Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Rare Diseases

Sarcoma

Chondrosarcoma

Sarcoma, Clear Cell

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Neoplasms, Connective Tissue

Soft Tissue Sarcoma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Atezolizumab

Immunoglobulins

Antibodies, Monoclonal

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

Immunologic Factors

Patients receive atezolizumab IV over 30-60 minutes on ay 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scans and undergo biopsy and collection of blood samples on study.

Biopsy

Biospecimen Collection

Computed Tomography

A P Chen

This phase II trial studies how well atezolizumab works in treating patients with chondrosarcoma or clear cell sarcoma that is newly diagnosed, cannot be removed by surgery (unresectable), or has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

PRIMARY OBJECTIVE:

I. Determine the objective response rates (ORR) using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 of atezolizumab in adult (\>= 18 years) patients with clear cell sarcoma (CCS) and chondrosarcoma (CS).

SECONDARY OBJECTIVES:

I. Determine duration of response (DOR) using RECIST v 1.1 and/or change in clinical symptoms (time frame: baseline until disease progression, death, loss to follow-up, initiation of another anti-cancer treatment, withdrawal of consent, or study termination).

II. Measure progression-free survival (PFS) time (time frame: baseline until disease progression, death, loss to follow-up, initiation of another anti-cancer treatment, withdrawal of consent, or study termination).

III. Assess the number of activated CD8+ T cells infiltrating the tumor before and after atezolizumab treatment, and correlate treatment-induced changes with clinical response.

EXPLORATORY OBJECTIVES:

I. Compare RECIST v 1.1 versus (vs) immune RECIST (iRECIST) in patients with CCS and CS on atezolizumab.

II. Examine changes in PD-1/PD-L1 expression in the tumor microenvironment before and after atezolizumab treatment, and correlate treatment-induced changes with clinical response.

III. Evaluate potential associations between atezolizumab activity and tumor genomic alterations.

OUTLINE:

Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scans and undergo biopsy and collection of blood samples on study.

After completion of study treatment, patients are followed up to 90 days.

Testing Atezolizumab in People 2-17 Years Old With Clear Cell Sarcoma or Advanced Chondrosarcoma

A Phase 2 Study of Anti-PD-L1 Antibody (Atezolizumab) in Chondrosarcoma and Clear Cell Sarcoma

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

Here is the number of participants with serious and/or 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.

ORR was measured using the Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1, which involves the following response definitions. Complete Response (CR): 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): at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. Progressive Disease (PD): at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.

Duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Complete Response (CR): 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): at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progression was measured using the Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 and/or change in clinical symptoms. Progressive Disease (PD): is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.

PFS is the time interval from start of treatment to documented evidence of disease progression, measured by the Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1, or death from any cause, whichever comes first. Progressive Disease (PD): at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.

Activated CD8+ T cells will be detected by multiplex immunofluorescence assays and will be defined by the expression of T cell receptor (TCR) activation (Zeta chain phosphorylation) or phosphorylated Zap70 (pY493); CD8+ cells present within the tumor section that are positive for these markers will be quantified.

National Cancer Institute (NCI)

The descriptions and grading scales found in the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 were utilized for adverse event (AE) reporting. An adverse event that began in one cycle and resolved in another cycle is considered a single adverse event.

Participants with clear cell sarcoma receive atezolizumab intravenous (IV) over 30-60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants undergo computed tomography (CT) scans and undergo biopsy and collection of blood samples on study.

Arm 1 Atezolizumab 1200 mg Intravenous (IV) on Day 1, Subgroup 1: Clear Cell Sarcoma (CCS)

Participants with conventional chondrosarcoma, grade 2 or 3, receive atezolizumab intravenous (IV) over 30-60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants undergo computed tomography (CT) scans and undergo biopsy and collection of blood samples on study.

Arm 1 Atezolizumab 1200 mg IV on Day 1, Subgroup 2: Conventional Chondrosarcoma (CS)(Grade 2 or 3)

Participants with dedifferentiated chondrosarcoma receive atezolizumab intravenous (IV) over 30-60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants undergo computed tomography (CT) scans and undergo biopsy and collection of blood samples on study.

Arm 1 Atezolizumab 1200 mg Intravenous on Day 1, Subgroup 3: Dedifferentiated Chondrosarcoma (CS)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Canada

United States

Region of Enrollment

Alice P. Chen

Complete Response

Partial Response

Stable Disease

Progressive Disease

Unknown (not assessed)

Objective Response Rates (ORR)

The analysis population was to include all participants with an objective response (complete or partial). Because no objective responses were observed, there was no evaluable population and data were not collected.

Duration of Response (DOR) or Change in Clinical Symptoms

Progression-free Survival (PFS) Time

Number of Activated Cluster of Differentiation 8 (CD8+) T Cells Infiltrating the Tumor

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

Overall Study

Decitabine

Belinostat

Guadecitabine

Decitabine and cedazuridine drug combination

Azacitidine

Antimetabolites

Enzyme Inhibitors

Histone Deacetylase Inhibitors

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 collection of blood during screening, tumor biopsy during screening and on study, and MRI or CT throughout the trial.

Decitabine and Cedazuridine

Magnetic Resonance Imaging

Mia Weiss

This phase II trial studies the effect of belinostat and SGI-110 (guadecitabine) or ASTX727 in treating patients with conventional chondrosarcoma that cannot be removed by surgery (unresectable) and has spread from where it first started (primary site) to other places in the body (metastatic). Belinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as guadecitabine and ASTX727, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving belinostat in combination with guadecitabine or ASTX727 may lower the chance of unresectable and metastatic chondrosarcoma growing or spreading.

PRIMARY OBJECTIVE:

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.

SECONDARY OBJECTIVES:

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).

CORRELATIVE OBJECTIVES:

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.

OUTLINE:

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 collection of blood during screening, tumor biopsy during screening and on study, and magnetic resonance imaging (MRI) or computed tomography (CT) throughout the trial.

After completion of study treatment, patients are followed up every 3 months for 24 months.

Testing the Combination of Belinostat and SGI-110 (Guadecitabine) or ASTX727 for the Treatment of Unresectable and Metastatic Conventional Chondrosarcoma

A Phase 2 Study of Belinostat and SGI-110 (Guadecitabine) or ASTX727 for the Treatment of Unresectable and Metastatic Conventional Chondrosarcoma

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

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.

Data from ribonucleic acid sequencing 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.

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.

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.

Adverse events will be recorded at each clinical visit and will be categorized according to National Cancer Institute Common Terminology Criteria for Adverse Events 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.

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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Testing Atezolizumab in People 2-17 Years Old With Clear Cell Sarcoma or Advanced Chondrosarcoma	NCT04458922	Central Chondro... Central Chondro... Dedifferentiate... Metastatic Clea... Metastatic Prim... Unresectable Pr...	Atezolizumab Biopsy Biospecimen Col... Computed Tomogr...	2 Years -	National Cancer Institute (NCI)
Testing the Combination of Belinostat and SGI-110 (Guadecitabine) or ASTX727 for the Treatment of Unresectable and Metastatic Conventional Chondrosarcoma	NCT04340843	Locally Advance... Metastatic Prim... Unresectable Pr...	Belinostat Biopsy Biospecimen Col... Computed Tomogr... Decitabine and ... Guadecitabine Magnetic Resona...	18 Years -	National Cancer Institute (NCI)
Testing Atezolizumab in People 2-17 Years Old With Clear Cell Sarcoma or Advanced Chondrosarcoma	NCT04458922	Central Chondro... Central Chondro... Dedifferentiate... Metastatic Clea... Metastatic Prim... Unresectable Pr...	Atezolizumab Biopsy Biospecimen Col... Computed Tomogr...	2 Years -	National Cancer Institute (NCI)
Testing the Combination of Belinostat and SGI-110 (Guadecitabine) or ASTX727 for the Treatment of Unresectable and Metastatic Conventional Chondrosarcoma	NCT04340843	Locally Advance... Metastatic Prim... Unresectable Pr...	Belinostat Biopsy Biospecimen Col... Computed Tomogr... Decitabine and ... Guadecitabine Magnetic Resona...	18 Years -	National Cancer Institute (NCI)

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