QUILT-2.008: Study of ALT-801 With Cisplatin in Patients With Metastatic Melanoma
QUILT-2.008: Study of ALT-801 With Cisplatin in Patients With Metastatic Melanoma
This is a Phase Ib/II, open-label, multi-center, competitive enrollment and dose-escalation
 study of ALT-801 combined with cisplatin. The purpose of this study is to evaluate the
 safety, determine the Maximum-Tolerated Dose (MTD), and characterize the pharmacokinetic
 profile of ALT-801 given with cisplatin in patients who are chemotherapy naïve and have
 metastatic melanoma that is considered surgically incurable. The anti-tumor responses of
 ALT-801 with cisplatin will also be assessed in this trial.
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 a p53 peptide fragment is significantly elevated in a wide range
 of human tumor tissues, particularly in melanoma, renal, lung, breast, colorectal, and
 osteosarcoma cancers. As a result, the feasibility of using soluble TCRs to target therapies
 against tumor cells that overexpress p53 is being investigated.

 Interleukin-2 (IL-2) is a well-characterized growth factor for immune effector cells which
 play critical roles in tumor control and rejection. As a result, recombinant human IL-2
 (e.g., Proleukin®, Chiron Novartis) has been approved for treatment of metastatic melanoma
 and renal cell carcinoma. IL-2 treatment provides significant benefit to a subset of patients
 with some maintaining durable responses for over ten years post-treatment. However, the major
 drawbacks of IL-2 therapy are its limited half-life and severe systemic toxicity. Hence, the
 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. The
 low dose IL-2 treatment, while less toxic and more convenient, produces lower response rates
 and appears to be less effective in treating metastatic tumors. Thus, there is a critical
 need for innovative strategies that enhance the effects of IL-2 or reduce its toxicity
 without compromising clinical benefit. Targeted approaches to concentrate therapeutic
 cytokines, such as IL-2, at the tumor sites that express p53 could provide considerable
 advantages over current treatment.

 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 peptides
 expressed on tumor cells. 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 if the
 ALT-801 treatment is given with cisplatin.

 Platinum-based analogues including cisplatin, alone or in combination with other
 chemotherapies, have been shown to be active in patients with metastatic melanoma.
 Additionally, it is known that cisplatin, an alkylating agent known to inhibit DNA synthesis
 of dividing cells, triggers increased intracellular level of p53. The synergistic effects of
 cisplatin and ALT-801 treatment may induce cisplatin-mediated increases in p53 peptide
 display on the tumors and subsequently enhance tumor targeting of ALT-801.
ENTRY CRITERIA:

 DISEASE CHARACTERISTICS:

 -  Locally advanced or metastatic melanoma

 -  Measurable

 -  Histologically or cytologically confirmed

 -  Surgically incurable

 -  HLA-A2 positive and tumors that present HLA-A2.1/p53aa264-272 complexes

 PRIOR/CONCURRENT THERAPY:

 -  If prior Proleukin treatment, must have had clinical benefit

 -  No prior systemic cytotoxic chemotherapy for melanoma

 -  No concurrent radiotherapy, chemotherapy, or other immunotherapy

 -  More than 4 weeks since prior major radiotherapy

 -  More than 8 weeks since prior CTLA-4 antagonist immunotherapy

 -  Not receiving other investigational agents

 PATIENT CHARACTERISTICS:

 Life expectancy

 -  > 3 months

 Performance status

 -  ECOG 0 or 1

 Bone marrow reserve

 -  Absolute neutrophil count (AGC/ANC) ≥ 1,500/uL

 -  Platelets ≥100,000/uL

 -  Hemoglobin ≥ 10g/dL

 Renal function

 -  Serum creatinine ≤ 1.5 mg/dL

 Hepatic function

 -  Total bilirubin ≤ 1.5 X ULN

 -  AST ≤ 2.5 X ULN

 -  Alkaline phosphatase ≤ 2.5 X ULN

 -  PT INR ≤ 1.5 X ULN

 -  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:

 -  Age ≥ 50

 -  History of abnormal EKG

 -  Symptoms of cardiac ischemia or arrhythmia

 Pulmonary

 -  Normal pulmonary function test (FEV1 ≥ 70% 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 CNS disease

 -  No active systemic infection requiring parental antibiotic therapy

 -  No systemic steroid therapy required

 -  No prior organ allograft or allogeneic transplantation

 -  Not receiving chronic medication for asthma

 -  Not pregnant or nursing

 -  Fertile patients must use effective contraception