Biodistribution Study of CMD-193 in Patients With Advanced Tumours Expressing the Lewis-Y Antigen

NCT00293215 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: LUD2004-015
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 2

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.

Conditions

Neoplasms

Outcome Measures

Primary Outcomes (6)

• Summary of 111-In-CMD-193 Biodistribution Based on Gamma Camera Images

  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.

  Up to 8 days

• Mean Effective Half-life of 111-In-CMD-193 Based on Gamma Camera Images

  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.

  Up to 8 days

• Mean Serum Half-lives of 111-In-CMD-193

  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.

  Approximately 15 days (i.e., Days 1, 3, 8, and 15)

• Mean Volume of Central Compartment of 111-In-CMD-193

  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.

  Approximately 15 days (i.e., Days 1, 3, 8, and 15)

• Mean Total Serum Clearance of 111-In-CMD-193

  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.

  Approximately 15 days (i.e., Days 1, 3, 8, and 15)

• Mean Area Under the Serum Concentration Curve Extrapolated to Infinite Time for 111-In-CMD-193

  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.

  Approximately 15 days (i.e., Days 1, 3, 8, and 15)

Secondary Outcomes (2)

• 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

Study Arms (2)

Cohort 1 (1.0 mg/m^2)

EXPERIMENTAL

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.

Drug: 111-Indium-CMD-193; Drug: CMD-193

Cohort 2 (2.6 mg/m^2)

EXPERIMENTAL

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.

Drug: 111-Indium-CMD-193; Drug: CMD-193

Interventions

111-Indium-CMD-193 DRUG

111-In-CMD-193 (3-7 mCi) was administered as an IV infusion over 60 (± 5) minutes.

Cohort 1 (1.0 mg/m^2); Cohort 2 (2.6 mg/m^2)

CMD-193 DRUG

CMD-193 was administered as an IV infusion over 60 (± 5) minutes.

Cohort 1 (1.0 mg/m^2); Cohort 2 (2.6 mg/m^2)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed and dated Institutional Review Board (IRB)-approved informed consent before any protocol-specific screening procedures were performed.
• Histologically confirmed malignant solid tumor that had progressed following standard therapy, or for which no standard effective treatment was available.
• Tumor expression of Lewis-Y antigen (≥20% tumor cells positive for Lewis-Y by immunohistochemistry assay).
• 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.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Life expectancy ≥ 18 weeks.
• Age ≥18 years.
• 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).
• Renal test: serum creatinine ≤ 1.5 x upper limit of normal (ULN).
• Hepatic tests: alanine aminotransferase (ALT) levels ≤2.5 x ULN and total bilirubin ≤1.5 x ULN.
• Pancreatic tests: amylase ≤1.5 x ULN and lipase ≤ 1.5 x ULN.
• 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).
• 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.
• 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.
• Willingness of female subjects to refrain from breastfeeding infants during the study or within 28 days after the last dose of CMD-193.

You may not qualify if:

• 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).
• 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.
• Significant prior allergic reaction to recombinant human or murine proteins.
• History of cirrhosis, current or chronic hepatitis B or C infections, or other significant active liver disease.
• 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.
• Other malignancy within 3 years prior to entry into the study, except for treated non-melanoma skin cancer and cervical carcinoma in situ.
• Any other condition that, in the Investigator's judgment, would have substantially increased the risk associated with the subject's participation in this study.

Sponsors & Collaborators

• Ludwig Institute for Cancer Research: lead
• Wyeth is now a wholly owned subsidiary of Pfizer: collaborator

Study Sites (2)

Cancer Care Services, Dept. of Medical Oncology, Royal Brisbane and Women's Hospital

Herston, Queensland, 4209, Australia

Location

Ludwig Institute Tumor Targeting Program, Austin Health

Heidelberg (Melbourne), Victoria, 3084, Australia

Location

Related Publications (3)

• 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.

  PMID: 10655437 BACKGROUND

• 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.

  PMID: 10673991 BACKGROUND

• 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.

  PMID: 19825951 RESULT

MeSH Terms

Conditions

Neoplasms

Limitations and Caveats

Following an interim review of primary endpoint data, the study was terminated early on the basis of abnormal distribution and lack of tumor targeting in both dose cohorts.

Results Point of Contact

• Title: Jonathan Skipper PhD
• Organization: Ludwig Institute for Cancer Research

jskipper@lcr.org

(212) 450-1539

Study Officials

• A/Prof. Andrew M Scott, MBBS MD DDU

  Ludwig Institute for Cancer Research

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 15, 2006
• First Posted: February 17, 2006
• Study Start: February 1, 2006
• Primary Completion: May 1, 2007
• Study Completion: May 1, 2007
• Last Updated: October 10, 2022
• Results First Posted: August 10, 2020

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

AU (2)