Advanced Solid TumorPhase 1/2NCT01131364
Combination Therapy of F16IL2 and Doxorubicin in Solid Tumour Patients
A Phase 1/2 study testing F16IL2 in combination with doxorubicin in people with Advanced Solid Tumor and Breast Cancer, run by Philogen S.p.A. at 5 sites in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced Solid Tumor, Breast Cancer
- What is being tested?
- F16IL2 in combination with doxorubicin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 29 participants
- Where
- 5 sitesItaly
- Study dates
- Jun 2008to Dec 2012
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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).
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- 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.
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
Italy5 sites
A.O. UNIVERSITARIA OSPEDALI RIUNITI - OSPEDALE UMBERTO I DI ANCONA - ANCONA (AN) (Italy)
Ancona
Irst - Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori - Meldola (Fc)
Meldola
European Institute of Oncology
Milan
A.O. UNIVERSITARIA POLICLINICO DI MODENA (Italy)
Modena
Azienda Ospedaliera Universitaria Senese
Siena
About this study
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
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.
Read the 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).
- Conditions
- Advanced Solid Tumor, Breast Cancer
- Being tested
- F16IL2 in combination with doxorubicin
- Keywords
- 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
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
F16IL2 in combination with doxorubicinDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| F16IL2 in combination with doxorubicin | Experimental | Not described Receives: Drug: F16IL2 in combination with doxorubicin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum tolerated and recommended dose (MTD) (RD)
Phase I: To establish the maximum tolerated dose (MTD) and the RD of F16IL2 when administered in combination with doxorubicin.
Measured: 28 days
Efficacy of F16IL2 in combination with doxorubicin
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.
Measured: 8 weeks
Secondary outcomes (6)
Safety/Tolerability
Phase I/II: To investigate the safety, tolerability of F16IL2 and doxorubicin when given as a combination
Measured: 8 weeks
Pharmacokinetics of F16IL2
Phase I: To investigate pharmacokinetics of F16IL2 and doxorubicin when given as a combination.
Measured: 2 weeks
Human anti-fusion protein antibodies
Phase I: To investigate the induction of human anti-fusion protein antibodies (HAFA).
Measured: 18 months
Antitumor activity
To investigate the antitumor activity of the combination of F16IL2 and doxorubicin in solid tumour patients.
Measured: 12 months
Median progression-free survival
For phase II to assess median progression-free survival of F16IL2 in combination with doxorubicin
Measured: 12 months
Median overall survival
For phase II to assess median overall survival of F16IL2 in combination with doxorubicin
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 May 2010 (estimated)
- Study startJun 2008
- Primary completionMar 2012
- Study completionDec 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Advanced Solid TumorStudies of the same condition, open and under way.
- More trials run by Philogen S.p.A.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 29 participants (actual)
Sponsor and investigators
- Lead sponsor
- Philogen S.p.A.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Chiara Matilde Catania, Dr, Principal investigator, European Institute of Oncology Milan, Italy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01131364
- Sponsor's protocol ID
- PH-F16IL2DOXO-04/07
- Other IDs
- 2007-006176-11
- Status last verified
- Feb 2014
- First submitted
- 25 May 2010
- Last updated
- 25 Feb 2014
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 25 Feb 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01131364
- Acronym / sponsor ID
- PH-F16IL2DOXO-04/07
- Conditions
- Advanced Solid Tumor, Breast Cancer
- Keywords
- Interleukin, IL2, F16, monoclonal, antibody, cytokine, doxorubicin, breast cancer
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Terminated
- Enrolment
- 29 participants (actual)
- Lead sponsor
- Philogen S.p.A.Industry (pharma, biotech, devices)
- Study start
- Jun 2008
- Primary completion
- Mar 2012 (actual)
- Study completion
- Dec 2012 (actual)
- First posted
- 26 May 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| F16IL2 in combination with doxorubicin | Experimental | Drug: F16IL2 in combination with doxorubicin |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (25 listed)
- 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.
- Histologically or cytologically confirmed breast cancer.
Key exclusion criteria (26 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| F16IL2 in combination with doxorubicinIntravenous (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. | Drug | F16IL2 in combination with doxorubicin |
Primary outcome
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.
6 secondary outcomes
Safety/Tolerability
Time frame: 8 weeks
Pharmacokinetics of F16IL2
Time frame: 2 weeks
Human anti-fusion protein antibodies
Time frame: 18 months
Antitumor activity
Time frame: 12 months
Median progression-free survival
Time frame: 12 months
Median overall survival
Time frame: 12 months
Results and safety
The study was stopped early. Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Feb 2014.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Chiara Matilde Catania, Dr principal investigator
European Institute of Oncology Milan, Italy
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing F16IL2 in combination with doxorubicin in people with Advanced Solid Tumor and Breast Cancer, run by Philogen S.p.A. at 5 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 25 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 25 Feb 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early. Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum tolerated and recommended dose (MTD) (RD) (time frame: 28 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Feb 2014.