Testing the Combination of Belinostat and SGI-110 (Guadecitabine) or ASTX727 for the Treatment of Unresectable and Metastatic Conventional Chondrosarcoma
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|ClinicalTrials.gov Identifier: NCT04340843|
Recruitment Status : Suspended (Other - Completed stage 1 accrual)
First Posted : April 10, 2020
Last Update Posted : June 8, 2022
|Condition or disease||Intervention/treatment||Phase|
|Locally Advanced Unresectable Primary Central Chondrosarcoma Metastatic Primary Central Chondrosarcoma Unresectable Primary Central Chondrosarcoma||Drug: Belinostat Procedure: Biopsy Procedure: Computed Tomography Drug: Decitabine and Cedazuridine Drug: Guadecitabine Procedure: Magnetic Resonance Imaging||Phase 2|
I. To conduct a phase 2 clinical trial to evaluate whether combination treatment with belinostat and decitabine and cedazuridine (ASTX727) shows preliminary evidence of clinical activity in unresectable or metastatic conventional chondrosarcoma (CS) using an objective response rate endpoint.
I. To evaluate the toxicity profile associated with the belinostat and ASTX727. II. To evaluate the progression free survival (PFS) associated with the belinostat and ASTX727.
III. To evaluate the toxicity profile, objective response rate and progression free survival among the initial six patients treated with belinostat and SGI-110 (guadecitabine) prior to Amendment 5 in which ASTX727 was substituted for SGI-110 (guadecitabine).
I. To determine the IDH1/2 mutational status of subject's tumors and to evaluate for a relationship between presence of IDH1/2 mutation and clinical benefit from study treatment.
II. To conduct ribonucleic acid sequencing (RNAseq) analysis using baseline and on-treatment tissue biopsies to study the effects of study treatment on CS gene expression patterns and identify candidate genes which may underlie treatment efficacy.
III. To evaluate for changes in global deoxyribonucleic acid (DNA) methylation levels using baseline and on-treatment biopsies and correlate changes in global methylation with clinical benefit from study treatment.
IV. To use multiplex immunohistochemistry to interrogate the immune microenvironment in baseline and on-treatment tissue biopsies to define changes in infiltrating immune cell subsets and PD-L1/major histocompatibility complex (MHC) expression by immune and tumor cells associated with study treatment.
Patients receive guadecitabine subcutaneously (SC) or ASTX727 orally (PO) on days 1-5. Patients also receive belinostat intravenously (IV) over 30 minutes on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo a tumor biopsy at baseline (within 21 days of the first cycle) and during cycle 2 (on day 3, 4, or 5). In addition, patients undergo magnetic resonance imaging (MRI) or computed tomography (CT) scans every 2 cycles (8 weeks) while receiving guadecitabine or ASTX727 and belinostat.
After completion of study treatment, patients are followed up every 3 months for 24 months.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||32 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 2 Study of Belinostat and SGI-110 (Guadecitabine) or ASTX727 for the Treatment of Unresectable and Metastatic Conventional Chondrosarcoma|
|Actual Study Start Date :||July 6, 2020|
|Estimated Primary Completion Date :||January 1, 2023|
|Estimated Study Completion Date :||January 1, 2023|
Experimental: Treatment (belinostat, guadecitabine, ASTX727)
Patients receive guadecitabine SC or ASTX727 PO on days 1-5. Patients also receive belinostat IV over 30 minutes on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo a tumor biopsy at baseline (within 21 days of the first cycle) and during cycle 2 (on day 3, 4, or 5). In addition, patients undergo MRI or CT scans every 2 cycles (8 weeks) while receiving guadecitabine or ASTX727 and belinostat.
Procedure: Computed Tomography
Drug: Decitabine and Cedazuridine
Procedure: Magnetic Resonance Imaging
- Objective response rate [ Time Frame: Within 6 months after initiating study treatment ]
- Presence of treatment related adverse events (AEs) [ Time Frame: Up to 24 months post treatment ]Adverse events will be recorded at each clinical visit and will be categorized according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The attribution of AEs to each of the study drugs will also be recorded. Adverse event rates that are possibly, probably, or definitely related to treatment will be reported as counts and percentages per AE by grade and the number of patients with a given maximal grade of toxicity. Will be reported separately for the population of patients receiving belinostat and SGI-110 (guadecitabine) and the population of patients receiving belinostat and ASTX727.
- Occurrence of dose limiting toxicity (DLT) [ Time Frame: During the first cycle (28 days) ]DLTs are defined as the following toxicities which are attributed to the study drug(s) and not to disease, and which occur (or first become evident) during a prespecified timeframe. Will also report the frequency and percentage of DLTs. Will be reported separately for the population of patients receiving belinostat and SGI-110 (guadecitabine) and the population of patients receiving belinostat and ASTX727.
- Progression free survival (PFS) [ Time Frame: Time from first treatment with the study drug to the earliest of either disease progression or death from any cause, assessed up to 24 months ]The Kaplan-Meier method will be used to evaluate time to event endpoints. Median PFS will be reported with a 95% confidence interval. Data will be presented as Kaplan Meier plots. Will be reported separately for the population of patients receiving belinostat and SGI-110 (guadecitabine) and the population of patients receiving belinostat and ASTX727.
- IDH1/2 mutational status [ Time Frame: Up to 24 months post treatment ]Will compare the difference in the objective response rate among patients with IDH1/2 mutations as compared those without IDH1/2 mutations using Fisher's exact test.
- Changes in expression of conventional chondrosarcoma genes [ Time Frame: Baseline up to 24 months post treatment ]Data from ribonucleic acid sequencing (RNAseq) will be analyzed. Differential expression profiles between baseline and on-treatment samples will be analyzed at the gene level and gene expression changes defined as significant based on absolute log2 fold changes > 2 and adjusted p values < 0.005 for each comparison with consideration of the false discovery rate.
- Changes in global deoxyribonucleic acid (DNA) methylation [ Time Frame: Baseline up to 24 months post treatment ]A Wilcoxon signed-rank test with continuity correction will be used to calculate P values for comparing methylation level distribution at the different time points.
- Changes in tumor microenvironment [ Time Frame: Baseline up to 24 months post treatment ]For quantitative immune multiplexing, data is derived from inForm software, and changes in defined immune cell subsets and expression between baseline and on-treatment samples will be assessed using paired T-tests.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04340843
|Principal Investigator:||Matthew Ingham||Yale University Cancer Center LAO|