Paraganglioma, Gastrointestinal Stromal Tumors, Carcinoma, Renal Cell, Renal Neoplasms, Pheochromocytoma
Conditions
Keywords
Renal Cancer, DNA Hypermethylation, Gastrointestinal Stromal Tumors, DNA Methyltransferase (DNMT) Inhibitor, Succinate Dehydrogenase (SDH) Deficiency
Brief 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. ...
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. * 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.
Interventions
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.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 99 Years
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With an Overall Response (Complete Response or Partial Response) of SGI-11 Using the Response Evaluation Criteria in Solid Tumors (RECIST) | After the first 4 weeks, then every 8 weeks up to 65 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Distress From Baseline | Baseline, end of cycle 4, and post therapy follow up, approximately 30 days after the final dose of study drug | 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). |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJohn W Glod, M.D.
National Cancer Institute (NCI)
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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
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. | 7 |
| 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
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. | 1 |
| Patients ≥ 12 Years of Age w/HLRCC-associated Renal Cell Ca 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. | 1 |
| Total | 9 |
Baseline characteristics
| Characteristic | Patients ≥ 12 Years of Age w/Wild-Type GIST | Patients ≥ 12 Years of Age w/PHEO/PGL With SDH-deficient PHE | Patients ≥ 12 Years of Age w/HLRCC-associated Renal Cell Ca | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 1 Participants | 1 Participants | 9 Participants |
| Age, Continuous | 34.86 years STANDARD_DEVIATION 16.03 | 41 years STANDARD_DEVIATION 0 | 23 years STANDARD_DEVIATION 0 | 34.22 years STANDARD_DEVIATION 14.64 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 1 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 5 Participants | 0 Participants | 1 Participants | 6 Participants |
| Region of Enrollment United States | 7 participants | 1 participants | 1 participants | 9 participants |
| Sex: Female, Male Female | 6 Participants | 0 Participants | 0 Participants | 6 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 1 | 0 / 1 |
| other Total, other adverse events | 7 / 7 | 1 / 1 | 1 / 1 |
| serious Total, serious adverse events | 4 / 7 | 1 / 1 | 0 / 1 |
Outcome results
Primary
Number of Participants With an Overall Response (Complete Response or Partial Response) of SGI-11 Using the Response Evaluation Criteria in Solid Tumors (RECIST)
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.
Time frame: After the first 4 weeks, then every 8 weeks up to 65 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Number of Participants With an Overall Response (Complete Response or Partial Response) of SGI-11 Using the Response Evaluation Criteria in Solid Tumors (RECIST) | Complete Response | 0 Participants |
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Number of Participants With an Overall Response (Complete Response or Partial Response) of SGI-11 Using the Response Evaluation Criteria in Solid Tumors (RECIST) | Partial Response | 0 Participants |
| Patients ≥ 12 Years of Age w/PHEO/PGL With SDH-deficient PHE | Number of Participants With an Overall Response (Complete Response or Partial Response) of SGI-11 Using the Response Evaluation Criteria in Solid Tumors (RECIST) | Complete Response | 0 Participants |
| Patients ≥ 12 Years of Age w/PHEO/PGL With SDH-deficient PHE | Number of Participants With an Overall Response (Complete Response or Partial Response) of SGI-11 Using the Response Evaluation Criteria in Solid Tumors (RECIST) | Partial Response | 0 Participants |
| Patients ≥ 12 Years of Age w/HLRCC-associated Renal Cell Ca | Number of Participants With an Overall Response (Complete Response or Partial Response) of SGI-11 Using the Response Evaluation Criteria in Solid Tumors (RECIST) | Complete Response | 0 Participants |
| Patients ≥ 12 Years of Age w/HLRCC-associated Renal Cell Ca | Number of Participants With an Overall Response (Complete Response or Partial Response) of SGI-11 Using the Response Evaluation Criteria in Solid Tumors (RECIST) | Partial Response | 0 Participants |
Secondary
Change in Distress From Baseline
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).
Time frame: Baseline, end of cycle 4, and post therapy follow up, approximately 30 days after the final dose of study drug
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Change in Distress From Baseline | End of cycle 4 | 4.5 Scores on a scale | Standard Deviation 1.5 |
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Change in Distress From Baseline | Baseline | 6.4 Scores on a scale | Standard Deviation 1.4 |
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Change in Distress From Baseline | Post therapy follow up, approximately 30 days after the final dose of study drug | 4.1 Scores on a scale | Standard Deviation 2.4 |
| Patients ≥ 12 Years of Age w/PHEO/PGL With SDH-deficient PHE | Change in Distress From Baseline | Post therapy follow up, approximately 30 days after the final dose of study drug | 3 Scores on a scale | — |
| Patients ≥ 12 Years of Age w/PHEO/PGL With SDH-deficient PHE | Change in Distress From Baseline | End of cycle 4 | 2 Scores on a scale | — |
| Patients ≥ 12 Years of Age w/PHEO/PGL With SDH-deficient PHE | Change in Distress From Baseline | Baseline | 7 Scores on a scale | — |
| Patients ≥ 12 Years of Age w/HLRCC-associated Renal Cell Ca | Change in Distress From Baseline | Baseline | 2 Scores on a scale | — |
Post Hoc
Area Under the Concentration Time Curve (AUC 0-5hr)
The AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption.
Time frame: Prior to first dose in cycle 1 and at 0.5 hour (+/- 15 minutes), 1 hour (+/- 15 minutes), 2 hour (+/-30 minutes), 4 hour (+/- 30 minutes), 6 hour (+/- 1 hour) and 24 hours (+/- 2 hours) after the first dose of drug in Cycle 1.
Population: 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).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Area Under the Concentration Time Curve (AUC 0-5hr) | 114.1 hr*ng/mL | Geometric Coefficient of Variation 48.1 |
Post Hoc
(CL/F) Apparent Total Body Clearance
Apparent total body clearance is the time it takes for all Guadecitabine (SGI-110) to be removed from the body.
Time frame: Prior to first dose in cycle 1 and at 0.5 hour (+/- 15 minutes), 1 hour (+/- 15 minutes), 2 hour (+/-30 minutes), 4 hour (+/- 30 minutes), 6 hour (+/- 1 hour) and 24 hours (+/- 2 hours) after the first dose of drug in Cycle 1.
Population: 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).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patients ≥ 12 Years of Age w/Wild-Type GIST | (CL/F) Apparent Total Body Clearance | Patient 2 | 452 L/hr |
| Patients ≥ 12 Years of Age w/Wild-Type GIST | (CL/F) Apparent Total Body Clearance | Patient 3 | 588 L/hr |
Post Hoc
Half Life (t1/2) of Guadecitabine (SGI-110)
Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half.
Time frame: Prior to first dose in cycle 1 and at 0.5 hour (+/- 15 minutes), 1 hour (+/- 15 minutes), 2 hour (+/-30 minutes), 4 hour (+/- 30 minutes), 6 hour (+/- 1 hour) and 24 hours (+/- 2 hours) after the first dose of drug in Cycle 1.
Population: 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).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Half Life (t1/2) of Guadecitabine (SGI-110) | Patient 2 | 1.73 hrs |
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Half Life (t1/2) of Guadecitabine (SGI-110) | Patient 3 | 1.35 hrs |
Post Hoc
Maximum Observed Plasma Concentration (Cmax) of Guadecitabine (SGI-110)
The maximum observed analyte concentration in serum was reported.
Time frame: Prior to first dose in cycle 1 and at 0.5 hour (+/- 15 minutes), 1 hour (+/- 15 minutes), 2 hour (+/-30 minutes), 4 hour (+/- 30 minutes), 6 hour (+/- 1 hour) and 24 hours (+/- 2 hours) after the first dose of drug in Cycle 1.
Population: 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).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Maximum Observed Plasma Concentration (Cmax) of Guadecitabine (SGI-110) | 45 ng/mL | Geometric Coefficient of Variation 42.7 |
Post Hoc
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
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.
Time frame: Date treatment consent signed to date off study, approx. 1 mos and 5 days for the Gastrointestinal stromal tumor (GIST) group; 3 mos and 25 days for the Pheochromocytoma/Paraganglioma (Pheo/PGL) group;and 30 mos and 2 days for the Renal Cell Cancer group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 7 Participants |
| Patients ≥ 12 Years of Age w/PHEO/PGL With SDH-deficient PHE | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 1 Participants |
| Patients ≥ 12 Years of Age w/HLRCC-associated Renal Cell Ca | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 1 Participants |
Post Hoc
Overall Survival (OS)
Time from treatment start date until date of death or date last known alive.
Time frame: Time from treatment start date until date of death or date last known alive, up to approximately 3 years, 2 months.
Post Hoc
Percent Decrease in Long Interspersed Nuclear Element -1 (LINE-1) Demethylation
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.
Time frame: Day 14 of cycle 1
Population: 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).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Percent Decrease in Long Interspersed Nuclear Element -1 (LINE-1) Demethylation | 45 Percent decrease |
Post Hoc
Progression Free Survival (PFS) Probability at 12 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
Time frame: 12 months
Population: Patient's progressed at 3.9 months and 1.1 month respectively, for the second and third groups.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Progression Free Survival (PFS) Probability at 12 Months | 53.6 Percent probability |
| Patients ≥ 12 Years of Age w/PHEO/PGL With SDH-deficient PHE | Progression Free Survival (PFS) Probability at 12 Months | 0 Percent probability |
| Patients ≥ 12 Years of Age w/HLRCC-associated Renal Cell Ca | Progression Free Survival (PFS) Probability at 12 Months | 0 Percent probability |
Post Hoc
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.
Time frame: 6 months
Population: Patient's progressed at 3.9 months and 1.1 month respectively, for the second and third groups.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Progression Free Survival Probability at 6 Months | 85.7 Percent probability |
| Patients ≥ 12 Years of Age w/PHEO/PGL With SDH-deficient PHE | Progression Free Survival Probability at 6 Months | 0 Percent probability |
| Patients ≥ 12 Years of Age w/HLRCC-associated Renal Cell Ca | Progression Free Survival Probability at 6 Months | 0 Percent probability |
Post Hoc
Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Mental 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.
Time frame: Baseline, at the end of cycle 4, and post therapy follow up, approximately 30 days after the final dose of study drug
Population: 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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Mental Health) | End of cycle 4 | 46.0 t-score |
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Mental Health) | Baseline | 43.2 t-score |
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Mental Health) | Post therapy follow up, approximately 30 days after the final dose of study drug | 41.2 t-score |
| Patients ≥ 12 Years of Age w/PHEO/PGL With SDH-deficient PHE | Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Mental Health) | Post therapy follow up, approximately 30 days after the final dose of study drug | 45.8 t-score |
| Patients ≥ 12 Years of Age w/PHEO/PGL With SDH-deficient PHE | Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Mental Health) | End of cycle 4 | 53.3 t-score |
| Patients ≥ 12 Years of Age w/PHEO/PGL With SDH-deficient PHE | Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Mental Health) | Baseline | 41.1 t-score |
| Patients ≥ 12 Years of Age w/HLRCC-associated Renal Cell Ca | Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Mental Health) | Baseline | 62.5 t-score |
Post Hoc
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 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.
Time frame: Baseline, at the end of cycle 4, and post therapy follow up, approximately 30 days after the final dose of study drug
Population: Participant off therapy due to progressive disease (PD) at the end of cycle 1 in the third Group.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Physical Health) | End of cycle 4 | 46.5 t-score |
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Physical Health) | Baseline | 45.9 t-score |
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Physical Health) | Post therapy follow up, approximately 30 days after the final dose of study drug | 44.2 t-score |
| Patients ≥ 12 Years of Age w/PHEO/PGL With SDH-deficient PHE | Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Physical Health) | End of cycle 4 | 61.9 t-score |
| Patients ≥ 12 Years of Age w/PHEO/PGL With SDH-deficient PHE | Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Physical Health) | Baseline | 54.1 t-score |
| Patients ≥ 12 Years of Age w/PHEO/PGL With SDH-deficient PHE | Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Physical Health) | Post therapy follow up, approximately 30 days after the final dose of study drug | 54.1 t-score |
| Patients ≥ 12 Years of Age w/HLRCC-associated Renal Cell Ca | Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Physical Health) | Baseline | 57.7 t-score |
| Patients ≥ 12 Years of Age w/HLRCC-associated Renal Cell Ca | Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Physical Health) | Post therapy follow up, approximately 30 days after the final dose of study drug | NA t-score |
| Patients ≥ 12 Years of Age w/HLRCC-associated Renal Cell Ca | Quality of Life (QOL) Relative to Any Degree of Response (Patient-Reported Outcomes Measurement Information System (PROMIS) Global Physical Health) | End of cycle 4 | NA t-score |
Post Hoc
Time to Maximum Observed Plasma Concentration (Tmax) of Guadecitabine (SGI-110)
Time it takes Guadecitabine (SGI-110) the reach the maximum concentration in plasma.
Time frame: Prior to first dose in cycle 1 and at 0.5 hour (+/- 15 minutes), 1 hour (+/- 15 minutes), 2 hour (+/-30 minutes), 4 hour (+/- 30 minutes), 6 hour (+/- 1 hour) and 24 hours (+/- 2 hours) after the first dose of drug in Cycle 1.
Population: 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).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Patients ≥ 12 Years of Age w/Wild-Type GIST | Time to Maximum Observed Plasma Concentration (Tmax) of Guadecitabine (SGI-110) | 4.0 hr |
Post Hoc
V(2)/F (Apparent Volume of Distribution)
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.
Time frame: Prior to first dose in cycle 1 and at 0.5 hour (+/- 15 minutes), 1 hour (+/- 15 minutes), 2 hour (+/-30 minutes), 4 hour (+/- 30 minutes), 6 hour (+/- 1 hour) and 24 hours (+/- 2 hours) after the first dose of drug in Cycle 1.
Population: 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).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patients ≥ 12 Years of Age w/Wild-Type GIST | V(2)/F (Apparent Volume of Distribution) | Patient 2 | 1127 L |
| Patients ≥ 12 Years of Age w/Wild-Type GIST | V(2)/F (Apparent Volume of Distribution) | Patient 3 | 1147 L |