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Ph II Nintedanib vs. Ifosfamide in Soft Tissue Sarcoma (ANITA)

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ClinicalTrials.gov Identifier: NCT02808247
Recruitment Status : Recruiting
First Posted : June 21, 2016
Last Update Posted : July 9, 2018
Sponsor:
Collaborator:
Boehringer Ingelheim
Information provided by (Responsible Party):
European Organisation for Research and Treatment of Cancer - EORTC

Brief Summary:

This is a prospective, multicentric, randomized, open label Phase II trial investigating whether the oral angiogenesis inhibitor nintedanib, as compared to the intravenous cytotoxic compound ifosfamide, given for patients with advanced, inoperable and/or metastatic STS after failure of first line chemotherapy prolongs progression-free survival.

The primary objective of the trial is to evaluate whether nintedanib given as second-line therapy for advanced, inoperable and/or metastatic STS prolongs progression-free survival when compared with ifosfamide.

Secondary objectives are to evaluate the efficacy of nintedanib as compared to ifosfamide in terms of progression-free survival rate at 12 weeks, overall survival, objective response rate, patient benefit rate, response duration, total duration of treatment with nintedanib safety, Health related Quality of Life and Health Economics.

Exploratory objectives include an analysis of putative predictive biomarkers for the anti-tumor effects of the investigational agent nintedanib.treatment.


Condition or disease Intervention/treatment Phase
Sarcoma, Soft Tissue Drug: Nintedanib Drug: Ifosfamide Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 185 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Multicenter Study Comparing the Efficacy of the Oral Angiogenesis Inhibitor Nintedanib With the Intravenous Cytotoxic Compound Ifosfamide for Treatment of Patients With Advanced Metastatic Soft Tissue Sarcoma After Failure of Systemic Non-oxazaphosporine-based First Line Chemotherapy for Inoperable Disease "ANITA"
Actual Study Start Date : July 7, 2017
Estimated Primary Completion Date : January 2021
Estimated Study Completion Date : January 2022


Arm Intervention/treatment
Experimental: Experimental arm (arm A): Nintedanib
Nintedanib 200 mg twice daily orally. Nintedanib will be given continuously until clinically relevant disease progression according to the investigator's assessment or until other criteria for treatment discontinuation are met as specified in the protocol. Dosing beyond RECIST 1.1 progression is allowed for the oral agent if the patient still derives benefit from the treatment.
Drug: Nintedanib
Pharmaceutical form: Soft gelatine capsule Pharmaceutical code: Nintedanib (BIBF1120) Source: Boehringer Ingelheim Pharma GmbH & Co. KG Unit strength: 100 mg and 150 mg capsules Daily dose: 400 mg (200 mg twice daily p.o.) Route of administration: oral
Other Name: BIBF1120

Active Comparator: Standard arm (arm B): Ifosfamide
Ifosfamide 3 g/m2 intravenously on days 1, 2 and 3 every 21 days for up to a maximum of 6 cycles.
Drug: Ifosfamide
Ifosfamide will be given at a dose of 3 g/m2 intravenously on days 1, 2 and 3 every 21 days. The total dose per cycle is 9 g/m2




Primary Outcome Measures :
  1. progression-free survival (PFS) [ Time Frame: 4 years from first patient in ]
    progression-free survival (PFS) defined according to RECIST 1.1.


Secondary Outcome Measures :
  1. Progression-free survival rate at 12 weeks (binary) [ Time Frame: 4 years from first patient in ]
  2. Overall survival [ Time Frame: 4 years from first patient in ]
  3. Objective response rate [ Time Frame: 4 years from first patient in ]
    Objective tumor response as defined by RECIST 1.1

  4. Clinical benefit rate [ Time Frame: 4 years from first patient in ]
  5. Response duration [ Time Frame: 4 years from first patient in ]
    Duration of response will be measured for patients achieving an objective response

  6. Total duration of treatment with nintedanib (including treatment beyond RECIST progression) [ Time Frame: 4 years from first patient in ]
  7. Safety (Common Toxicity Criteria CTCAE 4.0) [ Time Frame: 4 years from first patient in ]
  8. Health related quality of life (QLQ-C30) [ Time Frame: 4 years from first patient in ]
    Quality of life will be assessed with the EORTC QoL Questionnaire (QLQ-C30) version 3.0

  9. Health economics (EQ-5D-5L, health care resource utilities) [ Time Frame: 4 years from first patient in ]
    Patient reported utility: EQ-5D-5L



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria/Exclusion Criteria:

  • Histologically proven advanced, inoperable and/or metastatic malignant STS of intermediate or high grade, excluding the:
  • Well-differentiated liposarcoma/atypical lipoma
  • Embryonal rhabdomyosarcoma
  • Chondrosarcoma (extraskeletal myxoid chondrosarcoma is eligible)
  • Osteosarcoma (extraskeletal osteosarcoma is eligible)
  • Ewing family of tumors/primitive neuroectodermal tumor
  • Gastro-intestinal stromal tumor
  • Dermatofibrosarcoma protuberans
  • For STS where no established grading system exists, or sarcoma subtypes which are very indolent or have an unpredictable clinical behavior, patient entry requires prospective approval in writing, on a case-by-case basis by the Study Coordinator of this trial and EORTC Headquarters (HQ).
  • Representative formalin fixed, paraffin embedded tumor blocks or unstained tissue slides, either from the primary tumor or a metastatic lesion, must be available for histological central review. Histological central review is not required before treatment start but it is mandatory to send unstained tumor slides (blocks optional) at time of study entry. Local histopathological diagnosis will be accepted for entry into this trial.
  • Prior to study enrolment, all patients need to have confirmed RECIST 1.1 disease progression based on local investigator's assessment.
  • Presence of measurable disease according to RECIST 1.1.
  • Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are considered non-measurable unless there has been demonstrated progression (20 % increase) in the assessed lesion since the local treatment.
  • No radiographic evidence of cavitary lesions (either primary tumor or metastatic lesions).
  • No centrally located tumors with radiographic evidence of local invasion of major blood vessels.
  • No history of central nervous system metastasis or leptomeningeal tumor spread.
  • No active brain metastases (e.g. stable for <4 weeks, no adequate previous treatment with radiotherapy, symptomatic, requiring treatment with anti-convulsants; dexamethasone therapy will be allowed if administered as stable dose for at least one month before randomization).
  • One (and no less or more than one) line of previous systemic chemotherapy for advanced, inoperable and/or metastatic malignant STS.
  • Prior neoadjuvant, adjuvant and or first-line maintenance systemic chemotherapy for locally advanced or metastatic STS is allowed and does count as zero lines of treatment, provided that the disease did not progress during neoadjuvant and/or adjuvant therapy or within 12 weeks after completion of the perioperative treatment. In case the disease progressed during neoadjuvant, adjuvant and or first-line maintenance systemic chemotherapy or within 12 weeks after its completion, the treatment is counted as one line and the patient can theoretically participate in the trial, provided all other selection criteria are met.
  • No prior exposure to an oxazaphosphorine agent, including but not limited to ifosfamide, cyclophosphamide, trofosfamide or evofosfamide (TH-302).
  • No prior exposure to oral or intravenous angiogenesis inhibitors, including but not limited to tyrosine kinase inhibitors such as pazopanib, sunitinib, sorafenib, axitinib or similar or monoclonal antibodies targeting angiogenesis.
  • No other anti-cancer therapy (systemic therapy, radiotherapy (except for brain and extremities), surgery, limb perfusion, immunotherapy) within 28 days prior to randomization.
  • No treatment with another investigational agent within 28 days prior to randomization.
  • No treatment with another investigational agent concomitantly with the trial.
  • No known hypersensitivity to or known specific contraindications for the use of nintedanib or ifosfamide.
  • No known hypersensitivity to peanut or soy bean.
  • Age 18 years or older.
  • WHO performance status (PS) 0-2.
  • Life expectancy of at least 3 months.
  • Adequate bone marrow, liver and renal function and coagulation parameters:
  • neutrophils ≥ 1.5 x 109/L;
  • hemoglobin ≥ 9 g/dL (or ≥ 5.6 mmol/L). Blood transfusions or the administration of hematopoietic growth factors are allowed to achieve these baseline values;
  • platelets ≥ 100 x 109/L. Platelet transfusions or the administration of hematopoietic growth factors are allowed to achieve these baseline values;
  • Total bilirubin ≤ ULN;
  • Patients with Gilbert syndrome and/or bilirubin < 2xULN and normal AST/ALT are eligible;
  • SGPT/ALT and SGOT/AST ≤ 2.5 x ULN for patients with liver metastasis;
  • SGPT/ALT and SGOT/ AST ≤ 1.5x ULN for patients without liver metastasis;
  • Serum creatinine or creatinine clearance/eGFR within normal limits to baseline, assessed as per local standard method;
  • No proteinuria CTCAE grade 2 or greater;
  • International normalized ratio (INR) ≤ 2;
  • Prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 50% of institutional ULN.
  • No Child Pugh B or C hepatic impairment.
  • Normal cardiac function (left ventricular ejection fraction (LVEF) assessed by multi-gated acquisition scan or cardiac ultrasound within normal range of the institution), 12 lead electrocardiogram (ECG) without clinically relevant abnormalities. No Class III or IV congestive heart failure, angina pectoris, myocardial infarction within 1 year before registration/randomization, clinically significant cardiac arrhythmia or pericardial effusion.
  • No uncontrolled arterial hypertension defined at baseline as blood pressure ≥ 150/100 mmHg despite adequate medical therapy.
  • No use of therapeutic anticoagulation (except low-dose heparin and/or heparin flush as needed for maintenance of an indwelling intravenous devise) or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid < 325 mg per day).
  • No known inherited predisposition for bleeding or thromboembolism.
  • No history of clinically significant hemorrhagic or thromboembolic event in the past 6 months.
  • Absence of active or uncontrolled infections in particular if requiring systemic antibiotics or antimicrobial therapy.
  • No previous encephalopathy of any cause or other significant neurological condition.
  • No acute or chronic, clinically relevant inflammation of urinary bladder.
  • Absence of serious illnesses or medical conditions, including a history of chronic alcohol abuse, active and chronic hepatitis B or C, chronic infection with HIV or clinically relevant liver cirrhosis.
  • Absence of active gastrointestinal disorders or abnormalities that interfere with absorption of the study drug.
  • No major injuries and/or surgery within the past 28 days prior to randomization with incomplete wound healing and/or planned surgery during the on-treatment study period.
  • No persistence of clinically relevant therapy-related toxicity from previous chemotherapy and/or radiotherapy. Grade 1 or 2 adverse events (AEs) are acceptable.
  • No history, within the past five years, of malignancies other than STS (except: basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, resected prostate cancer staged pT1-2 with Gleason Score ≤ 6 and postoperative PSA < 0.5 ng/ml). Patients with a history of other malignancies who are disease-free from that condition for more than 5 years are eligible.
  • Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration/randomization in the trial.
  • No active alcohol or drug abuse.
  • Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 72 hours prior to randomization.
  • Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 3 months (nindetanib) and 6 months (ifosfamide) after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. Since the effect of nintedanib on the metabolism and efficacy of contraceptives has not been investigated, barrier methods should be applied as a second form of contraception, to avoid pregnancy.
  • Female subjects who are breast feeding should discontinue nursing prior to randomization and until 6 months after the last study treatment.
  • Sexually active male participants must use a barrier method of contraception (e.g., condom) during the study treatment period and for at least 3 months after the last study treatment.
  • Before patient registration/randomization, written informed consent must be obtained according to international conference on harmonisation/Good clinical practice (ICH/GCP) and national/local regulations.
  • Patients can only be randomized in this trial once. Important note: All eligibility criteria must be adhered to, in case of potential deviation a discussion with EORTC Headquarters and study coordinator is mandatory.

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 ClinicalTrials.gov identifier (NCT number): NCT02808247


Contacts
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Contact: EORTC HQ +3227741611 1506@eortc.org

Locations
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Belgium
Hopitaux Universitaires Bordet-Erasme - Institut Jules Bordet Recruiting
Brussels, Belgium, 1000
Contact: Gil Thierry    +32 25413188    thierry.gil@bordet.be   
Cliniques Universitaires Saint-Luc (121) Recruiting
Brussels, Belgium
Contact: Filomena Mazzeo       Filomena.Mazzeo@uclouvain.be   
U.Z. Leuven - Campus Gasthuisberg (147) Recruiting
Leuven, Belgium
Contact: Patrick Schöffski       patrick.schoffski@uzleuven.be   
France
Institut Bergonie Recruiting
Bordeaux, France, 33076
Contact: Antoine Italiano       a.italiano@bordeaux.unicancer.fr   
Centre Leon Berard (227) Recruiting
Lyon, France
Contact: Jean-Yves Blay       jean-yves.blay@lyon.unicancer.fr   
Gustave Roussy (225) Recruiting
Villejuif, France
Contact: Olivier Mir       olivier.mir@gustaveroussy.fr   
Lithuania
Vilnius University Hospital Santariskiu Santaros Clinics Klinikos (9453) Recruiting
Vilnius, Lithuania, 08661
Netherlands
The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis (301) Recruiting
Amsterdam, Netherlands, 1066
Leiden University Medical Centre (310) Recruiting
Leiden, Netherlands, 2300
Poland
Maria Sklodowska-Curie Memorial Cancer Centre Recruiting
Warsaw, Poland, 02 781
Contact: Piotr Rutkowski       rutkowskip@coi.waw.pl   
Spain
Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol (Institut Catala D'Oncologia) Recruiting
Barcelona, Spain, 08916
Contact: Anna Estival       estivalanna@gmail.com   
Hospital Universitario San Carlos (366) Recruiting
Madrid, Spain, 28040
United Kingdom
Royal Marsden Hospital - Chelsea, London (613) Recruiting
London, United Kingdom, SW3 6JJ
Sponsors and Collaborators
European Organisation for Research and Treatment of Cancer - EORTC
Boehringer Ingelheim
Investigators
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Principal Investigator: Patrick Schoeffski, MD U.Z. Leuven - Campus Gasthuisberg (147)

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Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier: NCT02808247     History of Changes
Other Study ID Numbers: EORTC-1506-STBSG
2016-002093-12 ( EudraCT Number )
First Posted: June 21, 2016    Key Record Dates
Last Update Posted: July 9, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by European Organisation for Research and Treatment of Cancer - EORTC:
advanced metastatic soft tissue sarcoma

Additional relevant MeSH terms:
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Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Ifosfamide
Isophosphamide mustard
Nintedanib
Angiogenesis Inhibitors
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors