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Gemcitabine Plus Rapamycin Versus Gemcitabine to Treat Advanced Soft Tissue Sarcoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01684449
Recruitment Status : Completed
First Posted : September 13, 2012
Last Update Posted : October 27, 2015
Information provided by (Responsible Party):
Grupo Espanol de Investigacion en Sarcomas

Brief Summary:

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 or disease Intervention/treatment Phase
Advanced Soft Tissue Sarcoma Drug: Gemcitabine + Rapamycin Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 28 participants
Intervention Model: Single Group Assignment
Masking: None (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
Study Start Date : January 2010
Actual Primary Completion Date : May 2013
Actual Study Completion Date : December 2013

Arm Intervention/treatment
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.

Primary Outcome Measures :
  1. Phase 1: Determination of dosage: Security and toxicity of the combination gemcitabine and rapamycin. [ Time Frame: 15 months ]
    Type, frequency, seriousness and relation with the treatment of the adverse events in patients treated with the investigational medicinal products.

  2. Phase 2: Progression Free Survival [ Time Frame: 12 months ]
    Progression free survival rate at 3 months to compare the effectiveness of the the treatment.

Secondary Outcome Measures :
  1. Phase 2: Overall Survival [ Time Frame: 12 months ]
    Overall survival rate of the patients included in the experimental arm.

  2. Phase 2: Toxicity [ Time Frame: 12 months ]
    Tolerance to the drugs combination of the patients treated with gemcitabine + sirolimus

  3. Phase 1 and 2: Assessment of molecular biomarkers [ Time Frame: 36 months ]
    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.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. 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.
  2. 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.
  3. Age ≥ 18 y ≤ 70 years.
  4. ECOG performance status: 0 - 1. In Phase 1 only patients with ECOG 0-1 will be enrolled.
  5. Disease measurable according to RECIST criteria. Proven relapsed disease.
  6. Adequate bone marrow function, defined as neutrophil count ≥ 1.500/mm^3 and platelets ≥ 100.000/mm^3.
  7. 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).
  8. Informed consent form signed by the patient prior to the beginning of the treatment.

Exclusion Criteria:

  1. History of previous cancer diagnosed or treated in the past 5 years except basal cell carcinoma, cervical carcinoma in situ or superficial bladder cancer.
  2. Presence of brain metastases.
  3. Active infection or other severe concomitant diseases.
  4. Concurrent treatment with other experimental drugs within 30 days prior to study entry.
  5. Pregnancy or breastfeeding.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01684449

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H. Universitario de Canarias
Tenerife, Santa Cruz de Tenerife, Spain, 38320
H. Sant Pau
Barcelona, Spain, 08024
Institut Català d'Oncologia - Hospital Duran i Reynals
L'Hospitalet de Llobregat, Spain
H. La Paz
Madrid, Spain
Hospital Universitario 12 de Octubre
Madrid, Spain
Hospital Universitario Puerta de Hierro
Majadahonda, Spain
H. Son Espases
Mallorca, Spain
Instituto Valenciano de Oncología
Valencia, Spain
H. Universitario Miguel Servet
Zaragoza, Spain, 50009
Sponsors and Collaborators
Grupo Espanol de Investigacion en Sarcomas
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Study Chair: Xavier García del Muro Solans, MD GEIS

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Grupo Espanol de Investigacion en Sarcomas Identifier: NCT01684449    
Other Study ID Numbers: GEIS-24
2009-017232-41 ( EudraCT Number )
First Posted: September 13, 2012    Key Record Dates
Last Update Posted: October 27, 2015
Last Verified: October 2015
Keywords provided by Grupo Espanol de Investigacion en Sarcomas:
Soft tissue sarcoma
mTOR inhibitor
Molecular biomarkers
Additional relevant MeSH terms:
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Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Antibiotics, Antineoplastic
Antifungal Agents