TLD-1, a novel liposomal doxorubicin, in patients (pts) with advanced solid tumors: Dose escalation and expansion part of a multicenter open-label phase I trial (SAKK 65/16).

3027 Background: TLD-1 is a novel liposomal doxorubicin that compared favorably to conventional liposomal formulations of doxorubicin in preclinical in vivo mouse breast cancer models. This phase I first-in-human trial is aiming to determine the recommended phase II dose (RP2D), toxicity profile, pharmacokinetics and preliminary activity. Methods: Patients with a maximum of 3 prior lines of systemic chemotherapy and preferably anthracycline-sensitive disease were eligible. TLD-1 was administered on day 1 iv over 60-90 minutes (depending on individual dose) q 21 days, for up to 6 or 9 cycles (according to prior anthracycline-exposure) with premedication of 8mg dexamethasone. Dose escalation with dose levels (DL) 1-7 of 10, 16, 23, 30, 35, 40 and 45mg/m2 started with an accelerated titration design, treating one pt at each DL up to DL6 (40mg/m2) followed by a modified continual reassessment method at DL7 due to observed toxicity. Results: 30 pts (F:M = 24:6) have been treated, one each at DLs 1-6, 15 pts at DL7 and an additional 9 pts at DL6. Most frequent tumor types included breast (n = 13), ovarian (n = 6), cervical cancer (n = 2) and cholangiocarcinoma (n = 2). Median age was 67.5 years (range:38-83), 13 pts were exposed to prior anthracyclines. The median number of cycles was 4 (range:1-9). No dose-limiting toxicities (DLT) occurred during cycle 1. At DLs 1 to 5, no treatment-related G3 AEs (TRAE) were observed. At DL6, there was one case of mucositis G3, one of palmar-plantar-erythrodysesthesia (PPE) G3 and one of anemia and neutropenia G3 each. One patient with pre-existing valvular cardiopathy developed symptoms of heart-failure G3 after 8 cycles. Echocardiography showed severe mitral regurgitation with normal LV-EF. In addition one case of urinary-tract infection G3 was seen. Dose-modifications or -delays due to AEs occurred in 7/50 cycles. At DL7, one case of mucositis G3, 3 events of PPE G3 and one case of fatigue G3 were reported. In addition, one case of infection with shingles occurred. Dose-modifications or -delays due to AEs occurred in 12/61 cycles. Shingles and heart failure were reported as SAEs. All toxicities listed above were categorized as TRAE. 29/30 pts were evaluable for response. Three breast cancer pts had a partial response, 2 at DL7 and 1 at DL6, 14 pts had stable disease. Conclusions: No DLT was observed up to DL7. RP2D was defined at 40mg/m2 due to cumulative PPE G3 at DL7. The trial is ongoing with a comparative PK-part evaluating the two iv liposomal formulations of doxorubicin TLD-1 and Caelyx. Clinical trial information: NCT03387917.