Dose Escalation and Safety Study of 188Re-PTI-6D2 in Patients With Metastatic Melanoma
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Multi-Center, Open-Label, Phase I, Dose-Escalation and Safety Study of 188Re-PTI-6D2 in Patients With Metastatic Melanoma|
- To determine the maximum tolerated dose (MTD) of 188Re-PTI-6D2 in patients with metastatic melanoma [ Time Frame: Daily/Weekly/Monthy ] [ Designated as safety issue: Yes ]
- to determine safety and tolerability; dose-limiting toxicities; evaluate the anti-tumor activity; to evaluate the HAMA response; and, to further characterize the pharmacokinetics, biodistribution, and dosimetry of 188Re-PTI-6D2 [ Time Frame: Daily/Weekly/Monthly ] [ Designated as safety issue: Yes ]
|Study Start Date:||January 2009|
|Study Completion Date:||June 2010|
|Primary Completion Date:||March 2010 (Final data collection date for primary outcome measure)|
Patients with confirmed Stage III (unresectable) or Stage IV melanoma who meet all eligibility criteria will undergo thorough physical examination and baseline tumor imaging to document baseline tumor measurements. Patients will be allowed to check in to the study center either the evening prior to dosing (Study Day 0) or the day of dosing (Study Day 1) based upon the principal investigators (PIs) discretion. All patients will be dosed and monitored as inpatients during the study.
Patients will receive an intravenous (IV) infusion of 188Re-PTI-6D2. Patients will undergo serial gamma scans at specified time points. Blood samples will be obtained prior to dosing and at specified intervals for PK measurements of the mAb as well as for measurement of serum radioactivity. Urine will be collected to measure excreted radioactivity. Patients will be closely monitored for safety throughout the duration of the study. Patients will remain at the study center for 48-72 hours after infusion of the radiolabeled dose to allow adequate time for post-treatment safety observation and rhenium decay. No investigational or commercial agents or therapies other than the study agent may be administered with the intent to treat the patient's malignancy during the inpatient treatment period.
After three evaluable patients have been followed for a minimum of 2-6 weeks after 188Re-PTI-6D2 infusion, the Principal Investigator and the PTI Medical Monitor will review safety data for patients at the current dose level. If there is no evidence of a dose-limiting toxicity, the dose of 188Re-PTI-6D2 will be escalated for the next cohort of patients. Dose escalation of 188Re-PTI-6D2 will occur according to the following titration scheme:
Level 1 = 20-30 mCi 188Re-PTI-6D2 / 10 - 50 mg of antibody
Level 2 = 40-60 mCi 188Re-PTI-6D2 / 10 - 50 mg of antibody
Level 3 = 75-100 mCi 188Re-PTI-6D2 / 50 - 100 mg of antibody
Level 4 = 125-150 mCi 188Re-PTI-6D2 / 50 - 100 mg of antibody
Level 5 = 175-200 mCi 188Re-PTI-6D2 / 50 - 100 mg of antibody
Dose-limiting toxicity will be defined as the following: Grade 4 hematological toxicity; ≥ Grade 3 non-hematological toxicity; or any adverse event that results in permanent discontinuation of the infusion. If at any time Grade 5 toxicity is observed, accrual will be suspended until further review. If 0 out of 3 patients experience DLT, the next cohort of 3 patients will be enrolled at the next dose level. If 1 out of 3 patients experience a dose-limiting toxicity, an additional three evaluable patients will be enrolled at the current dose level.
Dose escalation occurs until the maximum tolerated dose is determined. The MTD is defined as the dose preceding the dose at which 2 of 3 or 2 of 6 patients experience DLT.
Safety will be evaluated by vital signs (blood pressure, heart rate, respiratory rate and temperature), physical examinations, electrocardiograms (EKGs), clinical laboratory tests and adverse event monitoring. Laboratory studies will include hematology, chemistry and urinalysis at baseline, at the end of the inpatient treatment period, and at 2 weeks and 6 weeks after the infusion of the 188Re-PTI-6D2 dose. If hematological recovery has not occurred by week 6, patients will follow-up monthly until hematological recovery. In addition, thyroid function tests will be performed at baseline and at 6 weeks after infusion; then monthly until recovery (if has not occurred). Human anti-murine antibodies (HAMA) will be measured at baseline, 2 weeks, and 6 weeks after infusion .
Biodistribution of 188Re-PTI-6D2 will be evaluated by whole body imaging with a gamma camera immediately after infusion (0 - 2 hrs.), at 2.5 - 5 hours, at 6 - 8 hours, and 24 hours post-infusion. Whole body imaging at 48 and 72 hours post-infusion may be conducted at the discretion of the PI. Urine will be collected to measure cumulative radioactivity excretion up to 48-72 hours post-infusion (depending on the hospital discharge date). Pharmacokinetics of the mAb and radioactivity will be determined from blood samples taken through 48-72 hours post-infusion (depending on the hospital discharge date). Dosimetry calculations will be performed to determine estimated absorbed radiation doses to critical organs and to tumor.
Patients will be discharged from the study unit 48-72 hours after infusion with 188Re-PTI-6D2 or later as determined by the Investigator's clinical judgment. Patients will be required to return for post-treatment follow-up visits approximately 2 and 6 weeks (± two days) after infusion for safety monitoring. Ongoing follow-up visits will continue until disease progression every 4 weeks. Tumor measurements will be performed at baseline, and all follow-up visits to assess for tumor response. Patients with unacceptable adverse events will have events followed until resolution.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00734188
|Hadassah Hebrew University Hospital|
|Principal Investigator:||Eithan Galun, M.D.||Hadassah Hebrew University Hospital|