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The components of the anti-angiogenic cocktail we are developing, include both therapeutic and formulating agents which are all FDA approved.
These are all known therapeutics, with extensive published clinical safety records.
This means that the pathway to regulatory approval is likely to be relatively short.
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Preclinical Results
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Preclinical (animal) testing included toxicology studies in rats and dogs and efficacy tests in a mouse cancer model and in naturally occurring tumors in household dogs.
The cocktail's anti-angiogenic mechanism of action was further demonstrated in several independent animal model systems.
Toxicology studies:
No significant toxic effects were observed in the preclinical studies in rats and dogs.
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No significant differences were noted in body weight and survival rates between the treatment group and the control group. |
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Blood tests following treatment with the anti-angiogenic cocktail revealed no significant biochemical changes, nor irreversible changes in hematology indices. |
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Tissues examination in rats and dogs showed no systemic effects, and in particular, no signs of toxicity in the gastro-intestinal system, in the kidneys and in other organs |
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Efficacy tests:
Testing of the effectiveness of the Tiltan drug-combination in animal models was extensive. A few examples demonstrating the therapy's anti-angiogenic and anti-tumor effects are illustrated below.
As expected, the treatment demonstrated that anti-angiogenic activity correlates with a significant effect on tumor growth. Mice that received the drug-combination showed significantly diminished or suppressed (stable) tumor growth compared to control tumors which increased exponentially in size (see Figure 1 and Figure 2).
Treatment with the anti-angiogenic cocktail was also conducted in mice that were genetically engineered to undergo an angiogenic switch-on in their liver. In switched-on control mice there was massive angiogenesis, typified by large vessels and the infiltration of mononuclear cells (see Control in Figure 3). On the other hand, no significantly vasculature formation was evident in switched-on animals who were treated during this period with our anti-angiogenic cocktail (see Treatment in Figure 3). The cocktail's anti-angiogenic activity was also independently verified in an in-vivo mouse model of wound-healing.
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Figure 1 - Effect of our Anti-Angiogenic Treatment on Tumor Size in Mice
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| Figure 1: Graphic description of tumor growth kinetics. Treated mice received the cocktail 6 days a week, beginning at day 4 after tumor inoculation. The mice in the control group were injected with the inert vehicle solution. |
Figure 2 – Effect of our Anti-Angiogenic Treatment on Metastases Growth in Mice
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| Figure 2: MRI scans of an experimental mouse model for liver metastases of colon cancer, comparing mice receiving no treatment (control, left panels) and mice receiving the anti-angiogenic drug-combination (treatment, right panels). The metastases are marked in colored circles. Produced at the MRI lab of Hadassah Hospital by Dr. Rinat Abramovitch and Yifat Edrei. |
Figure 3 – Hematoxilin-Eosin (H&E) Staining of Liver Tissue (Mice)
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| Figure 3: H&E staining of liver histological sections from transgenic mice that underwent a pro-angiogenic "switch on". Larger sinuses are evident in the control section (left panel), as compared with the section from a treated mouse (right panel). These large cavities contain erythrocytes and represent an increase in liver blood vessel development. The dark purple cells are bone-marrow-derived monoclonal cells that play an active role in the angiogenic process. It is evident that a larger number of monoclonal cells is present in the sinuses of the control section (left panel), as compared with the section of the liver of the treated animal (right panel). |
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A Clinical Trial is on its Way
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Having completed pre-clinical trials with notable success, we commenced a clinical trial of our anti-angiogenic cancer treatment. The current study is an open, baseline-controlled Phase I/II dose escalation trial. The aim of this clinical trial is to determine the therapy's safety profile and its efficacy in cancer patients with solid tumors.
Therapy with the investigational product lasts 12 weeks during which full evaluations are preformed before the beginning of the trial, after 6 weeks, and after 12 weeks of therapy. Efficacy is evaluated by tumor imaging (e.g. CT, MRI) and by biochemical markers for tumors when applicable.
| Trial Name |
A Phase I/II Clinical Trial of an Anti-Angiogenic Drug Combination on Patients with Relapsed or Progressive Cancer |
| Medical Condition |
Cancer patients with solid tumors |
| Intervention |
A drug combination comprising of four active components:
One chemotherapeutic agent administrated at low doses, and three other non-cytotoxic drugs that complement each other to suppress angiogenesis.
The investigational product is an oral suspension administrated daily for 12 weeks
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| Inclusion Criteria |
1. Patient 18 years old or older
2. Patients with relapsed or progressive tumors for which no curative therapy exists.
3. Histologic or cytologic confirmation of a solid tumor
4. Absence of co-morbidities considered to potentially influence the outcome of treatment
5. Adequate renal function, hepatic function and bone marrow reserve
6. Patients capable of swallowing
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| Exclusion Criteria |
1. Pregnant women or nursing mothers
2. Patients of childbearing potential unwilling to take adequate contraceptive measures
3. Concurrent use of systemic antineoplastic therapy
4. Patients receiving other investigational agents within the past 30 days of study entry
5. Patients receiving systemic antineoplastic therapy within the past 21 days of study entry
6. Patients with evidence of circumstances that are likely to interfere with the absorption of orally administrated drugs
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| Study Type |
An open, non-randomized, baseline-controlled Phase I/II trial |
| Target Sample Size |
Approximately 100 patients completing 12 weeks of treatment |
| Research Ethics Review |
The study has received appropriate ethics committee approval |
| Recruitment Status |
The first patient was enrolled in December 2003
A small sub-study in High-Grade Gliomas is scheduled to begin recruiting patients in Israel around August 2007
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| Purpose |
The primary purpose of this trial is to study the safety of our drug combination in cancer patients with solid tumors.
The secondary purpose of this trial is to study how effective this anti-angiogenic drug combination is in controlling the progression of solid tumors, following 12 weeks of therapy |
| Sponsor |
Tiltan Pharma Ltd. |
| Contact |
For the general public and for scientific inquiries: info@tiltanpharma.com |
Important statements:
Please note: It cannot be guaranteed that patients taking part in this study will benefit from it.
The treatment may cause side effects and even be harmful. |
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