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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT00293215
Registration number
NCT00293215
Ethics application status
Date submitted
15/02/2006
Date registered
17/02/2006
Titles & IDs
Public title
Biodistribution Study of CMD-193 in Patients With Advanced Tumours Expressing the Lewis-Y Antigen
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Scientific title
Phase I Biodistribution Study of 111-Indium-CMD-193 in Patients With Advanced Tumours Expressing the Lewis-Y Antigen
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Secondary ID [1]
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LUD2004-015
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Neoplasms
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0
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Condition category
Condition code
Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - 111-Indium-CMD-193
Treatment: Drugs - CMD-193
Experimental: 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.
Experimental: 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.
Treatment: Drugs: 111-Indium-CMD-193
111-In-CMD-193 (3-7 mCi) was administered as an IV infusion over 60 (± 5) minutes.
Treatment: Drugs: CMD-193
CMD-193 was administered as an IV infusion over 60 (± 5) minutes.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Summary of 111-In-CMD-193 Biodistribution Based on Gamma Camera Images
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Assessment method [1]
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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.
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Timepoint [1]
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Up to 8 days
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Primary outcome [2]
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Mean Effective Half-life of 111-In-CMD-193 Based on Gamma Camera Images
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Assessment method [2]
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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.
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Timepoint [2]
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Up to 8 days
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Primary outcome [3]
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Mean Serum Half-lives of 111-In-CMD-193
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Assessment method [3]
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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. T½a and T½ß represent half lives of the initial and terminal phases of disposition.
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Timepoint [3]
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Approximately 15 days (i.e., Days 1, 3, 8, and 15)
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Primary outcome [4]
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Mean Volume of Central Compartment of 111-In-CMD-193
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Assessment method [4]
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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.
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Timepoint [4]
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Approximately 15 days (i.e., Days 1, 3, 8, and 15)
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Primary outcome [5]
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Mean Total Serum Clearance of 111-In-CMD-193
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Assessment method [5]
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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.
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Timepoint [5]
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Approximately 15 days (i.e., Days 1, 3, 8, and 15)
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Primary outcome [6]
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Mean Area Under the Serum Concentration Curve Extrapolated to Infinite Time for 111-In-CMD-193
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Assessment method [6]
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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.
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Timepoint [6]
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Approximately 15 days (i.e., Days 1, 3, 8, and 15)
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Secondary outcome [1]
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Number of Subjects With Best Tumor Response as Measured by the Response Evaluation Criteria in Solid Tumors (RECIST)
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Assessment method [1]
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Computed tomography (CT) scans were performed at screening, between Days 15 and 21 of Cycles 2 and 4, and at study completion. Response was assessed using RECIST version 1.0 (Therasse et al, J Natl Cancer Inst 2000; 92:205-16), and all response assessment was performed by a single experienced radiologist. Per RECIST, target lesions are categorized as follows: complete response (CR): disappearance of all target lesions (no evaluable disease); partial response (PR): = 30% decrease in the sum of the longest diameter of target lesions; progressive disease (PD): = 20% increase in the sum of the longest diameter of target lesions; stable disease (SD): small changes that do not meet above criteria.
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Timepoint [1]
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Up to 4 months
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Secondary outcome [2]
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Number of Subjects With Best Metabolic Tumor Response by European Organisation for Research and Treatment of Cancer (EORTC) Guidelines at End of Study
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Assessment method [2]
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Positron emission tomography with 18F-labeled fluorodeoxyglucose (18F-FDG-PET) was done at screening and between Days 15-21 of Cycles 2 and 4 or at study completion. Metabolic response was calculated using the target lesion with the greatest baseline standardized uptake value (SUV) and categorized per EORTC guidelines (Young et al. Eur J Cancer 1999;35:1773-82): progressive metabolic disease was an increase in 18F-FDG tumor maximum SUV (SUVmax) of \> 25% within the tumor ROI determined on baseline scans, visible increase in 18F-FDG tumor uptake (\>20% in the longest dimension) or new 18F-FDG uptake in metastatic lesions. Stable metabolic disease was an increase in tumor 18F-FDG SUVmax of \< 25% or decrease of \< 15% and no visible increase in 18F-FDG tumor uptake (\>20% in the longest dimension). Partial metabolic response was a reduction of 15-25% in tumor 18F-FDG SUVmax after 1 cycle and \> 25% after \> 1 cycle (reduced tumor 18F-FDG uptake was not required).
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Timepoint [2]
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Up to 4 months
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Eligibility
Key inclusion criteria
Inclusion criteria:
1. Signed and dated Institutional Review Board (IRB)-approved informed consent before any protocol-specific screening procedures were performed.
2. Histologically confirmed malignant solid tumor that had progressed following standard therapy, or for which no standard effective treatment was available.
3. Tumor expression of Lewis-Y antigen (=20% tumor cells positive for Lewis-Y by immunohistochemistry assay).
4. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST), including the presence of at least one measurable lesion at least 2 cm in size suitable for 18F-FDG PET imaging.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Life expectancy = 18 weeks.
7. Age =18 years.
8. Recovery to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) = Grade 1 toxicity from any significant effects of prior surgery, radiation therapy, and cancer therapy (except alopecia).
9. Renal test: serum creatinine = 1.5 x upper limit of normal (ULN).
10. Hepatic tests: alanine aminotransferase (ALT) levels =2.5 x ULN and total bilirubin =1.5 x ULN.
11. Pancreatic tests: amylase =1.5 x ULN and lipase = 1.5 x ULN.
12. Bone marrow tests: absolute neutrophil count (ANC) of =1500 mm^3 (=1.5 x 10^9/L) and platelet count of = 150,000/mm^3 (=150 x 10^9/L).
13. For women of childbearing potential, a negative serum pregnancy test result no longer than 48 hours before the first dose of CMD-193. A woman of childbearing potential was one who was biologically capable of becoming pregnant. This included women who were using contraceptives or whose sexual partners were either sterile or using contraceptives.
14. All subjects who were not surgically sterile or postmenopausal must have agreed and committed to the use of a reliable method of birth control for the duration of the study and for 28 days after the last dose of CMD-193.
15. Willingness of female subjects to refrain from breastfeeding infants during the study or within 28 days after the last dose of CMD-193.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
Exclusion Criteria
1. Chemotherapy, radiation therapy, other cancer therapy, or investigational agents within 21 days of the first dose of CMD-193 (42 days if the previous chemotherapy included nitrosoureas or mitomycin C).
2. Symptomatic or clinically active central nervous system (CNS) metastases. Subjects who had prior treatment with radiotherapy or surgical resection for CNS metastases were permitted if CNS metastases had remained stable and not required any treatment for at least 3 months prior to the first dose of CMD-193.
3. Significant prior allergic reaction to recombinant human or murine proteins.
4. History of cirrhosis, current or chronic hepatitis B or C infections, or other significant active liver disease.
5. Unstable or serious concurrent medical conditions. Examples included, but were not limited to, bleeding gastric ulcers, gastrointestinal bleeding, hepatitis, significant disorders of the immune system (eg, systemic lupus erythematosus), pancreatitis, congestive heart failure, serious active infections (e.g. requiring antibiotics or antiviral agents), unstable angina, recent myocardial infarction (within 6 months of screening), ongoing maintenance therapy for life-threatening ventricular arrhythmia, or uncontrolled major seizure disorder.
6. Other malignancy within 3 years prior to entry into the study, except for treated non-melanoma skin cancer and cervical carcinoma in situ.
7. Any other condition that, in the Investigator's judgment, would have substantially increased the risk associated with the subject's participation in this study.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Other
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Stopped early
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/02/2006
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
1/05/2007
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Sample size
Target
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Accrual to date
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Final
9
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Recruitment in Australia
Recruitment state(s)
QLD,VIC
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Recruitment hospital [1]
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Cancer Care Services, Dept. of Medical Oncology, Royal Brisbane and Women's Hospital - Herston
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Recruitment hospital [2]
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Ludwig Institute Tumor Targeting Program, Austin Health - Heidelberg (Melbourne)
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Recruitment postcode(s) [1]
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4209 - Herston
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Recruitment postcode(s) [2]
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3084 - Heidelberg (Melbourne)
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Funding & Sponsors
Primary sponsor type
Other
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Name
Ludwig Institute for Cancer Research
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Address
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Country
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Other collaborator category [1]
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Commercial sector/industry
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Name [1]
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Wyeth is now a wholly owned subsidiary of Pfizer
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Address [1]
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Country [1]
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/study/NCT00293215
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Trial related presentations / publications
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000 Feb 2;92(3):205-16. doi: 10.1093/jnci/92.3.205. Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, Pruim J, Price P. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer. 1999 Dec;35(13):1773-82. doi: 10.1016/s0959-8049(99)00229-4. Herbertson RA, Tebbutt NC, Lee FT, MacFarlane DJ, Chappell B, Micallef N, Lee ST, Saunder T, Hopkins W, Smyth FE, Wyld DK, Bellen J, Sonnichsen DS, Brechbiel MW, Murone C, Scott AM. Phase I biodistribution and pharmacokinetic study of Lewis Y-targeting immunoconjugate CMD-193 in patients with advanced epithelial cancers. Clin Cancer Res. 2009 Nov 1;15(21):6709-15. doi: 10.1158/1078-0432.CCR-09-0536. Epub 2009 Oct 13.
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Public notes
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Contacts
Principal investigator
Name
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A/Prof. Andrew M Scott, MBBS MD DDU
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Address
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Ludwig Institute for Cancer Research
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Phone
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Fax
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Email
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Contact person for scientific queries
Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
Type
Citations or Other Details
Journal
Herbertson RA, Tebbutt NC, Lee FT, MacFarlane DJ, ...
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More Details
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Results are available at
https://clinicaltrials.gov/study/NCT00293215