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

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Suspended
CT.gov ID
NCT04340843
Collaborator
(none)
32
39
1
29.9
0.8
0

Study Details

Study Description

Brief Summary

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 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.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

PRIMARY OBJECTIVE:
  1. 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:
  1. 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.

  2. 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:
  1. 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.

  2. 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.

  3. 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.

  4. 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 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 Design

Study Type:
Interventional
Anticipated Enrollment :
32 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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 :
Jul 6, 2020
Anticipated Primary Completion Date :
Jan 1, 2023
Anticipated Study Completion Date :
Jan 1, 2023

Arms and Interventions

Arm Intervention/Treatment
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.

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
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized Tomography
  • CT
  • CT Scan
  • tomography
  • Drug: Decitabine and Cedazuridine
    Given PO
    Other Names:
  • ASTX727
  • C-DEC
  • CDA Inhibitor E7727/Decitabine Combination Agent ASTX727
  • Cedazuridine/Decitabine Combination Agent ASTX727
  • Cedazuridine/Decitabine Tablet
  • DEC-C
  • Inqovi
  • 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
  • MR Imaging
  • MRI
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging
  • Outcome Measures

    Primary Outcome Measures

    1. Objective response rate [Within 6 months after initiating study treatment]

    Secondary Outcome Measures

    1. Presence of treatment related adverse events (AEs) [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.

    2. Occurrence of dose limiting toxicity (DLT) [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.

    3. Progression free survival (PFS) [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.

    Other Outcome Measures

    1. IDH1/2 mutational status [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.

    2. Changes in expression of conventional chondrosarcoma genes [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.

    3. Changes in global deoxyribonucleic acid (DNA) methylation [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.

    4. Changes in tumor microenvironment [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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    • Age >= 18 years. Chondrosarcoma is rarely encountered in children and adolescents

    • 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) or ASTX727 on the developing human fetus are unknown. For this reason, and because the DNA methyltransferase inhibitor decitabine, the active metabolite of SGI-110 (guadecitabine) and a component of ASTX727, 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 and for at least 6 months after the last dose of study drugs. 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) or ASTX727 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 ASTX727, 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 (UGT1A16, UGT1A128, 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, and ASTX727 contains the agent 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), ASTX727 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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Mayo Clinic Hospital in Arizona Phoenix Arizona United States 85054
    2 City of Hope Comprehensive Cancer Center Duarte California United States 91010
    3 Los Angeles County-USC Medical Center Los Angeles California United States 90033
    4 USC / Norris Comprehensive Cancer Center Los Angeles California United States 90033
    5 USC Norris Oncology/Hematology-Newport Beach Newport Beach California United States 92663
    6 University of Colorado Hospital Aurora Colorado United States 80045
    7 Yale University New Haven Connecticut United States 06520
    8 UM Sylvester Comprehensive Cancer Center at Coral Gables Coral Gables Florida United States 33146
    9 UM Sylvester Comprehensive Cancer Center at Deerfield Beach Deerfield Beach Florida United States 33442
    10 Mayo Clinic in Florida Jacksonville Florida United States 32224-9980
    11 University of Miami Miller School of Medicine-Sylvester Cancer Center Miami Florida United States 33136
    12 UM Sylvester Comprehensive Cancer Center at Plantation Plantation Florida United States 33324
    13 Moffitt Cancer Center Tampa Florida United States 33612
    14 Northwestern University Chicago Illinois United States 60611
    15 HaysMed University of Kansas Health System Hays Kansas United States 67601
    16 University of Kansas Cancer Center Kansas City Kansas United States 66160
    17 Lawrence Memorial Hospital Lawrence Kansas United States 66044
    18 University of Kansas Cancer Center-Overland Park Overland Park Kansas United States 66210
    19 Ascension Via Christi - Pittsburg Pittsburg Kansas United States 66762
    20 Salina Regional Health Center Salina Kansas United States 67401
    21 University of Kansas Health System Saint Francis Campus Topeka Kansas United States 66606
    22 University of Kansas Hospital-Westwood Cancer Center Westwood Kansas United States 66205
    23 Mayo Clinic in Rochester Rochester Minnesota United States 55905
    24 Siteman Cancer Center at West County Hospital Creve Coeur Missouri United States 63141
    25 Truman Medical Centers Kansas City Missouri United States 64108
    26 University of Kansas Cancer Center - North Kansas City Missouri United States 64154
    27 University of Kansas Cancer Center - Lee's Summit Lee's Summit Missouri United States 64064
    28 University of Kansas Cancer Center at North Kansas City Hospital North Kansas City Missouri United States 64116
    29 Washington University School of Medicine Saint Louis Missouri United States 63110
    30 Siteman Cancer Center-South County Saint Louis Missouri United States 63129
    31 NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center New York New York United States 10032
    32 Memorial Sloan Kettering Cancer Center New York New York United States 10065
    33 Ohio State University Comprehensive Cancer Center Columbus Ohio United States 43210
    34 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States 73104
    35 Thomas Jefferson University Hospital Philadelphia Pennsylvania United States 19107
    36 University of Pittsburgh Cancer Institute (UPCI) Pittsburgh Pennsylvania United States 15232
    37 M D Anderson Cancer Center Houston Texas United States 77030
    38 Huntsman Cancer Institute/University of Utah Salt Lake City Utah United States 84112
    39 Virginia Commonwealth University/Massey Cancer Center Richmond Virginia United States 23298

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Matthew Ingham, Yale University Cancer Center LAO

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT04340843
    Other Study ID Numbers:
    • NCI-2020-02187
    • NCI-2020-02187
    • 10330
    • 10330
    • UM1CA186686
    First Posted:
    Apr 10, 2020
    Last Update Posted:
    Aug 22, 2022
    Last Verified:
    Aug 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Aug 22, 2022