A Study of IMC-A12 in Participants With Tumors Who No Longer Respond to Treatment or For Whom No Treatment is Available

Phase I Study of Anti-Insulin-Like Growth Factor-I Receptor (IGF-IR) Monoclonal Antibody IMC-A12 in Patients With Advanced Solid Tumors Who No Longer Respond to Standard Therapy or for Whom No Standard Therapy is Available

The purpose of this study is to determine if IMC-A12 is safe for participants, and also to determine the best dose of IMC-A12 to give to participants.

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumors
• Intervention / Treatment: Biological: IMC-A12; Biological: IMC-A12; Biological: IMC-A12; Biological: IMC-A12; Biological: IMC-A12; Biological: IMC-A12

Detailed Description

The purpose of this study is to establish the safety profile and maximum tolerated dose (MTD) of the anti-IGF-IR monoclonal antibody IMC-A12 administered weekly in participants with advanced solid tumors who no longer respond to standard therapy or for whom no standard therapy is available

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • ImClone Investigational Site
  • Michigan
    • Detroit, Michigan, United States, 48201
      • ImClone Investigational Site
  • Washington
    • Seattle, Washington, United States, 98109
      • ImClone Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histopathologically-documented, measurable, advanced primary or recurrent solid tumors that no longer respond to standard therapy or for which no standard therapy is available.
• Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2 at study entry
• Able to provide written informed consent
• Life expectancy of >3 months
• Adequate hematologic functions, as defined by: absolute neutrophil count (ANC) ≥1500/cubic millimeter (mm³), hemoglobin level ≥10 grams/deciliter (gm/dL), platelet count ≥100,000/mm³
• Adequate hepatic function, as defined by: total bilirubin level ≤1.5 x the upper limit of normal (ULN), aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 x the ULN or ≤5 x the ULN if known liver metastases
• Adequate renal function, as defined by a serum creatinine level ≤1.5 x the ULN
• Ejection fraction within the normal institutional limits
• Use of effective contraception per institutional standard, if procreative potential exists
• At least 28 days must have elapsed from major surgery, prior chemotherapy, prior treatment with an investigational agent or device, prior radiation therapy (palliative radiation therapy is allowed), an open biopsy, or a significant traumatic injury to allow for adequate recovery. Ongoing side effects due to these agents must be ≤Grade 2 prior to entering the study.
• At least 6 weeks must have elapsed from nitrosoureas, mitomycin C, or monoclonal antibody [not targeting the insulin-like growth factor receptor (IGFR)] therapy to allow for adequate recovery. Ongoing side effects due to these agents must be ≤Grade 2 prior to entering the study.
• Accessible for treatment and follow-up. Participants enrolled in this trial must be treated at the participating center.

Exclusion Criteria:

• Any concurrent malignancy other than non-melanomatous skin cancer or carcinoma in situ of the cervix. Participants with a previous malignancy but without evidence of disease for ≥3 years will be allowed to enter the trial.
• Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection requiring parenteral antibiotics, symptomatic congestive heart failure, unstable angina pectoris, angioplasty, stenting or myocardial infarction within 6 months, uncontrolled hypertension, clinically significant cardiac arrhythmia, psychiatric illness/social situations that would compromise participant safety or limit compliance with study requirements, participants with symptomatic brain metastases
• Serious or nonhealing active wound, ulcer or bone fracture
• Know human immunodeficiency virus (HIV)-positive
• History of hemorrhagic or thrombotic disorder within 9 months
• Proteinuria ≥1+ by routine urinalysis (participants with a protein value of ≤500 milligrams (mg) confirmed by a 24-hour urine collection are eligible)
• Pregnant [confirmed by serum beta human chorionic gonadotropin (βHCG)] or breast feeding
• History of prior treatment with other agents specifically targeting IGFRs
• Known diabetes
• Inability or unwillingness to interrupt steroidal or hormonal therapy for the duration of treatment with IMC-A12
• Positive anti-IMC-A12 antibody response
• History of allergic reactions to monoclonal antibodies or other therapeutic proteins
• Employees of the investigator or study center with direct involvement in this study or other studies under the direction of the investigator or study center, as well as family members of the employees.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: IMC-A12; All participants will receive intravenous (I.V.) infusions of IMC-A12, with the dose depending on which cohort they are enrolled into. A minimum of three participants will be enrolled in each cohort. When all participants complete a cohort, dose escalation to the next cohort will occur.

Biological: IMC-A12; Cohort 1 3 milligrams/kilogram (mg/kg), I.V. once a week, for 4 weeks, followed by a 2-week observation period.; Other Names: Cixutumumab; LY3012217; Biological: IMC-A12; Cohort 2 6 mg/kg, I.V. once a week, for 4 weeks, followed by a 2-week observation period.; Other Names: Cixutumumab; LY3012217; Biological: IMC-A12; Cohort 3 10 mg/kg, I.V. once a week, for 4 weeks, followed by a 2-week observation period.; Other Names: Cixutumumab; LY3012217; Biological: IMC-A12; Cohort 4 15 mg/kg, I.V. once a week, for 4 weeks, followed by a 2-week observation period.; Other Names: Cixutumumab; LY3012217; Biological: IMC-A12; Cohort 5 21 mg/kg, I.V. once a week, for 4 weeks, followed by a 2-week observation period.; Other Names: Cixutumumab; LY3012217; Biological: IMC-A12; Cohort 6 27 mg/kg, I.V. once a week, for 4 weeks, followed by a 2-week observation period.; Other Names: Cixutumumab; LY3012217

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs) or Deaths	Data presented are the number of participants who experienced serious adverse events (SAEs), other non-serious AEs and deaths during the study including the 30-day follow-up. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Event module.	Enrollment to study completion up to 215 weeks
Maximum Tolerated Dose (MTD)	The MTD was defined as the dose preceding the dose level at which 2 participants experienced a dose-limiting toxicity (DLT). A DLT was defined as any Grade 3 or 4 hematologic or nonhematologic toxicity based on Common Terminology Criteria for AE (CTCAE), excluding alopecia, which was considered by the investigator to be definitely, probably, or possibly related to IMC-A12.	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Concentration (Cmax) of IMC-A12 Following Multiple Doses		Predose, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 hours after the infusion of Cycle 1
Observed Serum Concentration of IMC-A12 at 168 Hour Post End of Infusion Following Multiple Doses		Predose, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 hours after the infusion of Cycle 1
Area Under the Serum Concentration Versus Time Curve of IMC-A12 During One Dosing Interval (AUCτ) Following Multiple Doses		Predose, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 hours after the infusion of Cycle 1
Half-Life (t1/2) of IMC-A12 Following Multiple Doses	Half-Life (t1/2) is the time measured for the plasma concentration of the drug to decrease by one half. The analysis was not performed for the 6 mg/kg and 10 mg/kg dosing groups due to insufficient PK data.	Predose, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 hours after the infusion of Cycle 1
Clearance Rate of IMC-A12 at Steady State (CLss) Following Multiple Doses	CLss is the volume of plasma (or blood) from which the drug is completely removed, or cleared, in a given time at steady-state.	Predose, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 hours after the infusion of Cycle 1
Volume of Distribution of IMC-A12 at Steady State (Vss) Following Multiple Doses	Vss is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug at steady-state. The analysis was not performed for the 6 mg/kg and 10 mg/kg dosing groups due to insufficient PK data.	Predose, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 hours after the infusion of Cycle 1
Serum Anti-IMC-A12 Antibody Assessment (Immunogenicity)	Analysis was not performed due to lack of available assay.	Before the last infusion of each treatment cycle
Number of Participants With Best Overall Response	Stable Disease (SD) is neither sufficient shrinkage to qualify for partial response (PR) nor sufficient increase to qualify for progressive disease (PD). PR and PD were assessed by investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. PR is ≥30% decrease in sum of longest diameter of target lesions. PD is ≥20% increase in sum of longest diameter of target lesions and/or a new lesion. Participants with a global deterioration of their health status requiring discontinuation of treatment without objective evidence of disease progression at that time were to be reported as "symptomatic deterioration"	Enrollment to study completion up to 215 weeks

Collaborators and Investigators

• Sponsor: Eli Lilly and Company

Publications and helpful links

General Publications

• Higano CS, Berlin J, Gordon M, LoRusso P, Tang S, Dontabhaktuni A, Schwartz JD, Cosaert J, Mehnert JM. Safety, tolerability, and pharmacokinetics of single and multiple doses of intravenous cixutumumab (IMC-A12), an inhibitor of the insulin-like growth factor-I receptor, administered weekly or every 2 weeks in patients with advanced solid tumors. Invest New Drugs. 2015 Apr;33(2):450-62. doi: 10.1007/s10637-015-0217-7. Epub 2015 Mar 7.

Study record dates

Study Major Dates

• Study Start: October 1, 2005
• Primary Completion (Actual): January 1, 2011
• Study Completion (Actual): January 1, 2011

Study Registration Dates

• First Submitted: November 4, 2008
• First Submitted That Met QC Criteria: November 4, 2008
• First Posted (Estimate): November 5, 2008

Study Record Updates

• Last Update Posted (Actual): January 8, 2019
• Last Update Submitted That Met QC Criteria: December 13, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: Tumors; Antibodies, Monoclonal
• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Immunologic Factors; Antibodies, Monoclonal
• Other Study ID Numbers: 13932; CP13-0501 (Other Identifier: ImClone, LLC); I5A-IE-JAEH (Other Identifier: Eli Lilly and Company)