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Monotherapy combined with Low-Dose radiation

Rationale for Lipoplatin low-dose RT

Lipoplatin RT
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. Lipoplatin weekly 120 mg/m2 (D1). 5-FU weekly 400 mg/m2 (D1). Radiotherapy at 3.5-Gy fractions on Days 2,3,4.
RESULTS:
4 of 5 patients had complete response after 5 weekly cycles (Koukourakis et al, 2010 Int J Radiation Oncology Biol Phys 78, 150-155).
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 (Charest et al (2010) Concomitant treatment of F98 glioma cells with new liposomal platinum compounds and ionizing radiation. J Neurooncol. 97: 187–193).

Premedication

  • 250 mg Solu Cortef (Hydrocortisone Sodium Succinate). SOLU-CORTEF Sterile Powder is an anti-inflammatory glucocorticoid that contains hydrocortisone sodium succinate as the active ingredient.
  • Half an ampule of FENISTIL (5 mg) GlaxoSmithKline. Fenistil contains dimetindene maleate, an antihistamine/anticholinergic that is a selective H1 antagonist and is used as an antiallergic drug. Dimentidene is also administered orally to treat allergies, such as hay fever. Unlike first generation antihistamines, it causes only minimal drowsiness.
  • One ampule TAGAMET (CIMETIDINE - INJECTION) a histamine H2 receptor antagonist that inhibits stomach acid production. Cimetidine is used to treat ulcers of the stomach or intestines and to treat certain stomach and throat problems caused by high acidity or a backward flow of stomach acid into the esophagus.

Lipoplatin monotherapy low-dose RT

Lipoplatin monotherapy: A dose of 200 mg/m2 dose (approximately 2-3 vials of Lipoplatin 300-450 mg total in cisplatin) are diluted in 500 ml saline or 5% dextrose and infused iv with the help of a peristaltic pump over 4 h
No post or pre- or post-hydration is given to minimize loss of Lipoplatin through the urine.
The Lipoplatin treatment is given on Days 1 and 4 followed by low-dose radiation on the subsequent day (Days 2 and 5).
The treatment is repeated for 8 or more consecutive weeks.
Low-dose RT: A dose of 2 Gy against the major lesions (determined from the PET/CT) is given on the following day so that the nanoparticles have accumulated in the tumors and the low-dose radiation damages 14-fold more the tumor cell mass because of a radiosensitizing activity of Lipoplatin.

Highlights of clinical development of Lipoplatin

In a randomized Phase III in NSCLC, a statistically significant reduction of neutropenia, nephrotoxicity and asthenia of cisplatin was demonstrated by its replacement with Lipoplatin. 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
Also in a randomized Phase III in nonsquamous-NSCLC the partial response for the Lipoplatin arm was 59% compared to 42% for the cisplatin arm and the difference was statistically significant (p=0.036). 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.
Lipoplatin as monotherapy is showing astounding results in efficacy with absence of side effects
Cisplatin monotherapy: 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.
Lipoplatin monotherapy: Stathopoulos GP, Stathopoulos J, Dimitroulis J. Two consecutive days of treatment with liposomal cisplatin in non-small cell lung cancer. Oncol Lett. 2012, vol 5:1013-1016.

Monotherapy-Radiation in osteosarcoma

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 offers a new regiment against osteosarcomas without side effects and an amazing efficacy.

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

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.

Lipoplatin versus cisplatin and other platinum drugs

The lead drug of Regulon is destined to replace cisplatin that has been the drug of reference for lung cancer in the global market for the last 30 years
Regulon's drug is showing better efficacy and lower toxicity than the queen of chemotherapy, cisplatin, used in every hospital against epithelial malignancies (85% of cancers)
Carboplatin + paclitaxel shows 30% partial response in NSCLC (lung cancer)
Cisplatin + paclitaxel shows 42% partial response in NSCLC (lung cancer)
Lipoplatin+ paclitaxel shows 59% partial response in NSCLC (lung cancer)
Lipoplatin alone (at 3 to 4 times the dose) shows 38% partial response in NSCLC (lung cancer) as second and third line. No side effects. Grades ¾: zero% of patients
Cisplatin alone shows 11% partial response in NSCLC (lung cancer) as first line. Side effects: Grades ¾: Nausea and vomiting 21% and 19%; renal 2%; neurotoxicity 8.6% of patients
Lipoplatin alone (at 3 to 4 times the dose) over 60% partial response in NSCLC (lung cancer) as first line. No side effects. (Unpublished data, patent application in progress)
Lipoplatin plus low-dose radiation shows over 80% partial and complete response in NSCLC (lung cancer) as first line. No side effects. (Unpublished data, patent application in progress)

Lipoplatin versus other platinum drugs. Opinion of eminent leaders

With the progress that lipoplatin has already made, it seems poised on the brink of becoming the next platinum drug and could serve as an excellent validation and motivation for those researchers and companies seeking to develop nanodelivery devices to enhance platinum-based anticancer therapy (page 52 of this article)
Stephen J. Lippard
Review The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs (2016) Chem Rev. March 9; 116(5): 3436–3486.
Stephen James Lippard is Professor of Chemistry at the Massachusetts Institute of Technology (MIT). He is considered one of the founders of bioinorganic chemistry.

Lipoplatin in brain tumors

As a liposomal drug, Lipoplatin is expected to cross the blood-brain barrier (BBB) at a higher extend than cisplatin. BBB controls which drugs can gain access to the brain from the systemic blood circulation
Thus Lipoplatin is expected to have a better efficacy than most other intravenously administered drugs against brain tumors
The importance of Lipoplatin against brain tumors (including metastases to the brain from other cancers) arises from the fact that radiation against brain is often used to treat brain tumors.
Lipoplatin has a demonstrated superiority in radiosensitizing activity (14 times better than cisplatin). In simple terms, when the oncologist and the radiation therapist combine Lipoplatin with low-dose radiation, the efficacy of Lipoplatin becomes 14-times higher.
Our protocol against brain tumors involves Lipoplatin infusion followed by low-dose irradiation against the brain lesions at an accuracy of 1 mm on the following day.
During this one day period liposome nanoparticles carrying cisplatin (Lipoplatin) accumulate in the brain tumors; subsequent irradiation against the brain tumors with a precision radiation instrument (Elekta, for example) will result in severe damage of the brain tumor without affecting the surrounding normal tissue
Cisplatin causes DNA crosslinks. Radiation causes DNA strand breaks. Both damages to the DNA of cancer cells incurring simultaneously in our protocol pose an unsurmountable obstacle to tumor cells that perish by apoptosis

Summary of patient data from one clinic

All patients responded to the treatment, thus the success of Lipoplatin plus low-dose radiation is 100%. Patients expected to live a few months went on under the Lipoplatin low-dose radiation regimen for ~2 years.
Eminent among these 9 patients were 5 (two with osteosarcomas, one lung, one breast and one kidney cancer), all at stage IV, that were completely cured (free of disease in PET/CT or other imaging method).