Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Phase 1 Dose-finding Study of L19TNFα Plus Melphalan Using Isolated Inferior Limb Perfusion (ILP) in Subjects With Intransit Stage III/IV Melanoma

This study has been completed.
Sponsor:
Collaborators:
InnoPharma Inc.
Eudax
Information provided by (Responsible Party):
Philogen S.p.A.
ClinicalTrials.gov Identifier:
NCT01213732
First received: October 1, 2010
Last updated: September 22, 2011
Last verified: September 2011
  Purpose

In this study the recombinant human fusion protein L19TNFα will be associated in ILP with the standard treatment with melphalan 10mg/l limb volume in subjects affected by stage III/IV limb melanoma.

The recombinant human fusion protein L19TNFα was created with the intention to target TNFα directly to tumor tissues with the result in high and sustained intralesional bioactive TNFα concentrations.


Condition Intervention Phase
Patients With Intransit Stage III/IV Melanoma of Lower Extremity Distal to the Apex of the Femoral Triangle.
Other: Isolated inferior limb perfusion
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 1 Dose-finding Study of Tumor-targeting Human Monoclonal Antibody-cytokine Fusion Protein L19TNFα Plus Melphalan Using Isolated Inferior Limb Perfusion in Patients With In-transit Stage III/IV Melanoma.

Resource links provided by NLM:


Further study details as provided by Philogen S.p.A.:

Primary Outcome Measures:
  • Safety and Tolerability [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
    The safety and tolerability profile of L19TNFα/melphalan combination treatment in the ILP setting will be determined.

  • Recommended dose (RD) [ Time Frame: 29 days ] [ Designated as safety issue: No ]
    The recommended dose (RD) of L19TNFα when given in combination with melphalan in the ILP setting for subjects with limb stage III/IV melanoma will be determined.


Secondary Outcome Measures:
  • Objective response rate [ Time Frame: 10 weeks ] [ Designated as safety issue: No ]
    Objective response rate of L19TNFα plus melphalan.

  • Antitumor activity [ Time Frame: 4- 6 weeks ] [ Designated as safety issue: No ]
    Antitumor activity of L19TNFα plus melphalan (resection of residual tumor after 4- 6 weeks and histopathological response rate).

  • Pharmacokinetic [ Time Frame: 10 days ] [ Designated as safety issue: No ]
    Pharmacokinetic profile of L19TNFα when given with melphalan

  • Human anti-fusion protein antibody [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
    Assessment of possible induction of human anti-fusion protein antibody [HAFA] formation

  • 5-hydroxyindoleacetic acid [ Time Frame: 10 days ] [ Designated as safety issue: No ]
    Assessment of plasma profile of 5-hydroxyindoleacetic acid (5-HIAA), a surrogate marker of vascular damage and tumor response.


Enrollment: 19
Study Start Date: October 2008
Study Completion Date: September 2011
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: L19TNFα plus melphalan
Subjects will be sequentially assigned to one of 2 dose levels of L19TNFα: 325 µg or 650 µg. All subjects will receive a single dose of L19TNFα and Melfalan (10mg/ L Limb volume).
Other: Isolated inferior limb perfusion
Single Melphalan bolus perfused for 60 min after 30 min of L19TNFα bolus. Intra-arterial (IA) infusion via bolus at 39˚C to 40˚C (mild hyperthermia).

  Eligibility

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

Inclusion Criteria:

  1. Subjects aged >18 years.
  2. Histologically or cytologically confirmed intransit stage III/IV melanoma of lower extremity distal to the apex of the femoral triangle
  3. ECOG performance status ≤ 2.
  4. Subjects must have at least one unidimensional clinically measurable lesion as defined by RECIST criteria (see Section 8). This lesion must not have been irradiated within four weeks during previous treatments.
  5. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, and haemoglobin (Hb) ≥ 9.5 g/dl.
  6. All acute adverse effects (excluding alopecia) of any prior therapy (including surgery, radiation therapy, chemotherapy) must have been resolved to ≤ Grade 1, except elevated liver transaminases judged to be associated with tumor infiltration (see below) (graded according to National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events, version 3.0 [CTCAE, v.3.0].
  7. Alkaline phosphatase (AP), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN), and total bilirubin ≤ 2.0 mg/dL unless liver involvement by the tumor, in which case the transaminase levels up to 5 x ULN are allowed.
  8. Creatinine ≤ 1.5 ULN or 24 h creatinine clearance ≥ 60 mL/min.
  9. Testing negative for acute or chronic infection with hepatitis B or C virus, or human immunodeficiency virus 1 or 2.
  10. Negative pregnancy test for females of childbearing potential at the screening visit.
  11. Commitment from subject to practice medically appropriate/acceptable method of birth control (e.g., hormonal, condoms or other adequate barrier controls, intrauterine contraceptive device, or sterilization) beginning at the screening visit and continuing until 3 months following the treatment with study drug
  12. Able to provide written Informed Consent
  13. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion Criteria:

  1. Breastfeeding women
  2. Presence of active infections (e.g. requiring antimicrobial therapy) or other severe concurrent disease, which, in the opinion of the Investigator, would place the subject at undue risk or interfere with the study.
  3. Active autoimmune disease.
  4. Cardiac disease as manifested by any of the following:

    • > Grade II heart failure, graded per New York Heart Association (NYHA) criteria.
    • Unstable angina pectoris
    • Acute or subacute coronary syndromes, including myocardial infarction, occurring with 1 year prior to study treatment
    • Arrhythmia needing continuous treatment
    • Ejection fraction less than the institutional lower limit of normal as assessed by multigated radionuclide angiography (MUGA) scan or echocardiogram
  5. Uncontrolled hypertension.
  6. History of claudication or Ischemic peripheral vascular disease (Grade IIb-IV).
  7. Chronic obstructive pulmonary disease or other chronic pulmonary disease with PFTs less than 50% predicted for age.
  8. Symptomatic cerebrovascular disease.
  9. Active peptic ulcer disease.
  10. Concurrent infection of HIV.
  11. Severe diabetic retinopathy.
  12. Major surgery or trauma within 4 weeks prior to start of study treatment.
  13. Hypersensitivity to melphalan or TNFα or other intravenously administered human proteins/peptides/antibodies.
  14. Chemotherapy, radiation therapy or therapy with an investigational agent within 4 weeks prior to start of study treatment.
  15. Any regional therapy to the affected extremity within 2 months prior to start of study treatment.
  16. Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6 weeks before administration of study treatment.
  17. Growth factors or immunomodulatory agents within 7 days prior to the administration of study treatment.
  18. Subject requires or is taking corticosteroids or other immunosuppressant drugs on a long-term basis. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
  19. Participation in another interventional clinical trial during participation in this trial.
  20. Any conditions that in the opinion of the Investigator could hamper compliance with the study protocol.
  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: NCT01213732

Locations
Italy
Azienda Ospedaliera Universitaria San Martino
Genova, Italy
Fondazione IRCCS Istituto Nazionale dei Tumori
Milano, Italy
Sponsors and Collaborators
Philogen S.p.A.
InnoPharma Inc.
Eudax
Investigators
Principal Investigator: Franco De Cian, Prof IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
  More Information

No publications provided by Philogen S.p.A.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Philogen S.p.A.
ClinicalTrials.gov Identifier: NCT01213732     History of Changes
Other Study ID Numbers: PH-L19TNFαILP-01-08
Study First Received: October 1, 2010
Last Updated: September 22, 2011
Health Authority: Italy: National Institute of Health (Istituto Superiore di Sanità)
Italy: Ethics Committee

Keywords provided by Philogen S.p.A.:
L19, antibody, monoclonal, tumor targeting, TNFa, ILP, melanoma

Additional relevant MeSH terms:
Melanoma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Neuroendocrine Tumors
Nevi and Melanomas
Melphalan
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014