Study of ALT-801 With Cisplatin in Patients With Metastatic Melanoma

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Altor Bioscience Corporation
ClinicalTrials.gov Identifier:
NCT01029873
First received: December 9, 2009
Last updated: July 23, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
Metastatic Melanoma
Drug: Cisplatin
Biological: ALT-801
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase Ib/II Study of ALT-801 With Cisplatin in Patients With Metastatic Melanoma

Resource links provided by NLM:


Further study details as provided by Altor Bioscience Corporation:

Primary Outcome Measures:
  • To evaluate the safety of the ALT-801-Cisplatin regimen. [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • To assess the objective response (OR) which includes CR and PR. [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  • To assess the clinical benefit (CB) of the ALT-801-Cisplatin regimen which includes CR, PR and SD. [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  • To determine the MTD of the ALT-801-Cisplatin regimen. [ Time Frame: 7 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To assess the six-month and one-year survival rates. [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • To evaluate the immunogenicity and pharmacokinetic profile of ALT-801. [ Time Frame: 2 months ] [ Designated as safety issue: Yes ]

Enrollment: 25
Study Start Date: February 2010
Estimated Study Completion Date: September 2013
Primary Completion Date: November 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ALT-801 Drug: Cisplatin
Intravenous infusions; 2 treatment courses; 2 treatment cycles for each course; 70mg/m2 on day 1 of cycle 1 for each course
Biological: ALT-801

Intravenous infusions; cycle 1: day 3 and 5; cycle 2: day 1, 3 and 5; nine day rest period between cycles; seven day recovery period between courses

Stage 1: dose escalation (0.04 mg/kg, 0.06 mg/kg, 0.08 mg/kg)

Stage 2: dose expansion (dose at MTD)


Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01029873

Locations
United States, California
The Angeles Clinic and Research Institute
Los Angeles, California, United States, 90025
United States, Florida
MD Anderson Cancer Center Orlando
Orlando, Florida, United States, 32806
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
United States, Iowa
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States, 52242
United States, North Carolina
Carolinas Medical Center-Brumenthal Cancer Center
Charlotte, North Carolina, United States, 28204
United States, Pennsylvania
St. Luke's Hospital and Health Network
Bethlehem, Pennsylvania, United States, 18015
United States, Washington
University of Washington, Seattle Cancer Care Center
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Altor Bioscience Corporation
Investigators
Study Chair: Hing Wong, PhD Altor Bioscience Corporation
  More Information

Additional Information:
No publications provided

Responsible Party: Altor Bioscience Corporation
ClinicalTrials.gov Identifier: NCT01029873     History of Changes
Other Study ID Numbers: CA-ALT-801-02-09, R44CA097550
Study First Received: December 9, 2009
Last Updated: July 23, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Altor Bioscience Corporation:
cancer
immunotherapy
targeted
metastatic
interleukin-2
IL-2
Cisplatin
antitumor
melanoma
TCR
T-cell receptor
p53
p53 gene
p53 tumor suppressor protein

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Cisplatin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents

ClinicalTrials.gov processed this record on September 22, 2014