Doxorubicin vs. Trabectedin Plus Doxorubicin in Non Operable and/or Metastatic STS

Sponsor

Grupo Espanol de Investigacion en Sarcomas (Other)

Overall Status

Terminated

CT.gov ID

NCT01104298

Collaborator

(none)

115

Enrollment

Locations

Arms

53.9

Duration (Months)

5.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The proposed investigation intends to explore if the combination of trabectedin and doxorubicin in the first line of treatment of advanced sarcomas obtains better results than doxorubicin monotherapy

Condition or Disease	Intervention/Treatment	Phase
Sarcoma	Drug: Doxorubicin Drug: Trabectedin	Phase 2

Detailed Description

The proposed investigation intends to explore if the combination of trabectedin and doxorubicin in the first line of treatment of advanced sarcomas obtains better results than doxorubicin monotherapy.

This proposal arises from the need to bring to the first line of treatment of advanced STS agents that have shown activity in second line. The goal is to improve available standard treatments. Tumors in patients not previously exposed to chemotherapy have not been selected in their biological behavior and they are the best scenario to test antitumor activity of a new anticancer drug.

The combination of drugs with different mechanisms of action may be a clear advantage to obtain better results and potential synergy. On the other hand, the toxicity profiles of both study drugs are different and worsening or summative of adverse effects is not expected.

The purpose of this study is to determine the efficacy of the combination of trabectedin and doxorubicin in comparison with doxorubicin alone in patients with advanced non operable and/or metastatic Soft Tissue Sarcomas (STS).

Study Design

Study Type:

Interventional

Actual Enrollment :

115 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Randomized, Open, Multicenter, Prospective, Phase II Clinical Trial of Doxorubicin vs. Trabectedin Plus Doxorubicin in the First Line Treatment of Patients With Advanced Non Operable and/or Metastatic Soft Tissue Sarcomas

Study Start Date :

Nov 1, 2009

Actual Primary Completion Date :

Dec 1, 2012

Actual Study Completion Date :

May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm A Classic Doxorubicin (Adriamycin - Doxorubicin hydrochloride) Presentation: Solution with 10, 20, or 50 mg Doxorubicin Hydrochloride. Excipients: hydrochloric acid and sodium chloride 0.9%, q.s. 25 ml. Pharmaceutical form: concentrate for solution for infusion. Route of administration: Intravenous	Drug: Doxorubicin A maximum of 6 cycles every 3 weeks of doxorubicin monotherapy 75 mg/square meter will be given in the absence of progression or not acceptable toxicity. Other Names: Adriamycin
Experimental: Arm B Trabectedin Presentation: vials with trabectedin 1 mg and sucrose 400 mg. Pharmaceutical form: A white or whitish lyophilized powder as concentrate for solution for injection. Route of administration: for intravenous use after reconstitution and further dilution. Classic Doxorubicin (Adriamycin - Doxorubicin hydrochloride) Presentation: Solution with 10, 20, or 50 mg Doxorubicin Hydrochloride. Excipients: hydrochloric acid and sodium chloride 0.9%, q.s. 25 ml. Pharmaceutical form: concentrate for solution for infusion. Route of administration: Intravenous	Drug: Trabectedin A maximum of 6 cycles every 3 weeks of the combination (Trabectedin 1,1 mg/square meter + doxorubicin 60 mg/square meter) will be given in the absence of progression or not acceptable toxicity. Other Names: Yondelis

Arm

Intervention/Treatment

Active Comparator: Arm A

Classic Doxorubicin (Adriamycin - Doxorubicin hydrochloride) Presentation: Solution with 10, 20, or 50 mg Doxorubicin Hydrochloride. Excipients: hydrochloric acid and sodium chloride 0.9%, q.s. 25 ml. Pharmaceutical form: concentrate for solution for infusion. Route of administration: Intravenous

Drug: Doxorubicin

A maximum of 6 cycles every 3 weeks of doxorubicin monotherapy 75 mg/square meter will be given in the absence of progression or not acceptable toxicity.

Other Names:

Adriamycin

Experimental: Arm B

Trabectedin Presentation: vials with trabectedin 1 mg and sucrose 400 mg. Pharmaceutical form: A white or whitish lyophilized powder as concentrate for solution for injection. Route of administration: for intravenous use after reconstitution and further dilution. Classic Doxorubicin (Adriamycin - Doxorubicin hydrochloride) Presentation: Solution with 10, 20, or 50 mg Doxorubicin Hydrochloride. Excipients: hydrochloric acid and sodium chloride 0.9%, q.s. 25 ml. Pharmaceutical form: concentrate for solution for infusion. Route of administration: Intravenous

Drug: Trabectedin

A maximum of 6 cycles every 3 weeks of the combination (Trabectedin 1,1 mg/square meter + doxorubicin 60 mg/square meter) will be given in the absence of progression or not acceptable toxicity.

Other Names:

Yondelis

Outcome Measures

Primary Outcome Measures

To determine the efficacy of the combination of trabectedin and doxorubicin in comparison with doxorubicin alone in patients with advanced non operable and/or metastatic Soft Tissue Sarcomas (STS) [2012]
To determine the efficacy of the combination of trabectedin and doxorubicin in comparison with doxorubicin alone in patients with advanced non operable and/or metastatic Soft Tissue Sarcomas (STS). To this end, progression free survival will be compared between both groups of treatment.

Secondary Outcome Measures

To determine activity by means of RECIST objective responses in both study arms, trabectedin/doxorubicin combination and the control arm. [2012]
To determine activity by means of RECIST objective responses in both study arms, trabectedin/doxorubicin combination and the control arm.
To determine the tumor control (response rates plus stabilizations) in both arms of treatment. [2012]
To determine the tumor control (response rates plus stabilizations) in both arms of treatment.
Overall survival. [2012]
Overall survival.
To determine activity by tissue changes applying the Choi criteria to Soft Tissue Sarcomas (STS)(see radiological review sub study). [2012]
To determine activity by tissue changes applying the Choi criteria to Soft Tissue Sarcomas (STS)(see radiological review sub study).
To determine toxicity of trabectedin/doxorubicin combination and the control arm. [2012]
To determine toxicity of trabectedin/doxorubicin combination and the control arm.
To determine protein and mRNA expression of genes possibly involved in a potential profile of more favorable response or resistance to study drugs and to analyze the prognostic impact of them on predefined efficacy parameters. [2012]
To determine protein and mRNA expression of genes possibly involved in a potential profile of more favorable response or resistance to study drugs and to analyze the prognostic impact of them on predefined efficacy parameters.
To evaluate genomic instability, as well as protein expression that could influence response/resistance to the study drugs and make a correlation with efficacy endpoints. [2012]
To evaluate genomic instability, as well as protein expression that could influence response/resistance to the study drugs and make a correlation with efficacy endpoints.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

The patient must sign voluntarily the informed consent from before any study test is conducted that is not part of routine patient care, with the knowledge that he/she can abandon the study at any time without this affecting his/her previous care.
Aged between 18 and 70.
Pathological diagnosis of non operable and/or metastatic soft tissue sarcoma.
The following histological subtypes can be included:
Undifferentiated pleomorphic sarcoma (previously,malignant fibrous istiocytoma)
Leiomyosarcoma
Angiosarcoma
Liposarcoma
Synovial sarcoma
Fibrosarcoma
Hemangiopericytoma
Neurofibrosarcoma
Mixofibrosarcoma
Unclassified sarcoma
Measurable disease, according to RECIST criteria
Performance status 0-2 Eastern Cooperative Oncology Group(ECOG).
Adequate bone marrow function (hemoglobin > 10 g/dL, leukocytes ≥ 3.000/mm3, neutrophils ≥1.500/mm3, platelets ≥ 100.000/mm3). Patients with plasma creatinine ≤ 1,6 mg/dL, transaminases ≤2.5 times the upper limit of normal (ULN), total bilirubin ≤ upper limit of normal (ULN), CPK ≤ 2.5 times upper limit of normal (ULN), alkaline phosphatase ≤ 2.5 times the upper limit of normal (ULN) are acceptable. If the increase of alkaline phosphatase is > 2.5 times the upper limit of normal (ULN), then the alkaline phosphatase liver fraction and/or 5' nucleotidase and/or GGT must be ≤ upper limit of normal (ULN).
Men or women of child bearing potential should be using an effective method of contraception before entry into the study and throughout the same and for 6 months after ending the study. Women of childbearing potential must have a negative urine pregnancy test before study entry.
Normal cardiac function with a Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram or Multiple Uptake Gated Acquisition Scan (MUGA).

Exclusion Criteria:

Previous chemotherapy treatment.
Previous radiotherapy involving the only localization(s) of measurable tumoral disease.
Performance status> 2 Eastern Cooperative Oncology Group(ECOG).
Central Nervous System (CNS) metastases.
Plasma bilirubin > upper limit of normal(ULN).
Creatinine > 1.6 mg/dL.
History of other neoplastic disease with the exception of basalioma or in situ cervical cancer adequately treated.
Significant cardiovascular disease (for example, dyspnea > 2 NYHA)
Significant systemic diseases grade 3 or higher on the NCI-CTC version 3.0 scale, that limit patient availability, or according to investigator judgment may contribute significantly to treatment toxicity.
Uncontrolled bacterial, mycotic or viral infections.
Women who are pregnant or breast-feeding
Psychological, familial, social or geographic circumstances that limit the patient's ability to comply with the protocol or informed consent.
Patients participating in another clinical trial or receiving any other investigational product.
Patients who had participated in another clinical trial and/or had received any other investigational product in the last 30 days prior to inclusion.
The following histologic subtypes are excluded:
Rhabdomyosarcoma
Ewing's family of tumors
Desmoplastic small round cell tumor
Clear cell sarcoma
Alveolar sarcoma

Contacts and Locations

Locations

	Site	City	State	Country
1	Ico Hospitalet	L'Hospitalet	Barcelona	Spain
2	ICO Badalona	Badalona		Spain
3	H. Clinic Barcelona	Barcelona		Spain
4	H. Sant Pau	Barcelona		Spain
5	H. Provincial Castellón	Castellón		Spain
6	ICO Girona	Girona		Spain
7	H. Xeral Cies	Lugo		Spain
8	Clinica Puerta Hierro	Madrid		Spain
9	H. Clínico. San Carlos	Madrid		Spain
10	H. U. La Paz	Madrid		Spain
11	H.U. Gregorio Marañon	Madrid		Spain
12	H.U. Ramon Y Cajal	Madrid		Spain
13	H.U. Clinico de Malaga	Málaga		Spain
14	H. de Navarra	Navarra		Spain
15	H. C. Asturias	Oviedo		Spain
16	H. Son Dureta	Palma de Mallorca		Spain
17	H. Univ. Canarias	Santa Cruz de Tenerife		Spain
18	H.U. Virgen Del Rocio	Sevilla		Spain
19	Instituto Valenciano de Oncología	Valencia		Spain
20	H. Miguel Servet	Zaragoza		Spain