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Phase Ib/II Study of ALT-801 With Cisplatin in Patients With Metastatic Melanoma

Phase 1/Phase 2
18 Years
Open (Enrolling)
Metastatic Melanoma

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Trial Information

Phase Ib/II Study of ALT-801 With Cisplatin in Patients With Metastatic Melanoma

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

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.

Inclusion Criteria



- 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


- 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


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


- 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


- 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


- 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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To evaluate the safety of the ALT-801-Cisplatin regimen.

Outcome Time Frame:

12 months

Safety Issue:


Principal Investigator

Hing Wong, PhD

Investigator Role:

Study Chair

Investigator Affiliation:

Altor Bioscience Corporation


United States: Food and Drug Administration

Study ID:




Start Date:

February 2010

Completion Date:

September 2013

Related Keywords:

  • Metastatic Melanoma
  • cancer
  • immunotherapy
  • targeted
  • metastatic
  • interleukin-2
  • IL-2
  • Cisplatin
  • antitumor
  • melanoma
  • TCR
  • T-cell receptor
  • p53
  • p53 gene
  • p53 tumor suppressor protein
  • Melanoma



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