Clinical Trials /

Ph II Nintedanib vs. Ifosfamide in Soft Tissue Sarcoma

NCT02808247

Description:

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.

Related Conditions:
  • Soft Tissue Sarcoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ph II Nintedanib vs. Ifosfamide in Soft Tissue Sarcoma
  • 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"

Clinical Trial IDs

  • ORG STUDY ID: EORTC-1506-STBSG
  • SECONDARY ID: 2016-002093-12
  • NCT ID: NCT02808247

Conditions

  • Sarcoma, Soft Tissue

Interventions

DrugSynonymsArms
NintedanibBIBF1120Experimental arm (arm A): Nintedanib
IfosfamideStandard arm (arm B): Ifosfamide

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Experimental arm (arm A): NintedanibExperimentalNintedanib 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.
  • Nintedanib
Standard arm (arm B): IfosfamideActive ComparatorIfosfamide 3 g/m2 intravenously on days 1, 2 and 3 every 21 days for up to a maximum of 6 cycles.
  • Ifosfamide

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:progression-free survival (PFS)
Time Frame:4 years from first patient in
Safety Issue:
Description:progression-free survival (PFS) defined according to RECIST 1.1.

Secondary Outcome Measures

Measure:Progression-free survival rate at 12 weeks (binary)
Time Frame:4 years from first patient in
Safety Issue:
Description:
Measure:Overall survival
Time Frame:4 years from first patient in
Safety Issue:
Description:
Measure:Objective response rate
Time Frame:4 years from first patient in
Safety Issue:
Description:Objective tumor response as defined by RECIST 1.1
Measure:Clinical benefit rate
Time Frame:4 years from first patient in
Safety Issue:
Description:
Measure:Response duration
Time Frame:4 years from first patient in
Safety Issue:
Description:Duration of response will be measured for patients achieving an objective response
Measure:Total duration of treatment with nintedanib (including treatment beyond RECIST progression)
Time Frame:4 years from first patient in
Safety Issue:
Description:
Measure:Safety (Common Toxicity Criteria CTCAE 4.0)
Time Frame:4 years from first patient in
Safety Issue:
Description:
Measure:Health related quality of life (QLQ-C30)
Time Frame:4 years from first patient in
Safety Issue:
Description:Quality of life will be assessed with the EORTC QoL Questionnaire (QLQ-C30) version 3.0
Measure:Health economics (EQ-5D-5L, health care resource utilities)
Time Frame:4 years from first patient in
Safety Issue:
Description:Patient reported utility: EQ-5D-5L

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:European Organisation for Research and Treatment of Cancer - EORTC

Trial Keywords

  • advanced metastatic soft tissue sarcoma

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