Study Summary
This is a multicenter phase l I study designed to evaluate the safety, tolerability and clinical efficacy of long term oral administration of Neovastat (Æ 941) in patients presenting with solid tumors that are refractory to standard therapies or for whom no standard therapies are available.

Neovastat (Æ 941) is an aqueous extract of shark cartilage. Cartilage is an avascular tissue which has been studied for its potential to inhibit the angiogenic process (the development of new blood vessels). This process plays a major role in cancer development and is promoted by growth factors. Cartilage can also inhibit tumor progression by acting directly on the transformed cells to lower their proliferation rate. None of the factors responsible for these biological activities has yet been purified to homogeneity. Cartilage accounts for approximately 6% of the body weight in shark species thus making it a good source of anti-angiogenic factors. Research shows that the factor(s) responsible for the angiogenic activity of shark cartilage are hydrosoluble. An extraction and purification method of molecular fractions present in shark cartilage have been developed by Les Laboratoires Æterna. One of these fractions, namely Neovastat (Æ 941), has been used in vitro and in vivo in animals and results indicate an anti-tumoral potential without any signs of toxicity in animals. The origins of Neovastat began with the food supplement CarTCell a liquid shark cartilage extract, which has been commercially available for over 3 years in Canada, Europe and the USA. Neovastat (Æ 941) is a more concentrated formulation than CarTCell.

Early in 1997, a controlled phase l study of Neovastat (Æ 941) was implemented for patients with solid tumors of the breast, lung and prostate. The present study extends this potentially effective treatment to patients presenting with the following condition:
1. Patients with ovarian or lung cancer receiving concurrent platinum-based therapy or radiotherapy;
2. Breast cancer patients receiving any other established therapy;
3. Colon cancer patients receiving chemotherapy

As no adverse events related to the use of this investigational product at the highest tested dose (240 ml daily over a twelve-week period) have been reported, minimal side effects or toxicity are expected at the daily dosage of 60 ml proposed in this study.

This trial is based at the Jewish General Hospital and will be coordinated through the Clinical Research Unit. It should also be noted that in addition to the pre-case funding, all pharmaceutical costs as well as compensation for radiologic tests required specifically for the protocol, will be provided.

Gerald Batist, M.D.
Director-Clinical Research Unit

References:
1. Folkman, J. (1976). Vascularization of tumors. Sci. Am. 234:58-73. 2.Dupont et al. (1995). Extracts of shark cartilage having an anti-angiogenic activity and an effect on tumor regression: Process of making thereof. U.S. Patent 08/384,555 .3. Ferrara N, Houck K, Jakemen L, Leung DW.(1992). Molecular and biological properties of the vascular endothelial groqth factor family of proteins. Endocrine Rev. 13:18-32.

Lay Summary
Cartilage is an avascular tissue which has been studied for its potential to inhibit the development of new blood vessels which tumors require to grow. This process plays a major role in cancer development and is promoted by growth factors. Cartilage can also inhibit tumor progression by acting directly to slow tumor cell growth. The precise factors responsible for these effects are not yet known, but since cartilage accounts for approximately 6% of the body weight in sharks, they are an excellent source of these "anti-angiogenic factors". An extraction and purification method was developed by Les Laboratoires Æterna. One of these fractions, namely Neovastat (Æ 941), has been used in the laboratory in petri dishes as well as in live tumor bearing animals, and the results indicate an anti-tumoral potential without any signs of toxicity in animals.

Early in 1997, a phase l study of Neovastat (Æ 941) was implemented for patients with solid tumors of the breast, lung and prostate. The present study extends this potentially effective treatment to patients presenting with any type of solid tumor for which no standard therapies are likely to be curable. As no adverse events related to the use of this investigational product at the highest tested dose (240 ml daily over a twelve-week period) have been reported, minimal side effects or toxicity are expected at the daily dosage of 60 ml proposed in this study.

Eligibility Criteria
Patients can be included in this trial if he/she:
1) has a histologically confirmed Diagnosis of types of cancer described below that are refractory to standard therapies or for whom no standard therapies are available:
- Patients with ovarian or lung cancer receiving concurrent platinum-based therapy or radiotherapy;
- Breast cancer patients receiving any other established therapy;
- Colon cancer patients receiving chemotherapy.

2) Has measurable or evaluable disease defined as a lesion that is visualized by an appropriate scanning procedure for breast and lung cancers, or can be evaluated by an appropriate standard criteria for prostate cancers

3) Is 18 years of age or older

4) Weighs between 40 and 110 kg, inclusive

5) Has a performance status of 0 to 2 on the cooperative Oncology Group (ECOG) performance scale

6) Has a life expectancy of at least 6 months

7) If female, is not of child bearing potential or is practicing an adequate form of contraception, or is surgically sterile

8) Has adequate hematologic function defined as :
- Hematocrit > (or =) 35%
- Hematocrit > (or =) 10g/dL
- Platelet count > (or =) 100,000/mm ³
Or, if outside of these values, considered by the Investigator and Medical Safety Officer as not being a life-threatening condition

9) Has adequate serum chemistry defined as:
-All elements of clinical chemistry panel < (or =) 1.5 times the upper limit of normal except for the liver panel, whose limits are < (or =) 4 times the upper limit of normal

10) Has the ability to understand the requirements of the study, provide with written informed consent, abide by the study restrictions, agree to return for the required assessments