Phase I Biodistribution Study of 111-Indium-CMD-193 in Patients With Advanced Tumours Expressing the Lewis-Y Antigen
Trial Snapshot
- Phase
- Phase 1
- Status
- Terminated
- Enrollment
- 9
- Locations
- 2
- Primary Endpoint
- Summary of 111-In-CMD-193 Biodistribution Based on Gamma Camera Images
Study Overview
Brief Summary
This was a Phase 1 dose-escalation study of CMD-193, a humanized monoclonal antibody linked to the toxin calicheamicin, in subjects with advanced tumors expressing the Lewis-Y antigen. The primary study objective was to determine the biodistribution and pharmacokinetics (PK) of 111-In-CMD-193 (i.e., CMD-193 tagged with a small amount of radioactive Indium [111-In]), with secondary objectives of determining changes in tumor metabolism and describing the antitumor responses to CMD-193.
Detailed Description
Subjects received a single infusion of 111-In-CMD-193 on Day 1. Collection of blood for PK and whole body gamma camera imaging for assessment of biodistribution and tumor uptake were performed on Days 1, 2, 3 or 4, 5 or 6, and 7 or 8 following the 111-In-CMD-193 infusion. Subjects were evaluated for safety for 3 hours post-infusion on Day 1 of each cycle, with subsequent safety assessments performed on Days 8 and 15. Blood for human anti-human antibody (HAHA) response was collected pre-infusion, prior to each subsequent cycle (every 3 weeks) and at study discontinuation.
CMD-193 was administered on Day 1 of each subsequent 21-day cycle as a 60 (± 5) minute intravenous (IV) infusion at a dose of 1.0 mg/m^2 in Cohort 1 and 2.6 mg/m^2 in Cohort 2. Each subject received up to 6 cycles of CMD-193 (including the initial infusion of 111-In-CMD-193) until disease progression, unacceptable toxicity, or withdrawal of consent. Up to 6 additional cycles of CMD-193 were permitted if approved by the Sponsor in subjects who tolerated CMD-193 treatment and had evidence of response. Pretreatment medications (e.g., paracetamol, promethazine hydrochloride) were to be administered to reduce the incidence and severity of an anticipated infusion syndrome characterized by fever and chills, and less commonly hypotension.
Restaging by computed tomography (CT) scan was performed at the end of Cycles 2, 4, and 6. Assessment of tumor metabolism was performed by positron emission tomography with 18F-labeled fluorodeoxyglucose (18F-FDG-PET) prior to Cycle 1 and at the time of restaging at the end of Cycles 2 and 4.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Cohort 1 (1.0 mg/m^2)
Subjects received 111-In-CMD-193 on Day 1 of Cycle 1. Subjects received CMD-193 at a dose of 1.0 mg/m^2 on Day 1 of subsequent 21-day cycles.
Intervention: 111-Indium-CMD-193 (Drug)
Cohort 1 (1.0 mg/m^2)
Subjects received 111-In-CMD-193 on Day 1 of Cycle 1. Subjects received CMD-193 at a dose of 1.0 mg/m^2 on Day 1 of subsequent 21-day cycles.
Intervention: CMD-193 (Drug)
Cohort 2 (2.6 mg/m^2)
Subjects received 111-In-CMD-193 on Day 1 of Cycle 1. Subjects received CMD-193 at a dose of 2.6 mg/m^2 on Day 1 of subsequent 21-day cycles.
Intervention: 111-Indium-CMD-193 (Drug)
Cohort 2 (2.6 mg/m^2)
Subjects received 111-In-CMD-193 on Day 1 of Cycle 1. Subjects received CMD-193 at a dose of 2.6 mg/m^2 on Day 1 of subsequent 21-day cycles.
Intervention: CMD-193 (Drug)
Outcomes
Primary Outcomes
Summary of 111-In-CMD-193 Biodistribution Based on Gamma Camera Images
Time Frame: Up to 8 days
Biodistribution data were collected after subjects received a single infusion of 111-In-CMD-193 over 1 hour on Day 1 of Cycle 1. Gamma camera imaging with anterior and posterior whole body scans using conjugate view methodology were performed on Days 1, 2, 3 or 4, 5 or 6, and 7 or 8 following the 111-In-CMD-193 infusion. A standard was included in the field of view at each imaging time point. Single-photon emission computerized tomography (SPECT) imaging of relevant areas of disease were performed on at least one occasion following the 111-In-CMD-193 infusion. Biodistribution analysis was performed by examination of whole body and SPECT images by experienced nuclear medicine physicians.
Mean Effective Half-life of 111-In-CMD-193 Based on Gamma Camera Images
Time Frame: Up to 8 days
Gamma camera imaging with anterior and posterior whole body scans using conjugate view methodology were performed on Days 1, 2, 3 or 4, 5 or 6, and 7 or 8 following the 111-In-CMD-193 infusion. Whole body clearance, or biological half-time, was calculated from the whole body anterior and posterior planar images. A region of interest (ROI) was calculated to encompass the whole body, and for each ROI at each time point, the mean counts per pixel per minute was normalized to imaging time point Day 1. From this time-activity curve, an exponential clearance expression was fitted to obtain effective half-time. This was then corrected for the physical half-life of 111-In (67.45 hours) to account for physical decay to obtain the biological half-time.
Mean Serum Half-lives of 111-In-CMD-193
Time Frame: Approximately 15 days (i.e., Days 1, 3, 8, and 15)
During Cycle 1 (111-In-CMD-193 infusion) serum samples for pharmacokinetics were collected on Days 1 (pre-infusion and 1 and 4 hours after the start of the infusion), 3, 8 and 15. Serum obtained from subjects following infusion of 111-In-CMD-193 was aliquoted and counted in a gamma scintillation counter. Duplicate standards prepared from the injected material were counted at each time point with serum samples to enable calculations to be corrected for the isotope physical decay. A 2-compartment IV bolus model with macro-parameters, no lag time and first order elimination (WNL Model 8) was fitted to individual labelled infusions for each subject using un-weighted nonlinear, least squares with WinNonLin version 5.2. T½α and T½β represent half lives of the initial and terminal phases of disposition.
Mean Volume of Central Compartment of 111-In-CMD-193
Time Frame: Approximately 15 days (i.e., Days 1, 3, 8, and 15)
During Cycle 1 (111-In-CMD-193 infusion) serum samples for pharmacokinetics were collected on Days 1 (pre-infusion and 1 and 4 hours after the start of the infusion), 3, 8 and 15. Serum obtained from subjects following infusion of 111-In-CMD-193 was aliquoted and counted in a gamma scintillation counter. Duplicate standards prepared from the injected material were counted at each time point with serum samples to enable calculations to be corrected for the isotope physical decay. A 2-compartment IV bolus model with macro-parameters, no lag time and first order elimination (WNL Model 8) was fitted to individual labelled infusions for each subject using un-weighted nonlinear, least squares with WinNonLin version 5.2.
Mean Area Under the Serum Concentration Curve Extrapolated to Infinite Time for 111-In-CMD-193
Time Frame: Approximately 15 days (i.e., Days 1, 3, 8, and 15)
During Cycle 1 (111-In-CMD-193 infusion) serum samples for pharmacokinetics were collected on Days 1 (pre-infusion and 1 and 4 hours after the start of the infusion), 3, 8 and 15. Serum obtained from subjects following infusion of 111-In-CMD-193 was aliquoted and counted in a gamma scintillation counter. Duplicate standards prepared from the injected material were counted at each time point with serum samples to enable calculations to be corrected for the isotope physical decay. A 2-compartment IV bolus model with macro-parameters, no lag time and first order elimination (WNL Model 8) was fitted to individual labelled infusions for each subject using un-weighted nonlinear, least squares with WinNonLin version 5.2.
Mean Total Serum Clearance of 111-In-CMD-193
Time Frame: Approximately 15 days (i.e., Days 1, 3, 8, and 15)
During Cycle 1 (111-In-CMD-193 infusion) serum samples for pharmacokinetics were collected on Days 1 (pre-infusion and 1 and 4 hours after the start of the infusion), 3, 8 and 15. Serum obtained from subjects following infusion of 111-In-CMD-193 was aliquoted and counted in a gamma scintillation counter. Duplicate standards prepared from the injected material were counted at each time point with serum samples to enable calculations to be corrected for the isotope physical decay. A 2-compartment IV bolus model with macro-parameters, no lag time and first order elimination (WNL Model 8) was fitted to individual labelled infusions for each subject using un-weighted nonlinear, least squares with WinNonLin version 5.2.
Secondary Outcomes
- Number of Subjects With Best Tumor Response as Measured by the Response Evaluation Criteria in Solid Tumors (RECIST)(Up to 4 months)
- Number of Subjects With Best Metabolic Tumor Response by European Organisation for Research and Treatment of Cancer (EORTC) Guidelines at End of Study(Up to 4 months)