Last updated on March 2019

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

Brief description of study


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).


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


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


Participants will be screened with:

  • Physical exam
  • Urine tests
  • CT or MRI, or FDG-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.

Detailed Study Description


  • 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.

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

  • 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.
  • 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.

Clinical Study Identifier: NCT03165721

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