Administration of aldoxorubicin and 14 days continuous infusion of ifosfamide/mesna in metastatic or locally advanced sarcomas.

Abstract

11051 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. We studied the combination of A administered on Day 1 with continuous infusion (CI) of ifosfamide/Mesna (I-M) days 1-14, as first line therapy or second line therapy in patients with soft tissue sarcomas (STS) to evaluate efficacy and toxicity. Methods: 27 patients have entered the study at 250 mg/m2 ( 185 mg/m2 D equiv) administered on Day 1. I-M (1 g/m2 of each per day) was given up to 14 days as a CI via an out-patient portable pump. Chemotherapy cycles were repeated at 28 day interval. I-M was limited to a maximum of 6 cycles to avoid cumulative marrow toxicity, but A was continued per investigator decision in responding or SD patients for clinical benefit. Subjects were followed for tumor response (RECIST 1.1) by CT scans and echocardiogram/ECG for cardiac toxicity every 8 weeks along with standard labs. Enrollment continues up to 50 patients. Results: Demographics: Leiomyosarc. = 20%, liposarc. = 20%, synovial sarc. = 20%, rhabdosarc. = 8%, others = 32%. Caucasian, 11% Asian, 4% Black; 67% no prior tx, 26% 1 prior tx, 7% > 1 prior tx; Median cum. A = 1000 mg/m2 (740 mg/m2 D eq.; 185-4070 mg/m2 D eq.); I = 6.9 g/m2 (2.1-12.6 g/m2). Best response: 42% PR, 58% SD. Median PFS not reached. 10 subjects with either PR or SD had surgery to remove accesible tumors. Range of tumor necrosis = 70 to > 95%. Grade 3/4 AEs: neutropenia = 78%, febrile neutropenia = 9%, thrombocytopenia = 22%, anemia = 65%, nausea = 4%. Related SAEs = 4 (febrile neutropenia (2), pyrexia, stomatitis). No tx related deaths. No clinically significant cardiac AEs, no decrease in LVEF > 20% Conclusions: A can be administered for prolonged periods and safely with CI ifosfamide/mesna and achieves high ORR and SD with substantial tumor necrosis. Clinical trial information: NCT02235701.

Aldoxorubicin: a tumor-targeted doxorubicin conjugate for relapsed or refractory soft tissue sarcomas

“…Aldoxorubicin has also demonstrated tolerability and activity in combination with other chemotherapy agents in STS; in one study, aldoxorubicin was combined with doxorubicin with no DLTs and additional cardiotoxicity observed. 35 , 36 …”

“…A separate open-label, Phase I study demonstrated that aldoxorubicin can also be administered safely with other chemotherapy agents commonly used in the treatment of STS. 35 Here, aldoxorubicin administered at 250 mg/m 2 on day 1 with continuous infusion of ifosfamide and mesna (1 g/m 2 each per day up to 14 days for a maximum of 6 28-day cycles) in 27 patients with STS in the first- or second-line settings showed promising ORR with the most common AE being myelosuppression ( Table 1 ). There were 10 patients with PR or SD who had subsequent surgery to remove accessible tumors.…”

<p>Spotlight on aldoxorubicin (INNO-206) and its potential in the treatment of soft tissue sarcomas: evidence to date</p>

“…In another Phase II study, sarcoma patients received therapy with ALDOX at 170 mg/m 2 (125 mg/m 2 DE; n=7) or 250 mg/m 2 (185 mg/m 2 DE; n=38) on day 1 and IFOS at 1 g/m 2 /day on days 1–14 of a 28-day cycle. 72 , 73 The combination was given up to six cycles, but ALDOX could continue thereafter as monotherapy. Prominent toxicities included myelosuppession, nausea/vomiting, stomatitis, and febrile neutropenia.…”

Doxorubicin/Adriamycin Monotherapy or Plus Ifosfamide in First-Line Treatment for Advanced Soft Tissue Sarcoma: A Pooled Analysis of Randomized Trials

“…A recently published report showed that the median progression-free survival (PFS) was, respectively, 8.2 months and 4.8 months with objective response rates (ORRs) of 19.5% and 25.6% for AI and ADM (7). Additionally, single-arm data have also indicated the feasibility and tolerability of AI (8)(9)(10)(11)(12)(13)(14)(15).…”