Inclusion Criteria:
Subjects must meet the following inclusion criteria to be eligible and enroll:
1. Subjects must be willing and able to provide informed consent, undergo and comply with
all study assessments, and adhere to the protocol schedule.
2. Patients with recurrent malignant GBM or gliosarcoma will be eligible. Patients with
recurrent anaplastic astrocytoma with wild-type IDH-1 gene will also be eligible if
there is a significant enhancing mass on MRI (≥1.0 cm in diameter with upper limit of
5 cm maximal diameter) because their prognosis/behavior is similar to GBM. Subjects
with an initial diagnosis of an IDH-mutant grade 2 or 3 astrocytoma are also eligible
at recurrence if a biopsy at recurrence is determined to be IDH-mutant grade 4
astrocytoma, and there is a significant enhancing mass on MRI (≥1.0 cm in diameter
with upper limit of 5 cm maximal diameter). A pathology report constitutes adequate
documentation of histology for study inclusion.
3. Patients must show unequivocal evidence for tumor recurrence or progression by MRI
scan after failing prior surgical resection, biopsy, chemotherapy or radiation. A
baseline MRI must be performed within 24 days prior to registration. Biopsy is
encouraged at the time of recurrence if it is unclear that there is recurrent tumor.
However, biopsy is not required if the practicing physician thinks that there is
adequate radiographic and clinical evidence for recurrence.
4. Male or female patients ≥ 18 years of age.
5. Patients must be able to undergo endovascular treatment based on Doppler studies
showing ICA that is less than 50% occluded.
6. For patients undergoing resection for biological endpoints, tumors must be surgically
resectable at the time of baseline evaluation and craniotomy for tumor resection is
indicated as part of their standard medical care.
7. Tumors must be ≥1.0 cm in diameter with upper limit of 5 cm maximal diameter.
8. Patients must have a Karnofsky performance score ≥ 70.
9. Patients must have a life expectancy of at least 16 weeks.
10. Patients must have adequate bone marrow function (absolute granulocyte count > 1,500
and platelet count of > 75,000), adequate liver function (SGPT and SGOT and bilirubin
< 2 times institutional normal ranges), and adequate renal function (creatinine < 2.0
times institutional normal) prior to starting therapy.
11. Prothrombin time/international normalized ratio (PT/INR) or partial thromboplastin
time (PTT) ≤ 1.5x ULN.
12. Subjects who have received the following chemotherapies must have completed them
within the following time periods prior to Baseline/Day 0 of hMSC-DNX2401 delivery
with recovery from any drug-related toxic effects to Grade 1, or less, severity:
- - Four weeks from cytotoxic agents (3 weeks from procarbazine or Temozolomide, 2
weeks from vincristine)
- 6 weeks from nitrosoureas (CCNU, BCNU)
- Four weeks from any targeted investigational agent.
- - One week from non-cytotoxic agents.
13. This study was designed to include women and minorities, but was not designed to
measure differences of intervention effects. Males and females will be recruited with
no preference to gender.
14. No exclusion to this study will be based on race. Minorities will actively be
recruited to participate. The malignant glioma patient population treated at MDACC
over the past year is as follows:
- - American Indian or Alaskan Native - 0.
- - Asian or Pacific Islander - <2%
- Black, not of Hispanic Origin - 3%
- Hispanic - 6%
- White, not of Hispanic Origin - 88%
- Other or Unknown - 2%
- Total - 100%
15.
Patients must be 8 weeks from radiotherapy to minimize the potential for MRI changes
related to radiation necrosis that might be misdiagnosed as progression of disease, or
4 weeks if a new lesion, relative to the pre-radiation MRI, develops that is outside
the primary radiation field (beyond 80% isodose line). However, if a biopsy is
undertaken prior to these times and this biopsy documents histological evidence for
recurrent disease, then patients will be eligible regardless of the time after
radiation.
16. Patients must be willing to forego other cytotoxic and non-cytotoxic drug or radiation
therapy against the tumor while enrolled in the study.
17. Women of childbearing potential must have a negative urine or serum pregnancy test at
screening.
18. Subjects and their partners must be willing to use effective birth control during the
study and for up to 6 months following administration of hMSC-DNX2401. Birth control
that is acceptable to use in this study:
- - Using twice the normal protection of birth control (i.e., double-barrier) by
using a condom AND spermicidal jelly or foam, or a diaphragm AND spermicidal
jelly or foam.
A spermicidal jelly or foam must be used in addition to a barrier
method (e.g., condom or diaphragm)
- - Birth control pills ("The Pill")
- Depot or injectable birth control.
- - IUD (Intrauterine Device)
- Birth Control Patch (e.g., Othro Evra®)
- NuvaRing®
- Surgical sterilization (i.e., tubal ligation or hysterectomy for women or
vasectomy for men)
Exclusion Criteria:
1.
Histology other than GBM, gliosarcoma, IDH wild-type astrocytoma grade III or
IDH-mutant astrocytoma grade 4.
2. Tumor foci detected below the tentorium or beyond the cranial vault.
3. Tumor within the posterior fossa.
4. Tumor with leptomeningeal spread.
5. Difficulty in obtaining vascular access for percutaneous procedure.
6. Ipsilateral carotid stenosis (>50%, by Doppler studies).
7. Thrombophilias or primary hematological diseases.
8. Transfusions or medications (G-CSF) to treat pancytopenia or other hematological
conditions < 28 days prior to Baseline/Day 0/hMSC-DNX2401 administration.
9. Biologic/immunotherapy within 2 weeks of baseline.
10. Clinical or laboratory evidence of inflammatory and/or autoimmune disorders.
11. Any contraindication for undergoing MRI such as: individuals with pacemakers,
epicardial pacer wires, infusion pumps, surgical and/or aneurysm clips, shrapnel,
metal prosthesis, implants with potential magnetic properties, metallic bodies in the
eyes, etc. In addition, subjects must present with tumor that is evaluable by MRI.
12. Pregnant or nursing females.
13. Evidence of active uncontrolled infection or unstable or severe intercurrent medical
conditions. All subjects must be afebrile (i.e., <38.0° Celsius [C]).
14. Any medical condition that precludes surgery or endovascular treatment. 15. Alcoholism (dependency), alcohol or substance abuse within twelve (12) months prior to
screening that has caused health consequences.
16. Immunocompromised subjects or those with autoimmune conditions, active hepatitis
(Liver function tests > 2x normal) or human immunodeficiency virus (HIV)
seropositivity.
17. Evidence of bleeding diathesis or use of anticoagulant medication or any medication
that may increase the risk of bleeding that cannot be stopped prior to surgery. If the
medication can be discontinued prior to DNX-2401 injection then the subject may be
eligible following consultation with the Study Chair. Low weight heparin and Lovenox
(enoxaparin) administered on a temporary limited basis for post procedure DVT
prophylaxis is permitted.
18. History or current diagnosis of any medical or psychological condition that in the
Investigator's opinion might interfere with the subject's ability to participate or
inability to obtain informed consent because of psychiatric or complicating medical
problems.
19. Encephalitis, multiple sclerosis or other central nervous system (CNS) infection or
primary CNS disease that would interfere with subject evaluation.
20. Subjects with known Li-Fraumini Syndrome or with a known germ line deficit in the
retinoblastoma gene or its related pathways.
21. Subjects with significant systemic or major illnesses including but not limited to:
congestive heart failure, ischemic heart disease, cerebrovascular disease (history of
strokes or TIAs in large vessel or small vessel distribution), kidney disease or renal
failure, active liver disease, organ transplantation, or significant psychiatric
disorder.
22. Enrollment in a concomitant therapeutic clinical study.
23. Any condition that prevents compliance with the protocol or adherence to therapy.
24. For patients enrolled in the biological endpoint phase of the study, patients will be
excluded if in the assessment of the surgeon, after resecting the tumor, there is high
likelihood of injecting BM-hMSC-DNX2401 into the ventricles.
