First line therapy with aldoxorubicin and 14 days continuous infusion of ifosfamide/mesna in metastatic or locally advanced sarcomas: a phase I-II study

Abstract

Background: Aldoxorubicin (A) has demonstrated superior anti‐tumor efficacy and lack of cumulative cardiac toxicity in multiple studies. A is doxorubicin (D) with a linker which rapidly binds in vivo to albumin after iv administration. We studied the combination of A administered on Day 1 with continuous infusion (CI) of ifosfamide/ Mesna (I‐M) Da ys 1‐14, in patients with sarcomas to evaluate efficacy and toxicity. Methods: 27 patients entered the study at one of 2 dose levels of A:170 or 250 mg/m2 (125 or 185 mg/m2 D equiv) administered on Day 1. I‐M (1 g/m2 of each per Da y) was given up to 14 Da ys as a CI via an out‐patient portable pump. Chemotherapy cycles were repeated at 28 Da y interval. I‐M was limited to a maximum of 6 cycles to avoid cumulative marrow toxicity, but A was continued in responding patients for clinical benefit. Subjects were followed for tumor response by CT scans and echocardiogram for cardiac toxicity every 8 weeks along with standard labs. Results: Of the 27 patients enrolled as of May 1, 2016, the results of 24 evaluable patients are presented here. Twenty of the 24 patients had soft tissue sarcoma, 2 had metastatic osteosarcoma and 2 had dedifferentiated chondrosarcoma. Eight of 24 patients (33%) had a partial response (PR), 15/24 (62%) had stable disease (SD) and only 1/24 (5%) had progressive disease with over all disease control rate of 95% (PR + SD). Eleven of 24 (46%) patients had received at least 6 cycles of A (cumulative D equivalent more than 1000 mg/m2). Four patients were considered surgically resectable after 6 cycles of chemotherapy with percent of tumor necrosis of 95% and 90% in one patient each and 80% in two patients. Median duration of PFS was 6+ (2‐19+) months. The most prevalent toxicity was gr 3 or 4 neutropenia. Four patients had SAEs of febrile neutropenia. There was no clinical cardiac toxicity/ congestive heart failure. No patient had LVEF < 50% on echocardiograms at any time. Conclusions: The combination of A + I‐M appears to be superior in anti‐tumor efficacy to D/I‐M with durable responses. A + I‐M combination is quite tolerable with expected reversible hematologic toxicity. Of the 46% patients who received more than 1000 mg /m2 of D equivalent; no cardiac toxicity was observed.