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
Condition: Paraganglioma; Gastrointestinal Stromal Tumors; Carcinoma, Renal Cell; Renal Neoplasms; Pheochromocytoma
MeSH terms: Kidney Neoplasms; Carcinoma, Renal Cell; Gastrointestinal Stromal Tumors; Pheochromocytoma; Paraganglioma
Intervention: SGI-110 (guadecitabine)
Intervention description: SGI-110 will be administered subcutaneously at 45mg/m^2/day x 5 days on a 28-day cycle. Cycles may be repeated until there is evidence of tumor progression clinically or by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or there is intolerable toxicity that is not alleviated by dose reduction.
Intervention MeSH terms: Guadecitabine; Azacitidine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 9.0
Sex: All
Minimum age: 12 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Renal Cancer; DNA Hypermethylation; Gastrointestinal Stromal Tumors; DNA Methyltransferase (DNMT) Inhibitor; Succinate Dehydrogenase (SDH) Deficiency

Summary:

      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.

      ...
    

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.