Abstract C209: Strong synergistic activity of NKTR-102-pegylated liposomal doxorubicin (PLD) combination therapy in a nonclinical model of platinum-resistant A2780 human ovarian cancer.

Purpose: NKTR-102, a next generation topoisomerase I inhibitor, has been demonstrated to be superior to cisplatin, carboplatin and irinotecan in a mouse model of platinum-resistant A2780 Human Ovarian Cancer (Abstract 8015, ECCO 15-ESMO 34, 22 SEP 09). NKTR-102 as a single agent in women with platinum resistant/refractory ovarian cancer who have failed pegylated liposomal doxorubicin (PLD) therapy has demonstrated a confirmed ORR of 20% (RECIST, n = 30) to 36% (CGIC, n = 33) (JCO Vol 29, No 15_suppl, 2011: 5047). As a single agent, NKTR-102 appears highly active in the defined population; however, we hypothesize that the combination of NKTR-102 and PLD could result in synergistic activity through concurrent, long lasting inhibition of Topo I by NKTR-102 and Topo II by PLD, resulting in greater efficacy than observed as sequential single agents. This report is a presentation of the results of a study of NKTR-102 as a single agent, PLD as a single agent, and a combination of NKTR-102 and PLD in mice bearing A2780 Human Ovarian tumors that are minimally responsive to cisplatin. Methods: The MTD of PLD in mice was determined to be 10 mg/kg q7d×2 in a pilot study. NKTR-102 doses were limited to 150 mg/kg due to viscosity and dose volume limitations rather than tolerability. Mice bearing A2780 ovarian tumors (∼ 100 mm3) received either vehicle, PLD, NKTR-102, or a combination of NKTR-102 and PLD as follows: 5 or 10 mg/kg PLD on days 1 and 8; 100 or 150 mg/kg NKTR-102 on day 1; or 5/100, 10/100, 5/150, or 10/150 mg/kg PLD on days 1 and 8/NKTR-102 on day 1 (n = 10/treatment). Anti-tumor efficacy was evaluated based on tumor growth delay (TGD) and response rate. Results: Control tumors grew rapidly and uniformly to the 2000 mm3 endpoint in a median of 12 days. PLD administered at 5 and 10 mg/kg q7d×2 resulted in TGD of 7 and 24 days, respectively, with one partial response at the highest dose. Tumor growth was slower following PLD, but was continuous in all animals. NKTR-102 at single doses of 100 and 150 mg/kg resulted in TGDs of 32 and 38 days, respectively, with 100% (10 of 10) complete responses in each group. Following complete tumor regression in all animals, growth resumed after approximately 25 and 35 days in the 100 and 150 mg/kg treatment groups, respectively. TGD was 57 days (maximum possible value; 474% TGD) following any combination of NKTR-102 and PLD and all mice achieved complete response. There was no tumor regrowth within the 69-day observation period in 37 of 40 animals (93%). There was no accentuated weight loss in any dose group, indicating that the combination treatments were tolerated as well as single agent PLD. Conclusions: NKTR-102 as a single agent shows superior activity compared to PLD as a single agent in the A2780 ovarian tumor model, with a 100% complete response rate at all doses. NKTR-102 and PLD in combination showed marked synergism demonstrated by complete response in all animals with no tumor regrowth in 93%. Nektar intends to conduct a Phase I study of NKTR-102 with PLD in patients with advanced/metastatic refractory solid tumors, including those with platinum-resistant ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C209.