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|NCT02968940 : Avelumab With Hypofractionated Radiation Therapy in Adults With Isocitrate Dehydrogenase (IDH) Mutant Glioblastoma|
|Ages||Min: 18 Years Max: N/A|
1. Male or female subjects aged ?18 years.
2. Documentation of IDH1 or IDH2 mutation in any tumor specimen.
3. Pathologic evidence (diagnostic pathology slides available or pathology report) of a
diagnosis of WHO grade II or III glioma prior to treatment with temozolomide or PCV
4. Histopathological evidence of glioblastoma (WHO grade IV) on a progressive tumor
specimen after treatment with temozolomide or PCV chemotherapy. The diagnosis of
glioblastoma must be confirmed on central review by a study-designated
neuropathologist at NYULMC at screening. Exceptions to this eligibility include the
1. Any progressive glioma with IDH1 or IDH2 mutation, regardless of WHO grade or
histopathological diagnosis, may be eligible contingent on approval by the
overall Principal Investigator if the progressive tumor specimen is found to have
one of the genetic alterations below:
1. ?20 somatic mutations per Mb by whole-exome sequencing 2. Mutation in a mismatch repair
gene or other genes known to be associated with hypermutator phenotypes or microsatellite
instability, including but not limited to MSH2, MSH6, MLH1, POLE, PMS2, POLD as determined
by validated methods.
3. Microsatellite instability as identified by polymerase chain reaction (PCR) or other
validated methods 5. Availability of a paraffin-embedded or frozen tumor-tissue block with
a minimum of 1 cm2 of tumor surface area from a tissue specimen that demonstrates
pathological transformation to glioblastoma (WHO grade IV) or a progressive specimen that
harbors one of the genetic alterations specified in Inclusion Criteria 4a.
a. If a tumor block can not be submitted, then 20 unstained slides (preferably 10 slides
from two different tumor blocks from the same surgery) from the tumor specimen must be
6. Patients must have had treatment with temozolomide or PCV [procarbazine, lomustine
(CCNU), vincristine] chemotherapy prior to histopathologic transformation to glioblastoma
or prior to identification of one of the genetic alterations specified in Inclusion
Criteria 4a. Notes or records from the treating oncologist are required for documentation
of treatment history. Prior treatment with at least one of the following chemotherapy
schedules is required to be eligible:
1. At least one 6 week course of continuous daily temozolomide
2. At least six 28-day cycles given in one of the following schedules:
1. Daily for 5 days of a 28-day cycle
2. Daily for 21 days of a 28-day cycle
3. Daily for 14 days of a 28-day cycle
4. Alternating 7 days on/7 days per 28-day cycle
5. Continuous daily dosing of a 28-day cycle.
3. Other schedules of temozolomide may be considered after discussion with the overall
4. At least 3 cycles of PCV chemotherapy. 7. Patients who received anti-tumor therapy
after histopathologic transformation to glioblastoma must have shown unequivocal
radiographic evidence of tumor progression by contrast-enhanced MRI scan (or CT scan
if MRI is contraindicated).
8. Patients can have had any number of prior therapies. 9. Karnofsky performance
status (Attachment 2) of ?60. 10. Interval of at least 6 months from the completion of
any prior radiotherapy and registration. If patients have not passed an interval of at
least 6 months, they may still be eligible if they meet one or more of the following
a. New areas of tumor outside the original radiotherapy fields as determined by the
investigator, or b. Histologic confirmation of tumor through biopsy or resection, or c.
Nuclear medicine imaging, MR spectroscopy, or MR perfusion imaging consistent with true
progressive disease, rather than pseudoprogression or radiation necrosis obtained within 28
days of registration AND an interval of at least 90 days between completion of radiotherapy
11. The following time periods must have elapsed prior to start of study treatment, the
following time periods must have elapsed:
1. 5 half-lives from any investigational agent
2. 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from
3. 6 weeks from antibodies
4. Prior treatment with other immune modulating agents within fewer than 4 weeks prior to
the first dose of Avelumab.
1. Examples of immune modulating agents include blockers of PD-1/PD-L1, CTLA-4, 4-1BB
(CD137), OX-40, therapeutic vaccines, or cytokine treatments.
5. 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies.
12. An interval of at least 2 weeks (to start of study agent) between prior surgical
resection or one week for stereotactic biopsy.
13. Adequate hematologic, hepatic, and renal function defined by absolute neutrophil
count ?1.5 x 109/L, hemoglobin >9 g/dL, platelet count ? 100 x 109/L (may have been
transfused), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ?2.5
x upper limit of normal (ULN), total bilirubin ?1.5 x ULN, and estimated creatinine
clearance (CrCl) ? 30 mL/min according to the Cockcroft-Gault formula or local
institutional standard method).
14. Women of child-bearing potential (WOCBP) and men able to father a child must agree
to use highly effective contraception while on study drug and for 60 days after the
last dose of Avelumab. WOCBP must have a negative pregnancy test within 28 days of
initiation of dosing. (Note: The effects of the trial drug on the developing human
fetus are unknown; thus, WOCBP and men able to father a child must agree to use 2
highly effective contraception methods). Women may be included if they are either
surgically sterile (hysterectomy or bilateral oophorectomy at least 6 weeks prior with
confirmation of reproductive status by follow up hormone level assessment) or are
postmenopausal (natural, spontaneous amenorrhea with an appropriate clinical profile
for ?1 year or 6 months with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL).
Highly effective contraception is defined as a method with a failure rate of less than
1 % per year, including but not limited to:
a. True Abstinence: When this is in line with the preferred and usual lifestyle of the
subject. Periodic abstinence (e.g., calendar, ovulation, post-ovulation methods) and
withdrawal are not acceptable methods of contraception.
b. Sterilization: Surgical bilateral oophorectomy (with or without hysterectomy) as above,
or tubal ligation at least six weeks prior.
c. Male Partner Sterilization (with the appropriate post-vasectomy documentation of the
absence of sperm in the ejaculate). For female subjects on the study, the vasectomised male
partner should be the sole partner for that participant.
d. Use of a combination of any two of the following:
1. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 2. Barrier
methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with
spermicidal foam/gel/film/cream/vaginal suppository e. Appropriate hormonal contraceptives
(including any registered and marketed contraceptive agent that contains an estrogen and/or
a progestational agent - including oral, subcutaneous, intrauterine, or intramuscular
agents) 15. Willing to and capable of providing written informed consent, or have an
acceptable surrogate capable of giving consent on the subject's behalf, prior to any study
16. Ability and willingness to comply with all study requirements, including scheduled
visits, treatment plans, laboratory tests, and other study-related procedures.
1. Investigational drug use within 28 days of the first dose of Avelumab.
2. Planned participation in another study of an investigational agent or investigational
device or use of a therapeutic device intended for therapy of glioma.
3. Prior therapy with an agent that blocks the PD-1/PD-L1 pathway.
4. Primary brainstem or spinal cord tumor.
5. Prior re-irradiation or stereotactic radiosurgery for recurrent disease at the same
tumor location intended for HFRT in this study.
6. Patients with evidence of significant intracranial mass effect that requires >4 mg of
dexamethasone or bioequivalent per day for 5 consecutive days for management of
symptoms at any time within 14 days of registration.
1. Subjects on a standard high-dose steroid taper after craniotomy may receive a
higher dose of corticosteroids within 14 days of registration, however must be at
a dose ?4 mg of dexamethasone or bioequivalent per day within 7 days prior to
2. Administration of steroids through a route known to result in a minimal systemic
exposure (i.e., intranasal, intraocular, inhaled or topical corticosteroids (<5%
of body surface area) for the treatment of mild/moderate asthma, allergies or
dermatitis) are permitted.
3. Subjects requiring hormone replacement with corticosteroids are eligible if the
steroids are administered only for the purpose of hormonal replacement and at
doses ? 10 mg prednisone or bioequivalent per day.
7. Known immunosuppressive disease, active autoimmune disease requiring chronic
immunosuppressive therapy, prior organ transplant, including allogeneic stem cell
transplantation. The following are not exclusions:
1. Diabetes type I, Vitiligo, hypo- or hyperthyroid, or psoriasis that does not
require systemic immunosuppressive treatment are eligible
2. Prior corneal transplant may be allowed to enroll following approval from the
overall Principal Investigator.
8. Known history of, or any evidence of active, non-infectious pneumonitis within the
last 5 years.
9. Known severe (NCI-CTCAE v4.03 Grade 3 or 4) infusion-related allergy or acute
hypersensitivity reaction attributed to any monoclonal antibody, any history of
anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially
10. Active infection requiring systemic therapy, including known infection with human
immunodeficiency virus (HIV), or known active infection with hepatitis B or hepatitis
11. Has received a live vaccine within 4 weeks of the first dose of avelumab or while on
trial. Note: Seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are
live attenuated vaccines, and are not allowed.
12. Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 4.03; however,
alopecia and sensory neuropathy Grade ? 2 is acceptable
13. Patients with another active cancer [excluding basal cell carcinoma, cervical
carcinoma in situ or melanoma in situ]. Prior history of other cancer is allowed, as
long as there was no active disease within the prior 2 years.
14. Unstable or severe intercurrent medical or psychiatric conditions or uncontrolled
15. Pregnant or breastfeeding (negative pregnancy test required), or unable to maintain
use of contraception while on study and for 60 days after the last dose of Avelumab.
16. Known alcohol or drug abuse
17. All other significant diseases (for example, inflammatory bowel disease, uncontrolled
asthma), which, in the opinion of the Investigator, might impair the subject's
tolerance of trial treatment.
18. Any psychiatric condition that would prohibit the understanding or rendering of
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Facility: University of California, Los Angeles (UCLA)
Timothy Cloughesy, MD Phone: 310-825-5321
Click HERE to send email to this center
Facility: UCSF Medical Center
Jennie Taylor, MD, MPH Phone: 415-353-2966
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Facility: Massachusetts General Hospital
Isabel Arrillaga-Romany, MD, PhD Phone: 617-724-8770
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Facility: Laura & Isaac Perlmutter Cancer Center & NYU Langone Medical Center
Joshua Silverman, MD, PhD
Andrew S Chi, MD, PhD Phone: 212-731-6267
Click HERE to send email to this center