Gemcitabine Plus Rapamycin Versus Gemcitabine to Treat Advanced Soft Tissue Sarcoma
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Purpose
The soft tissue sarcomas (STS) constitute an infrequent group of malignant neoplasms of mesenchymal origin. In Spain, the approximate incidence is of 2 new cases per 100.000 inhabitants every year. In patients with metastatic STS, the average survival is very short, approximately 12 months. The systemic treatment of the metastatic disease has had a very limited development, with few satisfactory results. This facts reflect the urgent need to identify new active agents for treatment of these patients.
The molecular pathway of the serine/threonine kinase mammalian target of rapamycin (mTOR) plays a central role in the regulation of the proteins translation, cellular growth and metabolism (Meric-Bernstam F et al. 2009). Currently, the mTOR pathway is considered a relevant target for the development of anti-cancer drugs, as rapamycin. Preliminary results of some clinical trials suggest that mTOR inhibitors could have some clinical activity for different types of sarcoma, including STS (Chawla et al Proc.ASCO 2006; Schuetze et al. Proc.ASCO 2006).
Gemcitabine is a chemotherapy antimetabolite agent with a broad antitumoral spectrum. The activity of this drug to treat resistant sarcomas and its reduced toxicity make from gemcitabine an adequate candidate for its study in combination with new drugs addressed to molecular targets in the STS treatment.
Pre-clinical studies suggest that mTOR inhibitors could have a potential synergistic or additive effect with some chemotherapy agents. The combination of rapamycin and gemcitabine seems to be a reasonable strategy to explore for the STS treatment.
| Condition | Intervention | Phase |
|---|---|---|
|
Advanced Soft Tissue Sarcoma |
Drug: Gemcitabine + Rapamycin |
Phase 1 Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Phase 1/2, Randomized, Multicenter, Prospective Study of Gemcitabine and Rapamycin (Sirolimus) Combination Versus Gemcitabine Only to Treat Advanced Soft Tissue Sarcoma |
- Phase 1: Determination of dosage: Security and toxicity of the combination gemcitabine and rapamycin. [ Time Frame: 15 months ] [ Designated as safety issue: Yes ]Type, frequency, seriousness and relation with the treatment of the adverse events in patients treated with the investigational medicinal products.
- Phase 2: Progression Free Survival [ Time Frame: 12 months ] [ Designated as safety issue: No ]Progression free survival rate at 3 months to compare the effectiveness of the the treatment.
- Phase 2: Overall Survival [ Time Frame: 12 months ] [ Designated as safety issue: No ]Overall survival rate of the patients included in the experimental arm.
- Phase 2: Toxicity [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]Tolerance to the drugs combination of the patients treated with gemcitabine + sirolimus
- Phase 1 and 2: Assessment of molecular biomarkers [ Time Frame: 36 months ] [ Designated as safety issue: No ]Assess, both in models of sarcomas induced in immunodeficient mice and tumor samples from patients enrolled in the trial, the predictive value of the response to combination therapy of certain molecular markers for survival and mTOR pathway.
| Estimated Enrollment: | 27 |
| Study Start Date: | January 2010 |
| Estimated Study Completion Date: | December 2013 |
| Estimated Primary Completion Date: | March 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Phase 2: Experimental Arm
Gemcitabine + rapamycin at recommended dose of Phase 1. Recommended dose is defined as, the dose one level below of the (MTD). Being MTD, the dose of the cohort in which a maximum of one patient of 6 has presented dose-limiting toxicity (DLT).
|
Drug: Gemcitabine + Rapamycin
Gemcitabine + rapamycin at recommended dose of Phase 1. Recommended dose is defined as, the dose one level below of the (MTD). Being MTD, the dose of the cohort in which a maximum of one patient of 6 has presented dose-limiting toxicity (DLT). Every three weeks until disease progression or unacceptable toxicity. The treatment will last for 6 cycles if there is not progression or intolerable toxicity. Additionally, there will be a pharmacokinetic study in a minimum of 9 patients treated with the drug combination. |
Eligibility| Ages Eligible for Study: | 18 Years to 70 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Patients with anatomopathological diagnosis of metastatic or locally advanced unresectable soft tissue sarcoma (STS). Patients with the following STS types will be excluded: chondrosarcoma, Ewing's sarcoma and embryonal or alveolar rhabdomyosarcoma. In phase 1 it will be allowed to include patients having other types of advanced cancer which are resistant to the standard treatment and can benefit from any of the study drugs.
- Prior treatment with chemotherapy including doxorubicin and ifosfamide, or contraindication for its administration. The previous treatment with gemcitabine or inhibitors of mTOR is not allowed.
- Age ≥ 18 y ≤ 70 years.
- ECOG performance status: 0 - 2. In Phase 1 only patients with ECOG 0-1 will be enrolled.
- Disease measurable according to RECIST criteria. Proven relapsed disease.
- Adequate bone marrow function, defined as neutrophil count ≥ 1.500/mm^3 and platelets ≥ 100.000/mm^3.
- Adequate renal and hepatic function , defined as calculated creatinine clearance ≥ 60 ml/min, creatinine, total bilirubin, AST and/or ALT ≤ 1,5 times the upper limit of normal (ULN).
- Informed consent form signed by the patient prior to the beginning of the treatment.
Exclusion Criteria:
- History of previous cancer diagnosed or treated in the past 5 years except basal cell carcinoma, cervical carcinoma in situ or superficial bladder cancer.
- Presence of brain metastases.
- Active infection or other severe concomitant diseases.
- Concurrent treatment with other experimental drugs within 30 days prior to study entry.
- Pregnancy or breastfeeding.
Contacts and Locations| Contact: Xavier García del Muro Solans, MD | +34934344412 | secretaria@grupogeis.org |
| Spain | |
| H. Sant Pau | Recruiting |
| Barcelona, Spain, 08024 | |
| Contact: , MD 934344412 anna.deprado@mfar.net | |
| Principal Investigator: Antonio López, Dr. | |
| Institut Català d'Oncologia - Hospital Duran i Reynals | Recruiting |
| L'Hospitalet de Llobregat, Spain | |
| Principal Investigator: Xavier García del Muro Solans, MD | |
| Hospital Universitario 12 de Octubre | Recruiting |
| Madrid, Spain | |
| Principal Investigator: López Martín, MD | |
| H. La Paz | Active, not recruiting |
| Madrid, Spain | |
| Hospital Universitario Puerta de Hierro | Recruiting |
| Majadahonda, Spain | |
| Principal Investigator: Cubedo, MD | |
| H. Son Espases | Not yet recruiting |
| Mallorca, Spain | |
| Contact 934344412 anna.deprado@mfar.net | |
| Principal Investigator: Javier Martín Broto, MD | |
| Instituto Valenciano de Oncología | Active, not recruiting |
| Valencia, Spain | |
| H. Universitario Miguel Servet | Recruiting |
| Zaragoza, Spain, 50009 | |
| Contact 934344412 anna.deprado@mfar.net | |
| Principal Investigator: Javier Martínez Trufero, MD | |
| Study Chair: | Xavier García del Muro Solans, MD | GEIS |
More Information
No publications provided
| Responsible Party: | Grupo Espanol de Investigacion en Sarcomas |
| ClinicalTrials.gov Identifier: | NCT01684449 History of Changes |
| Other Study ID Numbers: | GEIS-24, 2009-017232-41 |
| Study First Received: | June 30, 2011 |
| Last Updated: | March 8, 2013 |
| Health Authority: | Spain: Agencia Española de Medicamentos y Productos Sanitarios Spain: Comité Ético de Investigación Clínica |
Keywords provided by Grupo Espanol de Investigacion en Sarcomas:
|
Soft tissue sarcoma Gemcitabine Rapamycin |
Sirolimus mTOR inhibitor Molecular biomarkers |
Additional relevant MeSH terms:
|
Sarcoma Neoplasms, Connective and Soft Tissue Neoplasms by Histologic Type Neoplasms Gemcitabine Sirolimus Everolimus Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Antineoplastic Agents |
Therapeutic Uses Antiviral Agents Anti-Infective Agents Enzyme Inhibitors Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Radiation-Sensitizing Agents Antibiotics, Antineoplastic Antifungal Agents Anti-Bacterial Agents |
ClinicalTrials.gov processed this record on June 17, 2013