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 ULN.
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
suppository. 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.
