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Guadecitabine

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SGI-110 administered subcutaneously at 45mg/m\^2/day x 5 days on a 28-day cycle

Gastrointestinal stromal tumor (GIST)

SGI-110 administered subcutaneously at 45mg/m\^2/day x 5 days on a 28-day cycle

Pheochromocytoma and Paraganglioma (PHEO/PGL) with succinate dehydrogenase (SDH)-deficient PHE

SGI-110 administered subcutaneously at 45mg/m\^2/day x 5 days on a 28-day cycle

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated Renal Cell Ca

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.

SGI-110 (guadecitabine)

John W Glod, M.D.

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.

...

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.
* Deoxyribonucleic acid (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-ketoglutarate dependent dioxygenases. The Ten-eleven Translocation (TET) family of alphaKG-dependent dioxygenase enzymes convert 5-methylcytosine to 5-hydroxymethylcytosine 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 Platelet Derived Growth Factor Receptor Alpha (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 National Cancer Institute (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 succinate dehydrogenase complex iron sulfur subunit B (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 Melanoma-associated antigen 1 (MAGE-A1) and New York esophageal squamous cell carcinoma 1 (NY-ESO-1) through decreased methylation.
* We are proposing a phase II trial with SGI-110 in these SDH-deficient and fumarate hydratase (FH)-deficient tumors.

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:

* 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/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.

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

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 activity of SGI-11 was assessed using the RECISTv1.1. Complete Response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.

Change in distress from baseline was assessed by The Distress Thermometer (DT) visual analog scale. An overall score is derived from specific physical, emotional and family issues identified by the participant to be stressful. No distress (0-4), moderate stress (5) and high distress (6-10).

National Cancer Institute (NCI)

Principal Investigator

SGI-110 administered subcutaneously at 45mg/m\^2/day x 5 days on a 28-day cycle

Gastrointestinal stromal tumor (GIST)

SGI-110 (guadecitabine): 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.

Patients ≥ 12 Years of Age w/Wild-Type GIST

SGI-110 administered subcutaneously at 45mg/m\^2/day x 5 days on a 28-day cycle

Pheochromocytoma and Paraganglioma (PHEO/PGL) with succinate dehydrogenase (SDH)-deficient PHE

SGI-110 (guadecitabine): 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.

Patients ≥ 12 Years of Age w/PHEO/PGL With SDH-deficient PHE

SGI-110 administered subcutaneously at 45mg/m\^2/day x 5 days on a 28-day cycle

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated Renal Cell Ca

SGI-110 (guadecitabine): 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.

Patients ≥ 12 Years of Age w/HLRCC-associated Renal Cell Ca

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. John Glod

Complete Response

Partial Response

Number of Participants With an Overall Response (Complete Response or Partial Response) of SGI-11 Using the Response Evaluation Criteria in Solid Tumors (RECIST)

Baseline

End of cycle 4

Post therapy follow up, approximately 30 days after the final dose of study drug

n=6 for the first Group at the end of cycle 4; this time data at this time point was not collected for one participant. Participant off therapy due to progressive disease (PD) at the end of cycle 1 for the third Group.

Change in Distress From Baseline

Time interval from start of treatment to documented evidence of disease progression. Progression were evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Disease progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progressions.

Patient's progressed at 3.9 months and 1.1 month respectively, for the second and third groups.

Progression Free Survival Probability at 6 Months

Time interval from start of treatment to documented evidence of disease progression. Progression were evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Disease progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progressions

Progression Free Survival (PFS) Probability at 12 Months

Time from treatment start date until date of death or date last known alive.

Overall Survival (OS)

Quality of Life (QOL) was assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Physical Health. Overall scores were derived from five quality of life domains: physical function, pain interference, fatigue, emotional health and social health). T-Score distributions are standardized so that a score of 50 represents the mean for the US general population with a standard deviation around that mean of 10 points.

Participant off therapy due to progressive disease (PD) at the end of cycle 1 in the third Group.

Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Physical Health)

Quality of Life (QOL) was assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Mental Health. Overall scores were derived from five quality of life domains: physical function, pain interference, fatigue, emotional health and social health). T-Score distributions are standardized so that a score of 50 represents the mean for the US general population with a standard deviation around that mean of 10 points.

n=6 for the first Group at the end of cycle 4; this time data at this time point was not collected for one participant. Participant off treatment at cycle 1 due to progressive disease (PD) in the third Group.

Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Mental Health)

Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

The maximum observed analyte concentration in serum was reported.

Gastrointestinal stromal tumor (GIST); Pheochromocytoma and Paraganglioma (PHEO/PGL) with succinate dehydrogenase (SDH)-deficient PHE; or Hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated Renal Cell Ca

SGI-110 administered subcutaneously at 45mg/m\^2/day x 5 days on a 28-day cycle

SGI-110 (guadecitabine): 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.

Patients≥12 Years of Age w/Wild-Type GIST, SDH-deficient PHEO/PGL, or HLRCC-associated Renal Cell Ca

Data was analyzed together for all participants because tumor type would not be expected to impact pharmacokinetic parameters or measures of pharmacodynamics that use peripheral blood mononuclear cells (LINE-1 demethylation).

Maximum Observed Plasma Concentration (Cmax) of Guadecitabine (SGI-110)

Percent decrease from baseline in long interspersed nuclear element -1 (LINE-1) demethylation in peripheral blood mononuclear cells (PBMC) using pyrosequencing and urine and plasma glycolytic metabolites.

Gastrointestinal stromal tumor (GIST); Pheochromocytoma and Paraganglioma (PHEO/PGL) with succinate dehydrogenase (SDH)-deficient PHE; or Hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated Renal Cell Ca SGI-110 administered subcutaneously at 45mg/m\^2/day x 5 days on a 28-day cycle SGI-110 (guadecitabine): 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.

Data was analyzed together for all patients because tumor type would not be expected to impact pharmacokinetic parameters or measures of pharmacodynamics that use peripheral blood mononuclear cells (LINE-1 demethylation).

Percent Decrease in Long Interspersed Nuclear Element -1 (LINE-1) Demethylation

Patient 2

Patient 3

Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half.

Half Life (t1/2) of Guadecitabine (SGI-110)

Time it takes Guadecitabine (SGI-110) the reach the maximum concentration in plasma.

Time to Maximum Observed Plasma Concentration (Tmax) of Guadecitabine (SGI-110)

The AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption.

Area Under the Concentration Time Curve (AUC 0-5hr)

Apparent volume of distribution is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma.

V(2)/F (Apparent Volume of Distribution)

Apparent total body clearance is the time it takes for all Guadecitabine (SGI-110) to be removed from the body.

Spots Global Cancer Trial Database for dna methyltransferase (dnmt) inhibitor