Soft-tissue sarcoma - Emerging treatments

Isolated limb perfusion/infusion

Isolated limb perfusion (ILP) and isolated limb infusion (ILI) may be considered for limb-sparing treatment for unresectable intermediate or high-grade extremity soft-tissue sarcoma (STS), and should only be done at institutions with experience in ILP/ILI.[11] ILP requires the use of tumour necrosis factor (TNF)-alpha along with chemotherapy, which is not approved in the US. ILI is a less invasive alternative to ILP for patients with unresectable STS of the extremities and can be used without TNF-alpha.[11] Evidence suggests that ILP with melphalan or doxorubicin in combination with TNF-alpha, or ILI with doxorubicin or melphalan and dactinomycin may be effective in the treatment of patients with unresectable STS of extremity, but further trials are needed to identify optimal treatment regimens.[77][78][79][80][81]

Aldoxorubicin

Aldoxorubicin is an investigational chemotherapeutic agent which consists of doxorubicin bound to albumin through a linker. In a phase 2b randomised trial of patients with advanced soft-tissue sarcoma, aldoxorubicin significantly improved median progression-free survival compared with doxorubicin (5.6 vs. 2.7 months, respectively).[82] Severe neutropenia was more common with aldoxorubicin, without increase in febrile neutropenia. Overall survival was not reported.[82] No phase 3 trial data have been published.

Idronoxil

An investigational new drug application for idronoxil, a first-in-class sphingosine-1-phosphate (S1P) inhibitor, in combination with doxorubicin, has been granted orphan drug designation by the US Food and Drug Administration (FDA). A phase 1, open-label dose escalation study of idronoxil given rectally (with concomitant doxorubicin) is under way in patients with metastatic soft-tissue sarcoma.[83]

Devimistat

Devimistat, an investigational anti-mitochondrial drug, has been granted orphan drug designation by the FDA for the treatment of clear cell soft-tissue sarcoma. Recruitment for athe phase 1 trial is under way.[84]

Annamycin

The FDA has granted fast track designation and orphan drug designation to annamycin, an investigational next-generation anthracycline, for the treatment of soft-tissue sarcoma lung metastases. Recruitment for a phase 1 trial is under way.[85]

Sotigalimab

Sotigalimab, an investigational first-in-class CD40 agonist, has received orphan drug designation from the FDA for the treatment of soft-tissue sarcoma. In an ongoing phase 2 clinical trial, sotigalimab is being evaluated in advanced soft-tissue sarcoma in combination with doxorubicin.[86]

Combination chemotherapy

Vincristine plus irinotecan in combination with temozolomide may be considered as second line treatment for rhabdomyosarcoma.[11] A randomised phase 2 study found that the addition of temozolomide to vincristine and irinotecan improved chemotherapy efficacy for patients with relapsed or refractory rhabdomyosarcoma.[87] In a phase 2 clinical trial, 90 patients were randomised to receive pazopanib (an oral multikinase inhibitor) with gemcitabine or pazopanib alone. The addition of gemcitabine to pazopanib resulted in a significantly higher progression-free survival rate at 12 weeks compared with pazopanib.[88]