Clinical Trials /

Trial of IDH305 in IDH1 Mutant Grade II or III Glioma



The purpose of this study is to found out if the drug IDH305 is safe and effective in subjects with IDH1 mutant grade II or III glioma that has progressed after observation or radiation therapy.

Related Conditions:
  • Glioma
Recruiting Status:



Phase 2

Trial Eligibility



  • Brief Title: Trial of IDH305 in IDH1 Mutant Grade II or III Glioma
  • Official Title: Phase 2 Study of IDH305 in Subjects With IDH1 Mutant Grade II or III Glioma That Has Progressed After Observation or Radiation Therapy

Clinical Trial IDs

  • ORG STUDY ID: 16-00589
  • NCT ID: NCT02977689


  • Glioma




The purpose of this study is to found out if the drug IDH305 is safe and effective in subjects with IDH1 mutant grade II or III glioma that has progressed after observation or radiation therapy.

Detailed Description

      IDH305 is an orally available, brain-penetrant, mutant-selective allosteric IDH1 inhibitor
      that blocks mutant IDH1-dependent production of 2-HG.

Trial Arms

IDH305ExperimentalIDH305 550 mg, oral, two times per day
  • IDH305

Eligibility Criteria

        Inclusion Criteria:

          1. Willing and able to provide written informed consent prior to any study related
             procedures and to comply with all study requirements.

          2. Subject must be ≥18 years of age.

          3. Patients must have written documentation of IDH1 mutation at the R132 locus by
             immunohistochemistry or DNA sequencing in their tumor.

          4. Histopathological diagnosis of a glioma of WHO grade II or III at initial diagnosis.
             Documentation of diagnosis by pathology report is sufficient for eligibility.

          5. First line management with observation alone or external beam radiation after surgery.
             Notes or records from the treating oncologist or radiation oncologist are required for
             documentation of treatment history.

          6. Patients must have unequivocal progression on brain MRI after observation or external
             beam radiation. If a patient was initially diagnosed with a non-enhancing tumor and
             the tumor develops new contrast-enhancement at progression, they will be excluded
             except for the following exceptions:

               1. Patients with tumors that were contrast-enhancing at initial diagnosis of grade
                  II or III glioma will be allowed if their tumors are contrast-enhancing at
                  progression as well.

               2. If a patient with a grade II or III glioma has a tumor that develops new
                  contrast-enhancement at progression, the enhancing portion of the progressive
                  tumor must be biopsy proven WHO grade II or III at progression.

          7. Measurable tumor of at least 1 cm x 1 cm in diameter by MRI. The measurable tumor may
             be contrast-enhancing or non-enhancing.

          8. Interval of at least 12 weeks from the completion of any prior radiotherapy and
             registration. If patients have not passed an interval of at least 12 weeks, they may
             still be eligible if they meet one or more of the following criteria:

               1. New areas of tumor outside the original radiotherapy fields as determined by the
                  investigator, or

               2. Histologic confirmation of tumor (as opposed to pseudo-progression or radiation
                  necrosis) through biopsy or resection

          9. Collection of an archival tumor block with a minimum of 1 cm2 surface area of viable
             tumor or at least 20 unstained 5 micron slides from the most recent surgery.

         10. Karnofsky performance status (KPS) ≥60.

         11. An interval of at least 2 weeks (to start of study agent) between prior surgical
             resection of glioma, or one week for stereotactic biopsy of glioma.

         12. Adequate hematologic, hepatic, and renal function defined by absolute neutrophil count
             ≥1.0 x 109/L, hemoglobin ≥8 g/dL, platelet count ≥ 75 x 109/L (may have been
             transfused), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x
             upper limit of normal (ULN), total bilirubin > 1 x ULN, and serum creatinine >1.5 x

        Exclusion Criteria:

          1. Glioblastoma (WHO grade IV) histopathology on any tumor sample

          2. Leptomeningeal gliomatosis

          3. Unable to tolerate a contrast-enhanced brain MRI or if MRI is contraindicated

          4. Two weeks since any major surgery treatment (mediastinoscopy, insertion of a central
             venous access device and insertion of a feeding tube are not considered major surgery)
             prior to registration, with the exception of stereotactic biopsy for glioma, in which
             case an interval of 1 week until registration is allowed.

          5. Patients who are currently receiving treatment with a prohibited medication or herbal
             remedy that cannot be discontinued at least one week prior to the start of treatment.

               1. Narrow therapeutic index substrates of CYP3A, CYP2C9, CYP2C19, and CYP2C8

               2. Medications, herbs and supplements that are strong inhibitors and strong inducers
                  of CYP3A

               3. Other herbal preparations and supplements

               4. Inhibitors of UGT1A1

          6. Prior exposure to a therapy targeting IDH1, including targeted inhibitors of IDH1 and
             anti-IDH1 vaccines.

          7. Prior treatment with any cytotoxic chemotherapy, including but not limited to
             temozolomide, lomustine, Nimustine Hydrochloride (ACNU), bis(chloroethyl) nitrosourea
             (BCNU), procarbazine, vincristine, carboplatin, irinotecan, Gliadel wafer,
             cyclophosphamide, etoposide, etc. Chemotherapy is associated with hypermutation
             phenotype at recurrence and therefore patients who have had prior treatment with these
             agents are excluded.

          8. Rapidly progressing neurological symptoms related to underlying disease requiring
             increasing doses of corticosteroids. Steroid use for management of gliomas is allowed
             but the dose must be stable for at least 1 week preceding the baseline MRI/CT. If the
             corticosteroid dose is increased between the date of imaging and the initiation of
             study treatment, a new baseline MRI is required.

          9. Malignant disease, other than that being treated in this study. Exceptions to this
             exclusion include the following: malignancies that were treated curatively and have
             not recurred within the prior 2 years from the time of registration; completely
             resected basal cell and squamous cell skin cancers; any malignancy considered to be
             indolent and that has never required therapy; and completely resected carcinoma in
             situ of any type.

         10. Patients with corrected QT using the Fridericia correction (QTcF) > 470 msec, or other
             clinically significant, uncontrolled heart disease, including acute myocardial
             infarction or unstable angina < 3 months prior to the first dose of IDH305.

         11. Any other medical condition that would, in the investigator's judgment, prevent the
             patient's participation in the clinical study due to safety concerns or compliance
             with clinical study procedures such as the presence of other clinically significant
             cardiac, respiratory, gastrointestinal, renal, hepatic, infectious, psychiatric or
             neurological disease.

         12. Patients with Gilbert's syndrome or other heritable diseases of bile processing.

         13. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
             female after conception and until the termination of gestation, confirmed by a
             positive hCG laboratory test.

         14. Women of child-bearing potential (WOCBP), defined as all women physiologically capable
             of becoming pregnant, unless they are using highly effective methods of contraception
             during dosing and for 30 days after the use of the investigational medication. Highly
             effective contraception methods include:

               -  Total abstinence (when this is in line with the preferred and usual lifestyle of
                  the patient). Periodic abstinence (e.g., calendar, ovulation, post-ovulation
                  methods) and withdrawal are not acceptable methods of contraception

               -  Female sterilization (have had surgical bilateral oophorectomy with or without
                  hysterectomy), total hysterectomy, or tubal ligation at least six weeks before
                  taking study treatment. In case of oophorectomy alone, only when the reproductive
                  status of the woman has been confirmed by follow up hormone level assessment

               -  Male sterilization (at least 6 months prior to screening). The vasectomized male
                  partner should be the sole partner for that patient

               -  Combination of any two of the following (a+b, a+c, or b+c):

                    1. Use of oral, injected or implanted hormonal methods of contraception or
                       other forms of hormonal, for example hormone vaginal ring or transdermal
                       hormone contraception.

                         -  In case of use of oral contraception women should have been stable on
                            the same pill for a minimum of 3 months before taking study treatment.

                    2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

                    3. Barrier methods of contraception: condom or occlusive cap (diaphragm or
                       cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal

         15. Women are considered post-menopausal and not of child bearing potential if they have
             had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
             (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral
             oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at
             least six weeks prior to screening. In the case of oophorectomy alone, only when the
             reproductive status of the woman has been confirmed by follow up hormone level
             assessment is she considered not of child bearing potential.

         16. Sexually active males must use a condom during intercourse while taking the drug and
             for 30 days after stopping treatment and should not father a child in this period. A
             condom is required to be used also by vasectomized men as well as during intercourse
             with a male partner in order to prevent delivery of the drug via semen.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Radiographic response rate
Time Frame:up to 8 weeks
Safety Issue:

Secondary Outcome Measures

Measure:Safety (adverse events) of the protocol therapy
Time Frame:up to 2 years
Safety Issue:
Description:The adverse events are evaluated per Common Terminology Criteria for Adverse Events (CTCAE) 4.03
Measure:Volumetric radiographic response rate
Time Frame:up to 6 months
Safety Issue:
Measure:Median duration of response
Time Frame:up to 6 months
Safety Issue:
Measure:Median progression-free survival (PFS)
Time Frame:up to 6 months
Safety Issue:
Measure:Progression-free survival at 6 months (PFS6)
Time Frame:up to 6 months
Safety Issue:
Measure:2-year overall survival (OS)
Time Frame:up to 2 years
Safety Issue:


Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Withdrawn
Lead Sponsor:NYU Langone Health

Trial Keywords

  • Isocitrate dehydrogenase (IDH)
  • R-2-Hydroxyglutarate (2-HG)
  • Gene encoding UDP-glucuronosyltransferase (UGT1A1)
  • Glioblastoma (GBM)
  • IDH305
  • IDHR132 mutations
  • Astrocytoma
  • Oligodendroglioma
  • Oligoastrocytoma
  • IDH1 R132H
  • IDH1

Last Updated

December 20, 2017