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
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
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:
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:
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
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:
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:
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.
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.
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.
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:
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:
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.