Clinical Trials /

ASTX727 in Recurrent/Progressive Non-enhancing IDH Mutant Gliomas

NCT03922555

Description:

this research study is evaluating the highest dose of ASTX727 that can be administered safely to recurrent/progressive non-enhancing IDH mutant gliomas patients.

Related Conditions:
  • Glioma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: ASTX727 in Recurrent/Progressive Non-enhancing IDH Mutant Gliomas
  • Official Title: Phase I Trial of ASTX727 in Recurrent/Progressive Non-enhancing IDH Mutant Gliomas

Clinical Trial IDs

  • ORG STUDY ID: 18-631
  • NCT ID: NCT03922555

Conditions

  • Neurological Cancer

Interventions

DrugSynonymsArms
ASTX727ASTX727 (Cedazuridine + Cytidine Antimetabolite Decitabine)

Purpose

this research study is evaluating the highest dose of ASTX727 that can be administered safely to recurrent/progressive non-enhancing IDH mutant gliomas patients.

Detailed Description

      This research study is a Phase I clinical trial, which tests the safety of an investigational
      drug and also tries to define the appropriate dose of the investigational drug to use for
      further studies. "Investigational" means that the drug is being studied.

      The FDA (the U.S. Food and Drug Administration) has not approved ASTX727 as a treatment for
      any disease.

      ASTX727 is made up of the 2 study drugs cedazuridine and decitabine. Cedazuridine is believed
      to work by slowing down how fast decitabine is broken down by the body. Decitabine is
      believed to work by blocking abnormal cells or cancer cells from growing.
    

Trial Arms

NameTypeDescriptionInterventions
ASTX727 (Cedazuridine + Cytidine Antimetabolite Decitabine)Experimental-ASTX727 administered orally for 5 or 6 consecutive days every 28d cycle and will de-escalate to 4 consecutive days every 28 d cycle.
  • ASTX727
Expansion CohortExperimentalOral ASTX727 will be administered daily for 4, 5 or 6 consecutive days Surgical resection will take place 12 days (+/- 1 day) after initiation of treatment
  • ASTX727

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must be ≥18 years of age.

          -  Participants must have histologically or cytologically confirmed glioma, with
             documented IDH1 and/or IDH2 gene-mutation.

          -  Participants must have radiographic evidence of non-enhancing disease
             progression/recurrence per RANO criteria for low grade gliomas (LGG).

          -  Patients who have received prior treatment with chemotherapy, radiation, or a
             combination of both are eligible. Also, patients who have not received any prior
             treatment for their glioma are also eligible.

          -  Participants must be ≥12 weeks from completion of radiation.

          -  Participants must have a baseline brain MRI scan within 28 days prior to Day 1 of
             treatment.

          -  Participants must be on a stable or decreasing dose of glucocorticoids for 7 days
             prior to registration.

          -  Participants must have archived primary tumor biopsies or surgical specimens for
             additional exploratory translational studies. At least 100-micron length of FFPE
             tissue or a tissue block should be available for enrollment and for shipment to the
             Sponsor, or a laboratory designated by the Principal Investigator. If less material is
             available, participants could still be eligible after discussion with the Principal
             Investigator who will assess and confirm that there is sufficient material for key
             evaluations.

          -  Participants must be able to understand and willing to sign an informed consent. A
             legally authorized representative may consent on behalf of a participant who is
             otherwise unable to provide informed consent, if acceptable to and approved by the
             site and/or site's Institutional Review Board (IRB)/Independent Ethics Committee
             (IEC).

          -  Participants must have KPS ≥ to 70

          -  Participants must have expected survival of ≥ 6 months.

          -  Participants must have adequate bone marrow function as evidenced by:

               -  Leukocytes ≥ 3,000/mcL

               -  Absolute neutrophil count ≥1500/mcL;

               -  Hemoglobin ≥10 g/dL

               -  Platelets ≥100,000/mcL

          -  Participants must have adequate hepatic function as evidenced by:

               -  Serum total bilirubin ≤1.5 x upper limit of normal (ULN), unless considered due
                  to Gilbert's disease

               -  Aspartate aminotransferase (AST), Alanine Aminotransferase (ALT), and alkaline
                  phosphatase (ALP) ≤3.0 x ULN.

          -  Participants must have adequate renal function as evidenced by:

               -  Serum creatinine ≤2.0 x ULN

               -  OR Creatinine clearance >40 mL/min based on the Cockroft-Gault glomerular
                  filtration rate (GFR) estimation: (140 − Age) × (weight in kg) × (0.85 if
                  female)/72 × serum creatinine

          -  Participants must be recovered from any clinically relevant toxic effects of any prior
             surgery, radiotherapy, or other therapy intended for the treatment of cancer.
             (Participants with residual Grade 1 toxicity due to prior chemotherapy are allowed).

          -  Female participants with reproductive potential must have a negative serum pregnancy
             test within 14 days prior to the first study drug administration. Participants with
             reproductive potential are defined as sexually mature women who have not undergone a
             hysterectomy, bilateral oophorectomy or tubal occlusion or who have not been naturally
             postmenopausal (i.e., who have not menstruated at all) for at least 24 consecutive
             months (i.e., have had menses at any time in the preceding 24 consecutive months).
             Women with reproductive potential as well as fertile men and their partners who are
             female with reproductive potential must agree to abstain from sexual intercourse or to
             use 2 effective forms of contraception from the time of giving informed consent,
             during the study, and for 90 days (females and males) following the last dose of
             ASTX727.

          -  Participants enrolling in the expansion cohort (Arm B) must meet all of the above
             criteria and must have surgically accessible tumors and be surgical candidates.

        Exclusion Criteria:

          -  Participants with enhancing disease on brain MRI.

          -  Participants who received systemic anticancer therapy <28 days prior to registration.
             One exception: participants on lomustine/CCNU must wait at least 42 days from last
             date of drug administration to registration.

          -  Participants who received an investigational agent <14 days prior to registration. In
             addition, the first dose of ASTX727 should not occur before a period ≥5 half-lives of
             the investigational agent has elapsed.

          -  Participants with prior treatment with bevacizumab (Avastin) are excluded.

          -  Participants who are pregnant or breast-feeding.

          -  Participants with an active severe infection that requires anti-infective therapy or
             with an unexplained fever >38.5°C during screening visits or on their first day of
             study drug administration.

          -  Participants with known additional malignancy that is progressing or requires active
             treatment within 2 years of start of study drug. Exceptions include basal cell
             carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer
             that has undergone potentially curative therapy, or surgically treated prostate
             cancer.

          -  Participants with known hypersensitivity to any of the components of ASTX727.

          -  Participants with a history of myocardial infarction within the 6 months prior to
             screening.

          -  Participants with a known history of severe and/or uncontrolled ventricular
             arrhythmias.

          -  Participants with QTc interval ≥450 msec or with other factors that significantly
             increase the risk of QT prolongation or arrhythmic events (e.g., family history of
             long QT interval syndrome).

          -  Participants with known infection with human immunodeficiency virus (HIV) or active
             hepatitis B or C.

          -  Participants with any other medical or psychological condition, deemed by the
             Investigator to be likely to interfere with a participant's ability to sign informed
             consent, cooperate, or participate in the study.

          -  Participants with known dysphagia, short-gut syndrome, gastroparesis, or other
             conditions that limit the ingestion or gastrointestinal absorption of drugs
             administered orally.

          -  Participants with evidence of intracranial or intratumoral hemorrhage either by MRI or
             CT scan. Participants with resolving post-surgical changes, punctate/micro-hemorrhage,
             or hemosiderin are eligible.

          -  Participants enrolling in the expansion cohort will be excluded is they are deemed by
             the treating physician or surgeon not to be suitable for surgery
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose
Time Frame:1 year
Safety Issue:
Description:Participants will be enrolled at escalating doses using a standard 3+3 dose escalation design until the maximum administered dose is reached or until dose limiting toxicities result in the end of dose escalation. The maximum tolerated dose is the highest administered dose level at which participants experienced experienced 1 or fewer dose limiting toxicities.

Secondary Outcome Measures

Measure:Median Progression Free Survival
Time Frame:From the time of randomization until disease progression or death, up to five years
Safety Issue:
Description:Progression-Free Survival (PFS) is defined as the time from randomization (or registration) to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation. Disease progression will be assessed using the Response Assessment in Neuro-Oncology (RANO) Working Group updated response assessment criteria for low-grade Gliomas.
Measure:Overall Survival
Time Frame:From the time of randomization until death, up to five years
Safety Issue:
Description:Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive.
Measure:Response Rate
Time Frame:1 Year
Safety Issue:
Description:The number of participants achieving a complete or partial tumor response as assessed using the the Response Assessment in Neuro-Oncology (RANO) Working Group updated response assessment criteria for low-grade Gliomas.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Massachusetts General Hospital

Trial Keywords

  • Neurological Cancer

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