krebs cycle components succinate dehydrogenase (SDH) complex or
fumarate hydratase (FH), has been identified as a mechanism of tumorigenesis in subsets
of gastrointestinal stromal tumor (GIST), pheochromocytoma and paraganglioma (PHEO/PGL),
and renal cell carcinoma.

- DNA hypermethylation has been demonstrated in these cancers. Loss of activity of SDH or
FH leads to accumulation of the metabolites succinate and fumarate, respectively.
Succinate and fumarate act as inhibitors of a broad array of
alpha-ketoglutaratedependent dioxygenases. The Ten-eleven Translocation (TET) family of
alphaKG-dependent dioxengenase enzymes convert 5-methylcytosine to
5-hydroxymethycytosine leading to DNA demethylation. Inhibition of these enzymes due to
SDH and FH deficiency causes DNA hypermethylation and has been verified in preclinical
models.

- Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the
gastrointestinal tract, resistant to cytotoxic chemotherapy and radiation therapy. KIT
and PDGFRA mutations have been identified as tumor initiating events in 85% of adult
patients with GIST and these tumors are responsive to the tyrosine kinase inhibitor,
Imatinib. In pediatric patients, however, 85% of GISTs lack KIT and PDGFRA mutations
(wild-type) and imatinib is not effective.

- Recent work in the Pediatric and Wild-Type (wt) GIST Clinic at the NCI led to the
identification of succinate dehydrogenase (SDH) deficiency in approximately 90% of
wildtype GIST.

- In addition to wild-type GIST, SDH deficiency is also present in 30% of pheochromocytoma
and paraganglioma (PHEO/PGL) and a subset of renal carcinoma. Loss of SDHB protein
expression is seen in PHEO/PGL and wtGIST either due to mutation in SDH subunit genes or
hypermethylation of the SDHC promoter region.

- Mutations leading to loss of function of FH have been identified in PHEO/PGL as well as
type II papillary renal cell carcinoma in patients with hereditary leiomyomatosis and
renal cell cancer (HLRCC). An FH-deficient paraganglioma had DNA hypermethylation as
demonstrated by array and immunohistochemistry showed increased 5hmC levels in
paragangliomas and pheochromocytomas.

- SGI-110 is a small molecule derivative of decitabine that acts as a DNA
methyltransferase (DNMT) inhibitor and is resistant to inactivation by cytidine
deaminase, hence may thus have a more favorable pharmacokinetic profile compared to
decitabine. Subcutaneously administered SGI-110 is gradually converted to decitabine
resulting in prolonged exposure with a several fold increase in apparent T1/2 compared
to intravenous decitabine. SGI-110 has been demonstrated in preclinical models to induce
a dose-dependent decrease in global DNA methylation and up-regulate expression of
specific genes including MAGE-A1 and NY-ESO-1 through decreased methylation.

- We are proposing a phase II trial with SGI-110 in these SDH-deficient and FH-deficient
tumors.

Objectives:

-To assess the clinical activity of SGI-110 in patients with wt-GIST, SDH-deficient PHEO/PGL,
and HLRCC-associated RCC using RECIST.

Eligibility:

- Adults and children (greater than or equal to 12 years of age) with wt-type GIST, SDH
deficient PHEO/PGL, or HLRCC-associated RCC and measurable disease will be eligible.

- Newly diagnosed patients with PHEO/PGL or HLRCC-associated RCC with localized,
resectable disease will not be eligible. Patients with PHEO/PGL or HLRCC-associated RCC
with unresectable localized disease and/or metastatic disease will be eligible.

- Newly diagnosed patients with wt-GIST with completely resectable disease will not be
eligible. Patients with wt-GIST with metastatic disease and/or residual or recurrent
tumor following surgical debulking will be eligible

- Patients with wt-GIST or HLRCC-associated RCC who have not previously received systemic
therapy are eligible as there are no standard chemotherapy regimens known to be
effective for these cancers.

- Must have adequate performance status, may not be pregnant or breastfeeding, and must
have adequate major organ function.

- No history of severe or uncontrolled inter-current illness including, but not limited
to, ongoing or active infection, symptomatic cardiovascular or pulmonary disease will be
excluded.

Design:

- This is a single site, open label, phase II study using a small optimal two-stage design
to evaluate the clinical response in three groups of patients:

1. wild-type GIST (GIST without KIT or PDGFRA mutation)

2. PHEO/PGL in patients with germline SDH subunit mutation, or

3. RCC associated with HLRCC

- SGI-110 will be administered subcutaneously at 45mg/m2/day x 5 days on a 28-day cycle to
the three groups of patients.

- SGI-110 activity will be assessed by imaging response of measurable disease using
RECISTv1.1, using CT, MRI and/or PET.

- Patients will be closely monitored for development of toxicity with regular physical
examinations and laboratory evaluations. Toxicity will be graded using version 4.0 of
the NCI Common Toxicity Criteria.

- SGI-110 related toxicities greater than or equal to grade 3 will be considered treatment
limiting toxicities, unless they are reversible within 72 hours with supportive care.
Following recovery from toxicity up to 2 dose reductions will be allowed.

- Initially 7 evaluable patients in each group (strata) will be enrolled and if 0 of the 7
have a response, then no further patients will be accrued in that strata. If 1 or more
the first 7 (14.3% or more) have a response, then accrual would continue until a total
of 21 patients have enrolled in that strata. If at least 3 responses (at least 14.3%)
are observed among the 21 evaluable patients, the agent should be considered worthy of
further testing in this disease.

- Enrolling 2 patients/month, it is estimated to require 3 years to complete accrual to a
maximum of 70 patients, a maximum of 63 evaluable patients allowing for a small number
(7) of inevaluable patients.

- INCLUSION CRITERIA:

Patients must:

- Have recurrent or refractory/unresectable disease for which there is no known curative
therapy.

---Wild type-GIST: Patients with recurrent or progressive disease will be eligible.
Newly diagnosed patients with resectable localized disease will not be eligible. Newly
diagnosed patients with metastatic disease and newly diagnosed patients with residual
tumor following surgical debulking will be eligible.

- PHEO/PGL: Patients with recurrent or progressive disease will be eligible. Newly
diagnosed patients with PHEO/PGL that is metastatic at diagnosis and/or
unresectable will be eligible Patients with PHEO/PGL with localized
(non-metastatic), resectable disease will not be eligible.

- Renal cell cancer associated with HLRCC: Patients with localized, resectable
HLRCC-associated renal cell cancer will not be eligible. Patients with metastatic
and/or unresectable HLRCC-associated renal cell cancer will be eligible.

- Have one of the following confirmed histologically, cytologically, or through
biochemical testing:

- wild-type GIST (GIST without KIT or PDGFRA mutation);

- PHEO/PGL with a germline mutation in SDHA, SDHB, SDHC, or SDHD;

--renal cell cancer associated with HLRCC.

- Testing will be performed in CLIA certified labs using genetic tests for KIT/PDGFRA
and testing panels developed for patients with PHEO/PGL. Results from outside labs
will be accepted. Pathologic diagnosis will be reviewed and verified at the Clinical
Center.

- Age: be greater than or equal to 12 years of age

Because there is no dosing or adverse event data currently available on the use of SGI-110
in children < 18 year of age, children < 12 years of age will be excluded from this study,
but may be eligible for future pediatric trials should the results of the study be
positive.

- Measurable disease:

Have measurable disease, defined as at least one lesion that can be accurately measured in
at least one dimension (longest diameter to be recorded for non-nodal lesions and short
axis for nodal lesions) as greater than or equal to 20 mm with conventional techniques or
as greater than 10 mm with spiral CT scan.

- Prior Therapy

- Prior therapy requirements:

---Wt-GIST: Because there are no standard chemotherapy regimens known to be effective
for wt-GIST, previously untreated participants are eligible.

--PHEO/PGL with germline SDH subunit mutation: 131I-MIBG in patients with MIBG avid
tumors or cytotoxic chemotherapy (CVD or temozolomide) is required prior to enrollment
on this trial. However, patients who have refused cytotoxic chemotherapy or for whom
treatment on this protocol prior to receiving cytotoxic chemotherapy is felt to be in
the best interest for the patient by the local investigator will also be eligible.

---HLRCC-associated renal cell cancer: Because there are no standard chemotherapy
regimens known to be effective for HLRCC-associated renal cell cancer, previously
untreated participants are eligible.

- Prior therapy wash-out period requirements

--Participants must be at least 4 weeks from prior surgical procedures and surgical
incisions must be healed.

---Participants must have had their last fraction of external beam radiation therapy
at least 4 weeks prior to enrollment. Participants with prior radiation therapy must
be at least 4 weeks post therapy and have had progression of disease outside the
radiation port.

- Participants must have had their last dose of cytotoxic chemotherapy at least 28
days prior to enrollment, their last dose of biological therapy, such as
biological response modifiers (e.g., cytokines), immunomodulatory agents,
vaccines, differentiating agents, used to treat their cancer at least 28 days
prior to enrollment, their last dose of a monoclonal antibody at least 28 days
prior to enrollment, and their last dose of any investigational agent at least 28
days prior to enrollment.

- Participants must have recovered from the acute toxic effects of prior therapy to
a grade 1 level prior to enrollment (does not apply to alopecia).

- Performance Level: ECOG performance status less than or equal 2 or Karnofsky greater
than or equal to 60% in patients greater than 16 years of age, Lansky greater than or
equal to 60 for patients less than or equal to 16 years of age.

- Have normal organ and marrow function as defined below:

- absolute neutrophil count greater than or equal to 1,500/mcL

- platelets greater than or equal to 100,000/mcL

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 x institutional upper limit of
normal

- creatinine within normal institutional limits

OR

----creatinine clearance greater than or equal to 60 mL/min/1.73 m^2 for patients with
creatinine levels above institutional normal.

-Birth Control:

The effects of SGI-110 on the developing human fetus are unknown. For this reason and
because decitabine is known to be teratogenic, women of child-bearing 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, and for 6
months following 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.

-Ability of subject or legal guardians (if the patient is <18 years old) to understand and
the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

Patients with any one the following will be excluded:

- Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor,
immunotherapy, or biologic therapy, including investigational agents for their
disease.

- History of allergic reactions to SGI-110 or decitabine.

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

- Pregnant or breastfeeding

Pregnant women are excluded from this study because SGI-110 is a derivative of decitabine
which has the potential for teratogenic or abortifacient effects. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to treatment of
the mother with SGI-110, breastfeeding should be discontinued if the mother is treated with
SGI-110.

These potential risks may also apply to other agents used in this study.

- Any evidence of severe or uncontrolled systemic disease, active infection, active
bleeding diatheses, or renal transplant, including any patient known to have hepatitis
B, hepatitis C, or human immunodeficiency virus (HIV) will be excluded. Patients with
HIV who have adequate CD4 count, not requiring antiretroviral medication, may be
enrolled.

- Patients who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study.