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F16IL2 Plus Paclitaxel in Metastatic Merkel Cell Carcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02054884
Recruitment Status : Terminated (Lack of enrollment)
First Posted : February 4, 2014
Last Update Posted : May 18, 2018
immatics Biotechnologies GmbH
Information provided by (Responsible Party):
Philogen S.p.A.

Brief Summary:

There is no standard treatment for Merkel cell carcinoma(MCC), as no randomized trials have been conducted to establish standard of care. Despite a sizable number of objective responses induced by combination cyototoxic chemotherapy, a prolongation of patients overall survival has never been demonstrated.

This open-label, randomized, double-arm, multi-centre, phase II study of F16IL2 in combination with paclitaxel versus paclitaxel monotherapy, proposes to test the therapeutic efficacy of F16IL2 plus paclitaxel in patients with metastatic Merkel cell carcinoma, who are not amenable to surgery.

A total of 90 patients with Merkel cell carcinoma will be enrolled and treated during the study; 45 patients will receive the combination treatment of F16IL2 and paclitaxel (Arm A), and 45 patients will receive paclitaxel monotherapy (Arm B).

Condition or disease Intervention/treatment Phase
Merkel Cell Carcinoma Drug: Arm A: F16IL2 in combination with paclitaxel Drug: Arm B: Paclitaxel Phase 2

Detailed Description:

F16IL2 has been studied in two clinical pase I/II trials in patients with different advanced cancer types. One of them (Nr. EudraCT: 2007-006457-42) tested the administration of therapeutic doses of paclitaxel (up to 90 mg/m2 on a weekly basis) together with escalating doses of F16IL2 (from 5 Mio IU of IL2 equivalents in a weekly administration schedule, until definition of MTD). More than 40 patients were treated in this clinical trial. As of today, the highest F16IL2 dose tested corresponds to 45 Mio IU, but the dose escalataion of the F16IL2/paclitaxel combination study is still ongoing.

In general, treatment of patients with F16IL2 plus paclitaxel was very well tolerated not exceeding the expected toxicity of chemotherapy alone. Multiple objective and durable tumor responses were observed in the F16IL2/paclitaxel combination trial(particularly in patients with non small cell lung cancer or melanoma who had previously failed several lines of chemotherapy). In addition to several disease stabilizations of previously progressive patients.

Paclitaxel promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerisation. This stability results in the inhibition of the normal reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel reduces abnormal arrays or bundles of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of the Tumor-targeting Human F16IL2 Monoclonal Antibody-cytokine Fusion Protein in Combination With Paclitaxel in Patients With Metastatic Merkel Cell Carcinoma
Actual Study Start Date : October 25, 2013
Actual Primary Completion Date : December 31, 2016
Actual Study Completion Date : December 15, 2017

Arm Intervention/treatment
Experimental: Arm A: F16IL2 in combination with paclitaxel Drug: Arm A: F16IL2 in combination with paclitaxel

Intravenous (i.v.) 1 hour infusions of paclitaxel 90 mg/m^2 followed, after 30 min pause, by 3 hour i.v. infusions of F16IL2 35 Mio IU on days 1, 8, 15 of each 28 day cycle.

Patients will receive 4 week cycles of study therapy for a maximum of 24 weeks, or until disease progression, unacceptable toxicity or withdrawal of consent.

Experimental: Arm B: Paclitaxel Drug: Arm B: Paclitaxel

Intravenous (i.v.) 1 hour infusions of Paclitaxel 90 mg/m^2 on days 1, 8, 15 of each 28 day cycle.

Patients will receive 4 week cycles of study therapy for a maximum of 24 weeks, or until disease progression, unacceptable toxicity or withdrawal of consent.

Primary Outcome Measures :
  1. Efficacy of F16IL2 in combination with paclitaxel vs. paclitaxel monotherapy (RECIST v1.1, irRC) [ Time Frame: 12 months ]

Secondary Outcome Measures :
  1. Overall survival rate [ Time Frame: 12 months ]
  2. Treatment efficacy (ORR, DCR) [ Time Frame: 36 months ]
  3. Safety and tolerability of the combination treatment with F16IL2 and paclitaxel [ Time Frame: 36 months ]
    Evaluation of the type and the number of adverse events eventually present

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients with advanced or metastatic Merkel cell carcinoma (MCC) not amenable to surgery and who have not received previous systemic therapy with taxanes; diagnosis of MCC must be histologically confirmed (evaluation of primary lesions or advanced disease) and endorsed by the IMMOMEC central dermatopathology center (central review of diagnosis at the Department of General Dermatology, Medical University of Graz). Patients must be amenable for paclitaxel treatment according to the discretion of the principal investigator
  • Patients aged ≥ 18 ≤ 75 years
  • ECOG performance status ≤ 1
  • Patients must have measurable disease including cutaneous and subcutaneous metastases as defined by RECIST v.1.1 criteria or immune related response Criteria (irRC) as assessed by CT or MRI and/or ultrasound within 4 weeks before the first study drug administration.
  • All acute side effects from any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.03) Grade ≤ 1;.
  • Adequate hematologic, liver and renal function:

    • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, haemoglobin (Hb) ≥ 9.0 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 ≤ 5 x ULN
    • Creatinine ≤ 1.5 UL or 24 h creatinine clearance ≥ 50 mL/min
  • 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 EC-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:

  • Life expectancy of less than 3 months
  • Any previous taxanes therapy
  • Previous or concurrent CLL patients
  • Any other malignancy from which the patient has been disease-free for less than 2 years prior to study entry, with the exception of adequately treated and cured cervical carcinoma in situ, basal or squamous cell carcinoma, superficial bladder cancer, or in situ melanoma
  • Presence of uncontrolled infections 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
  • Chronic-active hepatitis B, C, or HIV
  • Severe cardiovascular disease:

    • History 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 2D-ECHO or 12-lead ECG investigations
    • Uncontrolled hypertension
    • Ischemic peripheral vascular disease (Grade IIb-IV)
  • Severe rheumatoid arthritis; or other uncontrolled autoimmune disease
  • Severe diabetic retinopathy
  • History of allograft or stem cell transplantation
  • Major trauma including major surgery (e.g. visceral surgery) within 4 weeks of administration of study treatment
  • Known history of allergy to IL-2, taxanes, cremophor 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 European guideline ICH M3 rev 2.
  • Treatment with an investigational study drug within four weeks before beginning of treatment with F16IL2
  • Previous treatment with monoclonal antibodies for biological therapy in the four weeks before administration of study treatment
  • Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02054884

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Medical University Hospital
Graz, Austria
Herlev- University Hospital
Herlev, Denmark
Saint-Louis- Hospital
Paris, France
Charité- Medical University Hospital
Berlin, Germany
Universitätsklinik Essen
Essen, Germany
Eberhard-Karls- University Hospital
Tübingen, Germany
ICMiD- University Hospital
Barcelona, Spain
United Kingdom
Nottingham Trent- University Hospital
Nottingham, United Kingdom
Sponsors and Collaborators
Philogen S.p.A.
immatics Biotechnologies GmbH
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Principal Investigator: Jürgen C. Becker, Prof. Medical University of Graz, Austria
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Responsible Party: Philogen S.p.A. Identifier: NCT02054884    
Other Study ID Numbers: PH-F16IL2TAXO-03/12
First Posted: February 4, 2014    Key Record Dates
Last Update Posted: May 18, 2018
Last Verified: May 2018
Keywords provided by Philogen S.p.A.:
Interleukin, IL2, F16, monoclonal, antibody, cytokine Paclitaxel, Merkel cell carcinoma
Additional relevant MeSH terms:
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Carcinoma, Merkel Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Polyomavirus Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections
Carcinoma, Neuroendocrine
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action