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NCT01220999

A Phase I Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer

Completed Phase 1 Results posted Last updated 28 October 2022
What this trial tests

Phase 1 trial testing CS-1008 in Colorectal Neoplasms in 19 participants. Completed in 27 June 2012.

Timeline
12 October 2010
Primary endpoint
27 June 2012
27 June 2012

Quick facts

Lead sponsorLudwig Institute for Cancer Research
PhasePhase 1
StatusCompleted
Study typeINTERVENTIONAL
Allocationnon randomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment19
Start date12 October 2010
Primary completion27 June 2012
Estimated completion27 June 2012
Sites1 location across Australia

Drugs / interventions tested

Conditions studied

Sponsor

Ludwig Institute for Cancer Research

Who can join

18 and older, any sex, with Colorectal Neoplasms. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Subjects With Tumor Uptake of 111^In-CS-1008 in Target Lesions Based on Gamma Camera Imaging Following the Day 1 and Day 36 Infusions Primary · Up to 43 days

Tumor localization was assessed using gamma camera imaging performed after the initial infusion of 111\^In-CS-1008 on Day 1 and then on Days 2, 4/5, 7/8, and 11/12 (collectively, "After Day 1 Infusion" in the table) and after the second infusion of 111\^In-CS-1008 on Day 36 and then on Days 37, 39/40, and 42/43 (collectively, "After Day 36 Infusion" in the table). Dosimetry calculations were performed to determine the tumor localization properties of 111\^In-CS-1008. Calculation of whole body dose and doses to individual organs by 111\^In-CS-1008 were performed based on conjugate view images o

After Day 1 infusion: High, Specific Uptake
GroupValue95% CI
Cohort 10
Cohort 23
Cohort 33
Cohort 43
Cohort 53
After Day 1 infusion: No Uptake
GroupValue95% CI
Cohort 12
Cohort 21
Cohort 32
Cohort 40
Cohort 52
After Day 36 infusion: High, Specific Uptake
GroupValue95% CI
Cohort 10
Cohort 23
Cohort 33
Cohort 43
Cohort 53
After Day 36 infusion: No Uptake
GroupValue95% CI
Cohort 12
Cohort 21
Cohort 31
Cohort 40
Cohort 52
Mean Tumor Uptake of 111^In-CS-1008 Based on Gamma Camera Imaging Following the Day 1 and Day 36 Infusions Primary · Up to 43 days

Tumor localization was assessed using gamma camera imaging performed on Days 7/8 and 42/43. Dosimetry calculations were performed to determine the tumor localization properties of 111\^In-CS-1008. Calculation of whole body dose and doses to individual organs by 111\^In-CS-1008 were performed based on conjugate view images obtained from quantitative whole body images obtained at multiple time points. MIRD formalism was used in the calculation of doses.

Post-infusion tumor uptake: Day 7/8
GroupValue95% CI
Cohort 20.0042± 0.0013
Cohort 30.0063± 0.0004
Cohort 40.0044± 0.0015
Cohort 50.0043± 0.0006
Post-infusion tumor uptake: Day 42/43
GroupValue95% CI
Cohort 20.0045± 0.0005
Cohort 30.0061± 0.0011
Cohort 40.0044± 0.0012
Cohort 50.0036± 0.0007
Mean 111^In-CS-1008 Serum Half-life by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008 Primary · Up to 36 days

The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 1 infusion at the following time points: Day 1 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 2 (24 hours after Day 1 infusion), Day 4/5, Day 7/8 (pre-infusion and 5 minutes post-infusion if on Day 8), Day 11/12, and Day 36 (pre-infusion).

Initial half-life
GroupValue95% CI
Cohort 114.51± 5.95
Cohort 221.52± 5.76
Cohort 35.29± 4.76
Cohort 410.45± 6.85
Cohort 514.73± 4.72
Terminal half-life
GroupValue95% CI
Cohort 1284.76± 0.38
Cohort 2264.89± 122.12
Cohort 3163.08± 39.86
Cohort 4243.39± 52.21
Cohort 5247.5± 52.9
Mean 111^In-CS-1008 Serum Volume of Central Compartment by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008 Primary · Up to 36 days

The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 1 infusion at the following time points: Day 1 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 2 (24 hours after Day 1 infusion), Day 4/5, Day 7/8 (pre-infusion and 5 minutes post-infusion if on Day 8), Day 11/12, and Day 36 (pre-infusion).

GroupValue95% CI
Cohort 13209.83± 321.96
Cohort 22592.36± 303.21
Cohort 33329.11± 624.49
Cohort 42658.70± 112.60
Cohort 54037± 425
Mean 111^In-CS-1008 Serum Area Under the Curve by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008 Primary · Up to 36 days

The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 1 infusion at the following time points: Day 1 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 2 (24 hours after Day 1 infusion), Day 4/5, Day 7/8 (pre-infusion and 5 minutes post-infusion if on Day 8), Day 11/12, and Day 36 (pre-infusion).

GroupValue95% CI
Cohort 1986.58± 125.11
Cohort 25706.38± 2632.72
Cohort 38386.68± 855.70
Cohort 418714.05± 1511.25
Cohort 528492± 1598
Mean 111^In-CS-1008 Serum Total Clearance by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008 Primary · Up to 36 days

The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 1 infusion at the following time points: Day 1 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 2 (24 hours after Day 1 infusion), Day 4/5, Day 7/8 (pre-infusion and 5 minutes post-infusion if on Day 8), Day 11/12, and Day 36 (pre-infusion).

GroupValue95% CI
Cohort 114.92± 2.5
Cohort 212.31± 3.38
Cohort 318.23± 0.51
Cohort 412± 2.03
Cohort 518.52± 2.61
Mean 111^In-CS-1008 Serum Maximum Concentration by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008 Primary · Up to 36 days

The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 1 infusion at the following time points: Day 1 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 2 (24 hours after Day 1 infusion), Day 4/5, Day 7/8 (pre-infusion and 5 minutes post-infusion if on Day 8), Day 11/12, and Day 36 (pre-infusion).

GroupValue95% CI
Cohort 14.59± 0.89
Cohort 224.6± 3.75
Cohort 347.29± 10.19
Cohort 484.14± 11
Cohort 5131.3± 20.1
Mean 111^In-CS-1008 Serum Half-life by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008 Primary · Up to 50 days

The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 36 infusion at the following time points: Day 36 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 37 (24 hours after Day 36 infusion), Day 39/40, Day 43 (pre-infusion and 5 minutes post-infusion), and at the End of Cycle visit (Days 44-50).

Initial half-life
GroupValue95% CI
Cohort 212.21± 6.13
Cohort 315.84± 13.25
Cohort 415.01± 3.48
Cohort 515.56± 4.17
Terminal half-life
GroupValue95% CI
Cohort 2186.2± 36.3
Cohort 3247.5± 109.3
Cohort 4347± 202
Cohort 5260.5± 51.1
Mean 111^In-CS-1008 Serum Volume of Central Compartment by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008 Primary · Up to 50 days

The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 36 infusion at the following time points: Day 36 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 37 (24 hours after Day 36 infusion), Day 39/40, Day 43 (pre-infusion and 5 minutes post-infusion), and at the End of Cycle visit (Days 44-50).

GroupValue95% CI
Cohort 22510± 313
Cohort 33272± 733
Cohort 42742± 304
Cohort 53985± 660
Mean 111^In-CS-1008 Serum Area Under the Curve by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008 Primary · Up to 50 days

The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 36 infusion at the following time points: Day 36 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 37 (24 hours after Day 36 infusion), Day 39/40, Day 43 (pre-infusion and 5 minutes post-infusion), and at the End of Cycle visit (Days 44-50).

GroupValue95% CI
Cohort 29013± 1629
Cohort 39772± 626
Cohort 410990± 3205
Cohort 510465± 3286
Mean 111^In-CS-1008 Serum Total Clearance by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008 Primary · Up to 50 days

The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 36 infusion at the following time points: Day 36 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 37 (24 hours after Day 36 infusion), Day 39/40, Day 43 (pre-infusion and 5 minutes post-infusion), and at the End of Cycle visit (Days 44-50).

GroupValue95% CI
Cohort 214.11± 1.35
Cohort 315.29± 2
Cohort 410.73± 4.43
Cohort 519.00± 6.48
Mean 111^In-CS-1008 Serum Maximum Concentration by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008 Primary · Up to 50 days

The serum PK of CS-1008 was evaluated by gamma scintillation counting to assess serum radioactivity (111\^In-CS-1008) and CS-1008 protein concentration following the Day 36 infusion at the following time points: Day 36 (pre-infusion and 5 minutes and 1, 2, and 4 hours post-infusion), Day 37 (24 hours after Day 36 infusion), Day 39/40, Day 43 (pre-infusion and 5 minutes post-infusion), and at the End of Cycle visit (Days 44-50).

GroupValue95% CI
Cohort 251.08± 11.62
Cohort 347.10± 12.07
Cohort 440.98± 9.77
Cohort 547.38± 9.99

Adverse events — posted to ClinicalTrials.gov

Time frame: All adverse events (AEs) occurring between the signing of informed consent and the off-study date were documented, regardless of the causal relationship to study drug. AEs that occurred or worsened in severity after the first dose of study treatment were considered treatment emergent (i.e., TEAEs). The AE reporting period for this study was up to 7 months.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Cohort 1
Serious: 0/2 (0%)
Deaths: 0/2
Cohort 2
Serious: 0/4 (0%)
Deaths: 0/4
Cohort 3
Serious: 3/5 (60%)
Deaths: 0/5
Cohort 4
Serious: 1/3 (33%)
Deaths: 0/3
Cohort 5
Serious: 0/5 (0%)
Deaths: 0/5

Serious adverse events (7 terms)

ReactionSystemCohort 1Cohort 2Cohort 3Cohort 4Cohort 5
Vocal cord paralysisNervous system disorders
Rectal haemorrhageGastrointestinal disorders
Jaundice cholestaticHepatobiliary disorders
Escherichia sepsisInfections and infestations
PyelonephritisInfections and infestations
DehydrationMetabolism and nutrition disorders
NauseaGastrointestinal disorders
Other adverse events (44 terms — click to expand)

ReactionSystemCohort 1Cohort 2Cohort 3Cohort 4Cohort 5
NauseaGastrointestinal disorders
ConstipationGastrointestinal disorders
Upper respiratory tract infectionInfections and infestations
Back painMusculoskeletal and connective tissue disorders
DizzinessNervous system disorders
Iron deficiency anaemiaBlood and lymphatic system disorders
TachycardiaCardiac disorders
DiplopiaEye disorders
Lacrimation increasedEye disorders
Abdominal painGastrointestinal disorders
Gastrooesophageal reflux diseaseGastrointestinal disorders
VomitingGastrointestinal disorders
Abdominal distensionGastrointestinal disorders
Abdominal pain upperGastrointestinal disorders
DysphagiaGastrointestinal disorders
GastritisGastrointestinal disorders
OesophagitisGastrointestinal disorders
FatigueGeneral disorders
Oedema peripheralGeneral disorders
HyperbilirubinaemiaHepatobiliary disorders
Urinary tract infectionInfections and infestations
InfectionInfections and infestations
Lower respiratory tract infectionInfections and infestations
Oral candidiasisInfections and infestations
RhinitisInfections and infestations
Skin candidaInfections and infestations
Gamma-glutamyltransferase increasedInvestigations
AnorexiaMetabolism and nutrition disorders
Groin painMusculoskeletal and connective tissue disorders
Pain in extremityMusculoskeletal and connective tissue disorders
ArthralgiaMusculoskeletal and connective tissue disorders
Muscular weaknessMusculoskeletal and connective tissue disorders
Musculoskeletal chest painMusculoskeletal and connective tissue disorders
Neck painMusculoskeletal and connective tissue disorders
InsomniaPsychiatric disorders
DysuriaRenal and urinary disorders
Renal failure acuteRenal and urinary disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
HaemoptysisRespiratory, thoracic and mediastinal disorders
DysphoniaRespiratory, thoracic and mediastinal disorders

Most-reported serious reactions: Vocal cord paralysis, Rectal haemorrhage, Jaundice cholestatic, Escherichia sepsis, Pyelonephritis, Dehydration, Nausea.

Data from ClinicalTrials.gov NCT01220999 adverse events section.

Sponsor's own description

This was a Phase 1, open-label, single-center study of CS-1008, an immunoglobulin G subclass 1 (IgG1) humanized monoclonal antibody, in subjects with advanced colorectal carcinoma who had received ≥ 1 prior chemotherapy regimen for metastatic disease. Primary study objectives were to determine the influence of the CS-1008 dose on the biodistribution, pharmacokinetics (PK) and tumor uptake of radiolabeled CS-1008 following a single infusion and following continuous sequential doses of CS-1008. Secondary objectives were to evaluate changes in tumor metabolism, antitumor response, and changes in serum apoptosis biomarkers and tumor response markers following treatment with CS-1008.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Developing TRAIL/TRAIL death receptor-based cancer therapies.
    Yuan X, Gajan A, Chu Q, Xiong H, et al · · 2018 · cited 200× · PMID 29541897 · DOI 10.1007/s10555-018-9728-y
  2. Principles of antibody-mediated TNF receptor activation.
    Wajant H. · · 2015 · cited 111× · PMID 26292758 · DOI 10.1038/cdd.2015.109
  3. The evolution and heterogeneity of neutrophils in cancers: origins, subsets, functions, orchestrations and clinical applications.
    Liu S, Wu W, Du Y, Yin H, et al · · 2023 · cited 66× · PMID 37679744 · DOI 10.1186/s12943-023-01843-6
  4. Targeting cell death signaling in colorectal cancer: current strategies and future perspectives.
    Koehler BC, Jäger D, Schulze-Bergkamen H. · · 2014 · cited 42× · PMID 24587670 · DOI 10.3748/wjg.v20.i8.1923
  5. Phase I Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer.
    Ciprotti M, Tebbutt NC, Lee FT, Lee ST, et al · · 2015 · cited 29× · PMID 26124477 · DOI 10.1200/jco.2014.60.4256
  6. Increasing Stress to Induce Apoptosis in Pancreatic Cancer via the Unfolded Protein Response (UPR).
    Botrus G, Miller RM, Uson Junior PLS, Kannan G, et al · · 2022 · cited 25× · PMID 36614019 · DOI 10.3390/ijms24010577
  7. Targeting TRAIL Death Receptors in Triple-Negative Breast Cancers: Challenges and Strategies for Cancer Therapy.
    Kundu M, Greer YE, Dine JL, Lipkowitz S. · · 2022 · cited 25× · PMID 36496977 · DOI 10.3390/cells11233717
  8. Complex role of neutrophils in the tumor microenvironment: an avenue for novel immunotherapies.
    Zhang M, Qin H, Wu Y, Gao Q. · · 2024 · cited 23× · PMID 39297568 · DOI 10.20892/j.issn.2095-3941.2024.0192

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