Combination Therapy of F16IL2 and Paclitaxel in Solid Tumour Patients
This Phase Ib/II study is an open label, multicenter study.
The study is divided in two parts:
Phase I: an open-label, dose escalation study of F16IL2 in combination with paclitaxel for patients with solid tumours, bladder cancer, breast cancer, metastatic melanoma, mesothelioma, NSCLC, prostate cancer and sarcoma amenable to taxane therapy.
Phase II: a prospective, single-arm, multicentre study of a fixed dose of F16IL2 in combination with paclitaxel, equivalent to stage 1 of the Simon two-stage phase II design, for patients with metastatic melanoma, breast cancer and NSCLC amenable to taxane therapy.
Non-small Cell Lung Cancer (NSCLC),
Drug: F16IL2 in combination with paclitaxel
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase Ib/II Study of the Tumour-targeting Human F16IL2 Monoclonal Antibody-cytokine Fusion Protein in Combination With Paclitaxel in Patients With Advanced Solid Tumours|
- To establish the maximum tolerated dose (MTD) and the recommended dose (RD) of F16IL2 when administered in combination with paclitaxel (Phase I). [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]Safety evaluations performed days 1 through 28, including AEs, SAEs and standard laboratory assessments graded according to the NCI-CTCAE, v3, will be used for determination of dose limiting toxicity (DLT).
- To investigate the efficacy of F16IL2, in terms of objective response rate in combination with paclitaxel in metastatic melanoma, breast cancer and NSCLC patients amenable to taxane therapy (Phase II) [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]The primary efficacy endpoint is the proportion of patients achieving a Tumour Response at week 8.
- To investigate the safety and tolerability of F16IL2 and paclitaxel when given as a combination (Phase I/II). [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]Safety and tolerability will be assessed through physical examinations, vital signs, laboratory tests (including serum chemistries, hematology parameters) and the recording of adverse events. Treatment emergent adverse events will be summarized by NCI-CTCAE, version 3. Laboratory values and change in vital signs will be summarized.
- Investigate pharmacokinetics of F16IL2 and paclitaxel when given as a combination. [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]In order to investigate the PK profile of F16IL2 and paclitaxel, blood samples for PK measurements in serum will be collected at defined time points during weeks 1 and 2 (after the first dose of study drug) in order to assess accumulation of F16IL2/paclitaxel. PK samples will be collected from all patients enrolled in the phase I part of the study (from cohort 9 onwards, pharmacokinetics of F16IL2 only will be performed), and from the first 5 patients in each indication enrolled in the phase II part of the study.
- Human anti-fusion protein antibodies [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]Phase I: To investigate the induction of human anti-fusion protein antibodies (HAFA).
- Antitumor activity [ Time Frame: 12 months ] [ Designated as safety issue: No ]To investigate the antitumor activity of the combination of F16IL2 and paclitaxel in solid tumour patients, for cohorts 1 to 8, and in bladder cancer, breast cancer, metastatic melanoma, mesothelioma, non-small cell lung cancer (NSCLC), prostate cancer and sarcoma patients, for cohort 9 onward.
- Assessment of median progression-free survival and median overall survival. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
|Study Start Date:||June 2008|
|Estimated Study Completion Date:||May 2016|
|Estimated Primary Completion Date:||May 2015 (Final data collection date for primary outcome measure)|
|Experimental: F16IL2 in combination with paclitaxel||
Drug: F16IL2 in combination with paclitaxel
Intravenous (i.v.) infusions of F16IL2 (Dose escalation: from 5 to 35 MioIU, the dose could be further increased until MTD is reached, following a pharmacokinetic-guided design) on days 1, 8, 15, 29, 36 and 43 over 60 minutes via automated device (perfusor), followed by a 1 hour i.v. infusion of paclitaxel (Dose escalation: from 60 up to 90 mg/m2) on days 1, 8, 15, 29, 36 and 43.
Patients with objective tumor responses or stable disease will receive additional combination therapy for a maximum of 6 months, or until disease progression, unacceptable toxicity or withdrawal of consent.
Breast cancer is a major cause of cancer mortality, second only to lung cancer as a cause of cancer death in women. The five-year survival rate for localized breast cancer has increased from 80 percent in the 1950s to 98 percent today. However, the mortality rate in the most advanced forms remains unsatisfactory. Indeed, the extensive use of mammography within screening programs has led to cancers being detected earlier, when early treatments may be more effective. A greater understanding of the molecular biology and genetic expression of breast cancer has therefore led to new pre-surgical and post-surgical treatments, including hormone modulators and monoclonal antibodies. Many of these agents have led to decreased mortality and disease recurrence.
F16 is a human recombinant antibody fragment in the scFv (single chain Fragment variable) format that is directed against tenascin C, an angiogenesis marker common to most solid tumors independent of the tumor type. ScFv(F16) selectively localizes in tumor tissues in animal models as demonstrated both histologically and during mechanistic studies involving mice transfected with orthotopic human tumours.
IL2, the human cytokine interleukin-2, is a potent stimulator of the immune response. It has a central role in the regulation of T cell responses and effects on other immune cells such as natural killer cells, B cells, monocyte/macrophages and neutrophils (Smith, 1988). IL2 can induce tumor regression through its ability to stimulate a potent cell-mediated immune response in vivo (Rosenberg, 2000).
|Contact: Leonardo Giovannoni, Dr||(0039) 0577- 588 firstname.lastname@example.org|
|A.O. UNIVERSITARIA OSPEDALI RIUNITI - OSPEDALE UMBERTO I DI ANCONA - ANCONA (AN) (Italy)||Recruiting|
|Principal Investigator: Stefano Cascinu, Prof|
|Irst - Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori - Meldola (Fc)||Recruiting|
|Principal Investigator: Andrea Rocca, Dr|
|European Institute of Oncology||Recruiting|
|Milan, Italy, 20141|
|Principal Investigator: Chiara Matilde Catania, Dr|
|A.O. UNIVERSITARIA POLICLINICO DI MODENA (Italy)||Recruiting|
|Principal Investigator: Pierfranco Conte, Prof|
|Azienda Ospedaliera Universitaria Senese||Recruiting|
|Contact: Michele Maio, Dr.|
|Principal Investigator: Michele Maio, Dr|
|Principal Investigator:||Chiara Matilde Catania, Dr||European Institute of Oncology Milan (Italy)|