Clinical trial NCT01303094: Continuing vs Intermittent Trabectedin in Patients With Advanced Soft Tissue Sarcoma
Official title: Phase II Randomized Trial to Evaluate Two Strategies: Continuing Versus Intermittent (Drug-holiday) Trabectedin-regimen in Patients With Advanced Soft Tissue Sarcoma Experiencing Response or Stable Disease After the Sixth Cycle
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Soft Tissue Sarcoma
Uterine Sarcoma
Lead sponsor: Centre Oscar Lambret
Sponsor class: OTHER
Collaborators: name: French Sarcoma Group
name: Study Group of Bone Tumors
First posted: 2011-02-24
Enrollment: 53
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This randomization discontinuation trial will allow for concomitant evaluation of the following:

* Side effects and benefits of immediate continuation of Trabectedin after the sixth cycle
* Side effects and benefits of a drug holiday

Detailed description: Selection part (220 patients):

Trabectedin (depending on dose reductions : between 1.5 and 1 mg/m²/3 weeks; over 24 hour administration) until progression, intolerance or 6 cycles (according to the SPC of Trabectedin)

Randomized part (50 patients):

After the 6 first cycles, if there is not progression or unacceptable toxicity, the patients will be randomly assigned to continuous or "intermittent/holiday" therapy with CT-scan evaluation every 6 weeks in both arms

* Arm A Continuation of Trabectedin (between 1.5 and 1 mg/m²/3 weeks; over 24 hour administration) until progression or intolerance
* Arm B "Intermittent/holiday" therapy. Rechallenge of Trabectedin will be implemented in the event of progression; in this case administration of Trabectedin will occur until the second progression or intolerance

Eligibility criteria: Inclusion Criteria (for the selection part):

* Inoperable or metastatic soft tissue sarcoma and/or uterine sarcoma
* Measurable lesions (RECIST 1.1)
* Performance status ≤ 2
* Age ≥ 18
* Normal hematological parameters (polynuclear neutrophils ≥ 1500, hemoglobin level ≥ 9 g/dl, platelets counts ≥ 100,000)
* Adequate biological parameters :
* Adequate hepatic function (bilirubin ≤ ULN , SGPT/ALT and SGOT/AST ≤ 2.5 x ULN)
* Alkaline phosphatases ≤ 2.5 x ULN, If Alkaline phosphatases ≥ 2.5 ULN, hepatic isoenzymes 5-nucleotidases or GGT tests must be performed; hepatic isoenzymes 5- nucleotidases and/or GGT must be within the normal range
* Albumin ≥ 25 g/L
* Adequate renal function : Serum creatinine ≤ 1.5 x ULN
* Creatine phosphokinase ≤ 2.5 x ULN
* Adequate central venous access
* Pregnant or lactating women or men of reproductive potential must use effective contraceptive methods
* Patient covered by government health insurance
* Information sheet given to the patient (Patient information sheet 1)

Exclusion Criteria (for the selection part):

* Patients that have received more than one regimen of chemotherapy for metastatic or inoperable soft tissue or uterine sarcoma, after the failure/intolerance of doxorubicin and ifosfamide. Maintenance treatment does not count as treatment line
* The following histological subtypes : GIST, rhabdomyosarcoma, aggressive fibromatosis, desmoïd tumour, PNET, carcinosarcoma, and all bone sarcomas
* Single tumour in an irradiated region
* Other malignant tumour over the past five years (except basal cell carcinoma or cervical carcinoma in situ adequately treated)
* Currently active bacterial or fungus infection (\> grade 2 CTC \[CTCAE\] Version 4.02). Known HIV1, HIV2, hepatitis B or hepatitis C infections
* Presence of known leptomeningeal or brain metastasis
* Patients unable to receive corticotherapy
* Any circumstance that could jeopardise compliance or proper follow-up during the trial
* Pregnant or nursing women

Inclusion Criteria (for the randomized part):

* Patient registered in the selection part
* Stable tumour or objective response (CR + PR) after 6 Trabectedin (Yondelis®) cycles, according to local assessment
* Available copies of thoraco-abdominal and pelvic scan performed prior to the first cycle and after the sixth cycle
* Performance status ≤ 2
* Patients receiving at least 1 mg/m²/3 weeks of Trabectedin at the time of the sixth cycle
* Normal hematological parameters (polynuclear neutrophils ≥ 1500, hemoglobin level ≥ 9 g/dl, platelets counts ≥ 100,000)
* Adequate biological parameters :
* Adequate hepatic function (bilirubin ≤ ULN , SGPT/ALT and SGOT/AST ≤ 2.5 x ULN)
* Alkaline phosphatases ≤ 2.5 x ULN, If Alkaline phosphatases ≥ 2.5 ULN, hepatic isoenzymes 5-nucleotidases or GGT tests must be performed; hepatic isoenzymes 5- nucleotidases and/or GGT must be within the normal range
* Albumin ≥ 25 g/L
* Adequate renal function : Serum creatinine ≤ 1.5 x ULN
* Creatine phosphokinase (CPK) ≤ 2.5 x ULN
* Adequate central venous access
* Pregnant or lactating women or men of reproductive potential must use effective contraceptive methods
* Informed consent form signed by the patient or the patient's legal representative (patient information sheet 2 and informed consent)

Exclusion Criteria (for the randomized part):

* Tumour progression (according to RECIST 1.1) during the first six Yondelis cycles
* Non-availability of baseline scans prior to the first cycle and following the sixth cycle
* Currently active bacterial or fungus infection (\> grade 2 CTC \[CTCAE\] Version 4.02). Known HIV1, HIV2, hepatitis B or hepatitis C infections
* Presence of known leptomeningeal or brain metastasis
* Creatinine clearance less than 30 ml/min
* Patients unable to receive corticotherapy
* Any circumstance that could jeopardise compliance or proper follow-up during the trial
* Pregnant or nursing women
* Hypersensitivity to Trabectedin or any excipient in prior cycles

Primary outcomes:
measure: PFS rate 24 weeks after randomization
timeFrame: 24 weeks after randomization
Secondary outcomes:
measure: Response rate
timeFrame: 6, 12 and 18 weeks after randomization
measure: Progression free survival rates
timeFrame: 12 and 54 weeks after randomization
measure: Survival rates
timeFrame: 12 and 24 months after randomization
measure: Median progression-free and median overall survivals
timeFrame: Up to 5 years after randomization
measure: Tolerability - safety
timeFrame: Up to 30 days after the last study drg administration
measure: Clinical and biological predictive factors for non progression at the 6th cycle
timeFrame: At baseline
measure: Post-randomization cost of care
timeFrame: For one year after randomization
measure: Self estimation of general health status
timeFrame: For 1 year after randomization
Other outcomes:
Locations:
city: Besancon
country: France
facility: Saint-Jacques Hospital
city: Bordeaux
country: France
facility: Institut Bergonié
city: Caen
country: France
facility: Centre François Baclesse
city: Clermont Ferrand
country: France
facility: Centre Jean Perrin
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Léon Bérard Center
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Paoli Calmette Institute
city: Marseille
country: France
facility: CHU Timone Adultes
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Institut Curie
city: Rouen
country: France
facility: Centre Henri Becquerel
city: St Cloud
country: France
facility: Centre René Huguenin
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: Centre Oscar Lambret
name: Nicolas PENEL, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Le Cesne A, Blay JY, Domont J, Tresch-Bruneel E, Chevreau C, Bertucci F, Delcambre C, Saada-Bouzid E, Piperno-Neumann S, Bay JO, Mir O, Ray-Coquard I, Ryckewaert T, Valentin T, Isambert N, Italiano A, Clisant S, Penel N. Interruption versus continuation of trabectedin in patients with soft-tissue sarcoma (T-DIS): a randomised phase 2 trial. Lancet Oncol. 2015 Mar;16(3):312-9. doi: 10.1016/S1470-2045(15)70031-8. Epub 2015 Feb 11.