Colorectal Cancer
Conditions
Keywords
Colorectal cancer, Revlimid, Lenalidomide, Cetuximab, Erbitux, KRAS
Brief summary
The purpose of this study is to determine whether lenalidomide in combination with cetuximab is safe and effective in patients with KRAS mutant colorectal cancer.
Interventions
DRUGcetuximab
Intravenous infusions of cetuximab (400 mg/m\^2 Cycle 1 Day 1, thereafter 250 mg/m\^2), administered on days 1, 8, 15 and 22 of each 28 day cycle.
DRUGlenalidomide
Daily oral lenalidomide 25mg on days 1 to 28 of each 28 day cycle
Sponsors
Celgene Corporation
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
1. Metastatic colorectal adenocarcinoma. 2. Confirmed K-RAS mutant tumor 3. Disease progression on oxaliplatin- AND irinotecan-containing regimens, with at least one of these regimens containing bevacizumab. 4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.
Exclusion criteria
1. Use of chemotherapy, hormonal therapy, immunotherapy or any other cancer or experimental treatment ≤ 28 days prior to the first day of the first cycle. 2. Radiotherapy for up to ≥ 30% of the bone marrow. 3. Surgery ≤ 28 days before day 1 of the first cycle (minimally invasive interventions for diagnostic purposes or disease staging are permitted). 4. Previous treatment with cetuximab, panitumumab, pomalidomide (CC-4047), lenalidomide or thalidomide. 5. Untreated, symptomatic brain metastases (brain imaging not required). 6. Venous thromboembolism ≤ 6 months before day1 of the first cycle. 7. Current congestive heart failure (classes II to IV of the New York Heart Association). 8. Myocardial infarction ≤ 12 months before day1 of the first cycle. 9. Uncontrolled hypertension.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Dose Limiting Toxicities (DLTs) During the First Treatment Cycle of the Safety Lead-In Period | Up to Day 28 (Cycle 1) | The number of participants with DLTs determines the maximum tolerated dose of the combination therapy used in the Proof of Concept (POC) period: If \<2 of the initial 6 participants experience a DLT, then the POC will start with lenalidomide at 25 mg. If ≥2 of the initial 6 participants experienced a DLT, then 6 more subjects were to be enrolled at 20 mg lenalidomide. If \<2 of the additional 6 subjects experienced a DLT, then the lenalidomide starting dose for the POC was to be 20 mg. If ≥2 of the additional 6 subjects experienced a DLT, then 6 more subjects were to be enrolled at 15 mg lenalidomide. If \<2 of the additional 6 subjects experienced a DLT, then the POC was to start with lenalidomide at 15 mg. If ≥2 of the additional 6 subjects experienced a DLT, the dosing for the study was to be reassessed by Celgene Corporation and the investigators. |
| Percentage of Participants With a Response to Treatment During the Proof of Concept Period | week 9 up to week 24 | Tumor response was evaluated every 2 cycles beginning with Cycle 3 Day 1 and at treatment discontinuation. Response and progression were evaluated using the RECIST 1.1 criteria (Eisenhauer, 2009). Treatment response includes both complete response and partial response. * Complete response-disappearance of all lesions * Partial response-30% decrease in the sum of diameters of target lesions from baseline Analysis was not performed due to the early termination of the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Disease Control | up to week 24 | Known as the Disease Control Rate (DCR), participants with a complete response, partial response or stable disease contribute to the DCR. This analysis was not performed due to the early termination of the study. |
| Kaplan-Meier Estimates for Progression Free Survival (PFS) | up to week 24 | PFS was calculated as the time from randomization to the earlier of the first documentation of progressive disease (PD), or death on study due to any cause. Analysis was not performed due to the early termination of the study. |
| Participants With Treatment-Emergent Adverse Events (TEAE) | up to week 28 | TEAEs are any adverse event occurring or worsening on or after the first treatment of any study drug and within 28 days after the last dose of the last study drug received. Relation to study drug was determined by the investigator. Severity of AE is graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.0. Severity is a 5-point scale: 3= severe or medically significant but not life-threatening 4=life-threatening, urgent intervention required 5=death related to AE. |
| Kaplan-Meier Estimates for Overall Survival | up to 5.5 years | Overall survival was defined as the time between randomization and death. It was intended that participants would be followed for up to 5 years following discontinuation from treatment. Analysis was not performed due to the early termination of the study. |
| Kaplan-Meier Estimates for Duration of Response | up to week 24 | Duration of response was defined as the time from the initial response date to progressive disease (PD) for participants who achieved an objective confirmed complete response (CR) or partial response (PR). Analysis was not performed due to the early termination of the study. |
Countries
Australia, Belgium, Germany, Italy, Spain, Sweden
Participant flow
Pre-assignment details
Phase 2b Proof of Concept was designed to enroll 82 participants, however the study terminated early. Forty-three participants were enrolled, however, one was randomized to receive single agent lenalidomide but never received study drug and was excluded from the ITT and Safety populations.
Participants by arm
| Arm | Count |
|---|---|
| Lenalidomide Plus Cetuximab (Safety Lead-In) Combination therapy of lenalidomide plus cetuximab during the Safety Lead-in period. Lenalidomide dose of 25 mg/day in combination with cetuximab (IV injections of 400 mg/m\^2 first infusion only, then 250 mg/m\^2 subsequently administered on Days 1, 8, 15, and 22 of each 28-day cycle). | 8 |
| Lenalidomide (Proof of Concept) Single agent therapy of lenalidomide (25 mg/day) during the Proof of Concept period. | 21 |
| Lenalidomide Plus Cetuximab (Proof of Concept) Combination therapy of lenalidomide plus cetuximab during the Proof of Concept period. Lenalidomide dose of 25 mg/day in combination with cetuximab (IV injections of 400 mg/m\^2 first infusion only, then 250 mg/m\^2 subsequently administered on Days 1, 8, 15, and 22 of each 28-day cycle). | 21 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Proof of Concept | Adverse Event | 0 | 5 | 1 |
| Proof of Concept | Death | 0 | 1 | 2 |
| Proof of Concept | Lack of Efficacy | 0 | 1 | 0 |
| Proof of Concept | Never Received Study Drug | 0 | 1 | 0 |
| Safety Lead-in | Adverse Event | 1 | 0 | 0 |
| Safety Lead-in | Death | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Lenalidomide Plus Cetuximab (Proof of Concept) | Total | Lenalidomide Plus Cetuximab (Safety Lead-In) | Lenalidomide (Proof of Concept) |
|---|---|---|---|---|
| Age, Customized <= 65 years | 18 participants | 41 participants | 7 participants | 16 participants |
| Age, Customized >65 years | 3 participants | 9 participants | 1 participants | 5 participants |
| Eastern Cooperative Oncology Group Performance Status 0 | 14 participants | 30 participants | 6 participants | 10 participants |
| Eastern Cooperative Oncology Group Performance Status 1 | 7 participants | 19 participants | 2 participants | 10 participants |
| Eastern Cooperative Oncology Group Performance Status 2 | 0 participants | 1 participants | 0 participants | 1 participants |
| Eastern Cooperative Oncology Group Performance Status 3-5 | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Caucasian (White) | 20 participants | 49 participants | 8 participants | 21 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Non-Hispanic or Latino | 21 participants | 50 participants | 8 participants | 21 participants |
| Race/Ethnicity, Customized Other (Not Specified) | 1 participants | 1 participants | 0 participants | 0 participants |
| Sex: Female, Male Female | 9 Participants | 22 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 12 Participants | 28 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 21 | 29 / 29 |
| serious Total, serious adverse events | 9 / 21 | 14 / 29 |
Outcome results
Primary
Participants With Dose Limiting Toxicities (DLTs) During the First Treatment Cycle of the Safety Lead-In Period
The number of participants with DLTs determines the maximum tolerated dose of the combination therapy used in the Proof of Concept (POC) period: If \<2 of the initial 6 participants experience a DLT, then the POC will start with lenalidomide at 25 mg. If ≥2 of the initial 6 participants experienced a DLT, then 6 more subjects were to be enrolled at 20 mg lenalidomide. If \<2 of the additional 6 subjects experienced a DLT, then the lenalidomide starting dose for the POC was to be 20 mg. If ≥2 of the additional 6 subjects experienced a DLT, then 6 more subjects were to be enrolled at 15 mg lenalidomide. If \<2 of the additional 6 subjects experienced a DLT, then the POC was to start with lenalidomide at 15 mg. If ≥2 of the additional 6 subjects experienced a DLT, the dosing for the study was to be reassessed by Celgene Corporation and the investigators.
Time frame: Up to Day 28 (Cycle 1)
Population: All participants who took at least one dose of study medication. If a participant discontinued the study prior to completing the entire first cycle for reasons other than a DLT or if ≥7 days of lenalidomide and/or ≥1 dose of cetuximab were missed during the first cycle for reasons other than a DLT, a replacement would be added at that dose level.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Participants With Dose Limiting Toxicities (DLTs) During the First Treatment Cycle of the Safety Lead-In Period | 1 participants |
Primary
Percentage of Participants With a Response to Treatment During the Proof of Concept Period
Tumor response was evaluated every 2 cycles beginning with Cycle 3 Day 1 and at treatment discontinuation. Response and progression were evaluated using the RECIST 1.1 criteria (Eisenhauer, 2009). Treatment response includes both complete response and partial response. * Complete response-disappearance of all lesions * Partial response-30% decrease in the sum of diameters of target lesions from baseline Analysis was not performed due to the early termination of the study.
Time frame: week 9 up to week 24
Population: Efficacy Evaluable Population. Analysis was not performed due to the early termination of the study.
Secondary
Kaplan-Meier Estimates for Duration of Response
Duration of response was defined as the time from the initial response date to progressive disease (PD) for participants who achieved an objective confirmed complete response (CR) or partial response (PR). Analysis was not performed due to the early termination of the study.
Time frame: up to week 24
Population: Participants who took at least one dose of study treatment. Analysis was not performed due to the early termination of the study.
Secondary
Kaplan-Meier Estimates for Overall Survival
Overall survival was defined as the time between randomization and death. It was intended that participants would be followed for up to 5 years following discontinuation from treatment. Analysis was not performed due to the early termination of the study.
Time frame: up to 5.5 years
Population: Participants who took at least one dose of study treatment. Analysis was not performed due to the early termination of the study.
Secondary
Kaplan-Meier Estimates for Progression Free Survival (PFS)
PFS was calculated as the time from randomization to the earlier of the first documentation of progressive disease (PD), or death on study due to any cause. Analysis was not performed due to the early termination of the study.
Time frame: up to week 24
Population: Participants who took at least one dose of study treatment. Analysis was not performed due to the early termination of the study.
Secondary
Participants With Treatment-Emergent Adverse Events (TEAE)
TEAEs are any adverse event occurring or worsening on or after the first treatment of any study drug and within 28 days after the last dose of the last study drug received. Relation to study drug was determined by the investigator. Severity of AE is graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.0. Severity is a 5-point scale: 3= severe or medically significant but not life-threatening 4=life-threatening, urgent intervention required 5=death related to AE.
Time frame: up to week 28
Population: Participants who took at least one dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Participants With Treatment-Emergent Adverse Events (TEAE) | Serious TEAE related to lenalidomide | 2 participants |
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Participants With Treatment-Emergent Adverse Events (TEAE) | Serious TEAE | 5 participants |
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE leading to discontinuing cetuximab | 3 participants |
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE leading to reduction/interruption of lenalido | 2 participants |
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE leading to reduction/interruption of cetuxima | 1 participants |
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE related to lenalidomide | 5 participants |
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE related to cetuximab | 8 participants |
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE NCI CTC grade 3 or higher | 4 participants |
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE NCI CTC grade 3+ related to lenalidomide | 3 participants |
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE NCI CTC grade 3+ related to cetuximab | 2 participants |
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Participants With Treatment-Emergent Adverse Events (TEAE) | Serious TEAE related to cetuximab | 2 participants |
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE leading to discontinuing lenalidomide | 3 participants |
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE | 8 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE leading to reduction/interruption of lenalido | 6 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | Serious TEAE related to lenalidomide | 0 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE related to lenalidomide | 9 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE related to cetuximab | NA participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE leading to reduction/interruption of cetuxima | NA participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE NCI CTC grade 3 or higher | 13 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | Serious TEAE related to cetuximab | NA participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE NCI CTC grade 3+ related to lenalidomide | 4 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE | 20 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | Serious TEAE | 9 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE leading to discontinuing lenalidomide | 7 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE leading to discontinuing cetuximab | NA participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE NCI CTC grade 3+ related to cetuximab | NA participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE leading to discontinuing lenalidomide | 5 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE NCI CTC grade 3+ related to cetuximab | 7 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE leading to reduction/interruption of cetuxima | 7 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | Serious TEAE related to cetuximab | 2 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE | 21 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE related to lenalidomide | 13 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | Serious TEAE related to lenalidomide | 2 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE NCI CTC grade 3+ related to lenalidomide | 4 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE related to cetuximab | 19 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE leading to reduction/interruption of lenalido | 9 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | Serious TEAE | 9 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE NCI CTC grade 3 or higher | 12 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE leading to discontinuing cetuximab | 6 participants |
Secondary
Percentage of Participants With Disease Control
Known as the Disease Control Rate (DCR), participants with a complete response, partial response or stable disease contribute to the DCR. This analysis was not performed due to the early termination of the study.
Time frame: up to week 24
Population: Participants who took at least one dose of study treatment. Analysis was not performed due to the early termination of the study.
Post Hoc
Best Overall Response Assessed by an Independent Review Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) During the Proof of Concept Period Prior to Early Study Termination
Tumor response was evaluated every 2 cycles beginning with Cycle 3 Day 1 and at treatment discontinuation. Response and progression were evaluated using the RECIST 1.1 criteria (Eisenhauer, 2009). * Complete response-disappearance of all lesions * Partial response-30% decrease in the sum of diameters of target lesions from baseline * Stable disease-neither shrinkage nor increase of lesions. * Progressive Disease-20% increase in the sum of diameters of target lesions from nadir. Participants with evidence of objective tumor response have the response confirmed with repeat assessments performed at the next scheduled scan.
Time frame: Week 9 up to week 24
Population: Intent to treat population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Best Overall Response Assessed by an Independent Review Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) During the Proof of Concept Period Prior to Early Study Termination | Stable Disease | 3 participants |
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Best Overall Response Assessed by an Independent Review Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) During the Proof of Concept Period Prior to Early Study Termination | Complete Response | 0 participants |
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Best Overall Response Assessed by an Independent Review Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) During the Proof of Concept Period Prior to Early Study Termination | Partial Response | 0 participants |
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Best Overall Response Assessed by an Independent Review Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) During the Proof of Concept Period Prior to Early Study Termination | Progressive Disease | 13 participants |
| Lenalidomide Plus Cetuximab (Safety Lead-in) | Best Overall Response Assessed by an Independent Review Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) During the Proof of Concept Period Prior to Early Study Termination | Response Not Evaluable | 5 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Best Overall Response Assessed by an Independent Review Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) During the Proof of Concept Period Prior to Early Study Termination | Partial Response | 0 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Best Overall Response Assessed by an Independent Review Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) During the Proof of Concept Period Prior to Early Study Termination | Response Not Evaluable | 3 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Best Overall Response Assessed by an Independent Review Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) During the Proof of Concept Period Prior to Early Study Termination | Stable Disease | 5 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Best Overall Response Assessed by an Independent Review Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) During the Proof of Concept Period Prior to Early Study Termination | Complete Response | 0 participants |
| Lenalidomide Plus Cetuximab (Proof of Concept) | Best Overall Response Assessed by an Independent Review Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) During the Proof of Concept Period Prior to Early Study Termination | Progressive Disease | 13 participants |