PICASSO III: A Phase III, Placebo-Controlled Study of Doxorubicin With or Without Palifosfamide in Patients With Metastatic Soft Tissue Sarcoma

Abstract

Purpose Palifosfamide is the active metabolite of ifosfamide and does not require prodrug activation, thereby avoiding the generation of toxic metabolites. The PICASSO III trial compared doxorubicin plus palifosfamide with doxorubicin plus placebo in patients who had received no prior systemic therapy for metastatic soft tissue sarcoma. Patients and Methods Patients were randomly assigned 1:1 to receive doxorubicin 75 mg/m intravenously day 1 plus palifosfamide 150 mg/m/d intravenously days 1 to 3 or doxorubicin plus placebo once every 21 days for up to six cycles. The primary end point was progression-free survival (PFS) by independent radiologic review. Results In all, 447 patients were randomly assigned to receive doxorubicin plus palifosfamide (n = 226) or doxorubicin plus placebo (n = 221). Median PFS was 6.0 months for doxorubicin plus palifosfamide and 5.2 months for doxorubicin plus placebo (hazard ratio, 0.86; 95% CI, 0.68 to 1.08; P = .19). Median overall survival was 15.9 months for doxorubicin plus palifosfamide and 16.9 months for doxorubicin plus placebo (hazard ratio, 1.05; 95% CI, 0.79 to 1.39; P = .74). There was a higher incidence of grade 3 to 4 adverse events in the doxorubicin plus palifosfamide arm (63.6% v 50.9%) including a higher rate of febrile neutropenia (21.4% v 12.6%). Conclusion No significant difference in PFS was observed in patients receiving doxorubicin plus palifosfamide compared with those receiving doxorubicin plus placebo. The observed median PFS and overall survival in this large, international study can serve as a benchmark for future studies of doxorubicin in metastatic soft tissue sarcoma.

Local Cancer Recurrence: The Realities, Challenges, and Opportunities for New Therapies

“…In borderline resectable recurrences, neoadjuvant chemotherapy or radiotherapy may be used in an attempt to downsize the recurrent tumor . However, there is no defined role of chemotherapy for locally recurrent disease, and numerous trials have demonstrated no survival benefit for doxorubin‐based or second‐line regimens. Immunotherapy studies, including vaccines, checkpoint inhibitors, and adoptive T‐cell therapy, are under early‐stage investigation …”

GeDDiS: insight into frontline therapy in soft tissue sarcoma

“…On one hand, everolimus was associated with a reduction in the risk of progression in patients with advanced lung or gastrointestinal NETs. 4 This benefit was noted in all subgroups, with the exception of 71 patients with ileal NETs, 8 probably because these patients have less aggressive disease. 9 On the other hand, and as with almost all effective drugs, everolimus causes side-effects: twice as many adverse events were reported with everolimus than with placebo (grade 3-4, 140 [69%] of 205 vs 28 [29%] of 97), and more dose reductions or temporary treatment interruptions were noted (135 [67%] of 202 vs 29 [30%] of 98).…”

“…For example, miR-193a-3p EDV minicells have been identified as apoptosis inducers via MCL1 silencing, with evidence of growth inhibition in mesothelioma xenografts. 4 In the past few years, the range of promising molecular targets being investigated in mesothelioma-including gen etic or epigenetically stratified synthetic lethal approaches, 7,8 PD-1-targeted immune checkpoint blockade, 9 and mesothelin-directed antibody-directed conjugate therapy 10 -has expanded rapidly. miR-16 targomiRs can be added to this growing list, each member of which has the potential to improve outcomes and transform a setting of unmet clinical need.…”

“…6 Recently, several phase 3 studies have provided substantial insight into the use of anthracyclines and alkylators as first-line treatments for patients with advanced sarcoma. [7][8][9] The GeDDiS 6 trial iis the first to shed comparative light on the efficacy of gemcitabine and docetaxel versus doxorubicin alone in this setting. The primary endpoint of the trial-progression-free survival at 24 weeks-did not differ between the two treatment groups (46·3% [95% CI 37·5-54·6] in the doxorubicin group vs 46·4% [37·5-54·8] in the gemcitabine and docetaxel group).…”

Making the Best of Available Options for Optimal Sarcoma Treatment

“…1) [12], differences in the histological profiles of patient populations in phase II and subsequent confirmatory clinical trials can lead to inconclusive results. Indeed, histological variation is thought to explain in part the absence of efficacy confirmation in phase III studies of doxorubicin ± palifosfamide (an active metabolite of ifosfamide) [13], and doxorubicin ± evofosfamide (a hypoxia-activated prodrug of ifosfamide) [14], after positive results had been demonstrated in phase II studies.…”