L19TNFα in Combination With Doxorubicin in Patients With Advanced Solid Tumours

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Philogen S.p.A.
Sponsor:
Information provided by (Responsible Party):
Philogen S.p.A.
ClinicalTrials.gov Identifier:
NCT02076620
First received: February 24, 2014
Last updated: March 12, 2014
Last verified: March 2014
  Purpose

Phase Ib study of the tumor-targeting human L19TNFα monoclonal antibody-cytokine fusion protein in combination with doxorubicin in patients with advanced solid tumors.

This study foresees the recruitment of up to 28 patients with advanced solid tumors who in the opinion of the Principal Investigator are deemed suitable for combination therapy of L19TNFα and doxorubicin.


Condition Intervention Phase
Solid Advanced Tumors Amenable to Anthracycline Therapy
Breast Cancer Amenable to Anthracycline Therapy
Drug: Drug: L19TNFα in combination with doxorubicin
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of the Tumor-targeting Human L19TNFα 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 dose (MTD) and recommended dose (RD) [ Time Frame: 29 days ] [ Designated as safety issue: Yes ]
    Establish the MTD and the RD of L19TNFα when administered in combination with doxorubicin.

  • Safety and tolerability of L19TNFα in combination with doxorubicin [ Time Frame: 29 days ] [ Designated as safety issue: Yes ]
    To investigate the safety, tolerability of L19TNFα and doxorubicin when given as a combination


Secondary Outcome Measures:
  • Pharmacokinetics of L19TNFα [ Time Frame: 1 week ] [ Designated as safety issue: No ]
    Investigate the pharmacokinetics of L19TNFα

  • Human anti-fusion protein antibodies [ Time Frame: max. 12 months ] [ Designated as safety issue: Yes ]
    Investigate the potential induction of human anti-fusion protein antibodies (HAFA) through standard laboratory analysis.

  • Treatment efficacy (ORR, PFS, mOS) [ Time Frame: max. 12 months ] [ Designated as safety issue: No ]
    To investigate the antitumor activity in terms of objective response rate (ORR), progression -free survival (PFS) rate and median overall survival (mOS) of L19TNFα when administered in combination with a fixed dose of doxorubicin


Estimated Enrollment: 28
Study Start Date: January 2013
Estimated Study Completion Date: February 2016
Estimated Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: L19TNFα + doxorubicin
Only one arm is specified. Patients will be treated in three cohorts with 3 different dosages of L19TNFα in combination with 60 mg/m2 of doxorubicin.
Drug: Drug: L19TNFα in combination with doxorubicin

Intravenous (i.v.) infusions of L19TNFα (from 10.4, 13 and 17μg/kg) on days 1, 3, and 5 over 120 minutes via automated device (perfusor).

Doxorubicin will be administered as a 15 minutes i.v. infusion on day 1 of each 3-week cycle prior L19TNFα administration.

Study design:

Cohort 1 --> 10.4 μg/kg L19TNFα + Doxorubicin (fixed dose) Cohort 2 --> 13 μg/kg L19TNFα + Doxorubicin (fixed dose) Cohort 3 --> 17 μg/kg L19TNFα + Doxorubicin (fixed dose)

Patients with objective tumor responses or stable disease will receive repeated cycles of treatment starting on Day 22. Patients will receive additional cycles of combination therapy for a maximum of 4.5 months, or exhaustion of cumulative doxorubicin dose (360 or 550mg/m2) until disease progression, unacceptable toxicity, withdrawal of consent or at the discretion of the treating physician, whichever occurs first.


Detailed Description:

L19TNF is a recombinant fusion protein composed of a fully human recombinant monoclonal antibody (L19) and the human tumor necrosis factor-alpha, a primary mediator of immune regulation and inflammation.

As an anti-tumor agent, TNF exerts its major effects via a preferential toxicity for the endothelial cells of the tumor-associated vasculature and an increase of the antitumor immune response. Given at sufficient doses (e.g. intratumorally or in the ILP setting with melphalan), TNF causes significant tumor shrinkage in solid cancer subjects.

  Eligibility

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

Inclusion Criteria:

  • Patients with histologically or cytologically confirmed advanced solid cancer deemed suitable for combination therapy of L19TNFalfa and doxorubicin.
  • For breast cancer patients only:
  • Patients not suitable for trastuzumab therapy (i.e., no evidence of HER2-overexpressing disease, or trastuzumab therapy exhausted in HER2-overexpressing disease).
  • Patients not suitable for lapatinib plus capecitabine therapy in HER2-overexpressing disease.
  • Patients not suitable for lapatinib plus letrozolo therapy in HER2-overexpressing disease and HR + disease.
  • Patients aged >/= 18 years old with advanced or metastatic solid tumor in whom standard anticancer therapies have been exhausted, or who are amenable for a doxorubicin monotherapy according to the discretion of the Principal Investigators and previously treated with a cumulative dose of anthracyclines (</= 300 mg/mq), or chemotherapy- naive.
  • Eastern cooperative oncology group (ECOG) performance status </= 2.
  • Patients may have received previous chemotherapy (>/=4 weeks prior therapy) or radiation therapy (>/=6 weeks prior therapy), but they must be amenable for doxorubicin treatment according to the discretion of the Principal Investigator.
  • Patients must have at least one unidimensionally measurable lesion by computed tomography as defined by criteria version 1.1. This lesion must not have been irradiated during previous treatments.
  • 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/mq of doxorubicin, nor more than 500 mg/mq of epirubicin, nor more than 600 mg/mq of pegylated or non-pegylated liposomal doxorubicin prior to study entry, in order to avoid anthracycline-associated cardiotoxicity.
  • Life expectancy more than 3 months.
  • Absolute neutrophil count (ANC) </= 1.5 x 10^9/L, platelets </= 100 x 10^9/L and haemoglobin (Hb) </= 9.5 g/dl.
  • All acute adverse effects (excluding alopecia) of any prior therapy (including surgery, radiation therapy, chemotherapy) must have resolved to </= Grade 1, except elevated liver transaminases judged to be associated with tumor infiltration (see below) (graded according to the National Cancer Institute CTCAE v.4.02 dated September 15, 2009).
  • Alkaline phosphatase (AP), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) </= 2.5 x upper limit of normal (ULN), and total bilirubin </= 2.0 mg/gL, unless liver involvement by the tumor, in which case the transaminase levels up to 5 x ULN are allowed.
  • Creatinine </= 1.5 ULN or 24 h creatinine clearance </= 60 mL/min.
  • Testing negative for acute or chronic infection with hepatitis B or C virus, or human immunodeficiency virus 1 or 2.
  • Negative pregnancy test for females of childbearing potential at the screening visit.
  • Commitment from patient to practice medically appropriate/acceptable method of birth control beginning 30 days before study entry and continuing until 3 months following the last treatment with study drug. Excluding women without childbearing potential; menopause at least 2 years earlier, tubal ligation at least 1 year earlier, or total hysterectomy. The definition of effective contraception will be based on the guidelines ICH M3 rev2.
  • Evidence of a personally signed and dated EC-approved ICF 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.

ICF must be obtained for all the patients before enrollment into the study.

Exclusion Criteria:

  • Pregnancy or breast-feeding. Patients must agree to use effective contraception, or be surgically sterile or postmenopausal. The definition of effective contraception will be based on the guidelines ICH M3 rev2.
  • Presence of active infections (e.g. requiring antimicrobial therapy) or other severe concurrent disease, which, in the opinion of the investigator, would place the subject at undue risk or interfere with the study.
  • Presence of known brain metastases. If patient is symptomatic, negative CT scan within two months before study beginning is required. However, presence of controlled brain metastases (i.e., evaluated as SD of PR after radiotherapy) is allowed.
  • Known cancer of other primary origin within the prior 5 years.
  • History of chronic hepatitis B or C, or chronic active hepatitis or active autoimmune diseases.
  • Cardiac disease as manifested by any of the following:
  • > Grade II heart failure, graded per New York Heart Association (NYHA) criteria.
  • History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
  • Irreversible cardiac arrhythmias requiring permanent medication.
  • Ejection fraction less than the institutional lower limit of normal as assessed by MUGA scan or echocardiogram.
  • Uncontrolled hypertension.
  • Ischemic peripheral vascular disease (Grade IIb-IV).
  • Severe rheumatoid arthritis.
  • Severe diabetic retinopathy.
  • History of allograft or stem cell transplantation.
  • Major surgery or trauma within 4 weeks prior to start of study treatment.
  • Known history of allergy to TNFalfa, Anthracyclines or other intravenously administered human proteins/peptides/antibodies.
  • Chemotherapy (standard or experimental), or therapy with an investigational agent within 4 weeks prior to start of study treatment, and radiation within 6 weeks prior therapy.
  • Cumulative exposure to anthracycline-containing chemotherapy (patients received a cumulative anthracycline dose of more than 300 mg/mq of doxorubicin or of more than 500 mg/mq of epirubicin or pegylated or non-pegylated liposomal doxorubicin), prior to study entry precluding the application of at least an additional 150 mg/mq doxorubicin (total dose for 2 cycles of study therapy).
  • Treatment with an investigational study drug within six weeks before beginning of treatment with L19TNFalfa.
  • 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 prior to 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.
  • Concurrent therapy with warfarin at doses greater than 1 mg/day or equivalent doses of other coumarin derivatives.
  • Participation in another interventional clinical trial during participation in this trial.
  • Expectation that the patient will not be able to complete at least 6 weeks of therapy.
  • 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: NCT02076620

Contacts
Contact: Leonardo Giovannoni, Dr (0039) 0577 17816 regulatory@philogen.com

Locations
Germany
Universitätsklinikum Münster Recruiting
Münster, Germany
Contact: Christoph Schliemann, Dr         
Principal Investigator: Christoph Schliemann, Dr         
Italy
Fondazione IRCCS Istituto Nazionale dei Tumori Recruiting
Milan, Italy
Contact: Filippo De Braud, Dr         
Principal Investigator: Filippo De Braud, Dr         
Sponsors and Collaborators
Philogen S.p.A.
Investigators
Principal Investigator: Filippo De Braud, Dr Fondazione IRCCS Istituto Nazionale dei Tumori
Principal Investigator: Christoph Schliemann, Dr Universitätsklinikum Münster
  More Information

No publications provided

Responsible Party: Philogen S.p.A.
ClinicalTrials.gov Identifier: NCT02076620     History of Changes
Other Study ID Numbers: PH-L19TNFDOXO-01/12, 2012-000950-75
Study First Received: February 24, 2014
Last Updated: March 12, 2014
Health Authority: Italy: National Institute of Health
Italy: Ethics Committee
Germany: Paul-Ehrlich-Institut
Germany: Ethics Commission

Keywords provided by Philogen S.p.A.:
L19
monoclonal
antibody
doxorubicin
TNFα
solid tumour
breast cancer
anthracycline

Additional relevant MeSH terms:
Breast Neoplasms
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