Clinical Study Phase II of L19IL2 in Combination With Dacarbazine in Patients With Metastatic Melanoma

This study has been terminated.
Sponsor:
Collaborator:
Eudax S.r.l.
Information provided by (Responsible Party):
Philogen S.p.A.
ClinicalTrials.gov Identifier:
NCT01055522
First received: January 22, 2010
Last updated: February 24, 2014
Last verified: October 2012
  Purpose

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.


Condition Intervention Phase
Metastatic Melanoma
Drug: Arm 1: L19IL2 + Dacarbazine
Drug: Arm 3: Dacarbazine
Drug: ARM 2: L19IL2 + Dacarbazine
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


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

Primary Outcome Measures:
  • To establish the recommended dose (RD) of L19IL2 when administered in combination with a fixed dose of Dacarbazine [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
  • To evaluate Objective response rate (ORR) by CT or MRI [ Time Frame: 18 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To investigate the Pharmacokinetics of L19IL2, dacarbazine and 5-aminoimidazole -4 carboxamide (AIC). [ Time Frame: 42 days ] [ Designated as safety issue: No ]
  • To investigate the induction of human anti-fusion protein antibodies (HAFA) [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  • To investigate Antitumor activity of L19IL2 with dacarbazine in patients with metastatic melanoma by TC or MRI [ Time Frame: 18 weeks ] [ Designated as safety issue: No ]
  • Evaluation of the immunological activity of study treatment [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  • To estimate progression -free survival (PFS) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • To estimate overall survival (OS) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • To assess safety and tolerability [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

Enrollment: 102
Study Start Date: June 2008
Study Completion Date: February 2014
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ARM 1: L19IL2 + Dacarbazin Drug: Arm 1: L19IL2 + Dacarbazine

RD of L19IL2 determined in phase IIa. Induction Phase A: Intravenous (IV) infusion of L19IL2 on days 1, 3 and 5 of each 21-day cycle over 60 minutes via automated device (perfusor), for four consecutive 21-day cycles.

Induction Phase B: Intravenous (IV) infusion of L19IL2 on days 1, 8 and 15 of each 21-day cycle over 60 minutes via automated device (perfusor), for four consecutive 21-day cycles.

Maintenance: Intravenous (IV) infusion of L19IL2 on days 1, 8 and 15 of each 21-day cycle over 60 minutes via automated device (perfusor), for a maximum of 1 year after start of treatment.

DTIC 1,000mg/m2 every three weeks until disease progression, unacceptable toxicity, withdrawal of consent, or one year from initiation of therapy, whichever occurs first

Experimental: ARM 2: L19IL2 + Dacarbazin Drug: ARM 2: L19IL2 + Dacarbazine

RD of L19IL2 determined in phase IIa. Intravenous (IV) infusion of L19IL2 on days 1, 8 and 15 of each 21-day cycle over 60 minutes via automated device (perfusor), for for a maximum of 1 year after start of treatment.

DTIC 1,000mg/m2 every three weeks until disease progression, unacceptable toxicity, withdrawal of consent, or one year from initiation of therapy, whichever occurs first

Active Comparator: ARM 3: Dacarbazin
DTIC every three weeks until disease progression, unacceptable toxicity, withdrawal of consent, or for a maximum of 8 cycles, whichever occurs first
Drug: Arm 3: Dacarbazine
Dacarbazine Dosage: 1,000 mg/m2 DTIC every three weeks until disease progression, unacceptable toxicity, withdrawal of consent, or for a maximum of 8 cycles, whichever occurs first.
Other Name: DETICENE®

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  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: NCT01055522

Locations
Austria
Universitätsklinik Graz
Graz, Austria
Germany
Charité- Universitätsmedizin Berlin
Berlin, Germany
Universitätsklinikum Schleswig-Holstein-Campus Kiel
Kiel, Germany
University Hospital
Tuebingen, Germany, 72076
Italy
University Hospital Pisa
Pisa, Tuscany, Italy, 56126
A.O. UNIVERSITARIA OSPEDALI RIUNITI - OSPEDALE UMBERTO I DI ANCONA - ANCONA (AN) (Italy)
Ancona, Italy
European Institute of Oncology
Milan, Italy, 20141
Istituto Nazionale Per Lo Studio E La Cura Dei Tumori Fondazione Giovanni Pascale Di Napoli
Napoli, Italy
Azienda Ospedaliera Universitaria Senese
Siena, Italy
Switzerland
Universitäts Spital Zürich
Zürich, Switzerland
Sponsors and Collaborators
Philogen S.p.A.
Eudax S.r.l.
Investigators
Principal Investigator: Chiara Matilde Catania, Dr European Istitute of Oncology Milan (Italy)
Principal Investigator: Claus Garbe, Prof. M.D. University Hospital Tuebingen (Germany)
  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: NCT01055522     History of Changes
Other Study ID Numbers: PH-L19IL2DTIC-03/07, 2007-005737-11
Study First Received: January 22, 2010
Last Updated: February 24, 2014
Health Authority: Italy: Ethics Committee
Germany: Paul-Ehrlich-Institut
Germany: Ethics Commission

Keywords provided by Philogen S.p.A.:
Interleukin, IL2, monoclonal, antibody, cytokine, Dacarbazine, metastatic, melanoma, tumor targeting, Dose definition
, L19

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas

ClinicalTrials.gov processed this record on September 18, 2014