The primary objective of the trial is to evaluate whether nintedanib given as second-line therapy for advanced, inoperable and/or metastatic STSprolongs progression-free survival when compared with ifosfamide.Secondary objectives are to evaluate the…
ID
Source
Brief title
Condition
- Soft tissue neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint: Progression free survival (RECIST 1.1)
Secondary outcome
Secondary endpoints:
· Progression-free rate at 12 weeks (binary)
· Overall survival
· Objective response rate
· Clinical benefit rate
· Response duration
· Total duration of treatment with nintedanib (including treatment beyond
RECIST progression)
Background summary
Soft tissue sarcoma (STS) is a very heterogeneous family of rare malignant
tumors. In the case of localized disease, surgery is the most important and
potentially curative treatment option. Patients with inoperable primary tumors
or local relapses of STS, or metastatic disease are commonly treated with
systemic therapy. Systemic therapy is primarily based on chemotherapy.
The anthracycline cytotoxic compound doxorubicin is the most commonly applied
first-line treatment in STS. In case of progression after an anthracycline, the
few approved chemotherapy options include ifosfamide (all STS subtypes, but
preferential activity in synovial sarcoma), dacarbazine (all subtypes, mainly
active in leiomyosarcoma) and trabectedin (selected STS subtypes, available in
most countries only after failure of both anthracyclines and ifosfamide for
patients with leiomyosarcoma and liposarcoma). The oral angiogenesis inhibitor
pazopanib, a multi-targeted tyrosine kinase inhibitor against vascular
endothelial growth factor receptors [VEGFR] -1,-2,-3, platelet-derived growth
factor receptor [PDGFR] and KIT, is approved after failure of anthracyclines
and ifosfamide and can prolong progression-free survival after multiple lines
of cytotoxic therapy.
Nintedanib is an oral tyrosine kinase inhibitor that acts on platelet derived
growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) and
vascular endothelial growth factor receptor (VEGFR), which all are potentially
relevant and in part clinically validated targets in STS. The drug is generally
well tolerated and approved by regulatory agencies for treatment of idiopathic
pulmonary fibrosis and for adult patients with locally advanced metastatic or
locally recurrent non-small cell lung cancer after first-line chemotherapy. The
angiogenesis inhibitor nintedanib has not yet been studied in patients with STS.
The oral angiogenesis inhibitor pazopanib has already become part of the
treatment of STS after failure of chemotherapy and there is a good rationale to
test this or similar compounds in earlier lines of sarcoma treatment. The
current study will compare the efficacy of the oral angiogenesis inhibitor
nintedanib with ifosfamide in patients with advanced, inoperable and/or
metastatic STS in second line.
Study objective
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 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 treatment.
Study design
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.
Intervention
Experimental arm (A):
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.
Standard Arm:
Ifosfamide 3 g/m2 intravenously on days 1, 2 and 3 every 21 days for up to a
maximum of 6 cycles.
Study burden and risks
-possible side effects from the treatment with nintedanib
-patients are asked to complete questionnaires, prior to start of treatment,
during treatment, and possibly up to a year after treatment.
Avenue E. Mounier 83/11
Brussel 1200
BE
Avenue E. Mounier 83/11
Brussel 1200
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Listed location countries
Age
Inclusion criteria
SELECTION CRITERIA, *Written informed consent
*Histologically proven advanced, inoperable (medical or surgical) and/or
metastatic malignant STS of intermediate or high grade, excluding the following
tumor types:
* 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.
* One (and no less or more than one) line of previous systemic chemotherapy for
advanced, inoperable and/or metastatic malignant STS. Note: Patients treated in
first line with doxorubicin/olaratumab or doxorubicin/placebo +/-
olaratumab/placebo maintenance qualify for the trial and such treatment will be
considered as one line according to the protocol.
* 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.
* 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.
* 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 10^9/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 10^9/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;
* International normalized ratio (INR) <= 2;
*Prothrombin time (PT) and partial thromboplastin time (PTT) <= 1.5x ULN
*Normal cardiac function (left ventricular ejection fraction (LVEF)
* 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.
* Women of childbearing potential (WOCBP) must have a negative serum pregnancy
test within 72 hours prior to randomization., *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
* 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 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.
* 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.
Exclusion criteria
See section D4a
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-002093-12-NL |
| ClinicalTrials.gov | NCT02808247 |
| CCMO | NL60208.031.17 |