A Dose Finding Pharmacokinetic Study of the Tumour-targeting Human L19IL2 Monoclonal Antibody-Cytokine Fusion Protein in Patients With Advanced Solid Tumours - Full Text View

Purpose

This is a Phase I/II study for patients with solid tumors and renal cell carcinoma (RCC; for the Phase II part). L19-IL2 is a tumor targeted immunocytokine constituted of a single chain Fragment variable (scFv) format directed against the ED-B domain of fibronectin, one of the most important markers for neoangiogenesis, and the human cytokine interleukin-2 (IL2).

Condition	Intervention	Phase
Advanced Solid Tumours	Drug: L19IL2	Phase 1 Phase 2

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Dose Finding Pharmacokinetic Study of the Tumour-targeting Human L19IL2 Monoclonal Antibody-Cytokine Fusion Protein in Patients With Advanced Solid Tumours

Resource links provided by NLM:

MedlinePlus related topics: Cancer

U.S. FDA Resources

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

Primary Outcome Measures:

To determine the maximum tolerated dose (MTD) and recommended dose (RD) of the human L19IL2 fusion-cytokine. [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

To determine the pharmacokinetic profile. [ Time Frame: 5 days ] [ Designated as safety issue: No ]
To determine the qualitative and quantitative toxicity profile. [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
To assess the presence of anti-fusion protein antibodies in treated patients. [ Time Frame: 18 weeks ] [ Designated as safety issue: Yes ]
To evaluate the safety profile of repeated administrations of L19IL2 in patients treated at the RD. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
To identify early signs of antitumour activity. [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Enrollment:	33
Study Start Date:	November 2005
Study Completion Date:	November 2009
Primary Completion Date:	April 2008 (Final data collection date for primary outcome measure)

Intervention Details:

Route: i.v. infusion (60 min) Patients will receive a minimum of 2 cycles of treatment. Each cycle is comprised of treatment on Days 1, 3 and 5 followed by a 16 days rest (1 cycle= 21 days). Patients may receive up to 4 further cycles of treatment (max. of 6 cycles in total). Patients will be initially recruited into the study in cohorts of 3 and the starting dose of L19IL2 will be 5 Mio IU IL2 equivalent. Five steps of dose escalation are planned: 5, 10, 20, 30 and 40 Mio IU IL2 equivalent). After the MTD has been established, the RD will be determined. A further 12 patients (with RCC) will receive the RD dose for a minimum of 2 cycles. For patients in the RD part of the study, patients can switch to maintenance therapy. Maintenance therapy consists of 15 Mio IU IL2 every 2 weeks. The maximum duration of the study for a patient is 12 months.

Detailed Description:

This is an open-label, non-randomised, multicentre, Phase I/II study to assess safety, pharmacokinetics (PK), and early signs of activity of L19-IL2 monotherapy.

In the first part of the study, there will be 5 dose escalation steps in sequential cohorts of patients with advanced solid tumours. In the second part of the study, patients with advanced RCC will be given a fixed dose of L19IL2 at the RD.

Eligibility

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

Criteria

Inclusion Criteria:

For the first part of the study: histologically or cytologically confirmed solid cancer with evidence of advanced disease for which no other standard treatment is available or appropriate. For the second part of the study: Histologically or cytologically confirmed advanced RCC.
Patients must have at least one measurable lesion as detected by computed tomography (CT).
All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v3.0) Grade </=1.
Patients who have received autologous marrow/stem cell infusion using monoclonal antibody-purged specimens are eligible.
Adult patients of both sexes aged 18 years or older.
Eastern Cooperative Oncology Group (ECOG) performance status </=2.
Sufficient haematological, liver and renal function:
Absolute neutrophil count (ANC) >/=1.5 x 109/L, platelets >/=100 x 109/L, haemoglobin (Hb) >/=9.0 g/dL,
Alkaline phosphatase (AP) </=3 x upper limit of the reference range (ULN) and alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) </=3 x ULN, and bilirubin <1.5 x ULN; however, in the presence of liver metastases, AP </=5 x ULN and ALT and/or AST </=5 x ULN, and bilirubin <1.5 x ULN,
Creatinine </=ULN, or 24 h creatinine clearance >/=50 mL/min.
Pulse oximetry >94% on room air.
Negative serum pregnancy test for females of childbearing potential within 14 days of starting treatment.
Life expectancy of at least 3 months.
Evidence of a personally signed and dated informed consent indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the study.
Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.
Negative human immunodeficiency virus (HIV) test 2 to 3 weeks before administration of study treatment (with informed consent for test taken).

Exclusion Criteria:

Presence of active infections (eg requiring antibiotic therapy) or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.
Presence of known brain metastases.
Chronic aggressive hepatitis or active autoimmune diseases.
History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
Heart insufficiency (>Grade II New York Heart Association [NYHA] criteria).
Irreversible cardiac arrhythmias requiring permanent medication.
Uncontrolled hypertension.
Ischaemic peripheral vascular disease (Grade IIb-IV).
Severe rheumatoid arthritis.
Severe diabetic retinopathy.
Recovery from major trauma including surgery within 4 weeks of administration of study treatment.
Known history of allergy to intravenously administered proteins/peptides/antibodies.
Pregnancy or breast feeding. Female patients must agree to use effective contraception, or be surgically sterile or postmenopausal. The definition of effective contraception will be based on the judgement of the principal investigator or a designated associate.
Chemotherapy (standard or experimental) within 4 weeks of the administration of study treatment, or 6 weeks for nitrous ureas, l-phenylalanine mustard (LPAM) or temozolamide.
Radiation therapy within 4 weeks of the administration of study treatment.
Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6 weeks before administration of study treatment.
Growth factors or immunomodulatory agents within 7 days of the administration of study treatment.
Prior allografts (including bone marrow or stem cells).
Patient 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.
Investigational study drug taken within 4 weeks of the administration of study treatment or concurrent treatment with other anti-cancer therapy.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01058538

Locations

Germany
Campus Charité Mitte
Berlin, Germany, 10117
Italy
European Institute of Oncology
Milan, Italy, 20141

Sponsors and Collaborators

Philogen S.p.A.

INC Research

Investigators

Principal Investigator:	Filippo De Braud, Dr	European Institute of Oncology Milan (Italy)
Principal Investigator:	Manfred Johannsen, Dr	Champus Charitè Mitte Berlin (Germany)

More Information

No publications provided by Philogen S.p.A.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Johannsen M, Spitaleri G, Curigliano G, Roigas J, Weikert S, Kempkensteffen C, Roemer A, Kloeters C, Rogalla P, Pecher G, Miller K, Berndt A, Kosmehl H, Trachsel E, Kaspar M, Lovato V, González-Iglesias R, Giovannoni L, Menssen HD, Neri D, de Braud F. The tumour-targeting human L19-IL2 immunocytokine: preclinical safety studies, phase I clinical trial in patients with solid tumours and expansion into patients with advanced renal cell carcinoma. Eur J Cancer. 2010 Nov;46(16):2926-35. Epub 2010 Aug 24.

Responsible Party:	Dr. Tiziano Scalacci, Philogen
ClinicalTrials.gov Identifier:	NCT01058538 History of Changes
Other Study ID Numbers:	PH-L19IL2-01/05, 2005-002716-16
Study First Received:	January 27, 2010
Last Updated:	January 27, 2010
Health Authority:	Italy: National Institute of Health (Istituto Superiore di Sanità) Italy: Ethics Committee Germany: Paul-Ehrlich-Institut Germany: Ethics Commission

Keywords provided by Philogen S.p.A.:

Interleukin, IL2, monoclonal, antibody, cytokine, tumour targeting, solid tumours, dose finding, renal cell carcinoma, fusion protein, RCC,
L19

Additional relevant MeSH terms:

Neoplasms
Antibodies
Antibodies, Monoclonal
Interleukin-2
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

Antineoplastic Agents
Therapeutic Uses
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on May 22, 2013