A Phase 1 interventional study of 111-Indium-CMD-193 and CMD-193 in Neoplasms, sponsored by Ludwig Institute for Cancer Research. Terminated at 2 sites in Australia. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-10-10.
Sponsored by Ludwig Institute for Cancer Research · Phase 1, Interventional, and Treatment
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.
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.
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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
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
111-In-CMD-193 (3-7 mCi) was administered as an IV infusion over 60 (± 5) minutes.
CMD-193 was administered as an IV infusion over 60 (± 5) minutes.
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Approximately 15 days (i.e., Days 1, 3, 8, and 15)
Number of Subjects With Best Tumor Response as Measured by the Response Evaluation Criteria in Solid Tumors (RECIST)
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.
Time frame: 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
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).
Time frame: Up to 4 months
| Milestone | Cohort 1 (1.0 mg/m^2) | Cohort 2 (2.6 mg/m^2) |
|---|---|---|
| Started | 6 | 3 |
| Completed | 1 | 0 |
| Not completed | 5 | 3 |
| Withdrew: Progressive disease | 3 | 1 |
| Withdrew: Adverse event | 2 | 2 |
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.
| Participants | Cohort 1 (1.0 mg/m^2) | Cohort 2 (2.6 mg/m^2) |
|---|---|---|
| Initial blood pooling | 6 | 3 |
| Hepatic uptake by Day 2 persisting to Day 8 | 6 | 3 |
| Fast blood clearance | 6 | 3 |
| Tumor uptake | 0 | 0 |
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.
| hours | Cohort 1 (1.0 mg/m^2) | Cohort 2 (2.6 mg/m^2) |
|---|---|---|
| Mean Effective Half-life of 111-In-CMD-193 Based on Gamma Camera Images | 47.54 ± 3.16 | 48.37 ± 4.03 |
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.
| hours | Cohort 1 (1.0 mg/m^2) | Cohort 2 (2.6 mg/m^2) |
|---|---|---|
| T½α | 5.47 ± 1.99 | 3.32 ± 2.00 |
| T½β | 104.42 ± 37.94 | 99.79 ± 38.32 |
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.
| mL | Cohort 1 (1.0 mg/m^2) | Cohort 2 (2.6 mg/m^2) |
|---|---|---|
| Mean Volume of Central Compartment of 111-In-CMD-193 | 4366.18 ± 586.87 | 3481.31 ± 704.13 |
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.
| mL/hr | Cohort 1 (1.0 mg/m^2) | Cohort 2 (2.6 mg/m^2) |
|---|---|---|
| Mean Total Serum Clearance of 111-In-CMD-193 | 130.04 ± 61.25 | 79.56 ± 29.67 |
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.
| μg*hr/mL | Cohort 1 (1.0 mg/m^2) | Cohort 2 (2.6 mg/m^2) |
|---|---|---|
| Mean Area Under the Serum Concentration Curve Extrapolated to Infinite Time for 111-In-CMD-193 | 16.37 ± 6.13 | 56.45 ± 17.05 |
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.
| Participants | Cohort 1 (1.0 mg/m^2) | Cohort 2 (2.6 mg/m^2) |
|---|---|---|
| Stable disease | 3 | 2 |
| Progressive disease | 3 | 0 |
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).
| Participants | Cohort 1 (1.0 mg/m^2) | Cohort 2 (2.6 mg/m^2) |
|---|---|---|
| Partial metabolic response | 1 | 0 |
| Stable metabolic disease | 2 | 1 |
| Progressive metabolic disease | 3 | 1 |
Collected over All adverse events (AEs) occurring between the first dose of study treatment and the off-study date (i.e., up to 4 months) were documented, regardless of the causal relationship to study drug.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Cohort 1 (1.0 mg/m^2) | 0/6 (0%) | 1/6 (16.7%) | 6/6 (100%) |
| Cohort 2 (2.6 mg/m^2) | 1/3 (33.3%) | 1/3 (33.3%) | 3/3 (100%) |
| Event | Cohort 1 (1.0 mg/m^2) | Cohort 2 (2.6 mg/m^2) |
|---|---|---|
| Malignant pleural effusionRespiratory, thoracic and mediastinal disorders | 0/6 | 1/3 |
| Pleural effusionRespiratory, thoracic and mediastinal disorders | 0/6 | 1/3 |
| Biliary sepsisInfections and infestations | 1/6 | 0/3 |
| Event | Cohort 1 (1.0 mg/m^2) | Cohort 2 (2.6 mg/m^2) |
|---|---|---|
| ThrombocytopeniaBlood and lymphatic system disorders | 6/6 | 2/3 |
| LethargyGeneral disorders | 6/6 | 0/3 |
| AnorexiaMetabolism and nutrition disorders | 5/6 | 3/3 |
| HyperbilirubinaemiaHepatobiliary disorders | 2/6 | 3/3 |
| AnaemiaBlood and lymphatic system disorders | 5/6 | 1/3 |
| NauseaGastrointestinal disorders | 5/6 | 2/3 |
| LeukopeniaBlood and lymphatic system disorders | 1/6 | 2/3 |
| NeutropeniaBlood and lymphatic system disorders | 1/6 | 2/3 |
| VomitingGastrointestinal disorders | 2/6 | 2/3 |
| Alkaline phosphatase increasedInvestigations | 4/6 | 1/3 |
All enrolled subjects.
| Age, Continuous(years) | Cohort 1 (1.0 mg/m^2) | Cohort 2 (2.6 mg/m^2) | Total |
|---|---|---|---|
| Median | 53 (46 to 71) | 69 (46 to 77) | 53 (46 to 77) |
| Sex: Female, Male(Participants) | Cohort 1 (1.0 mg/m^2) | Cohort 2 (2.6 mg/m^2) | Total |
|---|---|---|---|
| Female | 2 | 2 | 4 |
| Male | 4 | 1 | 5 |
| Race (NIH/OMB)(Participants) | Cohort 1 (1.0 mg/m^2) | Cohort 2 (2.6 mg/m^2) | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 1 | 2 | 3 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 |
| White | 5 | 1 | 6 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(Participants) | Cohort 1 (1.0 mg/m^2) | Cohort 2 (2.6 mg/m^2) | Total |
|---|---|---|---|
| Australia | 6 | 3 | 9 |
| Primary tumor(Participants) | Cohort 1 (1.0 mg/m^2) | Cohort 2 (2.6 mg/m^2) | Total |
|---|---|---|---|
| Colon carcinoma | 3 | 0 | 3 |
| Cholangiocarcinoma | 1 | 0 | 1 |
| Gastric carcinoma | 1 | 1 | 2 |
| Gastro-esophageal junction carcinoma | 1 | 0 | 1 |
| Bronchoalveolar carcinoma | 0 | 1 | 1 |
| Pulmonary adenocarcinoma | 0 | 1 | 1 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)(Participants) | Cohort 1 (1.0 mg/m^2) | Cohort 2 (2.6 mg/m^2) | Total |
|---|---|---|---|
| 0 | 5 | 1 | 6 |
| 1 | 1 | 2 | 3 |
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Ludwig Institute for Cancer Research