Guadecitabine in Treating Patients with Wild-Type Gastrointestinal Stromal Tumor, Pheochromocytoma, Paraganglioma, or Kidney Cancer

Status: Active

Description

This phase II trial studies how well guadecitabine works in treating patients with wild-type gastrointestinal stromal tumor, pheochromocytoma, paraganglioma, or kidney cancer. Guadecitabine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Eligibility Criteria

Inclusion Criteria

  • 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 Clinical Laboratory Improvement Act (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
  • 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 >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan
  • 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-methyl-iodobenzylguanine (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 (Common Terminology Criteria for Adverse Events [CTCAE] v.5.0) level prior to enrollment (does not apply to alopecia)
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 or Karnofsky >= 60% in patients > 16 years of age, Lansky >= 60 for patients =< 16 years of age
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
  • Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • 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 legally guardians (if the patient is < 18 years old) to understand and the willingness to sign a written informed consent document

Exclusion Criteria

  • 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 women are excluded from this study; breastfeeding should be discontinued if the mother is treated with SGI-110
  • 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

Locations & Contacts

Maryland

Bethesda
National Institutes of Health Clinical Center
Status: Active
Contact: Site Public Contact
Phone: 800-411-1222

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To assess the clinical activity (complete response [CR] or partial response [PR]) of guadecitabine (SGI-110) in patients with wild-type (wt)-gastrointestinal stromal tumor (GIST), succinate dehydrogenase (SDH)-deficient pheochromocytoma (PHEO)/paraganglioma (PGL), and hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated renal cell carcinoma using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1).

SECONDARY OBJECTIVES:

I. Evaluate the toxicity, progression-free (PFS) and overall survival (OS), and pain and quality of life (QOL) of patients on treatment with SGI-110.

II. Better define the pharmacokinetics (PK) of SGI-110 in all patients.

EXPLORATORY OBJECTIVES:

I. Determine the serum and urine concentration of succinate, fumarate and 2-hydroxyglutarate in patients with wild-type GIST, pheochromocytoma and paraganglioma associated with SDH deficiency and HLRCC-associated kidney cancer prior to and on therapy with SGI-110.

II. Explore changes in deoxyribonucleic acid (DNA) methylation and gene expression including SDH, fumarate hydratase (FH), and tumor testis antigens in response to treatment with SGI-110.

III. Assess the global DNA methylation status in tumors by determining LINE-1 methylation in archival pre-treatment tumor samples and in on-treatment tumor samples when available.

OUTLINE:

Patients receive guadecitabine subcutaneously (SC) slowly (up to 1 minute) daily for 5 days. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of treatment, patients are followed up for 30 days.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
NCI - Center for Cancer Research

Principal Investigator
John W. Glod

Trial IDs

Primary ID 10012
Secondary IDs 17-C-0088, NCI-2016-00843
Clinicaltrials.gov ID NCT03165721