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ASTX727 in Recurrent/Progressive Non-enhancing IDH Mutant Gliomas

  • Clinicaltrials.gov identifier

    NCT03922555

  • Recruitment Status

    Recruiting

  • First Posted

    April 22, 2019

  • Last update posted

    September 9, 2020

Study Description

Brief summary:

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

  • Condition or Disease:Neurological Cancer
  • Intervention/Treatment: Drug: ASTX727
  • Phase: Phase 1

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.

Study Design

  • Study Type: Interventional
  • Estimated Enrollment: 18 participants
  • Allocation: Non-Randomized
  • Intervention Model: Sequential Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: Phase I Trial of ASTX727 in Recurrent/Progressive Non-enhancing IDH Mutant Gliomas
  • Actual Study Start Date: July 2019
  • Estimated Primary Completion Date: May 2022
  • Estimated Study Completion Date: May 2024

Arms and interventions

Arm Intervention/treatment
Experimental: ASTX727 (Cedazuridine + Cytidine Antimetabolite Decitabine)
-ASTX727 administered orally for 5 or 6 consecutive days every 28d cycle and will de-escalate to 4 consecutive days every 28 d cycle.
Drug: ASTX727
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.
Experimental: Expansion Cohort
Oral 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
Drug: ASTX727
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.

Outcome Measures

  • Primary Outcome Measures: 1. Maximum tolerated dose [ Time Frame: 1 year ]
    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: 1. Response Rate [ Time Frame: 1 Year ]
    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.
  • 2. Median Progression Free Survival [ Time Frame: From the time of randomization until disease progression or death, up to five years ]
    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.
  • 3. Overall Survival [ Time Frame: From the time of randomization until death, up to five years ]
    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.

Eligibility Criteria

  • Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
  • Sexes Eligible for Study: All
  • Accepts Healthy Volunteers: No

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 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

Contacts and Locations

Contacts

Contact: Isabel Arrillaga-Romany, MD 617-724-4000 iarrillaga@mgh.harvard.edu

Locations

United States, Massachusetts
Massachusetts General Hospital Cancer Center
Boston

United States, Massachusetts
Brigham and Women's Hospital
Boston

United States, Massachusetts
Dana Farber Cancer Institute
Boston

Sponsors and Collaborators

Massachusetts General Hospital

Astex Pharmaceuticals, Inc.

Investigators

Principal Investigator: Isabel Arrillaga-Romany Massachusetts General Hospital

More Information

  • Responsible Party: Massachusetts General Hospital
  • ClinicalTrials.gov Identifier: NCT03922555 History of Changes
  • Other Study ID Numbers: 18-631
  • First Posted: April 22, 2019 Key Record Dates
  • Last Update Posted: September 9, 2020
  • Last Verified: September 2020
  • Individual Participant
    Data (IPD) Sharing
    Statement:

  • Plan to Share IPD: Yes
  • Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: Dr. Isabel Arrillaga-Romany. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research
  • Supporting Materials: Study Protocol, Statistical Analysis Plan (SAP), Informed Consent Form (ICF)
  • Time Frame: Data can be shared no earlier than 1 year following the date of publication
  • Access Criteria: BCH - Contact the Technology & Innovation Development Office at www.childrensinnovations.org or email TIDO@childrens.harvard.edu BIDMC - Contact the Beth Israel Deaconess Medical Center Technology Ventures Office at tvo@bidmc.harvard.edu BWH - Contact the Partners Innovations team at http://www.partners.org/innovation DFCI - Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu MGH - Contact the Partners Innovations team at http://www.partners.org/innovation
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by Massachusetts General Hospital: Neurological Cancer
  • Additional relevant MeSH terms: Central Nervous System Neoplasms