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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

Phase 1/Phase 2
18 Years
Open (Enrolling)
Advanced Solid Tumor, Breast Cancer

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Trial Information

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

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).

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

• For phase I and II of the study:

- Patients aged ≥18 years.

- Patients recruited to Phase I, cohort I must be considered not suitable to
doxorubicin/anthracycline therapy in the opinion of the Principal Investigator.

- Only for phase I, patients must not have received more than 300 mg/m2 of doxorubicin
or 500 mg/m2 of epirubicin in prior chemotherapy.

- Patients must have at least one unidimensionally measurable lesion by computed
tomography as defined by RECIST criteria (see Section APPENDIX A). This lesion must
not have been irradiated during previous treatments.

- All acute toxic effects (excluding alopecia) of any prior therapy (including surgery,
radiation therapy, chemotherapy) must have resolved to National Cancer Institute
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v3.0) Grade ≤ 1.

- Sufficient hematologic, liver and renal function:

- Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L, platelets ≥ 100 x 10^9/L,
haemoglobin (Hb) ≥ 9.5 g/dl.

- Alkaline phosphatase (AP), alanine aminotransferase (ALT) and or aspartate
aminotransferase ≥ 3 x upper limit of reference range (ULN), and total bilirubin
≥ 2.0 mg/gL unless liver involvement by the tumor, in which case the
transaminase levels could be up to 5 x ULN.

- Creatinine ≥ 1.5 ULN or 24 h creatinine clearance ≤ 50 mL/min.

- Life expectancy of at least 12 weeks.

- Documented negative test for human immunodeficiency virus.

- Negative serum pregnancy test for females of childbearing potential within 14 days of
starting treatment.

- If of childbearing potential, agreement to use adequate contraceptive methods (e.g.,
oral contraceptives, condoms, or other adequate barrier controls, intrauterine
contraceptive devices, or sterilization) beginning at the screening visit and
continuing until 3 months following last treatment with study drug.

- Evidence of a personally signed and dated Ethics Committee-approved Informed Consent
form indicating that the patient (or legally acceptable representative) has been
informed of all pertinent aspects of the study.

- Willingness and ability to comply with the scheduled visits, treatment plan,
laboratory tests and other study procedures.

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

- 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

- Uncontrolled hypertension.

- Ischemic peripheral vascular disease (Grade IIb-IV).

- Severe rheumatoid arthritis.

- Severe diabetic retinopathy.

- Recovery from major trauma including surgery within 4 weeks of administration of
study treatment.

- Known history of allergy to IL-2, doxorubicin, or other intravenously administered
human proteins/peptides/antibodies.

- Pregnancy or breast feeding. Female patient must agree to use effective
contraception, or be surgically sterile or postmenopausal. The definition of
effective contraception will be based on the judgment of the principal investigator
or a designated associate.

- Phase I: Chemotherapy (standard or experimental) or radiation therapy within 4 weeks
of the administration of study treatment.

- Phase II:

- Chemotherapy (standard or experimental) within 4 weeks of the administration of
study treatment.

- Radiation therapy within 6 weeks of the administration of study treatment.

- Cumulative exposure to anthracycline-containing chemotherapy prior to study
entry precluding the application of at least an additional 150 mg/m2 doxorubicin
(total dose for 2 cycles of study therapy).

- Treatment with an investigational study drug within 6 weeks before beginning of
treatment with F16-IL2.

- Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6
weeks before administration of study treatment.

- Growth factors or immunomodulatory agents within 7 days of the administration of
study treatment.

- Neuropathy > Grade 1

- 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.

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated and recommended dose (MTD) (RD)

Outcome Description:

Phase I: To establish the maximum tolerated dose (MTD) and the RD of F16IL2 when administered in combination with doxorubicin.

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Chiara Matilde Catania, Dr

Investigator Role:

Principal Investigator

Investigator Affiliation:

European Institute of Oncology Milan, Italy


Italy: National Institute of Health (Instituto Superiore di Sanità)

Study ID:




Start Date:

June 2008

Completion Date:

March 2013

Related Keywords:

  • Advanced Solid Tumor
  • Breast Cancer
  • Interleukin
  • IL2
  • F16
  • monoclonal
  • antibody
  • cytokine
  • doxorubicin
  • breast cancer
  • solid tumour
  • Phase I: Advanced Solid Tumour Patients
  • Phase II: Breast Cancer Patients Amenable to anthracyclin Therapy
  • Breast Neoplasms
  • Neoplasms