Rectal Cancer, Colo-rectal Cancer
Conditions
Brief summary
The objectives of this study are to: 1. To assess dose-limiting toxicities (DLTs) of capecitabine +/- oxaliplatin in a combination regimen with capecitabine and radiotherapy (Phase 1) 2. To determine the maximum-tolerated dose (MTD) when capecitabine * oxaliplatin in a combination regimen with capecitabine and radiotherapy (Phase 1) 3. To determine the pathologic response rate of cetuximab +/- oxaliplatin in combination with capecitabine and radiotherapy (Phase 2)
Detailed description
Part of the treatment plan for this study is surgical removal of the tumor that is planned to occur 6 to 8 weeks after completion of radiotherapy (XRT). This study consists of 2 distinct phases (Phase 1 and Phase 2). In Phase 1, the objectives are to 1. Assess dose-limiting toxicities (DLTs) and 2. Determine a maximum-tolerated dose (MTD) The Phase 1 endpoints are assessed on an initial cohort of patients after the completion of the chemo-radiotherapy regimen at defined timepoints that precede surgery. Phase 2 is the efficacy assessment portion of this study. In Phase 2, the objective is to accrue an expansion cohort. Efficacy assessments for phase 2 are to be assessed across all study participants at the time of, or after, surgery, as measured by the pathologic response rate; downstaging; and survival at 5 years from the start of treatment.
Interventions
DRUGCetuximab
Cetuximab is a chimeric anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody, administered via a intravenous (IV) infusion at 400 mg/m² (initial loading dose) or 250 mg/m² (weekly dose). Dosage is based on m² of body surface area (BSA)
DRUGOxaliplatin
Oxaliplatin is a cancer medication used to treat colorectal cancer, and is administered on Days 2 and 23.
DRUGCapecitabine
Capecitabine is a cancer medication, and is administered based on m² of body surface area (BSA) delivered in equivalent morning and evening doses
RADIATIONRadiotherapy
Radiotherapy is administered on weekdays in 180 centigray fractions (doses), for 28 total fractions delivering a total dose of 5040 centigray (cGy)
Diphenhydramine HCl 50 mg (or equivalent) is administered as a per-medication for cetuximab
Sponsors
Bristol-Myers Squibb
George Albert Fisher
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Sequential design for 4 dose combinations (arms) through phase 1
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically-confirmed adenocarcinoma of the rectum. Clinical stages T3; T4; or N1 as determined by endoscopic ultrasound; or a rectal CT or MRI scan are eligible, including T3 N0; T3 N1; T4 N0; T4 N1; T1-4 N1. Rectal cancers are defined as those whose distal border extends to within 12 cm of the anal verge. * Age ≥ 18 * Karnofsky performance status (KPS) ≥ 70 * Leukocyte count \> 3,500 x 10e6/µL * Platelet count \> 100,000/µL * Serum glutamic-oxaloacetic transaminase (SGOT) \< 2.5 x institutional upper limits of normal (ULN) * Serum glutamic-pyruvic transaminase (SGPT) \< 2.5 x ULN * Alkaline phosphatase \< 2.5 x ULN * Total bilirubin \< 1.5x ULN * Creatinine: * Within normal institutional limits * OR * Creatinine clearance \> 60 mL/min/1.73 m2 (if serum creatinine levels above institutional normal) * Ability to swallow pills without difficulty * Women of child-bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG), within 72 hours prior to the start of study medication * Women of child-bearing potential must be using an adequate method of contraception to avoid pregnancy throughout the treatment
Exclusion criteria
* Metastatic (M1) or stage IV disease * Prior history of treatment with cetuximab or other therapy targeting EGFR * Prior history of anti-cancer murine monoclonal antibody therapy * Prior pelvic or whole abdominal radiotherapy * Uncontrolled intercurrent illness including, but not limited to: * Ongoing or active infection * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Psychiatric illness / social situations that would limit compliance with study requirements * Patients with a concurrent malignancy or previous malignancy within 5 years of screening will be excluded from this study (EXCEPTION: concurrent or previous non-melanoma skin cancer, hematolymphoid malignancy or carcinoma in-situ of the cervix may be allowed at the investigator's discretion) * Inability to sign written consent * Pregnant or breastfeeding * Unwilling or unable to use effective contraception in self or partner for the entire study period and for up to 4 weeks after the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-limiting Toxicity (DLT) - Number of DLTs by Treatment Group | 10 weeks | Dose-limiting Toxicity (DLT) is the measure used to establish overall Maximum-tolerated dose (MTD) of cetuximab + capecitabine + radiotherapy +/- oxaliplatin. MTD is defined as the highest dose level for which participants have a \< 30% incidence of dose-limiting toxicity (DLT). The outcome is expressed as the number of DLTs by treatment group. |
| Dose-limiting Toxicity (DLT) - Number of Participants Affected | 10 weeks | Dose-limiting Toxicity (DLT) is the measure used to establish overall Maximum-tolerated dose (MTD) of cetuximab + capecitabine + radiotherapy +/- oxaliplatin. MTD is defined as the highest dose level for which participants have a \< 30% incidence of dose-limiting toxicity (DLT). The outcome is expressed as the number of participants experiencing a DLT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time-to-Progression (TTP) | 5 years | Time-to-progression was assessed as the time from the date of surgical resection to the appearance of either local disease recurrence or distant metastases by any modality (eg, clinical exam, endoscopy, radiographic imaging). All relapses were to be confirmed by biopsy and pathology review. |
| Pathologic Response Rate | 12 to 14 weeks after radiotherapy | After treatment with capecitabine, cetuximab, radiotherapy, and oxaliplatin, the pathologic response rate was assessed based on the excised tumor taken at the time of surgical resection. Pathologic response rate was determined as the number and proportion of participants who experienced either downstaging of their disease, or complete response (CR, no detectable disease). A participant will be considered to have downstaging of the tumor as a result of the neoadjuvant therapy when the primary tumor (T) stage by pathology isless than the T stage by clinical (endoscopic) evaluation, or when the regional lymph node (N) tumor stage by pathology is less than the N stage by clinical (endoscopic) evaluation. |
| Survival at 5 Years | 5 years | Survival at 5 years was assessed as the number of participants alive 5 years after starting treatment. |
| Overall Survival (OS) | 72 months | Overall Survival (OS) was assessed as the mean survival from the date of entry on study though 72 months. |
| Tumor Downstaging at Surgical Resection | 12 to 14 weeks after radiotherapy | Downstaging means a reduction from the stage of disease observed at baseline to the stage of disease after treatment with cetuximab, radiotherapy, oxaliplatin, and capecitabine, as determined at the time of surgical removal of the tumor. Downstaging may be observed as improvements in tumor staging at the primary site of the tumor; in nearby (regional) lymph nodes; or in metastatic disease beyond the regional lymph nodes. This outcome specifically does not include participants that achieved a complete response, nor those that experienced no response or disease progression. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100 * Cetuximab 250 mg/m² / week
* Capecitabine 800 mg/m²
* Radiotherapy (XRT)
* Oxaliplatin 100 mg/m², Days 2 and 23 | 6 |
| Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85 * Cetuximab 250 mg/m² / week
* Capecitabine 700 mg/m²
* Radiotherapy (XRT)
* Oxaliplatin 85 mg/m², Days 2 and 23 | 6 |
| Group A - Cetuximab + Capecitabine-800 + XRT * Cetuximab 250 mg/m² / week
* Capecitabine 800 mg/m²
* Radiotherapy (XRT) | 4 |
| Group B - Cetuximab + Capecitabine-1000 + XRT * Cetuximab 250 mg/m² / week
* Capecitabine 1000 mg/m²
* Radiotherapy (XRT) | 7 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by subject - toxicity | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawn by investigator - unrelated AE | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100 | Total | Group B - Cetuximab + Capecitabine-1000 + XRT | Group A - Cetuximab + Capecitabine-800 + XRT | Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85 |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 3 Participants | 2 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 20 Participants | 5 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 22 Participants | 6 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Histology Adenocarcinoid Tumor | 0 Participants | 5 Participants | 4 Participants | 1 Participants | 0 Participants |
| Histology Adenocarcinoma, Nos | 6 Participants | 17 Participants | 3 Participants | 2 Participants | 6 Participants |
| Histology Adenosarcoma | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 19 Participants | 5 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 5 Participants | 18 Participants | 5 Participants | 4 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 6 | 1 / 6 | 0 / 4 | 0 / 7 |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 4 / 4 | 7 / 7 |
| serious Total, serious adverse events | 6 / 6 | 6 / 6 | 3 / 4 | 7 / 7 |
Outcome results
Primary
Dose-limiting Toxicity (DLT) - Number of DLTs by Treatment Group
Dose-limiting Toxicity (DLT) is the measure used to establish overall Maximum-tolerated dose (MTD) of cetuximab + capecitabine + radiotherapy +/- oxaliplatin. MTD is defined as the highest dose level for which participants have a \< 30% incidence of dose-limiting toxicity (DLT). The outcome is expressed as the number of DLTs by treatment group.
Time frame: 10 weeks
Population: All participants were formally part of the phase 1 portion of this study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100 | Dose-limiting Toxicity (DLT) - Number of DLTs by Treatment Group | 10 DLTs |
| Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85 | Dose-limiting Toxicity (DLT) - Number of DLTs by Treatment Group | 2 DLTs |
| Group A - Cetuximab + Capecitabine-800 + XRT | Dose-limiting Toxicity (DLT) - Number of DLTs by Treatment Group | 0 DLTs |
| Group B - Cetuximab + Capecitabine-1000 + XRT | Dose-limiting Toxicity (DLT) - Number of DLTs by Treatment Group | 0 DLTs |
Primary
Dose-limiting Toxicity (DLT) - Number of Participants Affected
Dose-limiting Toxicity (DLT) is the measure used to establish overall Maximum-tolerated dose (MTD) of cetuximab + capecitabine + radiotherapy +/- oxaliplatin. MTD is defined as the highest dose level for which participants have a \< 30% incidence of dose-limiting toxicity (DLT). The outcome is expressed as the number of participants experiencing a DLT.
Time frame: 10 weeks
Population: All participants were formally part of the phase 1 portion of this study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100 | Dose-limiting Toxicity (DLT) - Number of Participants Affected | 4 Participants |
| Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85 | Dose-limiting Toxicity (DLT) - Number of Participants Affected | 2 Participants |
| Group A - Cetuximab + Capecitabine-800 + XRT | Dose-limiting Toxicity (DLT) - Number of Participants Affected | 0 Participants |
| Group B - Cetuximab + Capecitabine-1000 + XRT | Dose-limiting Toxicity (DLT) - Number of Participants Affected | 0 Participants |
Secondary
Overall Survival (OS)
Overall Survival (OS) was assessed as the mean survival from the date of entry on study though 72 months.
Time frame: 72 months
Population: This outcome is defined per protocol as study phase 2, which did not occur. However, data are provided for phase 1 participants, for completeness. This study was terminated before all patients reached 5 years on study. Some patients are reported as the last known alive date.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100 | Overall Survival (OS) | 59.7 months | Standard Deviation 0.7 |
| Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85 | Overall Survival (OS) | 57.0 months | Standard Deviation 5.8 |
| Group A - Cetuximab + Capecitabine-800 + XRT | Overall Survival (OS) | 54.4 months | Standard Deviation 11.1 |
| Group B - Cetuximab + Capecitabine-1000 + XRT | Overall Survival (OS) | 53.7 months | Standard Deviation 11.3 |
Secondary
Pathologic Response Rate
After treatment with capecitabine, cetuximab, radiotherapy, and oxaliplatin, the pathologic response rate was assessed based on the excised tumor taken at the time of surgical resection. Pathologic response rate was determined as the number and proportion of participants who experienced either downstaging of their disease, or complete response (CR, no detectable disease). A participant will be considered to have downstaging of the tumor as a result of the neoadjuvant therapy when the primary tumor (T) stage by pathology isless than the T stage by clinical (endoscopic) evaluation, or when the regional lymph node (N) tumor stage by pathology is less than the N stage by clinical (endoscopic) evaluation.
Time frame: 12 to 14 weeks after radiotherapy
Population: This outcome is specifically defined per protocol as the phase 2 portion of the study, which did not occur. However, the data for this measure are available from the phase 1 participants (only), and are provided for completeness.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100 | Pathologic Response Rate | 4 Participants |
| Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85 | Pathologic Response Rate | 5 Participants |
| Group A - Cetuximab + Capecitabine-800 + XRT | Pathologic Response Rate | 3 Participants |
| Group B - Cetuximab + Capecitabine-1000 + XRT | Pathologic Response Rate | 5 Participants |
Secondary
Survival at 5 Years
Survival at 5 years was assessed as the number of participants alive 5 years after starting treatment.
Time frame: 5 years
Population: This outcome is defined per protocol as study phase 2, which did not occur. However, data are available from the phase 1 participants (only), and are provided for completeness. This study was terminated before all patients reached 5 years from study entry. Only patients known to be alive at 5 years are reported.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100 | Survival at 5 Years | 5 Participants |
| Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85 | Survival at 5 Years | 4 Participants |
| Group A - Cetuximab + Capecitabine-800 + XRT | Survival at 5 Years | 3 Participants |
| Group B - Cetuximab + Capecitabine-1000 + XRT | Survival at 5 Years | 3 Participants |
Secondary
Time-to-Progression (TTP)
Time-to-progression was assessed as the time from the date of surgical resection to the appearance of either local disease recurrence or distant metastases by any modality (eg, clinical exam, endoscopy, radiographic imaging). All relapses were to be confirmed by biopsy and pathology review.
Time frame: 5 years
Population: This study was terminated before all patients reached 5 years from the date of surgical resection. Only patients that progressed are reported, and since no patients progressed in Group 2, median and range are not reportable.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100 | Time-to-Progression (TTP) | 1.4 years |
| Group A - Cetuximab + Capecitabine-800 + XRT | Time-to-Progression (TTP) | 3.0 years |
| Group B - Cetuximab + Capecitabine-1000 + XRT | Time-to-Progression (TTP) | 3.9 years |
Secondary
Tumor Downstaging at Surgical Resection
Downstaging means a reduction from the stage of disease observed at baseline to the stage of disease after treatment with cetuximab, radiotherapy, oxaliplatin, and capecitabine, as determined at the time of surgical removal of the tumor. Downstaging may be observed as improvements in tumor staging at the primary site of the tumor; in nearby (regional) lymph nodes; or in metastatic disease beyond the regional lymph nodes. This outcome specifically does not include participants that achieved a complete response, nor those that experienced no response or disease progression.
Time frame: 12 to 14 weeks after radiotherapy
Population: This outcome is specifically defined per protocol as the phase 2 portion of the study, which did not occur. However, the data for this measure are available from the phase 1 participants (only), and are provided for completeness.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100 | Tumor Downstaging at Surgical Resection | 4 Participants |
| Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85 | Tumor Downstaging at Surgical Resection | 5 Participants |
| Group A - Cetuximab + Capecitabine-800 + XRT | Tumor Downstaging at Surgical Resection | 3 Participants |
| Group B - Cetuximab + Capecitabine-1000 + XRT | Tumor Downstaging at Surgical Resection | 5 Participants |