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

NCT01213732 | Completed Phase 1

• 1 other identifier: PH-L19TNFαILP-01-08
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Patients With Intransit Stage III/IV Melanoma

Keywords

L19, antibody, monoclonal, tumor targeting, TNFa, ILP, melanoma

Outcome Measures

Primary Outcomes (2)

• Safety and Tolerability

  The safety and tolerability profile of L19TNFα/melphalan combination treatment in the ILP setting will be determined.

  6 weeks

• Recommended dose (RD)

  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.

  29 days

Secondary Outcomes (5)

• Objective response rate

  10 weeks

• Antitumor activity

  4- 6 weeks

• Pharmacokinetic

  10 days

• Human anti-fusion protein antibody

  6 weeks

• 5-hydroxyindoleacetic acid

  10 days

Study Arms (1)

L19TNFα plus melphalan

EXPERIMENTAL

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

Interventions

Isolated inferior limb perfusion OTHER

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).

L19TNFα plus melphalan

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects aged \>18 years.
• Histologically or cytologically confirmed intransit stage III/IV melanoma of lower extremity distal to the apex of the femoral triangle
• ECOG performance status ≤ 2.
• 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.
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, and haemoglobin (Hb) ≥ 9.5 g/dl.
• 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 \[CTCAE, v.3.0\].
• 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.
• Creatinine ≤ 1.5 ULN or 24 h creatinine clearance ≥ 60 mL/min.
• Testing negative for acute or chronic infection with hepatitis B or C virus, or human immunodeficiency virus 1 or 2.
• Negative pregnancy test for females of childbearing potential at the screening visit.
• 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
• Able to provide written Informed Consent
• Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

You may not qualify if:

• Breastfeeding women
• 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.
• Active autoimmune disease.
• 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
• Uncontrolled hypertension.
• History of claudication or Ischemic peripheral vascular disease (Grade IIb-IV).
• Chronic obstructive pulmonary disease or other chronic pulmonary disease with PFTs less than 50% predicted for age.
• Symptomatic cerebrovascular disease.
• Active peptic ulcer disease.
• Concurrent infection of HIV.

Sponsors & Collaborators

• Philogen S.p.A.: lead
• InnoPharma Inc.: collaborator
• Eudax S.r.l.: collaborator

Study Sites (2)

Azienda Ospedaliera Universitaria San Martino

Genova, Italy

Location

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Italy

Location

Related Publications (1)

• Papadia F, Basso V, Patuzzo R, Maurichi A, Di Florio A, Zardi L, Ventura E, Gonzalez-Iglesias R, Lovato V, Giovannoni L, Tasciotti A, Neri D, Santinami M, Menssen HD, De Cian F. Isolated limb perfusion with the tumor-targeting human monoclonal antibody-cytokine fusion protein L19-TNF plus melphalan and mild hyperthermia in patients with locally advanced extremity melanoma. J Surg Oncol. 2013 Feb;107(2):173-9. doi: 10.1002/jso.23168. Epub 2012 Jun 4.

  PMID: 22674435 DERIVED

MeSH Terms

Conditions

Melanoma

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Franco De Cian, Prof

  IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 1, 2010
• First Posted: October 4, 2010
• Study Start: October 1, 2008
• Primary Completion: March 1, 2011
• Study Completion: September 1, 2011
• Last Updated: April 15, 2022

Record last verified: 2011-09

Locations

IT (2)