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

NCT01220999 | Completed Phase 1 Results

• 1 other identifier: LUD2010-002
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

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.

Conditions

Colorectal Neoplasms

Keywords

Clinical trial; CS-1008 mAb; monoclonal antibody CS-1008; Positron-Emission Tomography; Pharmacokinetics; Pharmacodynamics; apoptosis; caspases

Outcome Measures

Primary Outcomes (12)

• 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.

  Up to 43 days

• 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.

  Up to 43 days

• 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).

  Up to 36 days

• 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).

  Up to 36 days

• 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).

  Up to 36 days

• 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).

  Up to 36 days

• 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).

  Up to 36 days

• 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).

  Up to 50 days

• 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).

  Up to 50 days

• 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).

  Up to 50 days

• 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).

  Up to 50 days

• 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).

  Up to 50 days

Secondary Outcomes (2)

• Number of Subjects With Best Overall Tumor Response

  Up to 7 months

• Number of Subjects With Best Overall Metabolic Response

  Up to 50 days

Study Arms (5)

Cohort 1

EXPERIMENTAL

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.

Drug: CS-1008

Cohort 2

EXPERIMENTAL

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.

Drug: CS-1008

Cohort 3

EXPERIMENTAL

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.

Drug: CS-1008

Cohort 4

EXPERIMENTAL

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.

Drug: CS-1008

Cohort 5

EXPERIMENTAL

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.

Drug: CS-1008

Interventions

CS-1008 DRUG

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).

Also known as: Tigatuzumab

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Ludwig Institute for Cancer Research: lead
• Daiichi Sankyo: collaborator

Study Sites (1)

Ludwig Institute Tumor Targeting Program, Austin Health

Melbourne, Victoria, 3084, Australia

Location

Related Publications (3)

• 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.

  PMID: 19097774 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

• 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.

  PMID: 26124477 RESULT

Related Links

• Full-text of Ciprotti et al 2015

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

tigatuzumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Results Point of Contact

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

jskipper@lcr.org

(212) 450-1539

Study Officials

• Andrew M Scott, MBBS, MD, FRACP, DDU

  Ludwig Institute for Cancer Research & Austin Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

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

Study Record Dates

• First Submitted: October 12, 2010
• First Posted: October 14, 2010
• Study Start: October 12, 2010
• Primary Completion: June 27, 2012
• Study Completion: June 27, 2012
• Last Updated: October 28, 2022
• Results First Posted: September 23, 2019

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)