Clinical Trials /

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

NCT04340843

Description:

This phase II trial studies how well belinostat and SGI-110 (guadecitabine) work 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 and guadecitabine may lower the chance of chondrosarcoma growing or spreading.

Related Conditions:
  • Chondrosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Combination of Belinostat and SGI-110 (Guadecitabine) for the Treatment of Unresectable and Metastatic Conventional Chondrosarcoma
  • Official Title: A Phase 2 Study of Belinostat and SGI-110 (Guadecitabine) for the Treatment of Unresectable and Metastatic Conventional Chondrosarcoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-02187
  • SECONDARY ID: NCI-2020-02187
  • SECONDARY ID: 10330
  • SECONDARY ID: 10330
  • SECONDARY ID: UM1CA186686
  • NCT ID: NCT04340843

Conditions

  • Metastatic Primary Central Chondrosarcoma
  • Unresectable Primary Central Chondrosarcoma

Interventions

DrugSynonymsArms
BelinostatBeleodaq, PXD 101, PXD101Treatment (belinostat, guadecitabine)
GuadecitabineDNMT inhibitor SGI-110, S110, SGI-110Treatment (belinostat, guadecitabine)

Purpose

This phase II trial studies how well belinostat and SGI-110 (guadecitabine) work 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 and guadecitabine may lower the chance of 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (belinostat, guadecitabine)ExperimentalPatients 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.
  • Belinostat
  • Guadecitabine

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have biopsy-proven conventional 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

               -  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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate
Time Frame:Within 6 months after initiating study treatment
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Presence of treatment related adverse events (AEs)
Time Frame:Up to 24 months post treatment
Safety Issue:
Description: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.
Measure:Occurrence of dose limiting toxicity (DLT)
Time Frame:During the first cycle (28 days)
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

August 27, 2020