Peter,
<<Xcytrin has an excellent safety profile, particularly when compared with other chemo drugs and radiation itself.>>
I am not sure about this????
PIb/II protocol:
<<Radiosensitizer administration: PCI-0120 iv over 5-10 min, 2-5 hr prior to each radiotherapy fraction
Escalation scheme:
Cohort size: 3-5 patients Doses: 0.25 (start), 0.50, 0.80, 1.30, 1.80, 2.30, 3.10, and 4.10 micromoles/kg, then in 33% increments
No escalation until 2nd patient/cohort is observed >/= 7 days after completion of therapy and 3rd patient has at least completed therapy
If DLT occurs in:
0 of 3: escalation proceeds
1 of 3: 2 additional patients entered at same dose No further DLT (1 of 5): escalation proceeds
2 of 3-5: escalation stops; 20 new patients treated at next lower dose (the MTD)
From press release (PCYC) on PIb/PII:
<<Eighteen Phase II patients were evaluable for tumor response based on follow-up MRI scans. After a two-month follow up, tumor response, defined as greater than 50 percent reduction in tumor volume, was seen in 13 of 18 patients (72 percent), significantly higher than the 43 percent reported in previous studies of patients treated with standard whole brain radiation therapy alone. Death due to tumor progression in the brain was just 12 percent, compared to a rate of about 50 percent reported in previous studies of patients treated with radiation alone. MRI scanning showed visual enhancement of the brain metastases for 56 days following administration of Xcytrin, demonstrating how the drug localizes selectively and is retained in the tumors.
The treatment was well tolerated. The most common side effects observed were discoloration of the skin, urine and eyes due to the dark-green color of the drug. The discoloration developed gradually after repeated drug dosing, and cleared three to four days after the last dose.
"This is the first treatment of its kind that appears to enhance the beneficial effects of radiation therapy in a clinical setting," said Dr. Patrice Carde, Chef de Service, Department of Medicine, Institut Gustave Roussy, Villejuif, France, lead author of the study.>>
From JCO:
<<RESULTS: In phase Ib, the motexafin gadolinium dose was escalated in 39 patients (0.3 mg/kg to 8.4 mg/kg). In phase II, 22 patients received 5 mg/kg to 6.3 mg/kg motexafin gadolinium. Ten once-daily treatments were well tolerated. The MTD was 6.3 mg/kg, with dose-limiting reversible liver toxicity. Motexafin gadolinium’s tumor selectivity was established using MRI. The radiologic response rate was 72% in phase II. Median survival was 4.7 months for all patients, 5.4 months for recursive partitioning analysis (RPA) class 2 patients, and 3.8 months for RPA class 3 patients. One-year actuarial survival for all patients was 25%.
CONCLUSION: Motexafin gadolinium was well tolerated at doses up to 6.3 mg/kg, was selectively accumulated in tumors, and, when combined with WBRT of 30 Gy in 10 fractions, was associated with a high radiologic response rate.>>
Other:
<<Researchers observed that this treatment was well tolerated. Side effects included mild and transient skin discoloration, blistering of the fingertips and rashes. >>
<<"Xcytrin is taken up and retained in glioblastoma, but not in the normal brain, an impressive characteristic we have observed with Xcytrin in other tumor types," said Judith Ford, M.D., Ph.D., Assistant Professor, Department of Radiation Oncology, UCLA Medical Center in Los Angeles. "Xcytrin was rapidly cleared from the bloodstream and this regimen has been well tolerated over time. We are encouraged by the preliminary survival data so far, though further study is needed to confirm these findings.">>
As data indicate ( I didn’t read full JCO article), MTD are in range of 3.1-4.1 micromole/kg, which correspond to ~400 mg daily dose. Regardless that drug is rapidly cleared from blood, systemic toxicity does show (in this selected PII pts). First elevated liver, and than rush and fingertips blistering. I am wandering what else can surface in large PIII, non-selected pts, trial?
Did Company ever mentioned elevated liver enzyme as DLT?
Miljenko |
