Plitidepsin alone or with dacarbazine (DTIC) as first-line treatment for advanced unresectable melanoma (AUM) [JCO Abstract 9059]

Background: AUM remains incurable in most patients (pts). DTIC alone had a 8-15% response rate (RR), while plitidepsin (Aplidin [APL]) showed a 6% RR and a 14% stable disease (SD) in a Phase (Ph) II study in 35 relapsed/refractory pts after DTIC failure. Furthermore, APL + DTIC has additive activity in preclinical models. Methods: This multicenter Ph Ib study aim to determine the safe recommended dose (RD) of APL on days 1, 8 & 15 + DTIC only day 1 q4wk. RD was defined as the highest dose with >5 days G4 neutropenia or G4 thrombocytopenia (TC) and/or febrile neutropenia (FN); any drug-related ≥ G3 toxicity (except nausea/vomiting or hypersensitivity reaction) in cycle 1. Results: Of 28pts with AUM, 23 were evaluable for DLT; 57% were males, median (med) age was 48 y (20-77), med ECOG 0 (0-2) and med LDH was 226 IU/l (126-983). Most pts (96%) had metastasis with a median of 2 sites involved (1-5). Dose levels of APL + DICT (mg/m2), were: DL1 (1.8 + 800), 7 pts; DL2 (2.4 + 800), 8 pts; DL 2b (2.4 + 1000), 5 pts; DL3 (3.0 + 800), 8 pts. Pts received 4 (2-6), 2 (2-5), 2 (1-2), 2 (1-8) median cycles respectively. The number of DLTs were 1/6, 1/7, 2/4, 2/6, respectively. DLTs were G3 ALT in 4 pts and FN + TC in 1 pt. The MTD was at DL 2B and the RD was at DL 2. There were 3 partial responses (PR, 14%) and 4 SD > 3 months (19%); all PR at DL2/3. Five pts were not evaluable, 2 pts had G3 hypersensitivity reactions related to Cremophor oil (APL formulation) and 1 pt had a idiosyncratic reaction to DTIC with prolonged pancytopenia. One pt had a wrong diagnosis and 1 pt had early progressive disease (PD). Conclusions: APL + DTIC can be safely combined at ≥ 70% of their respective single- agent RD in AUM. Main DLTs were asymptomatic, transient and reversible ALT elevations. Ph Ib showed 14 % PR and 19% clinically meaningful SD. A randomised Ph II study of DTIC + APL vs APL alone is ongoing.