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

July 17, 2013 updated by: Altor BioScience

Phase I Study of ALT-801 in Patients With 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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 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.

Study Type

Interventional

Enrollment (Actual)

26

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Colorado
      • Aurora, Colorado, United States, 80045
        • University of Colorado, Anschutz Cancer Pavillion
    • Florida
      • Orlando, Florida, United States, 32806
        • MD Anderson Cancer Center Orlando
      • Tampa, Florida, United States, 33612
        • H. Lee Moffitt Cancer Center & Research Institute
    • Washington
      • Seattle, Washington, United States, 98109
        • University of Washington, Seattle Cancer Care Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The Safety and Toxicity of ALT-801 in Patients With Progressive Metastatic Malignancies
Time Frame: 18 months
Number of serious adverse events per cohort
18 months
The Maximum-tolerated Dose (MTD) of ALT-801
Time Frame: 18 months
Number of dose limiting toxicities (DLTs). A DLT is a toxicity that results in patient withdrawal from the study as defined in the protocol.
18 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical Antitumor Response to ALT-801
Time Frame: 24 months
Number of subjects with a complete response (CR), partial response (PR) or stable disease (SD). CR is defined as disappearance of all tumor lesions selected for measurement. PR is defined as at least 30% decrease in the sum of all tumor lesions selected for measurement. Stable disease is defined as neither sufficient tumor shrinkage to qualify for PR nor sufficient tumor increase to qualify for progressive disease (PD) which is defined as at least 20% increase the sum of the all tumor lesions selected for measurement.
24 months
ALT-801 Induced Cell-mediated Immune Responses
Time Frame: 24 months
Number of tumor-responsive (interferon-gamma positive (IFNg+)) immune cells in blood post dosing
24 months
Immunogenicity of ALT-801
Time Frame: 24 months
Titer of anti-drug Abs at week 4
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Altor BioScience

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2007

Primary Completion (Actual)

October 1, 2009

Study Completion (Actual)

October 1, 2009

Study Registration Dates

First Submitted

July 3, 2007

First Submitted That Met QC Criteria

July 3, 2007

First Posted (Estimate)

July 4, 2007

Study Record Updates

Last Update Posted (Estimate)

July 22, 2013

Last Update Submitted That Met QC Criteria

July 17, 2013

Last Verified

July 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CA-ALT-801-01-06

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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