Colorectal Cancer, Metastatic Colorectal Cancer
Conditions
Keywords
mCRC, chemorefractory metastatic colorectal cancer
Brief summary
The purpose of this study is to evaluate whether therapy with MORAb-004 is effective and safe in the treatment of metastatic, colorectal cancer.
Detailed description
Tumor endothelial marker-1 also referred to as TEM-1 is expressed in the supportive tissue, as well as, on the cells within the tumor. TEM-1, which is a cell surface glycoprotein, and is expressed in the stromal compartment (cells) of nearly all human tumors. In preclinical studies, it has been shown that TEM-1 plays a key role in tumor growth and the vascularization of tumors. There is evidence suggesting an association between the level of TEM-1, 7, 7R, 8 in relation to lymph node involvement and disease progression. MORAb-004 is a humanized immunoglobulin G (IgG1/κ) antibody directed against endosialin/TEM-1. Nonclinical pharmacological studies showed that MORAb-004 has the ability to block specific TEM-1 receptor-ligand interactions. Immunohistochemistry studies of human tumor biopsy samples demonstrate TEM-1 expression and MORAb-004 binding to tumor stromal cells, in particular mural cell compartment of neovessels and cancer-associated fibroblasts. All of which suggests a potential effective treatment. Researchers hypothesize that an antibody therapy that binds to TEM-1 may be efficacious in the treatment of metastatic, colorectal cancer. This clinical study is a proof of concept study to see if an anti-TEM-1 agent is safe and effective in the treatment of metastatic, colorectal cancer.
Interventions
DRUGMORAb-004
MORAb-004 8mg per kg IV once a week
DRUGPlacebo
Placebo - normal saline IV once a week
OTHERBest supportive care
Best supportive care to improve quality of life
Sponsors
Morphotek
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males and females \>18 years old * Diagnosis of metastatic, colorectal cancer * Significant medical conditions must be well-controlled and stable for at least 30 days prior to the first treatment infusion * Be willing and able to provide written informed consent
Exclusion criteria
* No prior treatment for metastatic colorectal cancer * Other serious systemic diseases (bacterial or fungal) * Clinically significant heart disease or an arrhythmia on an ECG within the past 6 months * Known allergic reaction to monoclonal antibody therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | From the date of randomization to the date of the first observation of PD or death due to any cause (up to approximately 1 year 7 months) | PFS based on Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 was defined as the time (in weeks) from the date of randomization to the date of the first observation of disease progression (PD) or death due to any cause. PD was defined as at least a 20 percent (%) increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. If progression or death was not observed for a participant, the PFS time was censored at the date of last tumor assessment without evidence of progression prior to the date of initiation of further antitumor treatment. PFS was summarized for each treatment group using Kaplan-Meier estimation curves. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | From the date of randomization to the first documentation of CR or PR (up to approximately 1 year 7 months) | ORR was defined as the percentage of subjects achieving either CR or PR using RECIST v.1.1. CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (\<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Time to Tumor Response (TTR) | From the date of randomization to first documentation of objective tumor response (CR or PR) (up to approximately 1 year 7 months) | Time to tumor response was defined for those participants with objective evidence of confirmed CR or PR as the time from randomization to first documentation of objective tumor response (CR or PR). CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Overall Survival (OS) | From the date of randomization to the date of death due to any cause (up to approximately 1 year 7 months) | OS was defined as the time (in months) from the date of randomization to the date of death, regardless of the cause. OS was summarized for each treatment group using Kaplan-Meier estimation curves. In the absence of death confirmation or for participants alive at the time of analysis, the survival time was censored at the last date known to be alive. |
| Biomarkers Based PFS, Within Treatment Group | From the date of randomization up to approximately 1 year 7 months | The statistical evidence to support the use of the biomarker identified in Stage 1 interim analysis for Stage 2 selection of participants as designed was not adequate to clearly define a biomarker responsive population. The study was terminated by the sponsor at the end of Stage 1 and enrollment of stage 2 did not occur due to futility, hence Stage 2 and biomarker based analysis for PFS was not carried out. |
| Biomarkers Based OS, Within Treatment Group | From the date of randomization up to approximately 1 year 7 months | The statistical evidence to support the use of the biomarker identified in Stage 1 interim analysis for Stage 2 selection of participants as designed was not adequate to clearly define a biomarker responsive population. The study was terminated by the sponsor at the end of Stage 1 and enrollment of stage 2 did not occur due to futility, hence Stage 2 and biomarker based analysis for OS was not carried out. |
| Duration of Response (DOR) | From the date of first objective response (CR or PR) to objective tumor progression or death regardless of cause (up to approximately 1 year 7 months) | The DOR was defined as the time from first documentation of objective response (CR or PR) to the first documentation of objective tumor progression or death due to any cause. CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 61 investigative sites in the United States from 27 March 2012 to 20 October 2013.
Pre-assignment details
A total of 154 participants were screened and enrolled (signed informed consent form), of which 28 were screen failures, 126 were randomized and 122 were treated. Study was terminated by the sponsor at the end of Stage 1 due to futility, hence Stage 2 was not carried out.
Participants by arm
| Arm | Count |
|---|---|
| MORAb-004 8.0 mg/kg + BSC Participants received MORAb-004 8 mg/kg, infusion IV, once weekly, in each 2-week treatment cycle along with the BSC which included those measures intended to provide palliation of all symptoms and improve quality of life, until disease progression or discontinuation from any reason (up to Cycle 24). | 84 |
| Placebo + BSC Participants received MORAb-004 matching placebo infusion IV, once weekly, in each 2-week treatment cycle along with the BSC which included those measures intended to provide palliation of all symptoms and improve quality of life, until disease progression or discontinuation from any reason (up to Cycle 24). | 42 |
| Total | 126 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Discontinuation of the study by sponsor | 11 | 9 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other | 6 | 4 |
| Overall Study | Progressive disease | 60 | 27 |
| Overall Study | Withdrawal by Subject | 6 | 2 |
Baseline characteristics
| Characteristic | Placebo + BSC | Total | MORAb-004 8.0 mg/kg + BSC |
|---|---|---|---|
| Age, Continuous | 61.8 years STANDARD_DEVIATION 10.61 | 61.5 years STANDARD_DEVIATION 11.32 | 61.4 years STANDARD_DEVIATION 11.72 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 7 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 115 Participants | 75 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 36 Participants | 110 Participants | 74 Participants |
| Sex: Female, Male Female | 16 Participants | 59 Participants | 43 Participants |
| Sex: Female, Male Male | 26 Participants | 67 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 13 / 82 | 4 / 40 |
| other Total, other adverse events | 77 / 82 | 40 / 40 |
| serious Total, serious adverse events | 31 / 82 | 15 / 40 |
Outcome results
Primary
Progression-Free Survival (PFS)
PFS based on Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 was defined as the time (in weeks) from the date of randomization to the date of the first observation of disease progression (PD) or death due to any cause. PD was defined as at least a 20 percent (%) increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. If progression or death was not observed for a participant, the PFS time was censored at the date of last tumor assessment without evidence of progression prior to the date of initiation of further antitumor treatment. PFS was summarized for each treatment group using Kaplan-Meier estimation curves.
Time frame: From the date of randomization to the date of the first observation of PD or death due to any cause (up to approximately 1 year 7 months)
Population: ITT population included all randomized participants, analyzed according to the treatment assigned by the IVRS/IWRS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MORAb-004 8.0 mg/kg + BSC | Progression-Free Survival (PFS) | 8.1 weeks |
| Placebo + BSC | Progression-Free Survival (PFS) | 8.1 weeks |
p-value: 0.733595% CI: [0.76, 1.67]One-sided log-rank test
Secondary
Biomarkers Based OS, Within Treatment Group
The statistical evidence to support the use of the biomarker identified in Stage 1 interim analysis for Stage 2 selection of participants as designed was not adequate to clearly define a biomarker responsive population. The study was terminated by the sponsor at the end of Stage 1 and enrollment of stage 2 did not occur due to futility, hence Stage 2 and biomarker based analysis for OS was not carried out.
Time frame: From the date of randomization up to approximately 1 year 7 months
Population: The study was terminated by the sponsor at the end of Stage 1 and enrollment of stage 2 did not occur due to futility, hence Stage 2 and biomarker based analysis for OS was not carried out.
Secondary
Biomarkers Based PFS, Within Treatment Group
The statistical evidence to support the use of the biomarker identified in Stage 1 interim analysis for Stage 2 selection of participants as designed was not adequate to clearly define a biomarker responsive population. The study was terminated by the sponsor at the end of Stage 1 and enrollment of stage 2 did not occur due to futility, hence Stage 2 and biomarker based analysis for PFS was not carried out.
Time frame: From the date of randomization up to approximately 1 year 7 months
Population: The study was terminated by the sponsor at the end of Stage 1 and enrollment of stage 2 did not occur due to futility, hence Stage 2 and biomarker based analysis for PFS was not carried out.
Secondary
Duration of Response (DOR)
The DOR was defined as the time from first documentation of objective response (CR or PR) to the first documentation of objective tumor progression or death due to any cause. CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From the date of first objective response (CR or PR) to objective tumor progression or death regardless of cause (up to approximately 1 year 7 months)
Population: ITT population included all randomized participants, analyzed according to the treatment assigned by the IVRS/IWRS. Here overall number analyzed N are the participants who had achieved CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + BSC | Duration of Response (DOR) | NA weeks |
Secondary
Overall Response Rate (ORR)
ORR was defined as the percentage of subjects achieving either CR or PR using RECIST v.1.1. CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (\<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From the date of randomization to the first documentation of CR or PR (up to approximately 1 year 7 months)
Population: ITT population included all randomized participants, analyzed according to the treatment assigned by IVRS/IWRS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MORAb-004 8.0 mg/kg + BSC | Overall Response Rate (ORR) | 0 percentage of participants |
| Placebo + BSC | Overall Response Rate (ORR) | 2.4 percentage of participants |
p-value: 0.33395% CI: [-6.992, 2.23]Fisher Exact
Secondary
Overall Survival (OS)
OS was defined as the time (in months) from the date of randomization to the date of death, regardless of the cause. OS was summarized for each treatment group using Kaplan-Meier estimation curves. In the absence of death confirmation or for participants alive at the time of analysis, the survival time was censored at the last date known to be alive.
Time frame: From the date of randomization to the date of death due to any cause (up to approximately 1 year 7 months)
Population: ITT population included all randomized participants, analyzed according to the treatment assigned by IVRS/IWRS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MORAb-004 8.0 mg/kg + BSC | Overall Survival (OS) | 4.8 months |
| Placebo + BSC | Overall Survival (OS) | 6.2 months |
p-value: 0.949895% CI: [0.93, 2.19]One-sided log-rank test
Secondary
Time to Tumor Response (TTR)
Time to tumor response was defined for those participants with objective evidence of confirmed CR or PR as the time from randomization to first documentation of objective tumor response (CR or PR). CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From the date of randomization to first documentation of objective tumor response (CR or PR) (up to approximately 1 year 7 months)
Population: ITT population included all randomized participants, analyzed according to the treatment assigned by the IVRS/IWRS.~Here overall number analyzed N are the participants who had achieved CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + BSC | Time to Tumor Response (TTR) | NA weeks |