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-

50.

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.
However, the biggest of the developments is cracking now after the application of Lipoplatin as monotherapy with low-dose radiation. Lipoplatin will get approval as first-line in breast and prostate cancers, the other leading cancer indications to cause a seismic cataclysm of events in the pharmaceutical industry and oncology globally. The same regimen can be applied to the vast majority of human cancers bringing, as Akesios has predicted, a true revolution in cancer treatment and making Lipoplatin the top selling drug.
Regulon is in discussions with top CROs (Clinical Research Organizations) for conducting various clinical studies mainly in EU and USA for EMA and FDA approval. However, our strategy is to include in the same studies patients from China, Japan, Canada and potential other countries in order to achieve Marketing Authorization (MA) in all these countries and globally very soon or simultaneously with EMA-FDA approval. Regulon feels that the statistical difference between the arm using Lipoplatin-Radiation compared to the Arm using the recommended treatment will be to our favor and that the number of patients required will be ~400 per study rather than 1,000 making the studies cost effective. Lipoplatin could potentially get FDA and EMA approval from a randomized Phase II like Glivek did but in a big indication such as lung, breast, urinary bladder or prostate cancers.

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.

Lipoplatin monotherapy

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).

http://www.regulon.org/publications/Clinical/2012stath.pdf

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.
All 21 patients were evaluable for toxicity. Grade 1 myelotoxicity in two (9.52%) patients. Grade 1 nausea and vomiting in 4 (19.05%) patients. Grade 1 fatigue and peripheral neuropathy in 3 (14.29%) patients. No alopecia.
During the time of the drug infusion, temporary myalgia was observed in 5 patients, but it lasted for only 5-10 min.
Notably, no renal toxicity was detected, even after the 6th treatment course.
The monotherapy study shows significant response rate of Lipo/Nanoplatin in
NSCLC mostly applied as second- and third-line. A partial response of 38% with
43% SD as second-line chemotherapy is considered significant rarely seen with other drugs.
Because this is the best result in monotherapy among 1,000 FDA-approved drugs Lipoplatin monotherapy can be applied to lung cancer as first-line treatment

Monotherapy with Lipoplatin vs other drugs

Cisplatin monotherapy induces to patients much higher toxicities (Grade 3, 4) compared to 0% Grade 3, 4 after Lipoplatin treatment. In addition, cisplatin displays a much lower efficacy than Lipoplatin in monotherapy studies (11.1% for cisplatin vs 38.1% for Lipoplatin). These facts are summarized in the Table that follows. Cisplatin is considered to be the best drug or the “Queen of Chemotherapy” among approximately 1,000 oncology products approved by FDA and EMA. Cisplatin has also a very broad spectrum against the vast majority of human cancers of epithelial origin (About 80-90% of cancers are epithelial malignancies). The fact that Lipoplatin displays such a big difference in efficacy compared to cisplatin advocates for the value of this drug in cancer management.

of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol

18:122-130, 2000.

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
120 mg/m2 (D1). 5-FU weekly 400 mg/m2 (D1). Radiotherapy at 3.5-Gy fractions on
D2,3,4
4 of 5 patients had complete response after 5 weekly cycles (Koukourakis et al, 2010
Int J Radiation Oncology Biol Phys 78, 150-155).
This was the first clinical demonstration of a very high efficacy of the combination of Lipoplatin + RT. Although the study included 12 patients it is hoped to stimulate oncologists to apply this treatment in larger trials.
A similar study by the same group has been extended to NSCLC using Lipoplatin
monotherapy + RT with excellent efficacy and low toxicity.
A Ph.D. Thesis in Canada has shown that Lipoplatin has the best synergistic effect with radiation therapy in cell culture or in animals against glioblastomas (brain tumors) compared to other platinum drugs (cisplatin, oxaliplatin, carboplatin). The explanation is that Lipoplatin increases the intracellular uptake of the drug and the damage to the cell is much higher; then concomitant treatment with radiation enhances the damage to the point where the cancer cell is unable to repair and commits apoptotic death.
Application of Lipoplatin on Day 1 and Day 2 on cancer patients (to divide the dose and avoid side effects) and its combination with low-dose radiation therapy (1 Gy on Day 2) enhances 14 times the radiosensitizing potential of Lipoplatin as shown in preclinical studies in Canada. In these studies, Lipoplatin™ and other platinum drugs were tested on the F98 glioma cells for their ability to improve the cell uptake and increase the synergic effect when combined with ionizing radiation. Lipoplatin was shown to have the best radiosensitizing potential among all platinum compounds on F98 glioma cells. After 4 h exposure with platinum compounds, cells were irradiated (1.5 to 6.6 Gy) with a 60Co source. Lipoplatin compared to cisplatin improved the cell uptake by 3-fold because of its liposomal nature, and its radiosensitizing potential was enhanced by 14-fold (Charest et al, 2010).

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.
Lipoplatin could become the drug of choice for all three major human cancers (lung, breast, prostate) but also in a number of smaller cancer indications. Furthermore, because of low toxicity could find application against pediatric tumors. Its liposomal nature enhances penetration through the blood-brain barrier for brain and spinal cord tumors whereas targeting of the bone marrow by liposomes makes our drug an excellent candidate for childhood and adult leukemias.
In the image below, a 95% tumor reduction of a high-grade osteosarcoma was obtained when the patient was treated with dose-intense Lipoplatin monotherapy and fractionated radiation over a 25-week period. The patient had failed first and second- line chemotherapy. Our treatment was void of toxicities.

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
200 mg/m2 D1 every week for 12 weeks (3 months) with low-dose radiation therapy (2 Gy on Day 2, total dose 24 Gy in 12 weeks) enhances at least 5 times
the efficacy of Lipoplatin.
The total radiation dose administered in hospitals is 50 Gy usually given 2 Gy daily for 5 days per week and for 5 tandem weeks. The patient suffers from side effects caused by radiation. The proposed radiation dose of 24 Gy in Regulon’s protocol is without side effects because it is given over a period of 12 weeks instead of 5 weeks and is half of the recommended dose. The 24Gy over 12 weeks given in this schedule is sufficient to enhance the activity of platin already internalized by the cancer cells and enhance the killing effect of Lipoplatin in addition to the killing effect of radiation causing double strand breaks on the DNA.
This could become a universal protocol for all cancers.