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

Primary Purpose

Colorectal Neoplasms

Status
Completed
Phase
Phase 1
Locations
Australia
Study Type
Interventional
Intervention
CS-1008
Sponsored by
Ludwig Institute for Cancer Research
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Colorectal Neoplasms focused on measuring Clinical trial, CS-1008 mAb, monoclonal antibody CS-1008, Positron-Emission Tomography, Pharmacokinetics, Pharmacodynamics, apoptosis, caspases

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Histologically proven metastatic colorectal cancer with 1 target lesion ≥ 2 cm and evaluable by gamma camera imaging. If this lesion was previously irradiated, progression must have been documented following radiotherapy.
  2. Received at least 1 prior course of chemotherapy for metastatic disease.
  3. Expected survival of at least 3 months.
  4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
  5. Age ≥ 18 years old.
  6. Able and willing to give valid written informed consent.

  7. Within the last 1 week prior to first study drug administration, laboratory parameters for vital functions were to be in the normal range. Laboratory abnormalities that were not clinically significant were generally permitted, except for the following laboratory parameters, which were to be within the ranges specified:

    • Neutrophil count: ≥ 1.5 x 10^9/L
    • Platelet count: ≥ 90 x 10^9/L
    • International normalized ratio: ≤ 1.5
    • Serum bilirubin: ≤ 1.5 x upper limit of normal (ULN)
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): ≤ 2 x ULN (≤ 5 x ULN if liver metastases)
    • Calculated creatinine clearance (Cockcroft-Gault formula): ≥ 55 mL/min

Exclusion Criteria:

  1. Active central nervous system metastases. Definitively treated metastases were allowed if stable for 6 weeks off therapy.
  2. Known immunodeficiency or human immunodeficiency virus positivity.
  3. Serious illnesses, e.g., serious infections requiring antibiotics, bleeding disorders, or any condition that in the opinion of the Investigator would have interfered with the ability of the subject to fulfill the study requirements.
  4. Other malignancy, apart from non-melanoma skin cancer, within 3 years prior to first study drug administration, that in the opinion of the Investigator had >10% risk of relapse within 12 months.
  5. Chemotherapy, radiotherapy, or investigational agent within 4 weeks prior to first study drug administration.
  6. Regular corticosteroid, nonsteroidal anti-inflammatory drug (NSAID) (other than paracetamol or low-dose aspirin) or other immunosuppressive treatment within 3 weeks prior to first drug administration. Intermittent dosing of corticosteroid or NSAID was permitted if less than 4 doses within a 3-day period.
  7. Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study.
  8. Lack of availability for clinical follow-up assessments.
  9. Pregnancy or breastfeeding.
  10. Women of childbearing potential: refusal or inability to use effective means of contraception.

Sites / Locations

  • Ludwig Institute Tumor Targeting Program, Austin Health

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Cohort 1

Cohort 2

Cohort 3

Cohort 4

Cohort 5

Arm Description

Subjects received an initial loading dose of 111^In-CS-1008 (0.2 mg/kg) on Day 1, CS-1008 (6 mg/kg) on Day 8, and subsequent weekly doses of CS-1008 (2 mg/kg) on Days 15, 22, 29, 36, and 43; the Day 36 dose was also radiolabeled with 111^In. Additional 4-week cycles of weekly CS-1008 (2 mg/kg) were permitted for subjects benefiting from treatment.

Subjects received an initial loading dose of 111^In-CS-1008 (1 mg/kg) on Day 1, CS-1008 (6 mg/kg) on Day 8, and subsequent weekly doses of CS-1008 (2 mg/kg) on Days 15, 22, 29, 36, and 43; the Day 36 dose was also radiolabeled with 111^In. Additional 4-week cycles of weekly CS-1008 (2 mg/kg) were permitted for subjects benefiting from treatment.

Subjects received an initial loading dose of 111^In-CS-1008 (2 mg/kg) on Day 1, CS-1008 (6 mg/kg) on Day 8, and subsequent weekly doses of CS-1008 (2 mg/kg) on Days 15, 22, 29, 36, and 43; the Day 36 dose was also radiolabeled with 111^In. Additional 4-week cycles of weekly CS-1008 (2 mg/kg) were permitted for subjects benefiting from treatment.

Subjects received an initial loading dose of 111^In-CS-1008 (4 mg/kg) on Day 1, CS-1008 (4 mg/kg) on Day 8, and subsequent weekly doses of CS-1008 (2 mg/kg) on Days 15, 22, 29, 36, and 43; the Day 36 dose was also radiolabeled with 111^In. Additional 4-week cycles of weekly CS-1008 (2 mg/kg) were permitted for subjects benefiting from treatment.

Subjects received an initial loading dose of 111^In-CS-1008 (6 mg/kg) on Day 1, CS-1008 (2 mg/kg) on Day 8, and subsequent weekly doses of CS-1008 (2 mg/kg) on Days 15, 22, 29, 36, and 43; the Day 36 dose was also radiolabeled with 111^In. Additional 4-week cycles of weekly CS-1008 (2 mg/kg) were permitted for subjects benefiting from treatment.

Outcomes

Primary Outcome Measures

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
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 obtained from quantitative whole body images obtained at multiple time points. MIRD formalism was used in the calculation of doses.
Mean Tumor Uptake of 111^In-CS-1008 Based on Gamma Camera Imaging Following the Day 1 and Day 36 Infusions
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.
Mean 111^In-CS-1008 Serum Half-life by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008
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).
Mean 111^In-CS-1008 Serum Volume of Central Compartment by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008
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).
Mean 111^In-CS-1008 Serum Area Under the Curve by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008
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).
Mean 111^In-CS-1008 Serum Total Clearance by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008
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).
Mean 111^In-CS-1008 Serum Maximum Concentration by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008
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).
Mean 111^In-CS-1008 Serum Half-life by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008
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).
Mean 111^In-CS-1008 Serum Volume of Central Compartment by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008
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).
Mean 111^In-CS-1008 Serum Area Under the Curve by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008
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).
Mean 111^In-CS-1008 Serum Total Clearance by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008
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).
Mean 111^In-CS-1008 Serum Maximum Concentration by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008
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).

Secondary Outcome Measures

Number of Subjects With Best Overall Tumor Response
Tumor responses were evaluated using appropriate imaging and categorized according to the Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, at Screening, at the end of every odd-numbered cycle (i.e., Cycles 1, 3, and 5, as applicable), and at the time of treatment discontinuation. Per RECIST 1.1, target lesions are categorized as follows: Complete Response (CR): Disappearance of all target lesions; 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 (Eisenhauer et al. Eur J Cancer 2009;45:228-47).
Number of Subjects With Best Overall Metabolic Response
Metabolic response to CS-1008 was assessed by fluorodeoxyglucose positron emission tomography (18^F-FDG PET) at Screening, Day 15, and at the End of Cycle 1/End of Study visit (Days 44-50). For each FDG-PET performed, the maximum standardized uptake value (SUVmax) corrected for body weight for all target lesions >2 cm identified on CT imaging was calculated using region of interest (ROI). The ROI was determined with the aid of the anatomical detail provided by the CT scan. Tumor metabolic response to CS-1008 was assessed by 18^F-FDG PET/CT calculated using the target lesion with the greatest baseline SUVmax, and was categorized according to the European Organization for Research and Treatment of Cancer (EORTC) guidelines (Young et al. Eur J Cancer 1999;35:1773-82).

Full Information

First Posted
October 12, 2010
Last Updated
October 3, 2022
Sponsor
Ludwig Institute for Cancer Research
Collaborators
Daiichi Sankyo, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01220999
Brief Title
A Phase I Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer
Official Title
A Phase I Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Completed
Study Start Date
October 12, 2010 (Actual)
Primary Completion Date
June 27, 2012 (Actual)
Study Completion Date
June 27, 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ludwig Institute for Cancer Research
Collaborators
Daiichi Sankyo, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
Detailed Description
Eligible subjects were to be enrolled into one of 5 dose-escalation cohorts to receive CS-1008 administered weekly as an intravenous (IV) infusion over 30 ± 10 minutes. Each cohort initially comprised 2 subjects but was expanded in up to 5 subjects if additional biodistribution and/or PK data were required. The initial infusion of CS-1008 on Day 1 was trace labeled with Indium-111 (111^In-CS-1008; 5-7 mCi) and was investigated at escalating doses up to the standard loading dose, as follows: Cohort 1 (0.2 mg/kg), Cohort 2 (1 mg/kg), Cohort 3 (2 mg/kg), Cohort 4 (4 mg/kg), and Cohort 5 (6 mg/kg). The initial 111^In-CS-1008 dose was followed by gamma camera imaging with blood sampling over a 10-day period to evaluate biodistribution, tumor uptake, PK, and serum biomarkers. Day 8 dosing comprised non-labeled CS-1008 at doses of 6 mg/kg in Cohorts 1-3, 4 mg/kg in Cohort 4, and 2 mg/kg in Cohort 5. Subsequent weekly infusions of standard dose CS-1008 (2 mg/kg) were administered on Days 15, 22, 29, 36, and 43. The Day 36 infusion of CS-1008 was also trace labeled with 111^In (5-7 mCi), with subsequent gamma camera imaging and blood sampling. Subjects were assessed for disease status using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, serum tumor biomarkers (carcinoembryonic antigen [CEA]), and human-anti-CS-1008-antibody development (HAHA). Subjects were assessed for changes in tumor metabolism following CS-1008 administration using computed tomography (CT) or fluorodeoxyglucose positron emission tomography (18^F-FDG PET) scans. Cycle 1 encompassed the first 7 weeks of therapy. Within 1 week (Days 44-50) after the last infusion of CS-1008, subjects completed an End of Study/End of Cycle 1 assessment. Subjects with stable disease or better (according to RECIST version 1.1) at the Day 44-50 reassessment were permitted to receive additional 4-week cycles of CS-1008 (2 mg/kg) until disease progression, unacceptable toxicity, or subject/physician decision.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Neoplasms
Keywords
Clinical trial, CS-1008 mAb, monoclonal antibody CS-1008, Positron-Emission Tomography, Pharmacokinetics, Pharmacodynamics, apoptosis, caspases

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
19 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1
Arm Type
Experimental
Arm Description
Subjects received an initial loading dose of 111^In-CS-1008 (0.2 mg/kg) on Day 1, CS-1008 (6 mg/kg) on Day 8, and subsequent weekly doses of CS-1008 (2 mg/kg) on Days 15, 22, 29, 36, and 43; the Day 36 dose was also radiolabeled with 111^In. Additional 4-week cycles of weekly CS-1008 (2 mg/kg) were permitted for subjects benefiting from treatment.
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
Subjects received an initial loading dose of 111^In-CS-1008 (1 mg/kg) on Day 1, CS-1008 (6 mg/kg) on Day 8, and subsequent weekly doses of CS-1008 (2 mg/kg) on Days 15, 22, 29, 36, and 43; the Day 36 dose was also radiolabeled with 111^In. Additional 4-week cycles of weekly CS-1008 (2 mg/kg) were permitted for subjects benefiting from treatment.
Arm Title
Cohort 3
Arm Type
Experimental
Arm Description
Subjects received an initial loading dose of 111^In-CS-1008 (2 mg/kg) on Day 1, CS-1008 (6 mg/kg) on Day 8, and subsequent weekly doses of CS-1008 (2 mg/kg) on Days 15, 22, 29, 36, and 43; the Day 36 dose was also radiolabeled with 111^In. Additional 4-week cycles of weekly CS-1008 (2 mg/kg) were permitted for subjects benefiting from treatment.
Arm Title
Cohort 4
Arm Type
Experimental
Arm Description
Subjects received an initial loading dose of 111^In-CS-1008 (4 mg/kg) on Day 1, CS-1008 (4 mg/kg) on Day 8, and subsequent weekly doses of CS-1008 (2 mg/kg) on Days 15, 22, 29, 36, and 43; the Day 36 dose was also radiolabeled with 111^In. Additional 4-week cycles of weekly CS-1008 (2 mg/kg) were permitted for subjects benefiting from treatment.
Arm Title
Cohort 5
Arm Type
Experimental
Arm Description
Subjects received an initial loading dose of 111^In-CS-1008 (6 mg/kg) on Day 1, CS-1008 (2 mg/kg) on Day 8, and subsequent weekly doses of CS-1008 (2 mg/kg) on Days 15, 22, 29, 36, and 43; the Day 36 dose was also radiolabeled with 111^In. Additional 4-week cycles of weekly CS-1008 (2 mg/kg) were permitted for subjects benefiting from treatment.
Intervention Type
Drug
Intervention Name(s)
CS-1008
Other Intervention Name(s)
Tigatuzumab
Intervention Description
CS-1008 was administered once weekly as an intravenous infusion over 30 ± 10 minutes at a dose range of 0.2 to 6 mg/kg. On Days 1 and 36, CS-1008 infusions were radiolabeled with 111^In (5-7 mCi).
Primary Outcome Measure Information:
Title
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
Description
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 obtained from quantitative whole body images obtained at multiple time points. MIRD formalism was used in the calculation of doses.
Time Frame
Up to 43 days
Title
Mean Tumor Uptake of 111^In-CS-1008 Based on Gamma Camera Imaging Following the Day 1 and Day 36 Infusions
Description
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.
Time Frame
Up to 43 days
Title
Mean 111^In-CS-1008 Serum Half-life by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008
Description
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).
Time Frame
Up to 36 days
Title
Mean 111^In-CS-1008 Serum Volume of Central Compartment by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008
Description
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).
Time Frame
Up to 36 days
Title
Mean 111^In-CS-1008 Serum Area Under the Curve by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008
Description
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).
Time Frame
Up to 36 days
Title
Mean 111^In-CS-1008 Serum Total Clearance by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008
Description
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).
Time Frame
Up to 36 days
Title
Mean 111^In-CS-1008 Serum Maximum Concentration by Gamma Counting Following the Day 1 Infusion of 111^In-CS-1008
Description
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).
Time Frame
Up to 36 days
Title
Mean 111^In-CS-1008 Serum Half-life by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008
Description
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).
Time Frame
Up to 50 days
Title
Mean 111^In-CS-1008 Serum Volume of Central Compartment by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008
Description
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).
Time Frame
Up to 50 days
Title
Mean 111^In-CS-1008 Serum Area Under the Curve by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008
Description
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).
Time Frame
Up to 50 days
Title
Mean 111^In-CS-1008 Serum Total Clearance by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008
Description
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).
Time Frame
Up to 50 days
Title
Mean 111^In-CS-1008 Serum Maximum Concentration by Gamma Counting Following the Day 36 Infusion of 111^In-CS-1008
Description
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).
Time Frame
Up to 50 days
Secondary Outcome Measure Information:
Title
Number of Subjects With Best Overall Tumor Response
Description
Tumor responses were evaluated using appropriate imaging and categorized according to the Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, at Screening, at the end of every odd-numbered cycle (i.e., Cycles 1, 3, and 5, as applicable), and at the time of treatment discontinuation. Per RECIST 1.1, target lesions are categorized as follows: Complete Response (CR): Disappearance of all target lesions; 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 (Eisenhauer et al. Eur J Cancer 2009;45:228-47).
Time Frame
Up to 7 months
Title
Number of Subjects With Best Overall Metabolic Response
Description
Metabolic response to CS-1008 was assessed by fluorodeoxyglucose positron emission tomography (18^F-FDG PET) at Screening, Day 15, and at the End of Cycle 1/End of Study visit (Days 44-50). For each FDG-PET performed, the maximum standardized uptake value (SUVmax) corrected for body weight for all target lesions >2 cm identified on CT imaging was calculated using region of interest (ROI). The ROI was determined with the aid of the anatomical detail provided by the CT scan. Tumor metabolic response to CS-1008 was assessed by 18^F-FDG PET/CT calculated using the target lesion with the greatest baseline SUVmax, and was categorized according to the European Organization for Research and Treatment of Cancer (EORTC) guidelines (Young et al. Eur J Cancer 1999;35:1773-82).
Time Frame
Up to 50 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histologically proven metastatic colorectal cancer with 1 target lesion ≥ 2 cm and evaluable by gamma camera imaging. If this lesion was previously irradiated, progression must have been documented following radiotherapy. Received at least 1 prior course of chemotherapy for metastatic disease. Expected survival of at least 3 months. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Age ≥ 18 years old. Able and willing to give valid written informed consent. Within the last 1 week prior to first study drug administration, laboratory parameters for vital functions were to be in the normal range. Laboratory abnormalities that were not clinically significant were generally permitted, except for the following laboratory parameters, which were to be within the ranges specified: Neutrophil count: ≥ 1.5 x 10^9/L Platelet count: ≥ 90 x 10^9/L International normalized ratio: ≤ 1.5 Serum bilirubin: ≤ 1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): ≤ 2 x ULN (≤ 5 x ULN if liver metastases) Calculated creatinine clearance (Cockcroft-Gault formula): ≥ 55 mL/min Exclusion Criteria: Active central nervous system metastases. Definitively treated metastases were allowed if stable for 6 weeks off therapy. Known immunodeficiency or human immunodeficiency virus positivity. Serious illnesses, e.g., serious infections requiring antibiotics, bleeding disorders, or any condition that in the opinion of the Investigator would have interfered with the ability of the subject to fulfill the study requirements. Other malignancy, apart from non-melanoma skin cancer, within 3 years prior to first study drug administration, that in the opinion of the Investigator had >10% risk of relapse within 12 months. Chemotherapy, radiotherapy, or investigational agent within 4 weeks prior to first study drug administration. Regular corticosteroid, nonsteroidal anti-inflammatory drug (NSAID) (other than paracetamol or low-dose aspirin) or other immunosuppressive treatment within 3 weeks prior to first drug administration. Intermittent dosing of corticosteroid or NSAID was permitted if less than 4 doses within a 3-day period. Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study. Lack of availability for clinical follow-up assessments. Pregnancy or breastfeeding. Women of childbearing potential: refusal or inability to use effective means of contraception.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrew M Scott, MBBS, MD, FRACP, DDU
Organizational Affiliation
Ludwig Institute for Cancer Research & Austin Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ludwig Institute Tumor Targeting Program, Austin Health
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3084
Country
Australia

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
19097774
Citation
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
Results Reference
background
PubMed Identifier
10673991
Citation
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.
Results Reference
background
PubMed Identifier
26124477
Citation
Ciprotti M, Tebbutt NC, Lee FT, Lee ST, Gan HK, McKee DC, O'Keefe GJ, Gong SJ, Chong G, Hopkins W, Chappell B, Scott FE, Brechbiel MW, Tse AN, Jansen M, Matsumura M, Kotsuma M, Watanabe R, Venhaus R, Beckman RA, Greenberg J, Scott AM. Phase I Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer. J Clin Oncol. 2015 Aug 20;33(24):2609-16. doi: 10.1200/JCO.2014.60.4256. Epub 2015 Jun 29.
Results Reference
result

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

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