Phase II Study of Combined Temozolomide and SGT-53 for Treatment of Recurrent Glioblastoma

The p53 is a vital human tumor suppressor gene. Loss of p53 suppressor function is present in
the majority of human cancers. The p53 protein has a diverse range of functions including
regulation of cell cycle checkpoints, cell death (apoptosis), senescence, DNA repair,
maintenance of genomic integrity, and control of angiogenesis. Abnormalities of the p53 gene
may impact the efficacy of standard anticancer treatments such as radiation and chemotherapy.
P53 mutation and pathway dysfunction are associated with poor clinical outcomes and the
presence of the p53 mutation correlates with resistance to chemotherapy and radiation. The
development of somatic gene therapy has created the potential to restore wild type function
of p53. SGT-53 is a complex of cationic liposome encapsulating a normal human wild type p53
DNA sequence in a plasmid backbone. This complex has been shown to efficiently and
specifically deliver the p53 cDNA to the tumor cells and to cross the blood-brain barrier.
Introduction of the p53 cDNA sequence is expected to restore wtp53 function in the apoptotic
pathway. P53 restoration has been shown most effective in enhancing cytotoxicity in
combination with an agent which results in DNA damage or initiates apoptosis. The primary
mechanism of resistance to current standard chemotherapeutic agent Temozolomide (TMZ) is
overexpression of O6-methylguanine-DNA-methyl transferase (MGMT), which repairs the
TMZ-induced DNA lesion by removing the o6-guanine adducts. Thus, a means to down modulate
MGMT activity would enhance the therapeutic effect of TMZ. A number of reports have indicated
that increasing wtp53 expression can down-regulate expression of DNA repair genes such as
MGMT and increases the sensitivity of tumor cells to alkylating agents. This is a Phase II
clinical trial of the tumor-targeted SGT-53 nanocomplex in combination with chemotherapeutic
agent, temozolomide which is the standard of care for Glioblastoma Multiforme (GBM) brain
tumors. We propose to test the combination of SGT-53 and standard temozolomide to determine
efficacy and safety in patients with confirmed glioblastoma who have proven tumor recurrence
or progression.

Inclusion Criteria:

- Histologically confirmed glioblastoma or gliosarcoma in 1st, 2nd or 3rd relapse.

- Radiographic demonstration of disease progression following prior therapy

- Measurable disease on MRI performed within 14 days prior to registration.

- Male or female patients ≥ 18 years of age.

- Recurrent disease with an:

- interval of ≥ 3 months following radiotherapy + TMZ;

- interval of ≥ 14 days between end of surgery and start of protocol therapy for
patients who have undergone surgery for recurrent disease.

- Patients who tolerated previous administration with TMZ

- Recovery from the effects of prior therapy:

- 4 weeks from cytotoxic agents

- 6 weeks from nitrosoureas

- 4 weeks from any investigational agent

- 1 week from non-cytotoxic agents

- 12 weeks from radiotherapy

- Karnofsky performance status ≥ 60%.

- Complete blood count/differential at screening with adequate bone marrow function

- If patient is receiving steroids, must be on stable or decreasing steroid dose within
5 days prior to treatment initiation with SGT-53.

- Patients must be willing to forego other cytotoxic and non-cytotoxic drug or radiation
therapy against the tumor while enrolled in the study.

- Women of childbearing potential must have a negative serum beta-HCG pregnancy test
documented within 3 days prior to study initiation.

- Women of childbearing potential must agree to use two reliable methods of
contraception from screening and up to 30 days after discontinuation of study
treatment

- Males not naturally or surgically sterile, who have a female partner of childbearing
potential, must agree to use two reliable methods of contraception from screening and
up to 30 days after discontinuation of study treatment

- Acceptable liver function

- Acceptable blood sugar control

- Urinalysis: No clinically significant abnormalities.

- PT and PTT ≤ 1.5 X ULN

- Have recovered from any previous therapy side effects or toxicities

- Organ function characterized by ≤ Grade 1

Exclusion Criteria:

- Histology other than astrocytoma grade IV

- Tumor foci detected below the tentorium or beyond the cranial vault.

- Glioblastoma or gliosarcoma disease with leptomeningeal spread.

- Patients with a history of any other cancer, unless in complete remission, and off all
therapy for that disease for a minimum of 5 years

- Patients with serum aspartate aminotransferase, alanine aminotransferase > 2.5 X the
upper limit of normal (ULN) and bilirubin >1.5 ULN

- Moderate to severe hepatic impairment.

- Positive results from HIV serology testing, if any available.

- Supine systolic blood pressure < 100 mmHg or supine diastolic blood pressure < 50 mmHg
at screening and baseline

- Renal insufficiency or serum creatinine >1.5 X ULN at screening.

- Females who are pregnant or lactating or plan to become pregnant during the course of
this study.

- Substance or alcohol abuse or dependence, within 12 months prior to screening.

- Prior chemotherapy for recurrent GBM with nitrosourea compounds including Gliadel®
wafers or bevacizumab.

- Prior focal radiotherapy within 3 months of screening.

- Planned treatment, or treatment with any investigational drug within 4 weeks prior to
screening.

- Severe, active co-morbidity

- Patients who are currently taking Coumadin or Coumadin derivatives other than to
maintain patency of venous access lines.

- Requiring renal dialysis

- Receiving hematopoietic growth factors

- Have significant baseline neuropathies

- Had prior exposure to gene vector delivery products within 6 months

- Any condition that prevents compliance with the protocol or adherence to therapy.

- Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic
therapy.

- Treated with antibiotics for infection within one week prior to study entry.

- Fever (> 38.1°C)

- Have diastolic blood pressure of > 90 mm Hg resting at baseline despite medication.

- Serious nonmalignant disease

- Enrollment in a concomitant clinical study

- Have a history of hypersensitivity reaction to any of the components of Temozolomide

- Have a history of hypersensitivity to dacarbazine (DTIC)