Summary of Phase I human clinical studies with VRCTC310; (Costa et al, 1997) Response of Disease.
No significant toxicities were found up to 0.013mg/Kg: the most common was local pain at the site of the injection (11 out of 15 patients). The study was not designed to assess clinical efficacy. Nonetheless some striking results were observed; all patients experienced subjective benefit from the treatment. In six cases, disease did not progress in the course of the study. Remission higher than 50% was found in one patient (Stage IV lung cancer), who entered the trial in April 1996. This patient is still alive and continues in remission, under treatment with VRCTC310 at 0.01mg/Kg (the dose he received in his second cycle in the trial, after completion of a first cycle at 0.005mg/Kg). Currently (July 1997) 6 patients (2 breast, lung, larynx, cervix and ovary) are alive, with more than 1 year’s survival after ending the trial.
(1 Partial Response, 5 Stable Disease)
Pilot Studies with Loco-Regional Inoculation with VRCTC310; (Costa et al, 1998)
From December 1996 to August 1997, five patients with histologic confirmed local advanced cancer (breast cancer 3, squamous cell cancer of the hand 1, chordoma 1) were treated at Bernardo Houssay Hospital, Oncology Unit with VRCTC310, at the full dose of 0.014mg/Kg once a week, inoculated peritumorally and distributed into four different injections around the tumour, for no less than eight courses. All patients gave written informed consent according to local ethics committee requirements. A complete response was observed in 3 patients (breast cancer 2, skin cancer of the hand 1), and a partial response was registered for the two other patients. No toxicities were observed, except for mild local pain at the site of the injection. We conclude that weekly VRCTC310 given by subcutaneous, peritumoral route is an active treatment for advanced skin metastatic tumours, well tolerated and safe. (3 Complete responses, 2 Partial Responses)
Summary of Phase I human clinical studies with Crotoxin; (Cura et al, 2002)
Response of Disease.
The presence of objectively measurable lesions was not included as requirement for patient eligibility in this study. Four patients showed no progression of the disease. A 66-year-old man with a colon carcinoma and hepatic metastases, treated at 0.06 mg/m2 crotoxin, had a 40% reduction of the hepatomegalia during a 60-day period. Thereafter, disease progression was reported. A 47-year-old man with a fibrosarcoma diagnosed by surgery and pelvic invasion, which produced an important edema in both legs, was treated with 0.21 mg/m2 crotoxin for 117 days. Edemas disappeared and no displacement of pelvic organs was observed by CAT-scan monitoring. Objectively measured partial responses were observed in 3 patients. A 52-year-old male having a local relapse of a larynx carcinoma with invasion of lymphatic nodes had tumors on the right and left sides of the neck. Thirty-day treatment at 0.12 mg/m2 showed a reduced lymphatic nodes mass in partial response to such treatment. A 62-year old man with non-differentiated thyroid carcinoma and metastases in the right axillary nodes, at a dose of 0.21 mg/m2 Crotoxin, showed a partial response on study day 90, which remained stable for another 30-day cycle. A 50-year-old woman having a rectal carcinoma and pelvic metastases, with a measurable non-resectable tumor in the upper vaginal area, received a dose of 0.21 mg/m2. A CAT-scan on day 78 showed reduced dimensions, which allowed surgical removal of the tumor. Finally, a patient with mammary carcinoma and metastasis in the right lung, pleural effusion, and multiple bone lesions received 0.21 mg/m2 Crotoxin. CAT-scan studies on day 90 showed a complete response (CR) in both lung and bone lesions, which lasted for 6 months after suspension of treatment. At the doses used, Crotoxin administration did not affect hematopoietic, hepatic, or renal functions.
Response of Pain:
18 of 23 evaluated patients reported a progressive but significant decrease or disappearance of pain (e.g., associated to bone metastasis or distension) starting on the second or third week of treatment. Pain decrease was assessed by reduction in consumption of analgesics and input of the patient. This effect was unexpected and at times remarkable. A 25-year old male with Ewing’s sarcoma increased mobility after diminishing of pain and gained muscular strength. A 46-year-old male patient with a rectal carcinoma and pelvic invasion suspended the regularly administered morphine after 3 weeks of treatment on 0.12 mg/m2 crotoxin. This effect persisted with no daily fluctuations, even when disease progression was detected. (1 Complete Response, 3 Partial Responses, 4 Stable Disease)
Summary of Phase I human clinical studies with i/v administration of Crotoxin with dose escalation Part 1; (Medioni et al, 2017)
One male and 5 females (pts) with prior heavily-treated advanced tumors were enrolled: colorectal adenocarcinoma, epithelioid mesothelioma, non-small-cell lung cancer, carcinoma of unknown primary site, invasive breast ductal carcinoma and ovarian papillary adenocarcinoma. Three patients reached the highest target dose level. DLT (dose limiting toxicity) or MTD (maximum tolerable dose) were not attained. In Cohort I grade 1 to 2 drug-related events occurred in 3/6 patients: anorexia, diplopia and nystagmus. There were no drug-related serious adverse events. Tumor assessment was performed after 8 weeks of dose escalation (day 54) and all subjects were determined to have progressive disease. At baseline, pain was reported for 5/6 subjects, surveys revealed a diminution of analgesic scores.
Crotoxin i.v. dose escalation protocol allowed administering 0.32 mg/m2/day without unexpected toxicity. Lack of anti-cancer benefit might be related to the long period of 6-8 weeks to reach this dose. A redesign of the protocol to escalate faster and to higher doses, without weekend breaks, is required.
Summary of Phase I human clinical studies with i/v administration of Crotoxin with dose escalation Part 2; (Delgado et al, 2018)
2/6 patients developed possibly drug-related G1 diplopia and 1/6 pts increased ASAT/ALAT. One patient recruited with pre-existent diarrhoea syndrome with uncontrolled G2 hypomagnesaemia, G3 hypokalaemia and G2 anaemia, developed complete arrhythmia with asymptomatic atrial fibrillation that resolved with amiodarone. Patient was hospitalised for observation and the event was classified as a possible study drug-related SAE as well as related to the digestive syndrome and tubulopathy resulting from previous chemotherapy (nivolumab and platinum salts). Stable disease was observed in 2/6 patients.
Conclusion: No DLT or MTD have been reached. CRTX dose escalation is safe but too slow, doses achieved too low and too late for advanced patients. In a new cohort, CRTX regimen will be continued starting from higher dose with faster dose escalation.
Celtic Biotech Planned Trials:
Phase I safety trials are principally geared to confirm or otherwise the safety of a therapeutic. The above described trials have cumulatively not only shown exceptional safety indications, particularly in comparison to many approved therapeutics, but also high levels of efficacy, unusual in Phase I, and pain relief (also a significant benefit of the drug). The Company plans a final Phase I part 3 trial, to achieve the maximum tolerated dose (MTD) and any dose limiting toxicity (DLT) in order to establish the optimum treatment doses for patients, before targeting efficacy in Phase II trials. The Phase I part 3 protocol is approved in France, the results of which trial will inform the design and protocol of the Phase II. This Phase I Open Label Clinical Trial of Intravenous Crotoxin is listed with the NIH, US National Library of Medicine.