Clinical trial NCT01055522: Clinical Study Phase II of L19IL2 in Combination With Dacarbazine in Patients With Metastatic Melanoma
Official title: Dose Definition and Activity Evaluation Study of the Tumor-Targeting Human L19IL2 Monoclonal Antibody-Cytokine Fusion Protein in Combination With Dacarbazine in Patients With Metastatic Melanoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Metastatic Melanoma
Keywords: Interleukin, IL2, monoclonal, antibody, cytokine, Dacarbazine, metastatic, melanoma, tumor targeting, Dose definition
, L19
Lead sponsor: Philogen S.p.A.
Sponsor class: INDUSTRY
Collaborators: name: Eudax S.r.l.
First posted: 2010-01-25
Enrollment: 102
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This Phase II clinical study is an open-label, multicenter study of L19IL2 in combination with Dacarbazine in patients with metastatic melanoma.

The study is divided in two parts: a phase IIa part, designed to establish the recommended dose (RD) of L19IL2 when administered in combination with a fixed dose of Dacarbazine, as well as to determine the preliminary tolerability profile; the second phase IIb part evaluates the objective response rate (ORR) including a randomized study with a fixed dose of Dacarbazine with or without L19IL2, dosed at the RD determined in phase IIa.

Detailed description: Dose limiting toxicity will be assessed during the dose-escalation part of Phase IIa from day 1 through day 21 of the first cycle.

Response will be measured using RECIST criteria every 6 weeks (after every 2 cycles of treatment). Patients with stable or responding disease at each assessment may receive additional treatment for a maximum of 6 cycles of induction. Patients with stable or responding disease after induction may receive L19IL2 (without dacarbazine) every 2 weeks as maintenance therapy.

Tumor expression of ED-B FN and tumor uptake of L19IL2 and of Dacarbazine will be assessed via immunohistochemistry and/or other methods deemed appropriate on tumor tissue biopsies. Tumor biopsy will be performed on superficial accessible cutaneous and/or subcutaneous lesions only. Tumor biopsy will be considered optional and will not preclude patient entry on to study should the patient refuse.

Pharmacokinetics of L19IL2, Dacarbazine and AIC will be assessed from serial blood samples using standard methods.

Overall response rate, PFS, survival rate at 6 and 12 months, and overall survival time for all patients and separately for the patients in the Phase IIb part will be assessed using standard methods.

Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed unresectable metastatic (stage IV) non-uveal melanoma
* Age \> 18 years
* Measurable disease defined as at least one lesion that can be accurately and serially measured per the modified RECIST criteria. Cutaneous lesions measuring at least 1 cm will be considered measurable.
* Prior therapy for metastatic melanoma:

  * Phase IIa - Dose definition: prior therapy allowed, including prior chemotherapy; previous treatment with DTIC: patients should be treated \> 6 months prior to study entry
  * Phase IIb -Activity Evaluation: no prior therapy except radiation. However, if radiation has been administered to a lesion, there must be radiographic evidence of progression of that lesion in order for that lesion to constitute measurable disease or to be included in the measured target lesions
* Fewer than 3 organs involved or cutaneous and/or subcutaneous metastasis only, for PhaseIIb patients
* ECOG performance status \< 2
* Life expectancy of at least 12 weeks
* Absolute neutrophil count \> 1.5 x 109/L, hemoglobin \> 9.0 g/dL and platelets \> 100 x 109/L
* Total bilirubin ≤ 30 µmol/L (or ≤ 2.0 mg/Dl)
* ALT and AST ≤ 2.5 x the upper limit of normal (5.0 x ULN for patients with hepatic involvement with tumor
* LDH \< 2.0 x ULN for Phase IIa patients and normal LDH for the Phase IIb ones.
* Serum creatinine \< 1.5 x ULN
* All toxic effects of prior therapy must have resolved to ≤ Grade 1 unless otherwise specified above
* Negative serum pregnancy test (for women of child-bearing potential only) at screening

Exclusion criteria:

* Primary ocular melanoma
* Evidence of brain metastases, negative CT scan within two months before study commence
* Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (TA, Tis \& Ti) or any cancer curatively treated \< 5 years prior to study entry
* History of HIV infection or chronic hepatitis B or C
* Presence of active infections (e.g. requiring antimicrobial 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.
* Inadequately controlled cardiac arrhythmias including atrial fibrillation
* 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).
* Uncontrolled hypertension.
* Ischemic peripheral vascular disease (Grade Iib-IV).
* Severe diabetic retinopathy.
* Active autoimmune disease
* History of organ allograft or stem cell transplantation.
* Recovery from major trauma including surgery within 4 weeks prior to administration of study treatment.
* Known history of allergy to IL2, dacarbazine, or other intravenously administered human proteins/peptides/antibodies.
* Breast feeding female.
* Anti-tumor 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.
* Previous DTIC treatment in the last 6 months prior to study entry
* Growth factors or immunomodulatory agents within 7 days of the administration of study treatment.
* 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.
* Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.

Primary outcomes:
measure: To establish the recommended dose (RD) of L19IL2 when administered in combination with a fixed dose of Dacarbazine
timeFrame: 21 days
measure: To evaluate Objective response rate (ORR) by CT or MRI
timeFrame: 18 weeks
Secondary outcomes:
measure: To investigate the Pharmacokinetics of L19IL2, dacarbazine and 5-aminoimidazole -4 carboxamide (AIC).
timeFrame: 42 days
measure: To investigate the induction of human anti-fusion protein antibodies (HAFA)
timeFrame: 1 year
measure: To investigate Antitumor activity of L19IL2 with dacarbazine in patients with metastatic melanoma by TC or MRI
timeFrame: 18 weeks
measure: Evaluation of the immunological activity of study treatment
timeFrame: 1 year
measure: To estimate progression -free survival (PFS)
timeFrame: 1 year
measure: To estimate overall survival (OS)
timeFrame: 1 year
measure: To assess safety and tolerability
timeFrame: 1 year
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Universitätsklinik Graz
city: Berlin
country: Germany
facility: Charité- Universitätsmedizin Berlin
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein-Campus Kiel
city: Tuebingen
country: Germany
facility: University Hospital
city: Pisa
country: Italy
facility: University Hospital Pisa
state: Tuscany
city: Ancona
country: Italy
facility: A.O. UNIVERSITARIA OSPEDALI RIUNITI - OSPEDALE UMBERTO I DI ANCONA - ANCONA (AN) (Italy)
city: Milan
country: Italy
facility: European Institute of Oncology
city: Napoli
country: Italy
facility: Istituto Nazionale Per Lo Studio E La Cura Dei Tumori Fondazione Giovanni Pascale Di Napoli
city: Siena
country: Italy
facility: Azienda Ospedaliera Universitaria Senese
city: Zürich
country: Switzerland
facility: Universitäts Spital Zürich
Study officials:
affiliation: European Istitute of Oncology Milan (Italy)
name: Chiara Matilde Catania, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital Tuebingen (Germany)
name: Claus Garbe, Prof. M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Eigentler TK, Weide B, de Braud F, Spitaleri G, Romanini A, Pflugfelder A, Gonzalez-Iglesias R, Tasciotti A, Giovannoni L, Schwager K, Lovato V, Kaspar M, Trachsel E, Menssen HD, Neri D, Garbe C. A dose-escalation and signal-generating study of the immunocytokine L19-IL2 in combination with dacarbazine for the therapy of patients with metastatic melanoma. Clin Cancer Res. 2011 Dec 15;17(24):7732-42. doi: 10.1158/1078-0432.CCR-11-1203. Epub 2011 Oct 25.