Clinical trial NCT03773510: Study on Leiomyosarcoma, Liposarcomas and Synovial Sarcoma With Trabectedin
Official title: Time to Secondary Resistance to Trabectedin After Interruption Versus Continuation in Responding Patients With Liposarcoma, Leiomyosarcoma and Synovial Sarcoma
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE3
Conditions: Leiomyosarcoma
Liposarcoma
Synovial Sarcoma
Keywords: trabectedin
soft tissue sarcoma
Lead sponsor: Italian Sarcoma Group
Sponsor class: NETWORK
Collaborators: name: PharmaMar
First posted: 2018-12-12
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, open-label , two arm study All the patients who will complete 6 cycles of treatment without disease progression will be be randomized to continue Trabectedin versus "treatment interruption" followed by re-challenge at progression. Patients randomized to discontinue treatment will be candidate to other 6 cycles of treatment and if they do not progress, to another interruption. The treatment will be resumed again at progression for other 6 cycles and this scheme of treatment will be proposed until progression under Trabectedin.
Primary purpose: TREATMENT

Brief summary: Two arm, randomized, open-label study, to determine the best time to secondary resistance between responding patients who discontinue treatment and resumed Trabectedin at the time of progression versus patients who continued treatment until progression. T

Detailed description: This is an Italian, multicenter, randomized, open-label , two arm, study, to determine the best time to secondary resistance between responding patients who discontinue treatment and resumed Trabectedin at the time of progression versus patients who continued treatment until progression. The aim is to evaluate the best clinical practice for responding patients as Trabectedin has an acceptable safety profile with no evidence of cumulative toxicity.

After signing informed consent and being assessed for eligibility criteria , eligible patients will start the trabectedin treatment.

All the patients who will complete 6 cycles of treatment without disease progression will be be randomized to continue Trabectedin versus "treatment interruption" followed by re-challenge at progression. Patients randomized to discontinue treatment will be candidate to other 6 cycles of treatment and if they do not progress, to another interruption. The treatment will be resumed again at progression for other 6 cycles and this scheme of treatment will be proposed until progression under Trabectedin.

The study will be conducted in Italy in approximately 12 centers, in order to recruit 330 evaluable patients over a 4 year period. The follow-up will last approximately 3 years.

Eligibility criteria: Inclusion Criteria:

1. The patient or legal representative must be able to read and understand the informed consent form and must have been willing to give written informed consent and any locally required authorization before any study-specific procedures, including screening evaluations, sampling, and analyses
2. Diagnosis of well differentiated/dedifferentiated liposarcoma, mixoid round cell liposarcoma, leiomyosarcoma or synovial sarcoma
3. Persistent or locally relapsed and/or metastatic disease
4. Pathology specimens available for centralized review (central review is not mandatory prior to start the treatment, but within a month from screening, tumor sample must be sent to central pathology reviewer for a retrospective diagnosis confirmation).
5. Age ≥ 18 years
6. Adequate bone marrow function
7. Adequate organ function,
8. Eastern Cooperative Oncology Group Performance Status ≤ 2
9. One or more previous systemic treatments with anthracyclines with or without ifosfamide (unless one or both are clinically contraindicated)
10. Measurable disease. Patient who received radiotherapy within 3 weeks form the treatment start, can be included as long there is a measurable lesion outside of the irradiation field
11. A minimum of 3 weeks since any previous chemotherapy treatment
12. Recovery from toxic effects of prior therapies to (Grade 1 or lower)
13. Female patients of child-bearing potential must have negative pregnancy test within 7 days before initiation each cycle of chemotherapy. Post-menopausal women must be amenorrhoeic for at least 12 months to be considered of non-childbearing potential. Male and female patients of reproductive potential must agree to employ an effective method of birth control throughout the study.

Exclusion Criteria:

1. Pregnant or breast-feeding women
2. Prior exposure to Trabectedin
3. Peripheral neuropathy, Grade 2 or higher
4. History of other malignancies (except basal cell carcinoma or cervical carcinoma in situ, adequately treated), unless in remission from 5 years or more and judged of negligible potential of relapse
5. Known central nervous system metastases
6. Active viral hepatitis or chronic liver disease
7. Unstable cardiac condition, including congestive heart failure or angina pectoris, myocardial infarction within six months before enrollment, uncontrolled arterial hypertension or arrhythmia
8. Active major infection
9. Previous treatment with any other investigational or not investigational agents within 14 days of first day of study drug dosing
10. Known history of human immunodeficiency virus infection
11. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
12. Other serious concomitant illnesses or any condition that may interfere with the subject's participation in the study or evaluation of the study results

Primary outcomes:
measure: Time secondary resistance to Trabectedin
timeFrame: Week 18
Secondary outcomes:
measure: Overall Survival
timeFrame: month 6,month 12, month 18, month 24, months 30, month 36, month 42, month 48, month 54, month 60
measure: Incidence of adverse event
timeFrame: Week 9, week 18, week 27, week 36, week 45, week 54, week 63, week 72, week 81
measure: Progression free survival
timeFrame: Week 9, week 18, week 27, week 36, week 45, week 54, week 63, week 72, week 81
Other outcomes:
Locations:
city: Alessandria
country: Italy
facility: A.O. SS Antonio e Biagio e Cesare Arrigo
state: AL
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori - IRST
state: FC
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
state: MI
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: MI
city: Aviano
country: Italy
facility: Centro di Riferimento Oncologico di Aviano
state: PD
city: Roma
country: Italy
facility: Policlinico Universitario Campus Biomedico
state: RM
city: Candiolo
country: Italy
facility: Fondazione del Piemonte per l'Oncologia IRCC Candiolo
state: Torino
city: Torino
country: Italy
facility: Ospedale Gradenigo
state: TO
city: Bologna
country: Italy
facility: Istituto Ortopedico Rizzoli - Unit of Chemotherapy of Muscoloskeletal Tumors
city: Firenze
country: Italy
facility: Azienda ospedaliero Universitaria Careggi di Firenze
city: Milano
country: Italy
facility: Fondazione IRCCS INT Milano
city: Napoli
country: Italy
facility: Policlinico Federico II
city: Padova
country: Italy
facility: Irccs Istituto Oncologico Veneto (Iov)
city: Palermo
country: Italy
facility: Ospedale Giaccone
city: Roma
country: Italy
facility: Istituti Fisioterapici Ospitalieri di Roma
Study officials:
affiliation: Fondazione IRCCS INT di Milano
name: Roberta Sanfilippo, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: D'Incalci M, Galmarini CM. A review of trabectedin (ET-743): a unique mechanism of action. Mol Cancer Ther. 2010 Aug;9(8):2157-63. doi: 10.1158/1535-7163.MCT-10-0263. Epub 2010 Jul 20.
citation: Demetri GD, von Mehren M, Jones RL, Hensley ML, Schuetze SM, Staddon A, Milhem M, Elias A, Ganjoo K, Tawbi H, Van Tine BA, Spira A, Dean A, Khokhar NZ, Park YC, Knoblauch RE, Parekh TV, Maki RG, Patel SR. Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial. J Clin Oncol. 2016 Mar 10;34(8):786-93. doi: 10.1200/JCO.2015.62.4734. Epub 2015 Sep 14.
citation: Sanfilippo R, Dileo P, Blay JY, Constantinidou A, Le Cesne A, Benson C, Vizzini L, Contu M, Baldi GG, Dei Tos AP, Casali PG. Trabectedin in advanced synovial sarcomas: a multicenter retrospective study from four European institutions and the Italian Rare Cancer Network. Anticancer Drugs. 2015 Jul;26(6):678-81. doi: 10.1097/CAD.0000000000000228.
citation: Grosso F, Dileo P, Sanfilippo R, Stacchiotti S, Bertulli R, Piovesan C, Jimeno J, D'Incalci M, Gescher A, Casali PG. Steroid premedication markedly reduces liver and bone marrow toxicity of trabectedin in advanced sarcoma. Eur J Cancer. 2006 Jul;42(10):1484-90. doi: 10.1016/j.ejca.2006.02.010. Epub 2006 Jun 5.
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.