Open Label Clinical Trial of Intravenous Crotoxin Part 3

Study Overview
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Brief Summary
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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.

Detailed Description
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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 double that off 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.

Official Title
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Open Label Phase I Clinical Trial of Crotoxin in Patients With Advanced Cancer Using an Intravenous Route of Administration

Conditions
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Cancer

Intervention / Treatment
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* Drug: Crotoxin


Participation Criteria
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Eligibility Criteria
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Subjects will: 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. Have an ambulatory PS (ECOG 0-1). Have tumor evaluation made within 28 days before study drug administration 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 Have a life expectancy greater than 3 months Have an age ≥ 18 years 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 Have no medically significant impairment of cardiac or respiratory functions< 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). Have no history of prior severe allergic reactions to venoms Have Creatinine clearance > 50 mL/min. 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. Not be pregnant or planning to become pregnant 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 Not have pleural effusion/ ascites, cystic lesions or bone metastases, as the only assessable lesions 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 Not have had recent major surgery (within 21 days). Not have a recent history of weight loss > 10% of current body weight. Not have serious intermittent medical illnesses which would interfere with the ability of the patient to carry out the treatment program. Not be on chronic steroid medication (> 20mg/day) Not have primary or paraneoplastic myasthenia gravis Be free of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; Will agree to participate in the study prior to starting with any specific study procedure, after having signed written informed consent. Be patients of childbearing age willing to use contraceptive for the duration of the study 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 3<br>The third cohort will include up to 24 patients with Crotoxin doses of 0.2 to 1.32 mg per m2 in which the dose escalation speed will be faster. Drug is administered over 48 hour intervals using ambulatory infusion pumps; treating on an outpatient basis. Subjects will receive increasing doses over the course of 35 treatment days (15 dose levels). | Drug: Crotoxin<br>* Intra patient dose escalation<br>* Other names: CB24;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability of intra-patient dose escalation | Assess the safety and tolerability of Crotoxin administered intravenously to Stage IV cancer patients using intra-patient dose escalation procedure. | 35 days | 
| Confirmation of the induction of drug tolerance | Confirm in a controlled phase I trial that human subjects can be made tolerant to intravenously administered Crotoxin thereby reducing the potential for adverse drug effects | 35 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of drug efficacy | Document any objective anti-tumour responses that occur in patients treated on this protocol. | 35 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antineoplastic agent