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Clinical Trials completed Comparison to other drugs

Clinical development of Lipoplatin: Phase I

>130 patients

Phase I-II trial of Lipoplatin (dose escalation) and Gemcitabine as a second-line chemotherapy in patients with advanced pancreatic cancer (24 patients)
Stathopoulos et al, Oncol Rep 15, 1201-1204 (2006)
Partial response in 2/24 patients (8.3%), disease stability in 14 patients (58.3%) for a median duration of 3 months (range 2-7 months) and clinical benefit in 8 patients (33.3%).
Phase I trial of Lipoplatin (dose escalation) and Gemcitabine as a second-line chemotherapy in patients with non small cell lung carcinoma (13 patients)
Froudarakis et al, Cancer 113:2752-60 (2008)
The first dose escalation and pharmacokinetic study reported for the combination of Lipoplatin and gemcitabine in advanced NSCLC population. Based on the excellent tolerability observed, this regimen deserves further testing in phase 2 trials in patients with advanced NSCLC
Pharmacokinetics and adverse reactions of a new liposomal cisplatin (Lipoplatin): Phase I study (27 patients)
Stathopoulos et al, Oncol Rep, 13: 589-595 (2005)
The half-life of Lipoplatin was 60-117 h depending on the dose. Urine excretion reached about 40% of the infused dose in 3 days. The data demonstrate that Lipoplatin up to a dose of 125 mg/m2 every 14 days has no nephrotoxicity and it lacks the serious side effects of cisplatin.
Phase I study of Lipoplatin monotherapy: 350 mg/m2 DLT, MTD: 300 mg/m2
Phase I study of Lipoplatin + paclitaxel. DLT: 250 mg/m2 Lipoplatin; 175 mg/m2 paclitaxel.
MTD: 200 mg/m2 Lipoplatin; 175 mg/m2 paclitaxel (66 patients)
Stathopoulos et al, Liposomal cisplatin dose escalation for determining the maximum tolerated dose and dose-limiting toxicity: a phase I study. Anticancer Res. 30:1317-21 (2010).
It seems that the dose of lipoplatin can reach a level that is double or even higher than that of cisplatin without increasing the toxicity

Clinical development of Lipoplatin: Phase II

>334 patients

GI cancer 1st line
Dr. M. Koukourakis,
Univ. Hosp. of Alexandroupolis
Lipoplatin 120mg/m2 D1 plus 5FU 400mg/m2 D1 plus RT (4Gy D2,3 to the pelvis) weekly for 4 weeks against locally advanced GI adenocarcinoma COMPLETED (12 pts)
Int. J. Radiation Oncology Biol. Phys. 2010 Sep 1;78(1):150-5
Minimal nephrotoxicity (18.2% Grade 1) and neutropenia (9% Grade 3) was noted. Fatigue Grade 2 appeared in 25% of cases. Abdominal discomfort was reported by 18% of patients. No liver, kidney, gastric, or in- testinal severe acute or late sequellae were documented. The response rates assessed with computed tomography, endoscopy, and biopsies confirmed 33% (2 of 6) tumor disappearance in patients treated with four cycles, which reached 80% (4 of 5) in patients receiving five cycles.
BREAST 1st line
American Univ. Hosp. Beirut, Lebanon
Lipoplatin 120 mg/m2 D1, 8, 15 plus Vinorelbine 30 mg/m2 D1, 8
(HER2/neu-negative metastatic cancer) COMPLETED (35 pts)
Farhat et al 2011 A Phase II Study of Lipoplatin (Liposomal Cisplatin)/Vinorelbine Combination in HER-2/neu-Negative Metastatic Breast Cancer. Clin Breast Cancer 11:384-9
The results of this trial reveal that vinorelbine/lipoplatin is effective in treating patients with MBC. This regimen is well tolerated with no grade 3/4 nephrotoxicity or neuropathy. The investigation of this regimen as first-line treatment in metastatic breast cancer is warranted.
NSCLC 1st line
Multicenter
Lipoplatin 120mg/m2 D 1,8,15 plus Gemcitabine 1000mg/m2 D 1,8 (21 days cycle) vs cisplatin-gemcitabine COMPLETED (88 pts)
Mylonakis et al Lung Cancer. 2010 68:240-7.
Eighty-eight patients (n = 88) entered the study; 47 patients were treated with LipoGem (Arm A) versus 41 patients treated with CisGem (Arm B).
Overal Rsponse Rate (ORR) was 31.7% in arm A versus 25.6% in arm B and Disease Control Rate (DCR) was 70.7% versus 56.4%, respectively. A preliminary efficacy of LipoGem versus CisGem in the adenocarcinoma histological subtype of NSCLC showed 16.7% versus 45.8% Progressive Disease (PD). Treatment in arm A was better tolerated with myelotoxicity and a transient mild elevation of serum creatinine as the dominant side effects; the only grade 4 adverse event was neutropenia noted in 2% of the patients. There was a significant reduction in nephrotoxicity in the LipoGem arm (0% versus 5% grade III, p-value<0.001) as well as in nausea vomiting (2% versus 12% grade III, p-value < 0.001).
Urinary & NSCLC
Patients with renal insufficiency. It shows the safety and efficacy of Lipoplatin for treating this group
Stathopoulos et al 2012 Journal of Drug Delivery & Therapeutics;, 2: 106-109
Forty-two patients, (14 with non-small-cell lung cancer, 2 with squamous cell carcinoma non-small-cell lung cancer, 16 with bladder cancer and 10 gastrointestinal tract cancer), were included. The 16 patients with bladder cancer had renal insufficiency; 14 of these patients received lipoplatin and gemcitabine treatment as a first-line chemotherapy and 2 as second-line therapy. Out of the total number of 16 bladder cancer patients the percentage of Complete Response (CR) was 31.25%. The treatment caused no renal toxicity; there was no increase in blood urea and serum creatinine and in some patients there was a reduction in these levels. In 10/16 patients with bladder cancer, the blood urea and serum creatinine levels decreased, towards normal levels; this reduction was observed in these patients who had had a urination obstruction, which after treatment returned to normal.

Clinical development of Lipoplatin: Phase III

>438 patients

NSCLC 1st line Arm A: Lipoplatin 200mg/m2 D1 plus Paclitaxel 135mg/m2 D1 versus Arm B: Cisplatin 75mg/m2 D1 plus Paclitaxel 135mg/m2 D1 14 days cycle 9 cycles/PD COMPLETED (236 pts)
Stathopoulos et al 2010 Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial
Annals of Oncology, 21:2227-32
Arm A patients showed statistically significant lower nephrotoxicity, grade 3 and 4 leucopenia, grade 2 and 3 neuropathy, nausea, vomiting and fatigue. There was no significant difference in median and overall survival and TTP between the two arms; median survival was 9 and 10 months in arms A and B, respectively, and TTP was 6.5 and 6 months in arms A and B, respectively.
Liposomal cisplatin in combination with paclitaxel has been shown to be much less toxic than the original cisplatin combined with paclitaxel. Nephrotoxicity in particular was negligible after liposomal cisplatin administration. TTP and survival were similar in both treatment arms.
Non-squamous NSCLC 1st line Arm A: Lipoplatin 200mg/m2 D1 plus Paclitaxel 135mg/m2 D1 vs Arm B: Cisplatin 75mg/m2 D1 plus Paclitaxel 135mg/m2 D1 14 days cycle, 9 cycles/PD COMPLETED (202 pts)
Stathopoulos et al; 2011 Comparison of liposomal cisplatin versus cisplatin in non-squamous cell non-small-cell lung cancer
Cancer Chemother Pharmacol. 68:945–950
A partial response was achieved by 59.22% of Arm A patients versus 42.42% of Arm B, and the differ- ence was statistically significant (P 0.036). The median survival time in months was 10 for Arm A and 8 for Arm B (P 0.1551). After 18 months, the number of surviving patients was double for Arm A versus Arm B.
The median follow-up time was 18 months. The study ended in February 2010; by the end of the trial, there were 32 patients alive, 21 from Arm A (28.39%) and 11 from Arm B (11.11%).
The median survival time for Arm A patients was 10 months (CI 95% 6.6–13.4) and for Arm B, 8 months (95% CI 5.4–10.6)
Adverse reactions were mainly observed in Arm B patients treated with cisplatin–paclitaxel. In both arms, peripheral neuropathy was observed; it was more common in Arm B, but not significant.

Lipoplatin Monotherapy plus low-dose Radiation: The future in cancer therapy

CR, Complete Response; PR, Partial Response; SD, Stable Disease; PD, Progressive Disease. Out of the 21 patients treated, 2 were chemonaive (1st line), 10 received Lipoplatin as second-line and 9 as third-line treatment.
This Table shows that Lipoplatin is 3.5 times more effective than cisplatin (38% vs 11% Partial Response). A higher PR is expected when Lipoplatin is applied as 1st line. When combined with low-dose radiation then the radiosensitizing activity of Lipoplatin vs cisplatin is anticipated to be 14-times higher, or ~50 times (14x3.5) higher in efficacy.
After demonstration that Lipoplatin has negligible toxicity, Regulon is applying Lipoplatin monotherapy (200 mg/m2 every week plus low-dose radiation, 2 Gy, on the following day as a universal protocol for cancer treatment. According to this protocol the liposome nanoparticles target the tumor and metastases by preferential extravasation whereas the subsequent radiation results in a over 10-fold destruction of tumors by the platinum atom absorbing the radiation energy. All cancer cases thus tested show an astounding efficacy and absence of side effects.
Regulon estimates 75 million Euros to finish its clinical trials on Lipoplatin monotherapy plus radiation in NSCLC, pancreatic, breast, prostate, gastric, glioblastomas and several other cancers and on second-generation Lipoplatin nanoparticles leading to Marketing Authorization in EU, USA and ROW.

Monotherapy with Lipoplatin vs other drugs

Lipoplatin in NSCLC (2nd and 3rd-line) PR 38% SD 43% PD 19% Grade 1 myelotoxicity, 9.5% Grade 1 nausea and vomiting, 19% Grade 1 fatigue and peripheral neuropathy, 14% temporary myalgia, 24% Renal toxicity, 0% Neuropathy, 0% Stathopoulos et al. Oncol Lett. 2012 4:1013-1016.
Cisplatin in NSCLC (1st line) PR 11% median survival 7.6 months; One-year survival 28%; Grades ¾: Nausea and vomiting 21% and 19%; renal 2%; neurotoxicity 8.6% Sandler et al, 2000 J Clin Oncol 18:122-130.
Oxaliplatin in colorectal PR 10% as 2nd-line PR 18% -24% as 1st –line First-line Grade 3 neuropathy in 13% Grade 3 neutropenia in 5.2% Grade 3 thrombopenia in 7.9% Grade 3/4 vomiting in 7.9% Grade 3 diarrhea in 2.6% Becouarn and Rougier 1998 Semin Oncol. 25: 23-31. Bécouarn et al 1998 J Clin Oncol. 1998 16: 2739-44.
SPI-077 in NSCLC (liposomal cisplatin of SEQUUS/ALZA/J&J) PR 4.5% Grade 1,2 anemia 81% Grade 1,2 nausea 38% Grade 3,4 nausea 7.7% Grade 3 itching 3.8% Grade 1,2 rash 15.3% White et al, 2006 Br J Cancer 95, 822-828
Avastin in ovarian cancer PR 16% Grade 3 to 4: hypertension (9.1%), proteinuria (15.9%), GI perforations (11.4%), arterial thromboembolic events (6.8%), deaths (6.8%), bleeding (2.3%), wound-healing complications (2.3%) Cannistra et al, J Clin Oncol. 2007 25:5180-6
Kyprolis (Onyx) for multiple myeloma (Carfilzomib is a modified tetrapeptidyl epoxide) PR 18% Grade 3 and 4 (Serious) adverse reactions: 45%. Fatigue, 56%; Anemia 47%; Nausea, 45%; Thrombocytopenia, 36%; Dyspnea, 35%; Diarrhea 33%; Pneumonia, 10%; Acute renal failure, 4%; Congestive heart failure, 3% Zangari et al 2011 Eur J Haematol. 86:484-7.

Monotherapy with Lipoplatin vs Cisplatin

Toxicities and response Cisplatin monotherapy Lipoplatin monotherapy
Grades 3/4 hematologic toxicities 0.8% 0%
Grades 3/4 Neutropenia and thrombocytopenia 4.5% and 3.6% 0%
Grades 3/4 Anemia (low hematocrit) 6.5% 0%
Grades 3/4 febrile neutropenia 0.8% 0%
Grades 3/4 Nausea and vomiting 21% and 19% 0%
Grades 3/4 renal toxicity 2% 0%
Grades 3/4 Neurotoxicity 8.6% 0%
Overall response rate 11.1% 38.1%
Publications Sandler AB, Nemunaitis J, Denham C, et al: Phase III trial 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.

SPI-077 vs. Lipoplatin

Lipoplatin’s talents: Competition to antiangiogenesis drugs (Avastin)

Antiangiogenesis properties. Lipoplatin nanoparticles are endowed with antiangiogenesis properties.
The antiangiogenesis property of Lipoplatin has been suggested from the encapsulation of the beta-galactosidase gene into a liposome of the same composition as the Lipoplatin liposome; after systemic delivery to SCID mice with human tumors (Figure) the foreign “blue” gene stained preferentially the vasculature that the tumors developed under the skin of the animals to supply the tumor with blood and nutrients. This shows that Regulon’s liposomes can target preferentially the vascular endothelial cells; in case of Lipoplatin, targeting of these cells with toxic cisplatin instead of the “blue” gene would cause their destruction. Thus, Lipoplatin limits tumor vascularization by attacking their endothelial cells in addition to the known property of cisplatin to attack the epithelial cells of the tumor.