- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02054884
F16IL2 Plus Paclitaxel in Metastatic Merkel Cell Carcinoma
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
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).
Study Overview
Status
Conditions
Intervention / Treatment
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).
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Graz, Austria
- Medical University Hospital
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Herlev, Denmark
- Herlev- University Hospital
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Paris, France
- Saint-Louis- Hospital
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Berlin, Germany
- Charité- Medical University Hospital
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Essen, Germany
- Universitätsklinik Essen
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Tübingen, Germany
- Eberhard-Karls- University Hospital
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Barcelona, Spain
- ICMiD- University Hospital
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Nottingham, United Kingdom
- Nottingham Trent- University Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Arm A: F16IL2 in combination with paclitaxel
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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
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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. |
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
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Efficacy of F16IL2 in combination with paclitaxel vs. paclitaxel monotherapy (RECIST v1.1, irRC)
Time Frame: 12 months
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12 months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Overall survival rate
Time Frame: 12 months
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12 months
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Treatment efficacy (ORR, DCR)
Time Frame: 36 months
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36 months
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Safety and tolerability of the combination treatment with F16IL2 and paclitaxel
Time Frame: 36 months
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Evaluation of the type and the number of adverse events eventually present
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36 months
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Jürgen C. Becker, Prof., Medical University of Graz, Austria
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Virus Diseases
- Infections
- Neoplasms by Histologic Type
- Neoplasms
- Adenocarcinoma
- Neoplasms, Glandular and Epithelial
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- DNA Virus Infections
- Tumor Virus Infections
- Neuroendocrine Tumors
- Polyomavirus Infections
- Carcinoma, Neuroendocrine
- Carcinoma
- Carcinoma, Merkel Cell
- Molecular Mechanisms of Pharmacological Action
- Antineoplastic Agents
- Tubulin Modulators
- Antimitotic Agents
- Mitosis Modulators
- Antineoplastic Agents, Phytogenic
- Paclitaxel
- Albumin-Bound Paclitaxel
Other Study ID Numbers
- PH-F16IL2TAXO-03/12
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Merkel Cell Carcinoma
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National Cancer Institute (NCI)Active, not recruitingAdvanced Merkel Cell Carcinoma | Metastatic Merkel Cell Carcinoma | Pathologic Stage III Cutaneous Merkel Cell Carcinoma AJCC v8 | Clinical Stage III Cutaneous Merkel Cell Carcinoma AJCC v8 | Clinical Stage IV Cutaneous Merkel Cell Carcinoma AJCC v8 | Pathologic Stage IIIA Cutaneous Merkel... and other conditionsUnited States
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National Cancer Institute (NCI)RecruitingMetastatic Merkel Cell Carcinoma | Refractory Merkel Cell Carcinoma | Locally Advanced Merkel Cell Carcinoma | Unresectable Merkel Cell Carcinoma | Clinical Stage III Cutaneous Merkel Cell Carcinoma AJCC v8 | Clinical Stage IV Cutaneous Merkel Cell Carcinoma AJCC v8United States
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National Cancer Institute (NCI)CompletedRecurrent Merkel Cell Carcinoma | Stage III Merkel Cell Carcinoma AJCC v7 | Stage IV Merkel Cell Carcinoma AJCC v7 | Stage IIIA Merkel Cell Carcinoma AJCC v7 | Stage IIIB Merkel Cell Carcinoma AJCC v7United States
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Melanoma and Skin Cancer Trials LimitedRecruitingNeuroendocrine Tumors | Merkel Cell Carcinoma | Merkel Cell Carcinoma, Stage I | Merkel Cell Carcinoma, Stage II | Merkel Cell Carcinoma, Stage III | Carcinoma Neuroendocrine SkinAustralia, New Zealand
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University of WashingtonEMD SeronoActive, not recruitingStage III Merkel Cell Carcinoma AJCC v8 | Stage IIIB Merkel Cell Carcinoma AJCC v8 | Stage IIIA Merkel Cell Carcinoma AJCC v8United States
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Fred Hutchinson Cancer CenterNational Cancer Institute (NCI)TerminatedRecurrent Merkel Cell Carcinoma | Stage IV Merkel Cell CarcinomaUnited States
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National Cancer Institute (NCI)SuspendedPathologic Stage I Cutaneous Merkel Cell Carcinoma AJCC v8 | Pathologic Stage II Cutaneous Merkel Cell Carcinoma AJCC v8 | Pathologic Stage III Cutaneous Merkel Cell Carcinoma AJCC v8United States
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University of WashingtonIncyte CorporationRecruitingMerkel Cell Carcinoma | Clinical Stage IV Merkel Cell Carcinoma AJCC v8 | Unresectable Clinical Stage III Merkel Cell Carcinoma AJCC v8United States
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ImmunityBio, Inc.UnknownStage IIIB Merkel Cell Carcinoma | Stage IV Merkel Cell CarcinomaUnited States
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Fred Hutchinson Cancer CenterNational Cancer Institute (NCI); EMD SeronoTerminatedStage IV Merkel Cell Carcinoma AJCC v7 | Merkel Cell Polyomavirus InfectionUnited States
Clinical Trials on Arm A: F16IL2 in combination with paclitaxel
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Philogen S.p.A.CompletedBreast Cancer | Solid Tumor | Metastatic Melanoma | Non-small Cell Lung Cancer (NSCLC)Italy
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AstraZenecaCompletedAdvanced or Metastatic Breast Cancer | ER+ve Advanced or Metastatic Breast CancerCanada, France, Korea, Republic of, Czechia, Peru, United Kingdom, Spain, Japan, Mexico, Singapore, Bulgaria
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Shanghai Junshi Bioscience Co., Ltd.WithdrawnPrimary Condition: Advanced TumorsChina
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Cancer Research UKRoyal Marsden NHS Foundation Trust; Hoffmann-La Roche; University of Manchester; University of BirminghamRecruitingSolid Tumor | Haematological MalignancyUnited Kingdom
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Philogen S.p.A.TerminatedBreast Cancer | Advanced Solid TumorItaly
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The West Clinic, MemphisUniversity of Tennessee West Cancer CenterCompletedBreast Cancer | FatigueUnited States
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Norwegian Breast Cancer GroupCompletedBreast NeoplasmNorway