Colorectal Cancer
Conditions
Keywords
Metastatic Colorectal Cancer with Disease Progression, Failed prior to Anti-EGFr Therapy
Brief summary
Participants with metastatic Colorectal Cancer (mCRC) who have progressed on a prior Anti-epidermal growth factor receptor (EGFR) regimen randomized to receive IMC-A12 monotherapy or combination therapy with cetuximab to assess response, survival, durations of response, safety and tolerability as well as pharmacodynamics of IMC-A12 and cetuximab
Interventions
BIOLOGICALIMC-A12
10 milligrams/kilogram (mg/kg) intravenous infusion every 2 weeks.
BIOLOGICALcetuximab
Participants will receive cetuximab 500 milligrams/square meter (mg/m²) intravenous over 2 hours every 2 weeks.
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The participant has histologically or cytologically-confirmed colorectal cancer with metastatic disease documented on diagnostic imaging studies * The participant has measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded), measuring ≥ 2 centimeter (cm) on conventional measurement techniques or ≥ 1 cm on spiral computed tomography (CT) scan * The participant has clinical documentation of disease progression during treatment or within 6 weeks after receiving the last dose of a therapeutic regimen for metastatic disease containing an anti-EGFR-component (cetuximab or panitumumab). Toxicity or planned treatment break will not be regarded as adequate evidence of disease progression and such participants will not be eligible for this trial * The participant has received at least one prior standard and/or investigational regimen for metastatic disease * The participant is age ≥ 18 years * The participant has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1 (Karnofsky ≥ 80% * The participant has adequate hematologic function as defined by an absolute neutrophil count ≥ 1500/microliter (μL), hemoglobin ≥ 9 grams/deciliter (g/dL), and a platelet count ≥ 100,000/μL * The participant has adequate hepatic function as defined by a total bilirubin ≤ 1.5 x the upper limit of normal (ULN), and aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x the ULN (or ≤ 5 x the ULN in the presence of known liver metastases) * The participant has adequate coagulation function as defined by international normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 1.5 x the ULN. Participants on full-dose anticoagulation must be on a stable dose of oral anticoagulant or low molecular weight heparin, and if on warfarin must have an INR between 2 and 3 and have no active bleeding or pathological condition that carries a high risk of bleeding (for example, tumor involving major vessels or invading the rectal lumen, or known varices) * The participant has adequate renal function as defined by serum creatinine ≤ 1.5 x the institutional ULN or creatinine clearance ≥ 60 milliliters/minute (mL/min) for participants with creatinine levels above the ULN, as well as urine protein ≤ 1+ on urine dipstick or routine urinalysis \[(UA), if urine dipstick/routine UA indicates ≥ 2+ protein, a 24-hour urine collection for protein must demonstrate \< 1000 milligrams (mg) of protein in 24 hours to allow participation in the study\] * The participant has fasting serum glucose \< 120 milligrams/deciliter (mg/dL) or below the ULN * The participant has a life expectancy of \> 3 months * Because the teratogenicity of IMC-A12 (cixutumumab) is not known, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation * The participant has the ability to understand and the willingness to sign a written informed consent document * The participant has a tumor that is K-ras wild-type (absence of mutations at codon 12 or 13, as determined by the DxS K-ras Mutation Kit \[polymerase chain reaction (PCR)-based analysis\]). * The participant experienced either a confirmed partial response or stable disease of ≥ 24 weeks duration during prior treatment with a cetuximab- or panitumumab-containing regimen except for participants with uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) promoter polymorphism, for example, Gilbert syndrome, confirmed by genotyping or Invader®UGT1A1 Molecular Assay prior to enrollment. Participants enrolled with Gilbert Syndrome must have a total bilirubin ≤ 3 x ULN. If the participant has liver metastases, total bilirubin must be ≤ 3 x ULN.
Exclusion criteria
* The participant has received chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or has not recovered from adverse events due to agents administered more than 4 weeks earlier. Neurotoxicity, if present, must have recovered to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 3.0 grade ≤ 2. * The participant is receiving any other investigational agent(s). * The participant has a history of treatment with other agents targeting the insulin-like growth factor receptor (IGFR). * The participant has known brain or leptomeningeal metastases. * The participant has a history of primary central nervous system tumors, seizures not well controlled with standard medical therapy, or history of stroke within 6 months prior to randomization. * The participant has a history of allergic reactions attributed to compounds of chemical or biologic composition similar to those of cetuximab or IMC-A12 (cixutumumab). * The participant has poorly controlled diabetes mellitus. Participants with a history of diabetes mellitus are allowed to participate, provided that their blood glucose is within normal range (fasting glucose \< 120 mg/dL or below ULN) and that they are on a stable dietary or therapeutic regimen for this condition. * The participant has an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral antibiotics, symptomatic congestive heart failure, uncontrolled hypertension, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * The participant is pregnant or lactating. * The participant is known to be positive for infection with the human immunodeficiency virus. * The participant is receiving therapy with immune modulators such as cyclosporine or tacrolimus. * The participant has a history of another primary cancer, with the exception of: a) curatively resected nonmelanomatous skin cancer; b) curatively treated cervical carcinoma in-situ; or c) other primary solid tumor curatively resected treated with no known active disease present and no treatment administered for the last 3 years.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Response (CR) or Partial Response [PR, Objective Response Rate (ORR)] | Start of randomization/treatment to date of objective progressive disease (PD) up to 28.3 weeks | ORR is the percentage of participants with a confirmed CR or PR, as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. CR is the disappearance of all target and non-target lesions; PR is a ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesions. ORR is calculated as a total number of participants with CR or PR from start of the treatment until disease progression or recurrence divided by the total number of participants treated, then multiplied by 100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Randomization/treatment to date of death from any cause up to 26.9 months | OS is defined as the duration from the date of randomization/treatment to the date of death from any cause. Participants who were alive at the time of the data inclusion cutoff, OS was censored at the last date the participant was known to be alive. |
| Duration of Stable Disease (SD) | Time from randomization/treatment to first date of PD up to 28.3 weeks | The duration of SD is measured from the date of randomization/treatment until the date of PD. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. RECIST criteria version 1.0 was used to asses PR and PD. 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 who had no PD or death at the time of the data inclusion cutoff, duration of SD was censored at their last tumor assessment prior to the cutoff date. |
| Duration of Overall Response | Time of response to time of measured PD or death up to 161 days | The duration of overall response (CR or PR) was defined as the time from first objective status assessment of CR or PR to the first time of PD or death due to any cause. CR, PR and PD were determined using RECIST criteria version 1.0. CR is the disappearance of all target and non-target lesions; PR is a ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesions; PD is ≥20% increase in sum of longest diameter of target lesions or the appearance of new lesions. For participants with CR or PR who had no PD or death at the time of the data inclusion cutoff, the duration of overall response was censored at their last tumor assessment prior to the cutoff date. Duration of overall response was not analyzed due to low number of participants with CR or PR. |
| Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Randomization/treatment up to 26.9 months | Data presented are the number of participants who experienced nonserious adverse events (AEs) during the study including the 30-day follow-up. A summary of serious AEs (SAEs) and other non-serious AEs regardless of causality is located in the Reported Adverse Events module. |
| Number of Participants Reporting Treatment-Emergent Severe Adverse Events | Randomization/treatment up to 26.9 months | Data presented are the number of participants who experienced serious adverse events (SAEs) or death 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 Events module. |
| Progression-Free Survival (PFS) | Randomization/treatment to measured PD up to 28.3 weeks | PFS was defined as the duration from the date of randomization/treatment to the date of PD or death from any cause. PD was determined using RECIST criteria version 1.0. PD is ≥20% increase in sum of longest diameter of target lesions or the appearance of new lesions. Participants who had no PD or death at the time of the data inclusion cutoff, PFS was censored at their last tumor assessment prior to the cutoff date. Participants who began a new antitumor treatment before evidence of PD were categorized as PD. |
| Minimum Concentration (Cmin) | Week 1 (Initial dose), Week 3 (Dose 2), Week 5 (Dose 3), Week 7 (Dose 4), Week 9 (Dose 5), and Week 11 (Dose 6) | — |
| Area Under Serum Concentration (AUC) | Week 1 (Initial dose), Week 3 (Dose 2), Week 5 (Dose 3), Week 7 (Dose 4), Week 9 (Dose 5), and Week 11 (Dose 6) | — |
| Percentage of Participants With Complete Response (CR) or Partial Response (PR, Response Rate) in Participants With Kirsten Rat Sarcoma (K-ras) Mutations | Treatment up to 26.9 months | The response rate in participants with K-ras mutations was not collected for analysis. |
| Expression of Type I Insulin-Like Growth Factor Receptors (IGF-IR) | Randomization/treatment up to 26.9 months | — |
| Expression of IGF Binding Proteins (IGFBP2, IGFBP3) | Randomization/treatment up to 26.9 months | — |
| Maximum Concentration (Cmax) | Week 1 (Initial dose), Week 3 (Dose 2), Week 5 (Dose 3), Week 7 (Dose 4), Week 9 (Dose 5), and Week 11 (Dose 6) | — |
Countries
United States
Participant flow
Pre-assignment details
Participants with progressive disease (PD) or death are considered having completed study.
Participants by arm
| Arm | Count |
|---|---|
| IMC-A12 Participants received 10 mg/kg IMC-A12 intravenous infusion over 1 hour every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent. | 23 |
| IMC-A12 + Cetuximab Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent. | 21 |
| IMC-A12 + Cetuximab (K-ras Wild-type) Participants with K-ras wild-type who experienced confirmed PR or SD ≥ 24 weeks on a prior anti-EGFR-containing therapy followed by disease progression were enrolled in this arm.
Participants received cetuximab 500 mg/m² intravenous infusion over 2 hours followed by 10 mg/kg IMC-A12 intravenous infusion over 1 hour. This sequence was repeated every 2 weeks until there was evidence of PD, unacceptable toxicity, or withdrawal of consent. | 20 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 |
| Overall Study | Eligibility Criteria Not Met | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | IMC-A12 + Cetuximab (K-ras Wild-type) | IMC-A12 + Cetuximab | IMC-A12 |
|---|---|---|---|---|
| Age, Continuous | 60.5 years FULL_RANGE 9.84 | 61.7 years FULL_RANGE 7.89 | 62.6 years FULL_RANGE 12.4 | 59.3 years FULL_RANGE 8.94 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 2 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 57 Participants | 18 Participants | 18 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 8 Participants | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Hispanic | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 51 Participants | 17 Participants | 17 Participants | 17 Participants |
| Region of Enrollment United States | 64 Participants | 20 Participants | 21 Participants | 23 Participants |
| Sex: Female, Male Female | 33 Participants | 10 Participants | 9 Participants | 14 Participants |
| Sex: Female, Male Male | 31 Participants | 10 Participants | 12 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 23 | 19 / 21 | 20 / 20 |
| serious Total, serious adverse events | 7 / 23 | 6 / 21 | 4 / 20 |
Outcome results
Primary
Percentage of Participants With Complete Response (CR) or Partial Response [PR, Objective Response Rate (ORR)]
ORR is the percentage of participants with a confirmed CR or PR, as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. CR is the disappearance of all target and non-target lesions; PR is a ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesions. ORR is calculated as a total number of participants with CR or PR from start of the treatment until disease progression or recurrence divided by the total number of participants treated, then multiplied by 100.
Time frame: Start of randomization/treatment to date of objective progressive disease (PD) up to 28.3 weeks
Population: All randomized/enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMC-A12 | Percentage of Participants With Complete Response (CR) or Partial Response [PR, Objective Response Rate (ORR)] | 0.0 percentage of participants |
| IMC-A12 + Cetuximab | Percentage of Participants With Complete Response (CR) or Partial Response [PR, Objective Response Rate (ORR)] | 4.8 percentage of participants |
| IMC-A12 + Cetuximab (K-ras Wild-type) | Percentage of Participants With Complete Response (CR) or Partial Response [PR, Objective Response Rate (ORR)] | 0.0 percentage of participants |
Secondary
Area Under Serum Concentration (AUC)
Time frame: Week 1 (Initial dose), Week 3 (Dose 2), Week 5 (Dose 3), Week 7 (Dose 4), Week 9 (Dose 5), and Week 11 (Dose 6)
Population: Zero participants analyzed. PK data was not collected for analysis due to the low number of participants in PK.
Secondary
Duration of Overall Response
The duration of overall response (CR or PR) was defined as the time from first objective status assessment of CR or PR to the first time of PD or death due to any cause. CR, PR and PD were determined using RECIST criteria version 1.0. CR is the disappearance of all target and non-target lesions; PR is a ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesions; PD is ≥20% increase in sum of longest diameter of target lesions or the appearance of new lesions. For participants with CR or PR who had no PD or death at the time of the data inclusion cutoff, the duration of overall response was censored at their last tumor assessment prior to the cutoff date. Duration of overall response was not analyzed due to low number of participants with CR or PR.
Time frame: Time of response to time of measured PD or death up to 161 days
Population: Zero participants analyzed. Duration of Response for CR or PR data was not collected for analysis due to N=0 CR and N=1 PR.
Secondary
Duration of Stable Disease (SD)
The duration of SD is measured from the date of randomization/treatment until the date of PD. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. RECIST criteria version 1.0 was used to asses PR and PD. 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 who had no PD or death at the time of the data inclusion cutoff, duration of SD was censored at their last tumor assessment prior to the cutoff date.
Time frame: Time from randomization/treatment to first date of PD up to 28.3 weeks
Population: All randomized/enrolled participants who received at least 1 dose of the study drug and achieved SD or better. The number of participants censored was 0 for IMC-A12 group, 0 for IMC-A12 + cetuximab group and 1 for IMC-A12 + cetuximab (K-ras wild-type) group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMC-A12 | Duration of Stable Disease (SD) | 11.1 weeks |
| IMC-A12 + Cetuximab | Duration of Stable Disease (SD) | 15.4 weeks |
| IMC-A12 + Cetuximab (K-ras Wild-type) | Duration of Stable Disease (SD) | 11.6 weeks |
Secondary
Expression of IGF Binding Proteins (IGFBP2, IGFBP3)
Time frame: Randomization/treatment up to 26.9 months
Population: Zero participants analyzed. No data collected for analysis.
Secondary
Expression of Type I Insulin-Like Growth Factor Receptors (IGF-IR)
Time frame: Randomization/treatment up to 26.9 months
Population: Zero participants analyzed. No data collected for analysis.
Secondary
Maximum Concentration (Cmax)
Time frame: Week 1 (Initial dose), Week 3 (Dose 2), Week 5 (Dose 3), Week 7 (Dose 4), Week 9 (Dose 5), and Week 11 (Dose 6)
Population: Zero participants analyzed. PK data was not collected for analysis due to the low number of participants in PK.
Secondary
Minimum Concentration (Cmin)
Time frame: Week 1 (Initial dose), Week 3 (Dose 2), Week 5 (Dose 3), Week 7 (Dose 4), Week 9 (Dose 5), and Week 11 (Dose 6)
Population: Zero participants analyzed. PK data was not collected for analysis due to the low number of participants in PK.
Secondary
Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs)
Data presented are the number of participants who experienced nonserious adverse events (AEs) during the study including the 30-day follow-up. A summary of serious AEs (SAEs) and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.
Time frame: Randomization/treatment up to 26.9 months
Population: All randomized/enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMC-A12 | Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | 18 Participants |
| IMC-A12 + Cetuximab | Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | 19 Participants |
| IMC-A12 + Cetuximab (K-ras Wild-type) | Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | 20 Participants |
Secondary
Number of Participants Reporting Treatment-Emergent Severe Adverse Events
Data presented are the number of participants who experienced serious adverse events (SAEs) or death 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 Events module.
Time frame: Randomization/treatment up to 26.9 months
Population: All randomized/enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMC-A12 | Number of Participants Reporting Treatment-Emergent Severe Adverse Events | Death Due to PD | 1 Participants |
| IMC-A12 | Number of Participants Reporting Treatment-Emergent Severe Adverse Events | SAEs | 7 Participants |
| IMC-A12 | Number of Participants Reporting Treatment-Emergent Severe Adverse Events | Death Due to SAE | 0 Participants |
| IMC-A12 + Cetuximab | Number of Participants Reporting Treatment-Emergent Severe Adverse Events | Death Due to PD | 0 Participants |
| IMC-A12 + Cetuximab | Number of Participants Reporting Treatment-Emergent Severe Adverse Events | SAEs | 6 Participants |
| IMC-A12 + Cetuximab | Number of Participants Reporting Treatment-Emergent Severe Adverse Events | Death Due to SAE | 1 Participants |
| IMC-A12 + Cetuximab (K-ras Wild-type) | Number of Participants Reporting Treatment-Emergent Severe Adverse Events | SAEs | 4 Participants |
| IMC-A12 + Cetuximab (K-ras Wild-type) | Number of Participants Reporting Treatment-Emergent Severe Adverse Events | Death Due to SAE | 0 Participants |
| IMC-A12 + Cetuximab (K-ras Wild-type) | Number of Participants Reporting Treatment-Emergent Severe Adverse Events | Death Due to PD | 0 Participants |
Secondary
Overall Survival (OS)
OS is defined as the duration from the date of randomization/treatment to the date of death from any cause. Participants who were alive at the time of the data inclusion cutoff, OS was censored at the last date the participant was known to be alive.
Time frame: Randomization/treatment to date of death from any cause up to 26.9 months
Population: All randomized/enrolled participants who received at least 1 dose of study drug. The number of participants censored was 5 for IMC-A12 group, 4 for IMC-A12 + cetuximab group and 11 for IMC-A12 + cetuximab (K-ras wild-type) group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMC-A12 | Overall Survival (OS) | 5.7 months |
| IMC-A12 + Cetuximab | Overall Survival (OS) | 4.5 months |
| IMC-A12 + Cetuximab (K-ras Wild-type) | Overall Survival (OS) | 10.9 months |
Secondary
Percentage of Participants With Complete Response (CR) or Partial Response (PR, Response Rate) in Participants With Kirsten Rat Sarcoma (K-ras) Mutations
The response rate in participants with K-ras mutations was not collected for analysis.
Time frame: Treatment up to 26.9 months
Population: Zero participants analyzed. Response rate data was not collected for analysis due to N=0 CR and N=1 PR.
Secondary
Progression-Free Survival (PFS)
PFS was defined as the duration from the date of randomization/treatment to the date of PD or death from any cause. PD was determined using RECIST criteria version 1.0. PD is ≥20% increase in sum of longest diameter of target lesions or the appearance of new lesions. Participants who had no PD or death at the time of the data inclusion cutoff, PFS was censored at their last tumor assessment prior to the cutoff date. Participants who began a new antitumor treatment before evidence of PD were categorized as PD.
Time frame: Randomization/treatment to measured PD up to 28.3 weeks
Population: All randomized/enrolled participants who received at least 1 dose of study drug. The number of participants censored was 0 for IMC-A12 group, 1 for IMC-A12 + cetuximab group and 1 for IMC-A12 + cetuximab (K-ras wild-type) group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMC-A12 | Progression-Free Survival (PFS) | 5.9 weeks |
| IMC-A12 + Cetuximab | Progression-Free Survival (PFS) | 6.1 weeks |
| IMC-A12 + Cetuximab (K-ras Wild-type) | Progression-Free Survival (PFS) | 9.4 weeks |