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:

Wild-type gastrointestinal stromal tumor (GIST) is a cancer in the esophagus, stomach, or intestines. It does not respond well to standard chemotherapy or radiation therapy. Most people with GIST are treated with imatinib. But it may not work in many children with GIST. Researchers think the drug SGI-110 may help treat people with GIST, pheochromocytoma and paraganglioma (PHEO/PGL), or kidney cancer related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC).

Objective:

To learn if SGI-110 causes GIST tumors to shrink or slows their growth. Also to test how it acts in the body.

Eligibility:

People ages 12 and older who have GIST, PHEO/PGL, or HLRCC that has not responded to other treatments

Design:

Participants will be screened with:

* Physical exam
* Urine tests
* Computed tomography (CT) or magnetic resonance imaging (MRI), or fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan: A machine takes pictures of the body.
* Blood tests

Participants will be injected with SGI-110 under the skin each day for 5 days. This cycle will repeat every 28 days. The cycles repeat until their side effects get too bad or their cancer gets worse.

Participants will have tests throughout study:

* Physical exam and blood and urine tests before each cycle
* Blood tests on days 1, 7, 14, and 28 of the first cycle.
* Scans before cycle 1 and then every other cycle.
* Questionnaires about their pain and quality of life
* Tumor biopsy for those 18 and older: A needle removes a small piece of tumor.

After they stop treatment, participants will have a final visit. This includes an evaluation of their health, pain, and quality of life.

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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.
* Deoxyribonucleic acid (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-ketoglutarate dependent dioxygenases. The Ten-eleven Translocation (TET) family of alphaKG-dependent dioxygenase enzymes convert 5-methylcytosine to 5-hydroxymethylcytosine 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 Platelet Derived Growth Factor Receptor Alpha (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 National Cancer Institute (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 succinate dehydrogenase complex iron sulfur subunit B (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 Melanoma-associated antigen 1 (MAGE-A1) and New York esophageal squamous cell carcinoma 1 (NY-ESO-1) through decreased methylation.
* We are proposing a phase II trial with SGI-110 in these SDH-deficient and fumarate hydratase (FH)-deficient tumors.

Objectives:

-To assess the clinical activity of SGI-110 in patients with wt-GIST, SDH-deficient PHEO/PGL, and HLRCC-associated renal cell carcinoma (RCC) using Response Evaluation Criteria in Solid Tumors (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/m\^2/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 Response Evaluation Criteria in Solid Tumors (RECIST)v1.1, using computed tomography (CT), magnetic resonance imaging (MRI) and/or positron emission tomography (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 National Cancer Institute (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.

Eligibility Criteria:
* INCLUSION CRITERIA:

Patients must:

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

  ---Wild type-gastrointestinal stromal tumors (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.
  * Paraganglioma-Pheochromocytoma (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 Hereditary leiomyomatosis and renal cell cancer (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 platelet derived growth factor receptor alpha (PDGFRA) mutation);
  * PHEO/PGL with a germline mutation in Succinate Dehydrogenase Complex Flavoprotein Subunit A (SDHA), Succinate Dehydrogenase Complex Flavoprotein Subunit B (SDHB), SDHC, or SDHD;

    --renal cell cancer associated with HLRCC.
* Testing will be performed in Clinical Laboratory Improvement Amendments (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 computed tomography (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 (cyclophosphamide, vincristine, and dacarbazine (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: Eastern Cooperative Oncology Group (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
  * Aspartate aminotransferase (AST) Serum glutamic oxaloacetic transaminase(SGOT)/Alanine aminotransferase (ALT) Serum glutamic pyruvic transaminase(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 cluster of differentiation 4 (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.