Combination Therapy of F16IL2 and Paclitaxel in Solid Tumour Patients

• 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 breast cancer 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, and from the first 6 patients 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.
• Assessment of median progression-free survival and median overall survival. [ Time Frame: 12 months ] [ Designated as safety issue: No ]

• 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, and from the first 6 patients 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.

This Phase Ib/II study is an open label, multicenter study for patients with solid tumours and breast cancer amenable to taxane therapy.

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.

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 breast cancer amenable to taxane therapy.

• Tumour
• Breast Cancer

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 paclitaxel/taxanes 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 paclitaxel treatment according to the discretion of the principal investigator.

• For Phase II of the study:

  • Histologically or cytologically confirmed breast cancer.
  • 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 Taxane therapy in the opinion of the Principal Investigator.
  • 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, Taxanes, 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 for patients recruited to the phase I part of the study.

• 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.
  • Treatment with an investigational study drug within six 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.