Combination Therapy of F16IL2 and Doxorubicin in Solid Tumour Patients

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
Philogen S.p.A.
ClinicalTrials.gov Identifier:
NCT01131364
First received: May 25, 2010
Last updated: February 24, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Advanced Solid Tumor
Breast Cancer
Drug: F16IL2 in combination with doxorubicin
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Maximum tolerated and recommended dose (MTD) (RD) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • Safety/Tolerability [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
    Phase I/II: To investigate the safety, tolerability of F16IL2 and doxorubicin when given as a combination

  • Pharmacokinetics of F16IL2 [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
    Phase I: To investigate pharmacokinetics of F16IL2 and doxorubicin when given as a combination.

  • 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 doxorubicin in solid tumour patients.

  • Median progression-free survival [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    For phase II to assess median progression-free survival of F16IL2 in combination with doxorubicin

  • Median overall survival [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    For phase II to assess median overall survival of F16IL2 in combination with doxorubicin


Enrollment: 29
Study Start Date: June 2008
Study Completion Date: December 2012
Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: F16IL2 in combination with doxorubicin Drug: F16IL2 in combination with doxorubicin

Intravenous (i.v.) infusions of F16IL2 (Dose escalation: from 5 up to 25 MioIU) on days 1, 8, 15, 29, 36 and 43 over 60 minutes via automated device (perfusor), followed by a 30-minute i.v. infusion of doxorubicin (Dose escalation: from 20 up to 25 mg/m2) on Days 1, 8, 15 29, 36 and 43.

Patients with objective tumor responses or stable disease will receive repeated cycles of treatment starting on Day 56. Patients will receive additional cycles of combination therapy for a maximum of 6 months, or until disease progression, unacceptable toxicity or withdrawal of consent.


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).

  Eligibility

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

  • 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 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).
  • 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.
  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: NCT01131364

Locations
Italy
A.O. UNIVERSITARIA OSPEDALI RIUNITI - OSPEDALE UMBERTO I DI ANCONA - ANCONA (AN) (Italy)
Ancona, Italy
Irst - Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori - Meldola (Fc)
Meldola, Italy
European Institute of Oncology
Milan, Italy
A.O. UNIVERSITARIA POLICLINICO DI MODENA (Italy)
Modena, Italy
Azienda Ospedaliera Universitaria Senese
Siena, Italy
Sponsors and Collaborators
Philogen S.p.A.
Investigators
Principal Investigator: Chiara Matilde Catania, Dr European Institute of Oncology Milan, Italy
  More Information

No publications provided

Responsible Party: Philogen S.p.A.
ClinicalTrials.gov Identifier: NCT01131364     History of Changes
Other Study ID Numbers: PH-F16IL2DOXO-04/07, 2007-006176-11
Study First Received: May 25, 2010
Last Updated: February 24, 2014
Health Authority: Italy: National Institute of Health (Instituto Superiore di Sanità)
Italy: Ethics Commissions

Keywords provided by Philogen S.p.A.:
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

Additional relevant MeSH terms:
Neoplasms
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Doxorubicin
Liposomal doxorubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 30, 2014