Clinical trial NCT01684449: Gemcitabine Plus Rapamycin Versus Gemcitabine to Treat Advanced Soft Tissue Sarcoma
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Advanced Soft Tissue Sarcoma
Keywords: Soft tissue sarcoma
Gemcitabine
Rapamycin
Sirolimus
mTOR inhibitor
Molecular biomarkers
Lead sponsor: Grupo Espanol de Investigacion en Sarcomas
Sponsor class: OTHER
First posted: 2012-09-13
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Phase 1: Determination of dosage: Security and toxicity of the combination gemcitabine and rapamycin.
timeFrame: 15 months
measure: Phase 2: Progression Free Survival
timeFrame: 12 months
Secondary outcomes:
measure: Phase 2: Overall Survival
timeFrame: 12 months
measure: Phase 2: Toxicity
timeFrame: 12 months
measure: Phase 1 and 2: Assessment of molecular biomarkers
timeFrame: 36 months
Other outcomes:
Locations:
city: Tenerife
country: Spain
facility: H. Universitario de Canarias
state: Santa Cruz de Tenerife
city: Barcelona
country: Spain
facility: H. Sant Pau
city: L'Hospitalet de Llobregat
country: Spain
facility: Institut Català d'Oncologia - Hospital Duran i Reynals
city: Madrid
country: Spain
facility: H. La Paz
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro
city: Mallorca
country: Spain
facility: H. Son Espases
city: Valencia
country: Spain
facility: Instituto Valenciano de Oncología
city: Zaragoza
country: Spain
facility: H. Universitario Miguel Servet
Study officials:
affiliation: GEIS
name: Xavier García del Muro Solans, MD
role: STUDY_CHAIR
References:
citation: Martin-Liberal J, Lopez-Pousa A, Martinez-Trufero J, Martin-Broto J, Cubedo R, Lavernia J, Redondo A, Lopez-Martin JA, Mulet-Margalef N, Sanjuan X, Tirado OM, Garcia-Del-Muro X. Phase II Study of Gemcitabine Plus Sirolimus in Previously Treated Patients with Advanced Soft-Tissue Sarcoma: a Spanish Group for Research on Sarcomas (GEIS) Study. Target Oncol. 2018 Feb;13(1):81-87. doi: 10.1007/s11523-017-0539-9.