Clinical development of Lipoplatin
A drug needs to go through Phase I, Phase II and Phase III clinical studies for its registration. Lipoplatin has successfully completed Phase I studies where the maximum tolerated dose as monotherapy and in combination with other anticancer (cytotoxic) drugs has been determined.
Four Phase I studies have been completed and published. Thus the Maximum
Tolerated Dose (MTD) and the Dose Limiting Toxicity (DLT) have been determined.
Nine phase II studies have demonstrated that Lipoplatin can be successfully applied in all human cancers tested: NSCLC, breast, pancreatic, urinary bladder, and gastrointestinal (GI) cancers.
Phase III Studies Planned and Completed.
Completed Phase III Studies
Lipoplatin has successfully completed two Phase III studies both in lung cancer. In a randomized Phase III in nonsquamous-NSCLC (50% of lung cancers) the partial response (PR, defined as shrinkage of all measurable tumors by more than 50%) for the Lipoplatin arm was 59% compared to 42% for the cisplatin arm and the difference was statistically significant (p=0.036). The same study also showed a tendency for a 2-month increase in Overall Survival (OS) in the Lipoplatin arm compared to the Cisplatin Arm that was not statistically significant because of the low sample of patients (100 in each arm). The same study showed a statistically-significant decrease in 3 toxicities by Lipoplatin when replacing cisplatin: leukopenia, asthenia and kidney toxicity.
Stathopoulos et al Comparison of liposomal cisplatin versus cisplatin in non- squamous cell non-small-cell lung cancer. Cancer Chemother Pharmacol. 2011 68:945-
Stathopoulos et al. Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial. Ann Oncol. 2010, 21:2227-32. Free PMC Article
Clinical trials in Phase I, Phase II and Phase III as well many preclinical studies took place in the last decade with important publications. During this period Regulon chased its dream to develop Lipoplatin™ as first-line treatment in a big cancer indication (lung cancer, number 1 cancer in Eastern Europe, Turkey, China, most Asian countries) in addition to the orphan drug status in pancreatic cancer. However, it has also tested successfully Lipoplatin against breast cancer, urinary bladder cancer, and in combinations of the drug with hyperthermia, photodynamic therapy and others.
Detailed Analysis of Phase III results
Superiority of Lipoplatin to cisplatin in response rate as first-line treatment against non-squamous non-small cell lung cancer (ns-NSCLC) from a randomized Phase III study
The introduction of cisplatin in 70s has revolutionized cancer chemotherapy, especially of epithelial malignancies, most notably, testicular cancer. Carcinomas of the head and neck, bladder, ovaries, testis, esophagus, and lung are the most common malignancies that are sensitive to cisplatin when combined with a second or third cytotoxic agent. Attempts to develop platinum compounds to reduce the side effects of cisplatin have resulted in the introduction of carboplatin and oxaliplatin. However, both 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; none of these has demonstrated superior efficacy to cisplatin in lung cancer. This study represents the first time a drug has improved on cisplatin’s response rate in non-squamous NSCLC, the largest subtype of lung cancers.
Dr. George Stathopoulos and his collaborators announced exciting data from a randomized Phase III study against non-squamous non-small cell lung cancer (ns- NSCLC) mainly representing adenocarcinomas of the lung using Lipoplatin™. The results of this trial were published in October 2011 in Cancer Chemother Pharmacol. Vol 68, pages 945-950 (Open access at http://www.springerlink.com/content/c2624362664404t5/). This study used Lipoplatin in combination with paclitaxel as first line treatment against ns-NSCLC and compared response rates and toxicities to a similar group of patients treated with cisplatin plus paclitaxel. This study has demonstrated an increase in tumor response rate in the Lipoplatin arm (59.22% of patients) versus the cisplatin arm (42.42%, of patients) that was statistically significant (p value = 0.036). Most major toxicities of cisplatin, especially nephrotoxicity were also reduced in the group of patients treated with Lipoplatin.
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 is being 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. Determining the gene expression profile of patients responsive to Lipoplatin is an important project; prediction of this group of patients from gene expression profiling in peripheral blood lymphocytes might result in fast track regulatory approvals by FDA and EMA.
The clinical development of Lipoplatin in adenocarcinomas establishes this drug as the most active platinum drug with significantly lower side effects.
Other Clinical Studies
Regulon has obtained the consent of EMA for a registrational Phase III study (~880 patients) with a Lipoplatin plus Alimta vs Cisplatin plus Alimta as first-line treatment of non-squamous NSCLC. This study has commenced in over 50 oncology centers across 10 EU countries, and is expected to recruit patients from USA centers of excellence as well as from oncology centers in Asian countries.
Dr. George Stathopoulos demonstrated that Lipoplatin monotherapy against adenocarcinomas of the lung can have very high efficacy (38% partial response,
43% stable disease) with only minimal (Grade I) toxicity applied as second-line chemotherapy (after failure of the recommended first-line treatment).
It is anticipated that the success of this treatment will be even higher when applied as first line.
A total of 21 patients (2 patients 1st-line, 10 as 2nd-line and 9 as 3rd-line) were treated in this study.
Monotherapy with Lipoplatin vs other drugs
of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol
Two consecutive days of treatment with liposomal cisplatin in non-small cell lung cancer. Oncol Lett.
2012, vol 5:1013-1016.
Lipoplatin Monotherapy with low-dose radiation
Clinical studies pioneered by Professor Koukourakis at the University Hospital of Alexandroupolis using fractions of radiation therapy (RT) in combination with Lipoplatin against gastric cancer patients have shown up to 80% complete response. Details of the study: Patients with locally advanced gastric cancer. Lipoplatin weekly
Charest et al (2010) Concomitant treatment of F98 glioma cells with new liposomal platinum compounds and ionizing radiation. J Neurooncol. 97: 187–193.
When a similar protocol is being applied to human cancer patients the efficacy of Lipoplatin is expected to increase by a factor of 14 by combining with low-dose radiation. Thus, the new treatment protocol is providing to the medical community a drug many times more efficacious than the queen of chemotherapy, cisplatin, and without side effects. This is bringing a true revolution in cancer treatment.
The images show PET/CT scans before (left) and after (right) Lipoplatin - radiation therapy in a patient with high-grade osteosarcoma. A significant lower metabolic activity of the mass can be seen consistent with approximately 95% response. Osteosarcoma, a bone cancer most
commonly seen in adolescents and young adults, is usually a high-grade malignancy treated with four “old” drugs, namely methotrexate, doxorubicin (Adriamycin), cisplatin, and ifosfamide that cause severe side effects. Unfortunately, the past 30 years have witnessed few, if any, survival improvements. Our treatment would offer a new regiment against osteosarcomas without side effects and an amazing efficacy.
Thus, when combined with external radiation to the tumors where the nanoparticles with their toxic payload have accumulated, the result is a much better efficacy unlike any other regimens in clinical practice. With this treatment, Lipoplatin monotherapy and low-dose radiation achieve spectacular results in the management of terminal cancer patients.
Regulon’s protocol and duration of treatment
Lipoplatin is already 3-4 times more efficient than cisplatin applied as monotherapy. Combination of Lipoplatin at 200 mg/m2 on D1,2 every 14 days or
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