A Study of SGT-53 in Children With Refractory or Recurrent Solid Tumors

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. 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. Though mutated p53 is uncommon in childhood cancer,
children with adrenocortical tumor and rhabdomyosarcoma have been found to have p53
mutations. Additionally, wild type p53 may be suppressed in tumors through pathway crosstalk.
For example, in sarcomas, a common childhood solid tumor, activation of MDM2 effectively
inactivates p53. Thus, the treatment proposed in this trial to reintroduce p53 may offer
benefit even in patients with p53 wild-type tumors. Moreover, the SGT-53 treatment can
significantly sensitize pediatric cancer cell lines to the killing effect of the standard
chemotherapeutic agents, topotecan and cyclophosphamide. Thus, we propose to assess the
efficacy of this combination therapy in pediatric patients with refractory or recurrent solid
tumors. This phase I clinical trial is to determine the dose limiting toxicities (DLT),
recommended phase 2 dose, and maximum tolerated dose (MTD) of SGT-53 (if reached) alone and
in combination with conventional chemotherapy in pediatric patients with recurrent or
refractory solid tumors. In addition, pharmacokinetics of escalating doses of SGT-53 is
studied.

Inclusion Criteria:

- All patients and/or their parents or legally authorized representatives must sign a
written informed consent.

- Patients must be > than 12 months and ≤ 21 years of age at the time of study
enrollment.

- Body surface Area (For Dose Level -1): Patients must be ≥ 0.38 m² at the time of study
enrollment.

- Patients with relapsed or refractory solid tumors (excluding primary central nervous
system tumors) are eligible. Patients must have had histologic verification of
malignancy at original diagnosis or relapse.

- Patients must have either measurable or evaluable disease.

- Patient's current disease state must be one for which there is no known curative
therapy or therapy proven to prolong survival with an acceptable quality of life.

- Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50 for patients ≤ 16 years
of age.

- Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer chemotherapy:

- At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if
prior nitrosourea).

- At least 14 days after the last dose of a long-acting growth factor (e.g.
Neulasta) or 7 days for short-acting growth factor.

- At least 7 days after the last dose of a biologic agent.

- At least 42 days after the completion of any type of immunotherapy, e.g. tumor
vaccines.

- At least 3 half-lives of the antibody after the last dose of a monoclonal
antibody.

- At least 14 days after local palliative XRT (small port); At least 150 days must
have elapsed if prior TBI, craniospinal XRT or if ≥ 50% radiation of pelvis; At
least 42 days must have elapsed if other substantial bone marrow radiation.

- No evidence of active graft vs. host disease and at least 84 days must have
elapsed after transplant or stem cell infusion.

- Patient must not have had prior exposure to gene vector delivery products within
3 months.

- Patients may not have had prior SGT-53. Patient who have received prior
topotecan, cyclophosphamide, or both are eligible.

- Adequate Bone Marrow Function:

- Peripheral absolute neutrophil count (ANC) ≥ 1000/mm³.

- Platelet count ≥ 100,000/mm³.

- Adequate Renal Function:

- Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m² OR age/gender
appropriate serum creatinine.

- Adequate Liver Function:

- Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN)
for age.

- SGPT (ALT) ≤ 110 U/L.

- Serum albumin ≥ 2 g/dL.

Exclusion Criteria:

- Are pregnant or breast-feeding women.

- Concomitant medications:

- Patients receiving corticosteroids who have not been on a stable or decreasing
dose of corticosteroid for at least 7 days prior to enrollment are not eligible.

- Patients who are currently receiving another investigational drug are not
eligible.

- Patients who are currently receiving other anti-cancer agents are not eligible.

- Patients who are receiving cyclosporine, tacrolimus or other agents to prevent
graft-versus-host disease post bone marrow transplant are not eligible for this
trial.

- Patients who have an uncontrolled infection are not eligible.

- Patients who have received a solid organ transplantation are not eligible.

- Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study are not eligible.