Phase I Trial of Conditionally Replication-Competent Adenovirus (DNX-2401) for Recurrent Malignant Gliomas
Frederick F. Lang
The goal of this clinical research study is to find the highest tolerable dose of DNX-2401 that can be injected directly into brain tumors and into the surrounding brain tissue where tumor cells can multiply. A second goal is to study how the new drug DNX-2401 affects brain tumor cells and the body in general.
Disease Group: Brain,CNS
Treatment Agent: DNX-2401
Treatment Location: Only at MD Anderson
Estimatated Length of Stay in Houston: 1-2 days for both groups for injection of DNX-2401 and another 3-5 days after ;resection of the tumor (Group B)
Return Visit: Grp A: Day 4, 7, 14, 28, mo 2, 3, 4, then Q 8 wks for 2 yrs, then Q 24 wks Grp B: Day 4, 7, 13. 15, 18, 21, 28, 42, mo 2, 3, 4, then Q 8 wks for 2 yrs, then Q 24 wks Grp B (Stage 2): Day 4, 7, 14, 28, mo 2, 3, 4, then Q 8 wks for 2 yrs, then Q 24 wks
Home Care: Patients in Group B will be sent home with the injection catheter in place ;(under the skin) for 2 weeks.
To determine the maximum tolerated dose of DNX-2401 (also referred to as Delta-24-RGD and Delta-24-RGD-4C), a conditionally replication-competent AdV with enhanced infectivity, administered by intratumoral injection and into the post-resection cavity in patients with recurrent malignant glioma. To determine the local and systemic toxicity of DNX-2401 administered by intratumoral injection and by injection into the post resection tumor cavity. To determine the biological effects at the molecular level of intratumoral administration of DNX-2401 by analyzing brain tumor specimens treated with DNX-2401 for the expression and distribution of viral proteins, the occurrence of cell death, and the induction of an immune response. To evaluate viral shedding. To identify potential anti-tumor activity and to evaluate time to disease progression.
IRB Review and Approval Date: 05/11/2005
Recruitment Status: Not Accepting
Projected Accrual: N/A
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 after failing prior surgical resection, biopsy, chemotherapy or radiation. A baseline MRI must be performed within 15 days prior to Day0/Baseline
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 treating physician subinvestigator and the principal investigator that injections will not deliver DNX-2401 into the ventricular system.
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 >/= 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%
15) Patients must have a stable steroid regimen for at least 1 week prior to DNX-2401 administration
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-2401 injection 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 DNX-2401 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
Information and next steps
Frederick F. Lang
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