Trial Information

Phase I Study of ALT-801 in Patients With Progressive Metastatic Malignancies

Most current cancer treatment strategies involve the use of chemotherapeutic or biological
drugs that exhibit variable efficacy and considerable toxicity. The limitations are often
the result of the adverse side effects of the therapeutic drug on normal tissues. One
approach to control these effects is to target the therapy to the tumor site. Of the
identified tumor antigens, the human p53 tumor suppressor protein is overexpressed in a wide
range of human malignancies. p53 is an intracellular tumor suppressor protein that acts to
arrest the proliferation of cells. When mutated, it loses its ability to suppress abnormal
proliferation and exhibits a longer half-life than the wild-type protein, allowing for its
accumulation in tumors. In addition, p53 overexpression correlates with tumor transformation
and aggression and is associated with lower overall survival rates and resistance to
chemotherapeutic intervention in cancer patients. Therefore, p53 appears to be a marker for
a considerable number of human malignancies and represents a good target for
immunotherapeutics. However, p53 cannot be used as a target for antibodies because it is
not displayed independently on the cell surface. Instead, the p53 protein is processed
intracellularly into peptide fragments that are then displayed on the cell surface in the
context of MHC. These peptide/MHC complexes are recognized by T-cells via their T-cell
receptors (TCRs). Recently it has been confirmed that the peptide fragment is significantly
elevated in a wide range of human tumor tissues, particularly in melanoma, renal, lung,
breast, colorectal, bladder, ovary, stomach, esophagus, lymphoma, liver, leukemia, and head
& neck cancer. Targeted approaches to concentrate therapeutic cytokines at the tumor sites
that express p53 could provide considerable advantages over current treatment.

Interleukin-2 (IL-2) is a well-characterized growth factor for immune effector cells which
play critical roles in tumor control and rejection. A recombinant human IL-2 has been
approved for treating metastatic melanoma and renal cell carcinoma. However, the major
drawback of IL-2 therapy is its severe systemic toxicity. As a result, use of high dose IL-2
is limited to specialized programs with experienced personnel and it is generally offered to
patients who are responsive and have excellent organ function. Thus, there is a critical
need for innovative strategies that enhance the effects of IL-2 or reduce its toxicity
without compromising clinical benefits.

The study drug, ALT-801, is a biologic compound composed of interleukin-2 (IL-2) genetically
fused to a humanized soluble T-cell receptor directed against the p53-derived antigen. This
study is to evaluate whether directing IL-2 activity using ALT-801 to the patient's tumor
sites that overexpress p53 results in clinical benefits.

The study drug will be administered by bolus intravenous infusion in an in-patient hospital
setting under the supervision of a qualified physician experienced in the use of anti-cancer
agents including high dose IL-2. An intensive care facility and specialists skilled in
cardiopulmonary or intensive care medicine must be available. There are two treatment
cycles. For each treatment cycle, patients will be admitted to the hospital, remain in the
hospital during the study drug infusion period, and be discharged from the hospital the day
after the last infusion at the Principal Investigator's discretion. There is a 10-day
resting period between the treatment cycles. Tumor assessments will be done at weeks 7 and
11 after starting the study drug.