(P 183) A PHASE 1B/2 STUDY OF LIPOSOMAL ANNAMYCIN (ANN) IN SUBJECTS WITH PREVIOUSLY TREATED SOFT-TISSUE SARCOMAS (STS) WITH PULMONARY METASTASES

Objective: The most common site of STS metastases is the lungs. Doxorubicin (DOX) remains a mainstay for standard treatment, but clinical benefit is not prolonged and toxicities, especially cardiotoxicity, limit its use. L-Annamycin (“ANN” or “Annamycin”)” is a multilamellar liposomal formulation active against multidrug-resistant tumors and does not elicit cardiotoxicity. As preclinical studies documented ANN localizes in pulmonary tissues at higher concentrations than DOX, it is an ideal candidate to explore in subjects with lung metastases. The primary objective of the Phase 1b portion of the study was to evaluate safety and to identify the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). The primary objective of Phase 2 was to assess efficacy, including, but not limited to, overall response rate (ORR), ORR targeted to pulmonary metastases, disease control rate (DCR), and progression-free and overall survival (PFS and OS, respectively).

Methods: ANN was administered on Day 1, followed by 20 days off. Safety monitoring included ECHOs, ECGs, cardiac biomarkers, and laboratory evaluations. Treatment continued every 21 days until disease progression, clinical deterioration, or unacceptable toxicity. Efficacy was monitored radiographically every 6 weeks while on therapy, then every 3 months. In Phase 1b, dose escalation proceeded according to a 3 + 3 design. During Phase 2, up to 25 subjects were to be enrolled at the RP2D. Eligible subjects were ≥18 years of age with a confirmed diagnosis of STS, unresectable, measurable disease in the lung, progression on prior therapy, and no significant comorbidities. Subjects evaluable for efficacy were assessed for response to treatment by radiologic imaging.

Results: 19 subjects were enrolled in the Phase 1b portion of the study. The median number of cycles administered was 2. There were no significant safety concerns or unexpected SAEs up to the 390 mg/m2 dose. The RP2D was defined as 330 mg/m2. The most frequently reported AEs related to ANN were in the system organ class of Investigations (Table 1). There was no evidence of cardiotoxicity as measured by ejection fraction, strain analyses, ECGs, and cardiac biomarkers including Troponin-I and T. To date in Phase 2, 11 subjects (median # of prior therapies = 3) have received at least 2 cycles of 330 mg/m2. Of these 11 subjects, 7 (64%) showed stable disease (SD) through 2 cycles (5 of whom continued to show SD through 4 cycles), and 2 (18%) showed SD through 5 cycles. Of these 2, one subject has maintained SD through the end of 6 cycles with the next imaging assessment expected at the end of cycle 8 (5.5 months). The other subject has had SD through 5 cycles with the next imaging assessment expected at the end of cycle 6 (4.1 months). 5 subjects continue to be followed for PFS, and all 11 subjects in the efficacy population are being followed for OS.

Conclusion: This trial has established the RP2D dosing regimen of ANN as 330 mg/m2. Preliminary efficacy findings at the RP2D are encouraging with a DCR of 64% at the end of cycle 2 in this heavily pretreated population. To date, there has been no evidence of cardiotoxicity. This further supports that ANN may have significant advantages over currently approved anthracyclines for which effectiveness and duration of treatment are hampered due to cardiotoxic properties. This Phase 2 trial will continue to enroll and follow patients to better quantify efficacy.