Open Label Clinical Trial of Intravenous Crotoxin Part 3

The primary objective of the study is to assess whether human subjects can be made tolerant to intravenously administered Crotoxin and achieve higher and more therapeutically effective doses levels without the previously reported adverse effects associated with bolus i.m. administration.

Crotoxin has been shown to induce neurotoxic tolerance in animals allowing them to receive high doses associated with effective anti-tumor activity in the absence of adverse side effects.

The study plans to demonstrate this effect in human subjects using two dose escalation protocols; slow and fast. It is believed that this approach will prevent toxic side effects to subjects.

The route of administration has not been employed clinically and is designed to avoid the myonecrotic effects of intramuscular injections. The target maximum dose is almost five times that of the previously reported MTD.

The revised protocol incorporates continuous infusion with a mobile pump and includes active suppression of the allergic reaction by pre-treatment administration of antihistamines.

Eligibility Criteria:
Subjects will:

1. Be adult patients with histologically confirmed advanced solid tumors (excluding basal cell, colon, pancreatic and stomach cancers) who have progressed despite standard therapy, or for whom no standard therapy exists.
2. Have an ambulatory PS (ECOG 0-1).
3. Have tumor evaluation made within 28 days before study drug administration
4. Have completed radiotherapy or chemotherapy or any other anticancer therapy (including experimental therapy) more than 4 weeks prior to enrolment into the trial and must have recovered from all acute side effects of these treatments
5. Have a life expectancy greater than 3 months
6. Have an age ≥ 18 years
7. Have normal marrow function with the following haematological parameters normal; Hb ≥10g/dl, WBC ≥4.0 x10E9/L, neutrophil count ≥ 2.0 x 10E9/L and platelets ≥100 x10E9 /L
8. Have no medically significant impairment of cardiac or respiratory functions\<
9. Have adequate hepatic function with Total bilirubin 1.5 x N and Transaminases \< 2.5 x N (\< 5 x N in case of liver metastasis).
10. Have no history of prior severe allergic reactions to venoms
11. Have Creatinine clearance \> 50 mL/min.
12. Be on stable doses of any drugs which may affect hepatic drug metabolism or renal drug excretion (e.g.--non-steroidal anti-inflammatory drugs, barbiturates, narcotic analgesics, probenecid). Such drugs should not be initiated while the patient is participating in this study.
13. Not be pregnant or planning to become pregnant
14. Not known to have brain metastases or leptomeningeal involvement. CT-scan or MRI is not required to rule this out unless there is clinical suspicion of central nervous system involvement
15. Not have pleural effusion/ ascites, cystic lesions or bone metastases, as the only assessable lesions
16. Not have a history of other malignancies, except for patients with a cancer free interval of \> 5 years after treatment completion, patients with prior history of adequately treated basal cell carcinoma of the skin or carcinoma in situ of the cervix
17. Not have had recent major surgery (within 21 days).
18. Not have a recent history of weight loss \> 10% of current body weight.
19. Not have serious intermittent medical illnesses which would interfere with the ability of the patient to carry out the treatment program.
20. Not be on chronic steroid medication (\> 20mg/day)
21. Not have primary or paraneoplastic myasthenia gravis
22. Be free of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule;
23. Will agree to participate in the study prior to starting with any specific study procedure, after having signed written informed consent.
24. Be patients of childbearing age willing to use contraceptive for the duration of the study
25. Not live alone and live no further than approximately 30 km away from the hospital, and for the study duration have continuous access to the use of mobile telephone in case of medical emergency