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Phase I Trial of Conditionally Replication-Competent Adenovirus (DNX-2401, Formerly Known as Delta-24-RGD-4C) for Recurrent Malignant Gliomas


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Brain Cancer, Central Nervous System Diseases

Thank you

Trial Information

Phase I Trial of Conditionally Replication-Competent Adenovirus (DNX-2401, Formerly Known as Delta-24-RGD-4C) for Recurrent Malignant Gliomas


The Study Drug:

DNX-2401 (formerly known as Delta-24-RGD-4C) is a virus that works by killing brain tumor
cells. It is made from a common cold virus, called adenovirus, type 5. This virus normally
causes the common cold, and most people around the world have been exposed many times to
this common, naturally-occurring virus during their lives. Two (2) changes have been made to
the adenovirus to make DNX-2401. The first change was to make the virus only grow in cancer
cells. The second change was made to allow DNX-2401 to enter cancer cells more easily.
These changes make DNX-2401 more able to multiply and kill cancer cells and less likely to
multiply in normal cells.

Study Groups:

Participants will eventually be divided into 2 groups (Groups A and B).

At first, all participants will only be enrolled into Group A. Participants in Group A will
receive the study drug but will not have the recurrent malignant glioma tumor removed by
surgery.

Enrollment into Group B will not start until the FDA has reviewed initial results on how the
treatment for participants in Group A effected brain tumor cells and the body in general.
Once approval for enrollment is given, all eligible participants will be assigned to Group B
and will receive the study drug and have their tumors removed by surgery. If you are to
receive surgery, you will be asked to sign a separate surgical consent form to help further
explain the operation.

If you are found to be eligible to take part in this study, you will be assigned to a dose
level of DNX-2401 based on when you joined this study. Up 8 dose levels of DNX-2401 will be
tested. Three (3) participants will be enrolled at each dose level. The first group of
participants will receive the lowest dose level. Each new group will receive a higher dose
than the group before it, if no intolerable side effects were seen. This will continue
until the highest tolerable dose of DNX-2401 is found. You will be informed of which dose
you will receive.

Study Drug Administration:

DNX-2401 is given by a surgical procedure where a neurosurgeon precisely injects DNX-2401
through a catheter (small tube) that is inserted into your brain tumor. You will stay in
the hospital and be watched closely afterward for up to 48 hours, but it may be longer if
your doctors feel that you are not ready to go home.

After receiving DNX-2401, all participants must wear a mask. You must also stay away from
pregnant women, babies, children under three years of age, elderly people and large groups
of people who may have weaker defenses to disease or those who can spread a disease. You
must also stay away from other patients who may have immune system problems, such as people
with AIDS, or people who are getting chemotherapy or radiation therapy. The study doctors
will decide how long you will need to follow these precautions. You should not donate blood
or sperm for at least 6 months after receiving DNX-2401.

Group A:

Before receiving DNX-2401, participants in Group A will have a sample (stereotactic biopsy)
of brain tumor tissue collected to confirm that recurrent malignant glioma is present. On
the morning of the biopsy, you will have an MRI (with dye). A metal frame will be placed on
your head and an MRI of your brain will be done. Before the MRI, a dye will be injected to
help give the doctors a better picture of your brain. The head frame allows the surgeon to
use MRI to identify the precise location of the tumor within the brain. The frame will stay
in place for several hours while the procedure is being performed.

A portion of your head will be shaved for the biopsy. You will have a small incision (cut)
in your head (about 2-3 inches). The protective covering of the brain (dura) will be opened
and a piece of brain tumor will be removed. If, under a microscope, the biopsy shows that
the tumor is still malignant glioma, you will then have an injection of DNX-2401. The
anesthesiologists (doctor who gives the anesthesia) may give you medication to make you
sedated (anesthesia). They will place a needle into your vein (intravenous line or "IV") to
give you this medicine. The anesthesia is given so that you do not feel any pain or
discomfort and do not move during the MRI or the surgery.

A small catheter will be placed into the tumor and the metal frame will help guide the
proper placement. Some anti-inflammatory medication (a steroid called dexamethasone) will be
given in your vein. Then DNX-2401 will be slowly injected into the tumor over about 10
minutes. After the injection, the incision will be closed in a standard and cosmetically
acceptable manner.

Group B:

Before receiving DNX-2401, participants in Group B will have a biopsy to confirm that the
tumor is recurrent glioma. The procedure will be exactly the same as described for those in
Group A. This is called "Stage 1." However, at the end of the biopsy and study drug
injection procedure, the catheter will be clipped off next to your skull and a portion of
the tube will remain inside the tumor and in place for the next 2 weeks. The scalp will be
closed over the clipped catheter to prevent any possibility of infection. The next day, you
will have a CT scan to check the tumor and placement of the catheter.

Group A Follow-up Visits:

You will come back to the study center for check-ups at 4, 7,14 and 28 days, then 2, 3, and
4 months after the injections, and then every 2 months for 2 years. After that, you will be
asked to return to the clinic every 4 months for the rest of your life. At each visit, the
following tests and procedures will be performed:

- You will be asked to give information about any new medications and therapies,
including vitamins, herbs, and supplements that you may be taking.

- You will be asked to describe any changes in your health or how you feel.

- You will have a neurological exam.

- Your weight will be measured on Day 28 and at 2, 3 and 4 months.

- Your vital signs will be measured.

- You will be asked to provide a blood sample (about 1 teaspoon), a urine sample and a
swab of your nose and throat will be taken.

- You will have blood tests (about 4 teaspoons) to evaluate your clinical status on Days
4, 7, 28, and at 2, 3 and 4 months.

- Blood (about 2 teaspoons) will be collected to look for the presence of anti-AD5 and
virus.

- Women who are able to become pregnant must have a blood (about 1 teaspoon) pregnancy
test on 1 and 4 month visit and all follow-up visits after that.

- You will have an MRI at each visit except for Day 4.

- After the 4 month visit, you will have an evaluation to see how you have responded to
treatment for the first 2 years and every 4 months after that.

Group B Follow-up Visits:

You will be seen in the study center for check-ups on Days 4, 7, and 13 after the injection
but before your craniotomy. At each visit the following tests and procedures will be
performed:

- You will be asked to give information about any new medications and therapies,
including vitamins, herbs, and supplements that you may be taking.

- You will be asked to describe any changes in your health or how you feel.

- You will have a neurological exam.

- Your vital signs will be measured.

- You will be asked to provide a blood sample (about 1 teaspoon), a urine sample and a
swab of your nose and throat will be taken.

- You will have a blood test (about 4 teaspoons) to evaluate your clinical status.

- Blood (about 2 teaspoons) will be collected to look for the presence of anti-AD5 and
virus.

- Women who are able to become pregnant must have a blood (about 1 teaspoon) pregnancy
test on Day 13, 1 and 4 month visits and all follow-up visits after that.

- You will have an MRI on Days 7 and 13 only.

If you are feeling well 14 days after the first injection of study drug, you will be brought
back to the operating room for a second procedure to remove the tumor. You will undergo a
craniotomy, in which the skull over the tumor is removed to get to the brain and tumor. The
neurosurgeon will try to remove the tumor as completely as possible with the catheter tip
from the first procedure in place. After the tumor has been removed, you will receive
another dose of DNX-2401 that will be injected into the brain tissue that surrounded the
tumor to try to kill any remaining tumor cells. This is called "Stage 2." The skull will
then be replaced and the skin closed. Within 6 hours of the craniotomy on Day 14, you will
have a neurological exam and your vital signs will be measured.

On the day of resection, a sample of the removed brain tumor tissue will be collected and
stored until the study is over. Analysis of the tissue will be performed to look for the
presence and activity of the virus, as well as any additional tests that are necessary for
protocol purposes.

Group B Follow-up Visits after Craniotomy:

After the surgery, you will be seen in the hospital or come back to the center on Days 15,
18, 21, 28, and 42, at 2, 3 and 4 months, and then every 2 months for 2 years. After that,
you will be asked to come back every 4 months for the rest of your life. At each visit, the
following tests and procedures will be performed:

- You will be asked to give information about any new medications and therapies,
including vitamins, herbs, and supplements that you may be taking.

- You will be asked to describe any changes in your health or how you feel.

- You will have a neurological exam.

- Your weight will be measured on Day 28, 42 and at 2, 3 and 4 months only.

- Your vital signs will be measured.

- You will be asked to provide a blood sample (about 1 teaspoon), a urine sample, and a
swab of your nose and throat.

- You will have a blood test (about 4 teaspoons) to evaluate your clinical status.

- Blood (about 2 teaspoons) will be drawn to look for the presence of anti-AD5 and
virus.

- Women who can become pregnant must have a blood (about 1 teaspoon) pregnancy test at
all visits except Day 15 and 18.

- You will have an MRI.

For participants who are clinically unable to wait 14 days for surgery because of the
tumor's size and/or location, or because they are experiencing serious neurological
symptoms, the study chair may decide to skip the biopsy.

Group B Follow-up Visits (Stage 2--Craniotomy Only):

After the surgery, you will be seen in the hospital or come back to the center on Days 1, 4,
7, 14, and 28; at 2, 3, and 4 months; and then every 2 months for 2 years. After that, you
will be asked to come back every 4 months for the rest of your life. At each visit, the
following tests and procedures will be performed:

- You will be asked to give information about any new medications and therapies,
including vitamins, herbs, and supplements that you may be taking.

- You will be asked to describe any changes in your health or how you feel.

- You will have a neurological exam.

- Your weight will be measured on Day 28 and at 2, 3, and 4 months.

- Your vital signs will be measured.

- You will be asked to provide a blood sample (about 1 teaspoon), a urine sample, and a
swab of your nose and throat.

- You will have a blood test (about 4 teaspoons) to evaluate your clinical status.

- Blood (about 2 teaspoons) will be drawn to look for the presence of anti-AD5 and
virus.

- Women who can become pregnant must have a blood (about 1 teaspoon) pregnancy test on 1-
and 4-month visit and all follow-up visits after that.

- You will have an MRI.

This is an investigational study. At this time, DNX-2401 is only being used in research.
Up to 96 patients will take part in this study (up to 48 in Group A and 48 in Group B). All
will be enrolled at MD Anderson.


Inclusion Criteria:



1. Patients with histologically proven recurrent malignant primary glioma will be
eligible. Glioma type will be restricted to: GBM, gliosarcoma (GS), anaplastic
gliomas [anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic
infiltrating glioma (AIG), mixed anaplastic glioma (MAG), anaplastic ependymoma]

2. Patients must show unequivocal evidence for tumor recurrence or progression by MRI
scan within 15 days prior to Day 0/Baseline procedure after failing prior surgical
resection, biopsy, chemotherapy or radiation

3. For patients entered in Group A (see Treatment Plan) tumors must be accessible for
stereotactic injection. Tumors must be between 1.0 - 5.0 cm in diameter

4. For patients entered in Group B (see Treatment Plan) tumors must be surgically
resectable, and surgical resection must be indicated at the time of baseline
evaluation. Tumors must be >1.0 cm in diameter.

5. Patients will consent to have a biopsy taken at the time of the stereotactic
injection to confirm the presence of malignant glioma (based on frozen section)
before injection of DNX-2401

6. For each patient there must be a consensus between the physician investigators in
this study that injection will not deliver DNX-2401 into the ventricular system.
Patients must have a stable steroid regimen for at least 1 week prior to DNX-2401
administration

7. Patients may or may not have had prior chemotherapy

8. Patients must be willing and able to give informed consent

9. Age > /= 18 years

10. Patients must have a Karnofsky performance status greater than or equal to 70

11. Patients must have recovered from the toxic effects of prior therapy (i.e., CTC grade
1 or less). For example, they must be at least two weeks after vincristine, 6 weeks
after nitrosoureas, and 3 weeks after procarbazine or temozolomide administration

12. Patients must have adequate bone marrow function (absolute granulocyte count > 1,500
and platelet count of > 100,000), adequate liver function (SGPT and alkaline
phosphatase < 2 times institutional normals and bilirubin <1.5 mg%), and adequate
renal function (BUN or creatinine <1.5 times institutional normal) prior to starting
therapy

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%

Exclusion Criteria:

1. Any radiotherapy within 4 weeks prior to date of DNX-2401 administration.

2. Active uncontrolled infection or severe intercurrent medical conditions. All patients
must be afebrile at baseline (i.e., < 38.0 Celsius [C])

3. 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 , based on the clinical judgment of the surgeon,
prior to DNX-2401 injection then patient may be eligible.

4. 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

5. Female who is pregnant and/or nursing. Because of the potential risk of a recombinant
virus containing a gene involved in cellular growth regulation and differentiation
which could potentially affect a developing fetus or growing infant, females who are
pregnant, at risk of pregnancy, or breast feeding a baby during the study period are
excluded

6. Tumor position that, in the Investigator's opinion, would pose the risk of
penetration of the cerebral ventricular system during injection with study drug. If,
during the DNX-2401injection procedure, penetration of the ventricular system is
suspected or confirmed, DNX-2401 administration will be aborted

7. Immunocompromised subjects, subjects with autoimmune conditions, active hepatitis (B
or C) or HIV seropositivity

8. Patients with Li-Fraumeni Syndrome or with a known germ line deficit in the
retinoblastoma gene or its related pathways

9. Multiple intracranial malignant glioma lesions at the time of recurrence. Multiple
enhancing areas within a single tumor will not be considered multiple glioma lesions

10. Tumor involvement which would require ventricular, brainstem or posterior fossa
injection or access through a ventricle in order to deliver the virus

11. Tumor involving the subependyma or suspected cerebrospinal fluid (CSF) dissemination

12. Documented extracranial metastasis

13. Biologic/immunotherapy (e.g., IL-2, IL-12, interferon) within 4 weeks of DNX-2401
administration

14. Concurrent chemotherapy, radiation or biological therapy

15. 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.

16. White blood cell (WBC) < 2.5 x 103/mm3, absolute neutrophil count (ANC) < 1.5 x
103/mm3, platelet < 100,000/mm3, hemoglobin (Hgb) < 10.0 gm/dL, prothrombin
time/international normalized ratio (PT/INR) or partial thromboplastin time (PTT) >
1.8 x control

17. Grade 4 hematological toxicity

18. Serum creatinine > 1.5 mg/dL

19. Liver transaminases (aspartate aminotransferase [AST] and/or alanine aminotransferase
[ALT]) or total bilirubin > 2x the upper limits of normal

20. Vaccinations of any kind within 30 days prior to Delta-24-RGD-4C administration

21. Current diagnosis of other cancer except curative cervical cancer in situ, basal or
squamous cell carcinoma of the skin. Patients with a history of another cancer, but
who are cancer free for a minimum of three years remain eligible

22. History of encephalitis, multiple sclerosis, other CNS infection or primary CNS
disease that would interfere with subject evaluation

23. Patients with history of prior gene transfer therapy or prior therapy with cytolytic
virus of any type, especially DNX-2401

24. Males or females who refuse to use a double-barrier form of birth control during the
study and for up to 6 months after injection with DNX-2401

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose (MTD) DNX-2401

Outcome Description:

Each cohort of three subjects each sequentially assigned to escalating doses of DNX-2401, with acceptable grade of neurotoxicity Common Toxicity Criteria (CTC) < grade 3, related to the study drug, and according to standard Gehan phase I dose-escalating criteria for toxicity.

Outcome Time Frame:

Assessed during 14 day waiting period between doses (every 28 days).

Safety Issue:

Yes

Principal Investigator

Frederick F. Lang, MD, BS

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

ID01-310

NCT ID:

NCT00805376

Start Date:

December 2008

Completion Date:

Related Keywords:

  • Brain Cancer
  • Central Nervous System Diseases
  • Brain
  • Brain Cancer
  • Central Nervous System Diseases
  • CNS
  • Conditionally Replication-Competent Adenovirus
  • Delta-24-RGD
  • DNX-2401
  • Recurrent Malignant Gliomas
  • malignant brain tumor
  • Brain Neoplasms
  • Central Nervous System Diseases
  • Glioma
  • Nervous System Diseases

Name

Location

UT MD Anderson Cancer CenterHouston, Texas  77030