L19TNFα in Patients With Advanced Solid Tumors
The recombinant human fusion protein L19TNFα was created with the intention to overcome the systemic toxicity of TNFα by directly targeting it to tumor tissues. Tumor-targeted L19TNFα would result in high and sustained intralesional bioactive TNFα concentrations.
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I/II Study of the Tumor-targeting Human L19TNFα Monoclonal Antibody-cytokine Fusion Protein in Patients With Advanced Solid Tumors|
- Phase I: Determination of the Maximum Tolerated Dose (MTD) and Recommended Dose (RD) [ Time Frame: day 1-29 ] [ Designated as safety issue: Yes ]Determination of the Maximum Tolerated Dose (MTD) and Recommended Dose (RD) of L19TNFα.
- Phase II: Investigation of the anti-cancer activity of L19TNFα as measured by Objective Response Rate (ORR) [ Time Frame: within day 42 ] [ Designated as safety issue: No ]Investigation of the anti-cancer activity of L19TNFα as monotherapy as measured by the Objective Response Rate (ORR) at the end of cycle 2 in subjects with relapsed or refractory locally advanced or metastatic colorectal cancer not amenable to standard systemic therapy.
- Investigation of serum concentrations of L19TNFα (pharmacokinetic properties) [ Time Frame: day 1-5 ] [ Designated as safety issue: No ]
- Investigation of the induction of human anti-fusion protein antibody (HAFA) [ Time Frame: 1-16 months ] [ Designated as safety issue: Yes ]
- Investigation of early signs of anti-tumor activity of L19TNFα [ Time Frame: 14 months ] [ Designated as safety issue: No ]Investigation of early signs of anti-tumor activity of L19TNFα as measured by Objective Response Rate (ORR) at the end of cycle 2, median Progression-Free Survival (PFS) and median Overall Survival (OS).
|Study Start Date:||September 2007|
|Study Completion Date:||September 2011|
|Primary Completion Date:||May 2011 (Final data collection date for primary outcome measure)|
Phase I: Prospective, open-label, dose escalation study.
Phase II: Prospective, single-arm, open-label study, equivalent to the stage 1 of the Simon two-stage phase II design.
Phase I: Sequential assignment of Patient cohorts to one of six dose levels of L19TNFa: 1.3, 2.6, 5.2, 7.8, 10.4, 13.0 µg/kg.
Phase II: The Recommended Dose (RD) of 13.0 µg/kg of L19TNFα determined in Phase I.
Schedule: Infusions of L19TNFα on days 1, 3 and 5 of each 21-day cycle. Patients may remain on treatment for a maximum of six 21-day cycles.
The primary purpose of this Phase I/II study is to define a safe and potentially active treatment regimen of L19TNFα as a monotherapy and to evaluate the antitumor activity of this regimen in relapsed metastatic colorectal cancer subjects, for whom standard treatment options are exhausted. L19TNFα is an investigational drug that specifically and effectively binds to ED-B, which is abundantly expressed in cancer tissue. Accordingly, treatment should result in a high and long-lasting intratumoral accumulation of biologically active rh-TNFα. Although combined therapies of TNFα with cytotoxic drugs (e.g. melphalan) seem to be strikingly more active against sarcoma and melanoma than with TNFα alone - at least for the ILP setting it seems possible that the repeated intratumoral delivery of TNFα via L19TNFα might produce additional biologic effects, such as the induction of an immunologic antitumor response or the sustained inhibition of tumor-associated angiogenesis (Lejeune, 2006), that potentially could benefit advanced cancer subjects.
|A.O. UNIVERSITARIA OSPEDALI RIUNITI - OSPEDALE UMBERTO I DI ANCONA - ANCONA (Italy)|
|European Istitue of Oncology Milan (Italy)|
|Principal Investigator:||Filippo De Braud, Dr.||European Istitute of Oncology Milan (Italy)|