The clinical development of Lipoplatin started in 2001. Human studies have shown a different pharmacokinetic and biodistribution profile to that of cisplatin with serum longevity, a prelude to the extravasation and tumor invasion process by Lipoplatin nanoparticles.Total platinum levels in plasma were dose-dependent and a half-life of 40-120 h was estimated for total platinum in sera of patients compared to 6h for cisplatin. Its urine excretion was also much slower and about 40% of the dose was excreted in the urine in 3 days compared again to ~8h for 50% excretion for cisplatin. Additional studies on patients who underwent Lipoplatin infusion followed by prescheduled surgery have demonstrated a 10- to 200-fold higher accumulation in primary tumors and in metastases compared to the adjacent normal tissue. These are exciting results establishing Lipoplatin and Regulon’s liposome technology as a means to achieve high targeting. Even micrometastases, invisible in chest x-rays or CT scans, were proposed to be targeted by Lipoplatin because of the microvasculature sprouting in progress. The nanoparticle drug was inferred to target endothelial cells in tumor vasculature and its antioangiogenesis potential was proposed in addition to the classical chemotherapy activity.

Overall, Lipoplatin has proven to be a safe drug, the main toxicity being myelotoxicity. A Phase I study, where Lipoplatin was used as monotherapy, failed to reach the MTD. When used in combination with Gemcitabine, the dose of 120 mg/m2 was defined as MTD; higher doses were associated with increased myelotoxicity. A subsequent Phase I study determined the DLT for Lipoplatin monotherapy at 350 mg/m2 and the MTD at 300 mg/m2. For Lipoplatin-paclitaxel combination therapy, the DLT was 250 mg/m2for Lipoplatin and 175 mg/m2 for paclitaxel whereas the MTD was 200 mg/m2 for Lipoplatin and 175 mg/m2 for paclitaxel (Stathopoulos et al, 2010, Anticancer Res 30, 1317-1322).

In a Phase II randomized comparative study on the efficacy and toxicity of 120 mg/m2 D1,8,15 Lipoplatin in combination with 1,000 mg/m2 gemcitabine D1,8 compared to 100 mg/m2 cisplatin D1 with same schedule of gemcitabine as first-line against NSCLC there were statistically significant less toxicities in the Lipoplatin arm and a better efficacy profile, especially in the non-squamous histological subtype. This schedule was promoted into a randomized Phase III study and an interim report  showed statistically significant reduction in nephrotoxicity, asthenia, and neurotoxicity  and enhanced efficacy in NSCLC adenocarcinoma.

The results of a different randomized comparative Phase III study on the efficacy and toxicity of Lipoplatin 200 mg/m2 D1 in combination with paclitaxel 135 mg/m2 D1 in a 14-day schedule compared to cisplatin 75 mg/m2 D1 with paclitaxel 135 mg/m2 D1 as first-line against NSCLC were reported with 114 and 115 patients in each arm. The study  (see 9.12) demonstrated a statistically significant reduction in nephrotoxicity (6.1% vs 40%), and also a reduction of most other adverse effects including anemia, neutropenia and asthenia. The efficacy results established the noninferiority of Lipoplatin compared to cisplatin.

In a Phase II trial the toxicity and efficacy of Lipoplatin 120 mg/m2 D1,8,15 in combination with vinorelbine 30 mg/m2 D1,8 against breast cancer was studied. Of the 35 patients, 15 had previously received neoadjuvant treatment based on anthracyclines, 11 treatment with taxanes and 6 patients with both.  The objective response rate was 53.1% and the median survival time was 22 months. Grade 3/4 neutropenia was observed in 44% of cycles, and febrile neutropenia was seen in 4 patients (11.4%). No grade 3/4 nephrotoxicity or neuropathy was noted. This combination was effective and well tolerated in patients with MBC. The authors proposed this scheme as first-line treatment.

In a Phase II study on the efficacy and toxicity of Lipoplatin in combination with 5-fluorodeoxyuridine and radiation therapy against advanced gastric tumors 4 out of 5 patients (80%) receiving five weekly cycles of treatment achieved complete response and in a follow up of nine months (Koukourakis et al, 2009). The high response rate observed in this Phase II study is suggested to arise from the high vascularization of gastric tumors compared to other solid tumors thus resulting in high Lipoplatin concentration (similar data were also observed in the patient tumor targeting study) and from rupture of the nanoparticles by the process of radiation therapy (see Mechanism of Action). Thus, radiation therapy might be proven the most efficacious combination for Lipoplatin.

Phase II studies are continuing in advanced breast cancer with vinorelbine and gastrointestinal cancers with radiotherapy and 5-fluorouracil.

A registrational Phase II/III study against pancreatic cancer is in progress under the orphan drug status granted to Lipoplatin by the European Medicines Agency. The Company has received scientific advice by EMEA for a pivotal randomized Phase III study using Lipoplatin 200 mg/m2 D1,8 in combination with pemetrexed as first line in non-squamous NSCLC compared to cisplatin with pemetrexed.

Lipoplatin has successfully completed a Phase III trial for non-small cell lung cancer (NSCLC) (Stathopoulos et al, 2010).

In a publication in Cancer Chemother Pharmacol, (Stathopoulos et al, 2011), exciting data were announced from a randomized Phase III study on Lipoplatin™ in the treatment of non-squamous non-small cell lung cancer (NSCLC). This study used Lipoplatin in combination with paclitaxel as first line treatment against non-squamous NSCLC and compared response rates and toxicities to a similar group of patients treated with cisplatin plus paclitaxel. This study has demonstrated statistically significant (p value = 0.036) increase in tumor response rate in the Lipoplatin arm (59.22% of patients) versus the cisplatin arm (42.42%, of patients) while also reducing most major toxicities of cisplatin, especially nephrotoxicity.

Attempts to develop platinum compounds to reduce the side effects of cisplatin have resulted in the introduction of carboplatin and oxaliplatin. However, both of these drugs have proven to have inferior response rates to cisplatin especially in lung cancer. Other cytotoxic agents such as taxanes (paclitaxel, docetaxel), gemcitabine, vinorelbine, pemetrexed, and irinotecan have also been used as substitutes of cisplatin; however, none of these agents has demonstrated superior efficacy to cisplatin in lung cancer. This Lipoplatin study represents the first time a drug has improved on cisplatin’s response rate in non-squamous NSCLC.

Median survival times were 10 months for the Lipoplatin arm and 8 months for the cisplatin arm, with a p-value of 0.155. The median duration of response was 7 months for the Lipoplatin arm and 6 months for the cisplatin arm. Although not statistically significant, these results suggest the potential for superior overall survival (OS) for Lipoplatin compared to cisplatin, a hypothesis that will be tested in a larger trial. Furthermore, among the responders to Lipoplatin a subgroup of patients demonstrated a substantially higher overall survival than a comparable subgroup of cisplatin responders. After 10 months, 30% of patients in the Lipoplatin arm, as compared with just 16% of patients in the cisplatin arm, were without disease progression. By the end of the trial, there were 32 patients alive, 21 from the Lipoplatin arm (20.39%) and 11 from the cisplatin arm (11.11%). Thus, after 18 months, the number of surviving patients was approximately double for Lipoplatin versus cisplatin.

The clinical development of Lipoplatin in adenocarcinomas establishes this drug as the most active platinum drug with significantly lower side effects.

Regulon has obtained the consent of EMA for a registrational Phase III study (884 patients) with a Lipoplatin plus pemetrexed vs Cisplatin plus pemetrexed as first-line treatment of non-squamous NSCLC. This study is expected to commence in over 80 oncology centers across 10 EU countries, as well as including patients from the USA and Asia.

In conclusion, the clinical data support replacement of cisplatin by Lipoplatin. Lipoplatin has substantially reduced the renal toxicity, peripheral neuropathy, ototoxicity, myelotoxicity as well as nausea/vomiting and asthenia of cisplatin in Phase I, II and III clinical studies with enhanced or similar efficacy to cisplatin.


Important drug & healthcare information can be obtained by visiting: The LipoPlatin™ Website.

Regulon Inc. , Grigoriou Afxentiou 7, 17455, Alimos, Greece, Tel: +30 2109858453 , +30 2109858454