A phase II study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcomas

Abstract

Background: Relapsed and refractory sarcomas continue to have poor survival rates. The cancer stem cell (CSC) theory provides a tractable explanation for the observation that recurrences occur despite dramatic responses to upfront chemotherapy. Preclinical studies demonstrated that inhibition of the mechanistic target of rapamycin (mTOR) sensitizes the CSC population to chemotherapy.

Methods: Here we present the results of the Phase II portion of a Phase I/II clinical trial that aimed to overcome the chemoresistance of sarcoma CSC by combining the mTOR inhibitor temsirolimus (20 mg/m2 weekly) with the chemotherapeutic agent liposomal doxorubicin (30 mg/m2 monthly).

Results: Fifteen patients with relapsed/refractory sarcoma were evaluable at this recommended Phase 2 dose level. The median progression free survival was 315 days (range 27-799). Response rate, defined as stable disease or better for 60 days, was 53%. Nine of the patients had been previously treated with doxorubicin. Therapy was well tolerated. In a small number of patients, pre- and post- treatment tumor biopsies were available for assessment of ALDH expression as a marker of CSCs and showed a correlation between response and decreased ALDH expression. We also found a correlation between biopsy-proven inhibition of mTOR and response.

Conclusions: Our study adds to the literature supporting the addition of mTOR inhibition to chemotherapy agents for the treatment of sarcomas, and proposes that a mechanism by which mTOR inhibition enhances the efficacy of chemotherapy may be through sensitizing the chemoresistant CSC population. Further study, ideally with pre- and post-therapy assessment of ALDH expression in tumor cells, is warranted.Trial registration The trial was registered on clinicaltrials.gov (NCT00949325) on 30 July 2009. http://www.editorialmanager.com/csrj/default.aspx.

Keywords: Aldehyde dehydrogenase; Cancer stem cell; Chemoresistance; Sarcoma; mTOR.

Figures

Fig. 1

a Event-Free Survival (EFS) and Progression-free Survival (PFS) of the 15 patients treated at the RP2D. A Kaplan–Meier curve indicating the time from beginning of treatment to withdrawal from study (EFS) or beginning of treatment to first objective evidence of disease progression by RECIST 1.1 criteria (PFS). b EFS and PFS of the 18 patients treated at the RP2D and the dose level above. A Kaplan–Meier curve indicating the time from beginning of treatment to withdrawal from study (EFS) or beginning of treatment to first objective evidence of disease progression by RECIST (PFS). c A waterfall plot of the best responses for the 15 patients treated at R2PD

Fig. 2

Progression-Free Survival of subjects who had previously received doxorubicin compared with the entire study population. A Kaplan–Meier curve indicating the PFS of the 11 subjects who had previously received doxorubicin compared with the PFS of the total population of subjects

Fig. 3

Spaghetti plot of patient weights during treatment. Each line represents an individual patient and the number of cycles of therapy is indicated on the Y axis

Fig. 4

Correlation between mTOR inhibition and response to therapy. Cells obtained from a core biopsy at week 4 were stained for either pS6K (a) or pAKT (b), and compared with staining from the diagnostic biopsy. Inhibition of phosphorylation was compared with response or nonresponse to treatment