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

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ClinicalTrials.gov Identifier: NCT04340843
Recruitment Status : Recruiting
First Posted : April 10, 2020
Last Update Posted : January 11, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE April 9, 2020
First Posted Date  ICMJE April 10, 2020
Last Update Posted Date January 11, 2021
Actual Study Start Date  ICMJE July 6, 2020
Estimated Primary Completion Date January 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 9, 2020)
Objective response rate [ Time Frame: Within 6 months after initiating study treatment ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 27, 2020)
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 9, 2020)
  • 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.
  • Occurrence of dose limiting toxicity (DLT) [ Time Frame: During the first cycle (28 days) ]
    DLTs are defined as those are attributed to the study drugs and not to disease, and which occur (or first become evident) during the first cycle (28 days) of treatment. Will also report the frequency and percentage of DLTs.
  • 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.
Current Other Pre-specified Outcome Measures
 (submitted: December 10, 2020)
  • 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.
Original Other Pre-specified Outcome Measures
 (submitted: April 9, 2020)
  • 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 in collaboration with the MoCha lab, 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 T-cell receptor repertoire [ Time Frame: Baseline up to 24 months post treatment ]
    T-cell receptor sequencing will be performed using the immunoSEQ platform from Adaptive Biotechnologies. Changes in T-cell receptor clonality will be analyzed in an exploratory fashion using a non-parametric two-sided Mann-Whitney test.
  • 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.
 
Descriptive Information
Brief Title  ICMJE Testing the Combination of Belinostat and SGI-110 (Guadecitabine) for the Treatment of Unresectable and Metastatic Conventional Chondrosarcoma
Official Title  ICMJE A Phase 2 Study of Belinostat and SGI-110 (Guadecitabine) for the Treatment of Unresectable and Metastatic Conventional Chondrosarcoma
Brief Summary This phase II trial studies the effect of belinostat and SGI-110 (guadecitabine) combination therapy in treating patients with conventional chondrosarcoma that cannot be removed by surgery (unresectable) and has spread 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, 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 may lower the chance of unresectable and metastatic chondrosarcoma growing or spreading.
Detailed Description

PRIMARY OBJECTIVE:

I. To conduct a phase 2 clinical trial to evaluate whether combination treatment with belinostat and SGI-110 (guadecitabine) 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 combination treatment. II. To evaluate the progression free survival (PFS) associated with the combination treatment.

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) and belinostat intravenously (IV) over 30 minutes on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Locally Advanced Unresectable Primary Central Chondrosarcoma
  • Metastatic Primary Central Chondrosarcoma
  • Unresectable Primary Central Chondrosarcoma
Intervention  ICMJE
  • Drug: Belinostat
    Given IV
    Other Names:
    • Beleodaq
    • PXD 101
    • PXD101
  • Procedure: Biopsy
    Undergo biopsy
    Other Names:
    • BIOPSY_TYPE
    • Bx
  • Procedure: Computed Tomography
    Undergo CT
    Other Names:
    • CAT
    • CAT Scan
    • Computerized Axial Tomography
    • Computerized Tomography
    • CT
    • CT Scan
    • tomography
  • Drug: Guadecitabine
    Given SC
    Other Names:
    • DNMT inhibitor SGI-110
    • S110
    • SGI-110
  • Procedure: Magnetic Resonance Imaging
    Undergo MRI
    Other Names:
    • Magnetic Resonance Imaging Scan
    • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
    • MR Imaging
    • MRI
    • MRI Scan
    • NMR Imaging
    • NMRI
    • Nuclear Magnetic Resonance Imaging
Study Arms  ICMJE Experimental: Treatment (belinostat, guadecitabine)
Patients receive guadecitabine SC and belinostat IV over 30 minutes on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: Belinostat
  • Procedure: Biopsy
  • Procedure: Computed Tomography
  • Drug: Guadecitabine
  • Procedure: Magnetic Resonance Imaging
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 9, 2020)
26
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 1, 2022
Estimated Primary Completion Date January 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must have biopsy-proven conventional chondrosarcoma (CS) which is:

    • Either metastatic or locally advanced and unresectable, and
    • Measurable at study entry according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria, and
    • Amenable to biopsy with imaging guidance at no or acceptable risk to the patient as defined by institutional guidelines for research-related biopsies or the treating investigator's assessment
    • In addition, the following criteria must be met:

      • Patients must have at least one lesion measurable by RECIST version 1.1 criteria which has not been previously irradiated
      • Patients who have histologic evidence of grade 1 chondrosarcoma only must either be symptomatic from their disease in the opinion of the treating investigator or demonstrate radiographic evidence of disease progression in the 3 months prior to initiation of study treatment
    • Note: Pathology review and confirmation of diagnosis will occur at the site enrolling the patient on this study
  • Patients may have been treated with any number of prior systemic therapies. Because there are no Food and Drug Administration (FDA)-approved treatments for this disease, patients who have received no prior systemic therapy are also eligible. However, disease must be deemed surgically unresectable
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Absolute neutrophil count >= 1,000/mm^3
  • Hemoglobin 8 g/dL
  • Platelet count >= 75,000/mm^3
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 x institutional ULN
  • Creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 45 mL/min/1.73 m^2
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
  • Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression, if patients have been clinically asymptomatic, and if patients have not received systemic corticosteroids for at least 28 days. Patients with brain metastases not meeting these criteria are not eligible
  • Patients must be disease-free of prior invasive malignancies for > 5 years, with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.

    • NOTE: If there is a history of prior malignancy, patients must not be receiving other specific treatment for that cancer
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
  • The effects of belinostat and SGI-110 (guadecitabine) on the developing human fetus are unknown. For this reason, and because the DNA methyltransferase inhibitor decitabine, the active metabolite of SGI-110 (guadecitabine), is known to be teratogenic, and because belinostat may cause teratogenicity and/or embryo-fetal lethality by virtue of targeting actively dividing cells, 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. 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. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of belinostat and SGI-110 (guadecitabine) administration
  • Patients must be able to understand and willing to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible

Exclusion Criteria:

  • Patients with dedifferentiated, mesenchymal, or clear cell chondrosarcoma are not eligible
  • Patients who have not recovered from adverse events (AEs) (i.e., have residual toxicities > grade 1) due to prior anti-cancer therapy are not allowed, with the exceptions of alopecia and endocrinopathies from prior immunotherapy-based treatments that are well-controlled with hormone replacement. In addition, the following time periods must elapse between the last dose of prior anti-cancer treatment and initiation of study treatment on this protocol:

    • Cytotoxic chemotherapy or biologic, including immunotherapy: 28 days
    • Small molecule targeted drug: 21 days or 5 half-lives, whichever is shorter. If 5 half-lives is shorter than 21 days, then 21 days applies.
    • Radiation: 28 days, except for palliative radiation, for which 14 days applies
  • Patients who are receiving any other investigational agents
  • Patients with known history of allergic reactions or sensitivity attributed to compounds of similar chemical or biologic composition to SGI-110 (guadecitabine), its active metabolite decitabine, or belinostat
  • Chronic use of any medications or substances that are strong inhibitors of UGT1A1 is not allowed. Patients must switch to alternative medications 7-14 days before treatment with belinostat. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
  • Patients with any known UGT1A1 polymorphism, heterozygous or homozygous, associated with reduced function (UGT1A1*6, UGT1A1*28, or UGT1A1*60)
  • Patients with uncontrolled intercurrent illness
  • Patients with psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study because SGI-110 (guadecitabine) is a derivative of decitabine, which has the potential for teratogenic or abortifacient effects, and because belinostat may cause teratogenicity and/or embryo-fetal lethality by virtue of targeting actively dividing cells. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with SGI-110 (guadecitabine) and belinostat, breastfeeding should be discontinued
  • Prolongation of the heart-rate corrected QT (QTc) interval >= 450 ms (i.e., grade 1 or higher) on the screening electrocardiogram (ECG) prior to initiation of study treatment. If baseline QTc on screening ECG is >= 450 ms (i.e., grade 1 or higher):

    • Check potassium and magnesium serum levels, and
    • Correct any identified hypokalemia and/or hypomagnesemia and repeat ECG to confirm a QTc interval < 450 ms
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04340843
Other Study ID Numbers  ICMJE NCI-2020-02187
NCI-2020-02187 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10330 ( Other Identifier: Yale University Cancer Center LAO )
10330 ( Other Identifier: CTEP )
UM1CA186686 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: 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.
URL: https://grants.nih.gov/policy/sharing.htm
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Matthew Ingham Yale University Cancer Center LAO
PRS Account National Cancer Institute (NCI)
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP