Safety and Efficacy Study of ALT-801 to Treat Progressive Metastatic Malignancies

This is a Phase 1, open-labeled, non-randomized, multi-center, competitive enrollment and dose-escalation study of ALT-801, the study drug. The purpose of this study is to evaluate the safety, determine the maximum-tolerated dose (MTD) and characterize the pharmacokinetic profile of ALT-801 in previously treated patients with progressive metastatic malignancies. ALT-801, a recombinant fusion protein with a interleukin-2 (IL-2) component, has a targeting mechanism that recognizes tumor cells with a specific tumor marker.

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 major histocompatibility complex (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.

Eligibility Criteria:
ENTRY CRITERIA:

DISEASE CHARACTERISTICS:

* Locally advanced or metastatic malignancies
* Histologically or cytologically confirmed
* Evaluable
* Surgically and medically incurable
* Not responding to standard therapy or no other standard therapy exists
* Human leukocyte antigen (HLA)-A2.1/p53 positive

PRIOR/CONCURRENT THERAPY:

* No prior Proleukin therapy within one year
* No concurrent radiotherapy, chemotherapy, or other immunotherapy
* More than 4 weeks since prior major radiotherapy
* More than 4 weeks since prior cytotoxic therapy
* More than 6 weeks since prior nitrosoureas therapy
* More than 8 weeks since prior monoclonal antibody therapy

PATIENT CHARACTERISTICS:

Life expectancy

* \> 3 months

Performance status

* Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1

Bone marrow reserve

* Absolute neutrophil count (AGC/ANC) ≥ 1,500/microliters (uL)
* Platelets ≥100,000/uL
* Hemoglobin ≥ 10g/dL

Renal function

* Serum creatinine ≤ 1.5 X Upper limit of normal (ULN)

Hepatic function

* Total bilirubin ≤ 1.5 X ULN
* Aspartate Aminotransferase (AST) ≤ 2.5 X ULN
* Alkaline phosphatase ≤ 2.5 X ULN
* Prothrombin time (PT) or international normalized ratio (INR) ≤ 1.5 X ULN
* Activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN

Cardiovascular

* May be safely tapered off anti-hypertensives if currently on anti-hypertensives
* New York Heart Association classification I or II
* No congestive heart failure \<6 months
* No unstable angina pectoris \<6 months
* No myocardial infarction \<6 months
* No history of ventricular arrhythmias
* Normal cardiac stress test required if any of the following is present:

  * Over age 50
  * History of abnormal EKG
  * Symptoms of cardiac ischemia or arrhythmia

Pulmonary

* Normal pulmonary function test (FEV1 ≥ 75% of predicted value) if any of the following is present:

  * Prolonged history of cigarette smoking
  * Symptoms of respiratory dysfunction

Other

* No known autoimmune disease
* No known HIV positive
* No psychiatric illness/social situations that would limit study compliance
* No history or evidence of central nervous system (CNS) disease
* No active systemic infection requiring parental antibiotic therapy
* No systemic steroid therapy required
* No prior organ allograft
* Not receiving other investigational agents
* Not receiving chronic medication for asthma
* Not pregnant or nursing
* Fertile patients must use effective contraception