Phase I dose escalation study of the PKCι inhibitor aurothiomalate for advanced non-small-cell lung cancer, ovarian cancer, and pancreatic cancer

Abstract

Objective Protein kinase C iota (PKCι) is overexpressed in non-small cell lung (NSCLC), ovarian and pancreatic cancers where it plays a critical role in oncogenesis. The gold compound aurothiomalate (ATM) has been shown to inhibit PKCι signaling and exhibits potent anti-tumor activity in preclinical models. We sought to determine the maximum tolerated dose (MTD) of ATM. Methods We conducted a phase I dose escalation trial of ATM in patients with NSCLC, ovarian or pancreatic cancer. Patients received ATM IM weekly for three cycles (cycle duration 4 weeks) at 25 mg, 50 mg or 75 mg in a 3+3 design. The dose was not escalated for individual patients. Blood samples were analyzed for elemental gold levels. Patients were evaluated every four weeks for toxicity and every eight weeks for response. Results Fifteen patients were enrolled in this study. Six patients were treated at 25 mg, 7 patients at 50 mg, and 2 at 75 mg. There was 1 dose limiting toxicity at 25 mg (hypokalemia), one at 50 mg (urinary tract infection), and none at 75 mg. There were 3 grade 3 hematologic toxicities. The recommended MTD of ATM is 50 mg. Patients received treatment for a median of 2 cycles (range 1-3). There appeared to be a dose-related accumulation of steady-state plasma concentrations of gold consistent with linear pharmacokinetics. Conclusions In summary, this phase I study was successful in identifying ATM 50 mg IM weekly as the MTD. Future clinical investigations targeting PKCι are currently in progress.

The protein kinase C (PKC) inhibitors combined with chemotherapy in the treatment of advanced non-small cell lung cancer: meta-analysis of randomized controlled trials

“…Thus, inhibition of specific isoenzymes of PKC may be a reasonable approach to achieve therapeutic benefit. Within the last decade, several small molecular weight inhibitors and antisense molecules have been developed, targeting the calcium-dependent classical isoforms of PKC, for the treatment of NSCLC, such as bryostatin I [6], UCN-01 [7,8], PKC412 [9], LY90003 [10], LY317615 [11], aurothiomalate (ATM) [12], and et al…”

Targeting protein kinase C in sarcoma

“…Trial discontinued due to severe myalgia in more than 50% of patients [119] ATM (aurothiomalate) Phase I trial in NSCLC, ovarian cancer and pancreatic cancer n = 15 Good tolerance [120] Translation inhibitors ISIS 3521 Phase I trial in advanced cancer (21-day infusion) n = 21 3 PR (ovarian cancer) 2 CR (lymphoma) 1 SD (NSCLC) [121] Phase I trial in advanced cancer (24-hour infusion) Not well tolerated [122] Phase II trial in low-grade non-Hodgkin's lymphoma n = 26 3 PR 10 SD [123] Phase II trial in colorectal cancer n = 16 No clinical activity [124,125] Phase II trial in high-grade astrocytomas n = 21 No clinical activity [124,125] Phase II trial in ovarian cancer n = 36 0 CR/PR 1 CA125 response [126] Phase I/II trial in combination with carboplatin and paclitaxel in NSCLC n = 53 Response rate 48% [127] Phase III trial in combination with gemcitabine in NSCLC n = 670 No clinical activity [128] Atu027…”

Targeting oncogenic protein kinase Cι for treatment of mutantKRASLADC

“…47 ANF is currently being evaluated clinically as an anti-tumor agent in lung and ovarian cancer patients. 48,49 These compounds are well tolerated in the oncology setting and exhibit promising therapeutic potential. 49 Though ATM and ANF exhibit efficacy as single agents in pre-clinical models, it is likely they will find optimal clinical use in strategic combination with other agents.…”

“…48,49 These compounds are well tolerated in the oncology setting and exhibit promising therapeutic potential. 49 Though ATM and ANF exhibit efficacy as single agents in pre-clinical models, it is likely they will find optimal clinical use in strategic combination with other agents. In this regard, we have demonstrated synergistic pre-clinical efficacy of ANF in combination with a SMO inhibition in LSCC.…”