Trial Information

A Phase Ib/II Study of ALT-801 in Patients With Bacillus Calmette-Guerin (BCG) Failure Non-muscle Invasive Bladder Cancer

Bladder cancer is the fifth most common cancer in the United States with an estimated 71,000
new cases and approximately 14,000 deaths in 2009. Bladder cancer is also the costliest to
treat per patient of all cancers, with annual direct medical expenditures in excess of $3.7
billion in the United States. This is largely because approximately 70% of all new cases of
bladder cancer present as non-muscle invasive bladder cancer (NMIBC), which tends to recur,
requiring repeated interventions and long-term follow-up.

NMIBC tumors are usually treated by surgical resection and intravesical chemotherapy and
immunotherapy. Immunotherapy usually consists of intravesical administration of Bacillus
Calmette-Guerin (BCG). Recent studies suggest that BCG is superior in terms of efficacy and
decreasing disease recurrence compared to other therapies. Although the mechanism of action
for BCG therapy leading to clinical efficacy is unclear, macrophages, T lymphocytes and
natural killer (NK) cells are implicated as the critical mediators of the anti-tumor immune
response. Consequently, BCG is associated with significant toxicity, and approximately 20%
of patients fail to complete the course of therapy. In addition, as many as 30% of patients
either fail to respond to therapy or suffer disease recurrence within 5 years. Of these,
30% will eventually die of bladder cancer and 50% will undergo radical cystectomy. Thus, a
novel therapy, either as first-line or salvage therapy, is desperately needed for NMIBC to
prevent disease progression and allow for bladder preservation to preserve quality of life
of patients. Alternatively, a novel therapy that moderates the significant and often
treatment-limiting side effects of BCG immunotherapy is also warranted.

Additionally, immunotherapy is a well-established approach for treating other cancer types.
One strategy that has received attention is treatment with cytokines such as IL-2 to enhance
anti-tumor immunity. IL-2 has been implicated as playing a pivotal role in the efficacy of
BCG treatment of patients with NMIBC. Studies have demonstrated that a direct IL-2
intervention could be of benefit to patients who are refractory or resistant to BCG
treatment. Unfortunately, the considerable toxicity associated with this treatment makes it
difficult to achieve an effective dose at the site of the tumor and limits the population
that can be treated. Thus, there is a critical need for innovative strategies that enhance
the effects of IL-2, to reduce its toxicity without compromising clinical benefit, and to
treat other diagnoses including NMIBC.

Recombinant human IL-2 (rhIL-2; Proleukin®) is an approved agent for the treatment of adults
with metastatic melanoma and renal cell carcinoma (RCC). In particular, high dose
intravenous IL-2 treatment has demonstrated durable objective response rate in these
indications. However, the major toxicities associated with this regimen have precluded its
widespread application.

Altor Bioscience Corp. has developed a tumor-targeted IL-2 fusion protein, ALT-801,
comprising human recombinant IL-2 genetically linked to a TCR domain capable of binding a
tumor associated human p53 peptide presented in the context of HLA-A2. Animal studies have
indicated that ALT-801 could be useful in a therapeutic approach for activating immune
effector cells, bringing together effector cells and tumor cells and stimulating immune
cell-mediated activity. In addition, pre-clinical studies of ALT-801 in an NMIBC tumor model
indicate that ALT-801 monotherapy may provide clinical benefit to patients with NMIBC.
Various mouse xenograft models also demonstrate that ALT-801 increases the efficacy but
lessens the side effects of high-dose rhIL-2.

Moreover, the results of a concluded phase I clinical study of a monotherapy with ALT-801 in
patients with metastatic malignancies indicate that ALT-801 given daily for two 4-day cycles
at a dose level of 0.04 mg/kg is well tolerated, exhibits a favorable PK drug profile and
immunological potency, and provides clinical benefit in cancer patients. Also, a higher
dosing level (0.08 mg/kg) of ALT-801 was associated with better clinical benefit.

Based on these findings, ALT-801 will be evaluated as to whether it can prevent disease
progression and allow for bladder preservation to maintain the quality of life for patients
with BCG failure, defined as refractory, relapsing or intolerant, non-muscle invasive
bladder cancer who refuse or are not medically fit to undergo a radical cystectomy
recommended by the participating urologist as the standard next therapy per urologic
guidelines.