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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

NCT03165721

Description:

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 - 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. ...

Related Conditions:
  • Gastrointestinal Stromal Tumor
  • Hereditary Leiomyomatosis and Renal Cell Cancer
  • Paraganglioma
  • Renal Cell Carcinoma
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: A Phase II Trial of the DNA Methyl Transferase Inhibitor, SGI-110 (Guadecitabine), In Children And Adults With Wild Type GIST, Pheochromocytoma And Paraganglioma Associated With Succinate Dehydrogenase Deficiency And HLRCC-Associated Kidney Cancer

Clinical Trial IDs

  • ORG STUDY ID: 170088
  • SECONDARY ID: 17-C-0088
  • NCT ID: NCT03165721

Conditions

  • Paraganglioma
  • Gastrointestinal Stromal Tumors
  • Carcinoma, Renal Cell
  • Renal Neoplasms
  • Pheochromocytoma

Interventions

DrugSynonymsArms
SGI-110 (guadecitabine)Arm 1

Purpose

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 - 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 Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1ExperimentalSGI-110 administered subcutaneously at 45mg/m2/day x 5 days on a 28-day cycle
  • SGI-110 (guadecitabine)

Eligibility Criteria

        -  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.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Assess clinical activity of SGI-11 using RECIST
Time Frame:After the first 4 weeks, then every 8 weeks
Safety Issue:
Description:Efficacy

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Renal Cancer
  • DNA Hypermethylation
  • Gastrointestinal Stromal Tumors
  • DNA Methyltransferase (DNMT) Inhibitor
  • Succinate Dehydrogenase (SDH) Deficiency

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