A Dose-finding, Pharmacokinetic, Phase Ib/II Study of the Tumour-targeting Human F16IL2 Monoclonal Antibody-cytokine Fusion Protein in Combination With Doxorubicin in Patients With Advanced Solid Tumours
Overview
- Phase
- Phase 1
- Intervention
- F16IL2 in combination with doxorubicin
- Conditions
- Advanced Solid Tumor
- Sponsor
- Philogen S.p.A.
- Enrollment
- 29
- Locations
- 5
- Primary Endpoint
- Maximum tolerated and recommended dose (MTD) (RD)
- Status
- Terminated
- Last Updated
- 12 years ago
Overview
Brief Summary
This Phase Ib/II study is an openlabel, multicenter study for patients with solid tumors and breast cancer amenable to anthracyclin therapy.
The study is divided in two parts:
Phase I: an open-label, dose escalation study of F16IL2 in combination with doxorubicin for patients with solid tumors.
Phase II: a prospective, single-arm, multicentre study of a fixed dose of F16IL2 in combination with doxorubicin, equivalent to stage 1 of the Simon two-stage phase II design, for patients with breast cancer amenable to anthracyclin therapy.
Detailed Description
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).
Investigators
Eligibility Criteria
Inclusion Criteria
- •For Phase I of the study:
- •For patient of Phase I cohort 1 i.e. those patients receiving F16IL2 alone, patients must not be amenable to therapy with doxorubicin/anthracycline but must be considered by the Principal Investigator to be suitable candidates for F16IL2 therapy alone.
- •Histologically or cytologically confirmed solid cancer with/without evidence of locally advanced or metastatic disease (Appendix B).
- •For advanced solid cancer patients, patients may have received previous chemotherapy or radiation therapy, but they must be amenable for doxorubicin treatment according to the discretion of the principal investigator.
- •For Phase II of the study:
- •Histologically or cytologically confirmed breast cancer.
- •Previous anthracycline therapy, including liposomal doxorubicin, for metastatic and/or adjuvant disease is allowed. However, patients must not have received a cumulative anthracycline dose of more than 300 mg/m2 of doxorubicin or of more than 600 mg/m2 of epirubicin or pegylated or non-pegylated liposomal doxorubicin, prior to study entry, in order to avoid anthracycline-associated cardiotoxicity.
- •Prior radiation therapy is allowed, if the irradiated area is not the only source of measurable or assessable disease.
- •Patients not suitable for trastuzumab therapy (i.e., no evidence of HER2-overexpressing disease, or trastuzumab therapy exhausted in HER2-overexpressing disease).
- •For phase I and II of the study:
Exclusion Criteria
- •Presence of active infections (e.g. 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. However, presence of controlled brain metastases (i.e., evaluated as SD of PR after radiotherapy) is allowed.
- •Known to have a second uncontrolled cancer of other primary origin within the last 5 years.
- •Chronic active 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.
- •LVEF ≤ 50% and/or abnormalities observed during baseline MUGA, ECHO or ECG investigations.
- •Uncontrolled hypertension.
- •Ischemic peripheral vascular disease (Grade IIb-IV).
Arms & Interventions
F16IL2 in combination with doxorubicin
Intervention: F16IL2 in combination with doxorubicin
Outcomes
Primary Outcomes
Maximum tolerated and recommended dose (MTD) (RD)
Time Frame: 28 days
Phase I: To establish the maximum tolerated dose (MTD) and the RD of F16IL2 when administered in combination with doxorubicin.
Efficacy of F16IL2 in combination with doxorubicin
Time Frame: 8 weeks
Phase II: To investigate the efficacy in terms of objective response rate of F16IL2 in combination with doxorubicin in breast cancer patients amenable to anthracyclin therapy.
Secondary Outcomes
- Safety/Tolerability(8 weeks)
- Pharmacokinetics of F16IL2(2 weeks)
- Human anti-fusion protein antibodies(18 months)
- Antitumor activity(12 months)
- Median progression-free survival(12 months)
- Median overall survival(12 months)